module 12 - pharmacotherapy for neurological disorders

Geriatric Pharmacy Review

Module 12: Pharmacotherapy for Neurological Disorders

Copyright 2011 American Society of Consultant Pharmacists

Accreditation Information

ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This home study web activity has been assigned 3.5 credit hours.

ACPE UPN: 0203-0000-10-095-H01-P

Release Date: 6/14/2010

Expiration Date: 7/1/2013

To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the on-line assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.

Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.


Current Content Experts

Henry Cohen, PharmD, BCPP Associate Professor of Pharmacy Practice The Arnold & Marie Schwartz College of Pharmacy and Health Services

Mitch Emerson, PhD Assistant Professor of Pharmaceutical Sciences Midwestern University College of Pharmacy

Marty L. Eng, PharmD Clinical Assistant Professor Kansas University

R. Ronald Finley, BS Pharm, RPh Clinical Pharmacist Univerisity of California, San Fransisco

Jennifer Hardesty, PharmD Geriatrics Resident University of Maryland School of Pharmacy

Ann Marie Nye, PharmD Assistant Professor Campbell University School of Pharmacy

Elmer V. Schmidt, PharmD, CGP, FASCP Consultant Pharmacist Anthem Care Management


Legacy Content Experts

Kevin W. Chamberlin, PharmD Assistant Clinical Professor University of Connecticut School of Pharmacy & Clinical Pharmacy Specialist, Internal Medicine/Geriatrics University of Connecticut Health Center

Jack J. Chen, PharmD, BCPS, CGP Assistant Professor of Pharmacy Practice (Neurology) College of Pharmacy Western University of Health Sciences

Henry Cohen, MS, PharmD, BCPP, CGP Director of Pharmacotherapy Services Kingsbrook Jewish Medical Center & Associate Professor Arnold & Marie Schwartz College of Pharmacy Long Island University

Sean M. Jeffery, PharmD, CGP, FASCP Assistant Clinical Professor University of Connecticut School of Pharmacy

Sudha Narayanaswamy, BS, PharmD, CGP Coordinator of Pharmacotherapy Services and Pharmacy Residency Programs Kingsbrook Jewish Medical Center

Trinh Pham, PharmD, BCOP Assistant Clinical Professor University of Connecticut School of Pharmacy & Clinical Pharmacy Specialist, Oncology Yale New Haven Hospital

Phillip L. Thornton, RPh, PhD, CGP, FASCP Clinical Pharmacist Stanly Regional Medical Center


Current Content Expert Disclosure

Henry Cohen, MS, PharmD, BCPP, CGP discloses the following relationships: •  Speakers Bureau: Merck, Pfizer, BI

Marty L. Eng, PharmD, has no relevant financial relationships to disclose.

Mitch Emerson, PhD, has no relevant financial relationships to disclose.

R. Ronald Finley, BS Pharm, RPh, discloses the following relationships: •  Speakers Bureau: Pfizer, Novartis, Forest

Jennifer Hardesty, PharmD, has no relevant financial relationships to disclose.

Ann Marie Nye, PharmD, discloses the following relationship: •  Honoraria: Watson Pharmaceuticals

Elmer V. Schmidt, PharmD, CGP, FASCP, has no relevant financial relationships to disclose.


Legacy Content Expert Disclosure

Kevin W. Chamberlin, PharmD has no relevant financial relationships to disclose.

Jack J. Chen, PharmD, BCPS, CGP has no relevant financial relationships to disclose.

Henry Cohen, MS, PharmD, BCPP, CGP discloses the following relationships: •  Speakers Bureau: Merck, Pfizer, BI

Sean M. Jeffery, PharmD, CGP, FASCP has no relevant financial relationships to disclose.

Sudha Narayanaswamy, BS, PharmD, CGP discloses the following relationships: •  Speakers Bureau: BI

Trinh Pham, PharmD, BCOP has no relevant financial relationships to disclose.

Phillip L. Thornton, RPh, PhD, CGP, FASCP has no relevant financial relationships to disclose.


Delirium and Dementia

Learning Objectives:

By the end of this Review Concept you should be able to:

•  Identify lobes of the brain and their associated function(s).

•  Differentiate symptoms of delirium and dementia.

•  Identify clinical and associated features of delirium.

•  List medical and pharmacological causes of delirium.

•  Describe management strategies for the patient with delirium.

•  Compare and contrast the etiology of dementias.

•  Comprehend the pathophysiology and clinical presentation of dementias.

•  Describe treatment options for vascular dementia, Lewy body dementia, and frontotemporal dementia.


Brief Introduction to Neuroanatomy

It is important to have a basic understanding of the functions of the various parts of the brain. The most organized way of doing this is to understand the lobes of the brain and their functions. In this illustration you will notice that there are four lobes that are observable from the surface of the brain. A fifth lobe, the limbic lobe, underlies the temporal lobe and includes the hippocampus and amygdala.

This 5th lobe is associated with establishment of short term memory in the case of the hippocampus and emotions via the amygdala. The frontal cortex is associated with higher cognitive processes including long-term memory, planning and execution (e.g., speech, movement), judgment, and calculation to name a few. The temporal lobe is associated with hearing and speech recognition as well as memory and emotion. Some people consider the limbic lobe to be a part of the temporal lobe so you may also hear that the temporal lobe is associated with memory and emotion. However, most experts agree that the limbic lobe is separate from the temporal lobe. The occipital lobe is associated with vision by taking the neural impulses generated from the eye and forming comprehendible visions.

Lastly, the parietal lobe is associated with sensory stimulation – receiving sensations from peripheral nerves and interpreting the locus and source of the sensation. This is an area that is affected late in dementia and is probably one of the reasons that demented patients become aggressive when they are touched by someone without first gaining visual contact with the demented patient


Overview

• Delirium

• Dementia

• Alzheimer’s disease • Vascular dementia • Dementia of Lewy bodies • Frontotemporal dementia • Pick disease

Alterations in cognition are an inevitable part of aging. By their mid-sixties, most older adults show declining ability in secondary memory, divided attention and constructive tasks. Abstraction and naming ability are markedly affected by the seventies. However, these decrements are often associated with speed of function – it takes an older person longer to recall information but they generally can and will recall the information.

For older adults, these natural cognitive changes do not interfere with the activities of daily living or the quality of life. It is only when organic disease temporarily or progressively disrupts cognition that medical intervention may become necessary. The two clinical syndromes primarily responsible for this are known as delirium and dementia.


Epidemiology of Delirium

• Delirium is a common cause of mortality and morbidity in elderly hospitalized patients. Loss of independence and increased health care costs has been noted as well to result from delirium. • The point prevalence of delirium is 1.1% in age 55 and older person in the general population • 10-15% of elderly upon hospital admission • 10-40% diagnosed with delirium during hospitalization, • Up to 60% of nursing home residents age 75 years and older may be delirious at any given time • Up to 80% of patients with terminal illness develop delirium near death • About 15% of elderly patient with delirium die within a month and up to 25% die within 6 months after discharge, 35-40% within a year.

Ref: http://online.statref.com/Search.aspx

Patients with delirium may present with any combination of core and associated symptoms. Core symptoms include impaired consciousness, cognition and perception. These symptoms are visibly manifested as disorientation, delusions, attention deficit, misinterpretation and hallucinations.

Associated symptoms include a disturbed sleep cycle or sun downing, and psychomotor disturbances such as slowness, slurred speech and tremor. Affective disturbances such as irritability, excitability and apprehension may also be seen. A physical exam will reveal autonomic symptoms such as dilated pupils, tachycardia and fever.


Differentiating Delirium and Dementia

Delirium Demen*a

History: acute chronic

Onset: rapid insidious

Dura*on: days-‐weeks months-‐years

Course: fluctuates progressive

Level of Consciousness(LOC): fluctuates normal

Orienta*on: periodically impaired ini8ally intact

Affect: anxious, irritable less anxious

Thinking: o<en disconnected decreased clarity

Memory: recent memory impaired

all memory impaired

Percep*on: visual hallucina8ons sundowning

Motor: retarded, agitated, mixed normal

Sleep: disrupted less disrupted


Differentiating Delirium and Dementia

It is important to differentiate between delirium and dementia, since accurate diagnosis is essential to treatment selection, prognosis and patient monitoring. Delirium is a condition of acute cognitive dysfunction that develops over a period of hours to days, and fluctuates symptomatically over the course of the episode. It is often associated with reversible causes and careful evaluation of potential causes can improve dementia symptoms and improve quality of life without the need for additional, unnecessary medication. In contrast, dementia is a persistent and progressive loss of more than one cognitive function, producing among other symptoms, memory loss, aphasia, apraxia, or agnosia. Dementia can also affect social functioning, especially the relationship between the resident and family members. The clinician must be careful not to confuse the transient symptoms of delirium with the more permanent changes associated with dementia.

Delirium Demen*a

ADen*on: permanently impaired less impaired

Reversible? o<en usually not


Symptoms of Delirium

Core Symptoms:

• Impaired consciousness • Impaired cognition • Impaired perception

Associated Symptoms:

• Disturbed sleep-wake cycle • Psychomotor disturbance • Affective disturbance • Autonomic disturbance • Electroencephalography (EEG) changes

Patients with delirium may present with any combination of core and associated symptoms. Core symptoms include impaired consciousness, cognition and perception. These symptoms are visibly manifested as disorientation, delusions, attention deficit, misinterpretation and hallucinations. Associated symptoms include a disturbed sleep cycle or sundowning, and psychomotor disturbances such as slowness, slurred speech and tremor. Affective disturbances such as irritability, excitability and apprehension may also be seen. A physical exam will reveal autonomic symptoms such as dilated pupils, tachycardia and fever. The symptoms may be different depending on whether the patient has hypoactive or hyperactive subtypes of delirium.


Dementia or Delirium: First Rule Out Delirium!

D - Drugs E - Emotional illness (i.e., depression) M- Metabolic/endocrine disorders E - Eye/ear/environment N - Nutrition/neurologic T - Tumors/trauma I - Infection/impaction A - Alcoholism/anemia/atherosclerosis

The first step in differentiating delirium from dementia is to rule out all causes of delirium. The acronym DEMENTIA is a tool to help clinicians remember the various causes of delirium. The D stands for "drugs" which are a common cause for delirium and important factor for a pharmacist to review. As a senior care pharmacist it is imperative that you are aware of the drugs that can impair cognition and make a person delirious. Avoid these medications in individuals that are delirious or have a history of delirium. Also important in the differential diagnosis is the role of concomitant comorbidities such as depression, insomnia, stress, thyroid disease, uncontrolled diabetes, visual and hearing deficits, infection (especially urinary tract infections), fecal impactions, B-12 or folate deficiency and finally it is important to also consider environmental concerns such as excessive noise or light or disruptive patients. Keep in mind that the cause(s) of delirium is/are commonly thought to be multifactorial and more than one factor could be identified as contributing to the delirium. Also, in light of the increasing demands of regulations for documentation, an assessment tool such as the Confusion Assessment Method may be helpful.

Space occupying lesions in the brain can result in either destruction of tissue or alteration in blood flow resulting in impaired oxygenation of the brain and delirium. When suspected an MRI or CT scan to rule out tumors or vascular disease. When fluid spontaneously accumulates on the brain, an uncommon condition called Normal Pressure Hydrocephalous (NPH) develops. Patients commonly exhibit acute onset ataxia, urinary incontinence confusion and often mild dementia. It is very important that any patient displaying these symptoms be thoroughly evaluated as this condition can sometimes be reversed by placing a shunt to drain excessive fluid off the brain.


Etiology of Delirium

Medical Conditions: • Cerebrovascular diseases • Fluid & electrolyte imbalance • Infection (especially UTIs) • Metabolic disorders • Cardiovascular disease • Anemia (especially if onset is rapid)

Medications: • Antiarrhythmics - disopyramide, quinidine, tocainide • Antibiotics - cephalexin, cephalothin, ofloxacin • Anticholinergics - benztropine, homatropine, scopolamine • Antidepressants - amitriptyline, imipramine, fluoxetine • Anticonvulsants - phenytoin, valproic acid, carbamazepine • Antiemetics - promethazine, hydroxyzine, metoclopramide • Antihypertensives - propranolol, metoprolol, prazosin • Antineoplastic agents - chlorambucil, cytarabine, interleukin 2 • Antimanic agents - lithium • Antiparkinsonian agents - levodopa, pergolide, bromocriptine • Antihistamines/decongestants- diphenhydramine, chlorpheniramine, pseudoephedrine • Cardiac agents - digoxin • Corticosteroids - hydrocortisone, prednisone • H2- receptor blockers - cimetidine, ranitidine • Immunosuppressive agents - cyclosporine, interferon


Etiology of Delirium

Narcotic analgesics – codeine, hydrocodone, oxycodone Muscle relaxants - baclofen, cyclobenzaprine, methocarbamol NSAIDS - aspirin, ibuprofen, indomethacin Sedative-hypnotic agents - alprazolam, diazepam, lorazepam, phenobarbital, butabarbital

Delirium can be caused by a host of conditions, including cerebrovascular diseases such as stroke or transient ischemic attack, fluid and electrolyte imbalance, and metabolic changes such as hypoxia, hypoglycemia, and thyroid disease. Cardiovascular conditions such as congestive heart failure and arrhythmia can also cause delirium. In the elderly, drugs are an important factor in the etiology of delirium since older adults generally take multiple medications for various age-related conditions. Drugs known to cause or contribute to the cognitive impairment characteristic of delirium are listed on your screen. A careful drug regimen review should be conducted when diagnosing residents with symptoms of either delirium or dementia. Remember that disease presentations in older adults may present atypically.


Management of the Patient with Delirium

• Review drug regimen • Discontinue nonessential medications • Monitor vital signs and fluids • Obtain medical history • Conduct lab studies [CBC, ESR, chemistries, liver function tests (LFTs), kidney function tests (RFTs), UA, toxicology, EEG, ECG] • Implement pharmacological and nonpharmacological treatment measures

Based on the results of the drug regimen review, all nonessential medications should be discontinued or tapered off. The patient should be observed for adverse effects of discontinuation and consistently monitored for vital signs, fluids and electrolytes. It has been suggested that even longstanding medications could contribute to delirium and should be re-evaluated for continued need. A complete medical history should be obtained and lab studies initiated, including complete blood cell count, erythrocyte sedimentation rate, chemistries, kidney and liver function tests, urinalysis, and toxicology screening. An EEG and ECG should also be recorded. Once the results have been analyzed, pharmacological and nonpharmacological treatment measures may be implemented.


Treatment of Delirium and Associated Symptoms

Nonpharmacological Measures: • Decrease external stimuli • Increase comfort and safety • Provide reassurance

Pharmacological Measures: • High potency antipsychotic agents – i.e., IM haloperidol (Haldol ®) • Other psychoactive agents – i.e., oral or IM lorazepam (Ativan®)

Treatment goals for the delirious patient include decreasing the psychotic symptoms and any associated agitation while increasing the comfort and safety of the patient, family members, caregivers and other patients. Once nonpharmacological measures are implemented, pharmacologic treatment with antipsychotic drugs can be considered. Low doses of highly potent antipsychotic agents such as haloperidol are effective at managing the psychotic symptoms but may cause tremor, dystonia and akathisia.

Antipsychotic agents in acute situations given intramuscularly will alleviate aggressive psychotic patients until the cause of the delirium is identified and treatment begun. Other options may include the use of oral or intramuscular lorazepam to treat agitation or insomnia. Dosage amounts should be individualized based on patient’s response. Neither the antipsychotic nor other psychoactive medications should be considered a solution or long-term treatment option in patients with delirium.

Evidence for the use of atypical antipsychotics and acetylcholinesterase inhibitors is weak and limited to small uncontrolled trials. Therefore, haloperidol and lorazepam remain the pharmacologic treatments of choice at this time. Once the underlying cause of the delirium is addressed and the symptoms are resolved, the psychoactive medications should be tapered off to minimize the incidence of extrapyramidal syndromes, falls, and confusion.


Epidemiology of Dementia

• Affects 11% > 65 years, 50% > 85 years • Affects 87% of nursing home residents • 10-20% of cases are reversible • Common types of dementia:

• Alzheimer’s disease (75% of all dementias) • Vascular dementia (15-20%) • Lewy body dementia (15-20%)

The most common form of dementia is Alzheimer’s disease. Other common types of dementia include vascular dementia, Lewy body dementia, and mixed dementia. An estimated 4.5 million Americans have Alzheimer’s disease, according to data based on the number of cases detected in an ethnically diverse population sample and the 2000 U.S. census. Those data show that by the year 2050, the number of Americans with Alzheimer’s could range from 11.3 million to 16 million. Finding a treatment that could delay onset by five years could reduce the number of individuals with Alzheimer’s disease by nearly 50 percent after 50 years.

Increasing age is the greatest risk factor for Alzheimer’s. One in 10 individuals over 65 and nearly half of those over 85 are currently affected. Other rare, inherited forms of dementia can strike individuals as early as their 30s and 40s. Once diagnosed, a person with Alzheimer’s disease will live an average of eight years and as many as 20 years or more from the onset of symptoms. The result of such a long and protracted illness is that the national direct and indirect annual costs of caring for individuals with Alzheimer’s disease are at least $100 billion, according to estimates used by the Alzheimer’s Association and the National Institute on Aging.


Epidemiology of Dementia

Fortunately more than 7 out of 10 people with Alzheimer’s disease live at home, where almost 75 percent of their care is provided by family and friends. The remainder is "paid” care costing an average of $12,500 per year. Families pay almost all of that out of pocket. Currently half of all nursing home residents have Alzheimer’s disease or a related disorder. The average lifetime cost of care for an individual with Alzheimer’s is currently estimated at $174,000.

By 2010, Medicare costs for beneficiaries with Alzheimer’s are expected to increase 54.5 percent, from $31.9 billion in 2000 to $49.3 billion, and Medicaid expenditures on residential dementia care will increase 80 percent, from $18.2 billion to $33 billion in 2010, a report commissioned by the Alzheimer’s Association concludes.


Etiology of Reversible Dementia

Medications and other Chemical Agents: • Antidepressants • Antipsychotics • Barbiturates • Poisoning by pesticides, heavy metals

Medical Conditions: • Chronic alcoholism • Depression • Nutritional disorders (B12 deficiency) • Brain disorders • Other diseases (e.g. syphilis)

Dementia is considered irreversible, however some forms are treatable. Drug induced dementia, which often occurs when changes in metabolic functioning interfere with the patient’s ability to break down the drug in body, are usually reversible with appropriate dosage modification. As discussed earlier in this review concept, antidepressants, antihistamines, antipsychotics, anxiolytics, and barbiturates are some of the drug classes that can produce dementia-like cognitive impairment. Other causes of dementia that are sometimes reversible if caught early enough include chronic alcoholism and poisoning induced by inhalation or exposure to pesticides and heavy metals such as lead, mercury and carbon monoxide. Nutritional disorders, such as vitamin B-12 deficiency, can produce lethargy, apathy and other symptoms of dementia. Brain disorders, such as subdural hematomas, normal pressure hydrocephalous, tumors, and infections such as meningitis should be considered. Additionally, certain metabolic syndromes such as hypothyroidism and liver disease may all cause dementia as well. B12 and TSH are among the routine labs recommended at initial evaluation by the American Academy of Neurology (2001)


Etiology of Irreversible Dementia

Vascular Dementia: • Cell and tissue damage due to cerebrovascular disease • Multi-infarct dementia is most common form

Alzheimer’s Disease: • Progressive, degenerative • Impairs memory, cognition and behavior

Dementia of Lewy bodies: • Inclusion bodies of α-synuclein (also found in Parkinson’s disease and multisystem atrophy) • Extrapyramidal signs (tremor or bradykinesia) • Gait disturbance • Hallucinations (80%)

Frontotemporal Dementia: • Cortical atrophy is major finding • Language and personality changes common

Irreversible forms of dementia include vascular dementia, Alzheimer’s disease, dementia of Lewy bodies, and frontotemporal dementia.

Vascular dementia can arise subsequent to any kind of cerebrovascular disease.


Etiology of Irreversible Dementia

Multi-infarct dementia is the most common form of vascular dementia. Criteria for diagnosis of vascular dementia include onset of symptoms within three months following a stroke, abrupt deterioration in cognitive function, or fluctuating, stepwise progression of cognitive deficit. Alzheimer’s disease is discussed separately in another review concept.

Dementia of Lewy bodies is often misdiagnosed as Parkinson’s disease and/or Alzheimer’s disease. The pathophysiology of dementia of Lewy bodies includes Lewy body inclusions of α-synuclein. Its symptoms include bradykinesia and rigidity (but not much resting tremor early in the disease, but may be present later), visual hallucinations early in the disease are a hallmark of DLB, and fluctuations in cognitive impairment (delirium). For instance, the person might appear very demented one day and completely lucid the next (note: this can occur within minutes in some cases). Frequent falls are also very common throughout the course of DLB. Lastly, dementia of Lewy bodies is more commonly found in men whereas Alzheimer’s disease and frontotemporal dementia are more prevalent in women.

Frontotemporal dementia (FTD) is another form of dementia and some consider it a subset of Alzheimer’s disease. However, FTD patients often don’t have the hallmark features of plaques and tangles and generally the onset is in younger individuals (typically before age 65) than Alzheimer’s disease. In addition, speech abnormalities and aggression are much more commonly observed in FTD whereas memory impairments are generally not as pronounced as in Alzheimer’s disease. These patients tend not to respond well to treatment. Acetylcholinesterase inhibitors are of little value and there is limited evidence that SSRIs may be beneficial.


Treatment for Vascular Dementia (VaD)

Lifestyle Changes: • Diet • Exercise

Medications: • Antiplatelet agents

• ASA 325mg QD • Clopidogrel 75mg QD

• Cholinesterase inhibitors • Donepezil 5-10mg QD • Galantamine 8-12mg BID • Rivastigmine 3-6mg BID • Memantine 10mg BID

• Hemorheologic Agents • Pentoxifylline 400mg BID

Treatment of vascular dementia is based on treatment of the underlying vascular disease, such as hypertension and diabetes. Lifestyle changes, such as changes in diet and exercise, will help lessen the symptoms of vascular dementia. One antiplatelet agent being used in vascular dementia patients is clopidogrel. This agent appears to be effective in preventing or reducing further ischemic events and may thus prevent subsequent neuronal loss. The only therapies at present that have been shown to reduce or slow the progression of vascular dementia are the cholinesterase inhibitors and aspirin. The cholinesterase inhibitors that are commonly used today show improvement in cognitive functioning and behavioral measures and slow the decline in cognition associated with vascular dementia. The cholinesterase inhibitors are discussed in detail in the Alzheimer’s disease review concept 12.02.

Memantine, the new N-methyl-D-aspartate receptor antagonist that was recently approved for late stage Alzheimer’s disease, was also shown in a small study to improve cognition in the ADAS-COG and Mini Mental State Exam. While it is not FDA approved for use in vascular dementia, memantine has shown cognitive benefits in mild-moderate vascular dementia in at least two randomized controlled trials. Prevention of vascular dementia has also generated a great deal of discussion by controlling risk factors for further cardiovascular events.


Treatment for Vascular Dementia (VaD)

Since one of the strongest risk factors of vascular dementia is arterial hypertension, controlling hypertension in stroke patients to goal, less than 130/80, reduces the incidence of vascular dementia from 0.74% to 0.33%.

Other prevention strategies are aimed at preventing further strokes by encouraging cessation from smoking, treating hyperlipidemia and diabetes mellitus, and encouraging exercise. Recent clinical trials suggested a potential role for pentoxifylline in vascular dementia. In theory, by lowering the viscosity, improving the erythrocyte flexibility and inhibiting platelet aggregation and thrombus formation, suppressing leukocyte adhesion, the hemorheologic agents improve blood flow which may result in improved cognitive function. However, few controlled studies have been performed.

The dietary supplement, Gingko biloba, has also been studied and shown in at least two good quality randomized trials to be beneficial for cognitive function in mixed Alzheimer and vascular dementia populations. Doses ranged from 40-80 mg three times a day for up to 12 months.


Treatment for Dementia of Lewy Bodies (DLB)

• Acetylcholinesterase inhibitors cognitive symptoms, visual hallucinations • Atypical antipsychotics hallucinations • Levodopa, dopamine agonists motor symptoms (parkinsonism)

Diagnostic criteria state that neuroleptic sensitivity may be suggestive of DLB. However, about 50% of DLB patients receiving either conventional or atypical neuroleptics do not express severe neuroleptic sensitivity. In other words, the absence of neuroleptic sensitivity does not exclude diagnosis of DLB, but when present, is strongly suggestive of DLB. In any event, neuroleptics should be avoided when possible in patients with suspected DLB. When deemed necessary, an atypical antipsychotic should be utilized with close monitoring for the development of EPS.

As discussed earlier, dementia of Lewy bodies is very different from AD. Similar to AD, however, is the use of cholinesterase inhibitors as first-line therapy. Of note, cholinesterase inhibitors have also been noted to mitigate mild hallucinations in open label studies with DLB patients. Clinicians must then determine whether the hallucinations or Parkinson’s symptoms are more troublesome.

One caveat is that levodopa and dopamine agonists will increase the incidence and severity of the hallucinations and are often minimally effective in controlling the bradykinesia and rigidity. Conversely, the atypical antipsychotics (such as risperidone, olanzapine, and ziprasidone) will often worsen the Parkinson’s symptoms as these patients are very sensitive to the D2 blocking activity of the antipsychotic medications. It is therefore very important to choose an agent that has low anticholinergic properties and low D2 antagonist properties, such as quetiapine, or potentially aripiprazole, which appears to have the lowest D2 binding properties. However, limited data exist to recommend the use of aripriprazole for DLB in older patients.

Recent clinical trials indicate that the use of atypical antipsychotics in elderly patient with dementia-related psychosis is associated with an increased risk of cardiovascular events, such as stroke, transient ischemic attacks, and death.


Treatment for Frontotemporal Dementia (FTD)

• Acetylcholinesterase inhibitors • Atypical antipsychotics • Serotonin Selective Reuptake inhibitors (SSRIs)

Frontotemporal dementia or FTD is also very difficult to treat. These patients are often very violent and usually require long term antipsychotic therapy. An agent with low extrapyramidal symptoms and low anticholinergic properties is desired to decrease incidence of tardive dyskinesia and drug-induced cognitive impairment. Risperidone is generally regarded as the agent of choice and should only be used at the lowest effective dose. Extrapyramidal symptoms are only observed in doses > 1 milligram per day and are prevalent in the elderly only in doses > 2 milligrams per day. It should be noted that use is anecdotal. FTD is rare and thus it is difficult to recruit study participants. Antipsychotics have not been studied in this population but rather are used because severe behavioral symptomatology mimics symptoms which typically respond to antipsychotics. FTD patients show significant deficits in serotonergic neurotransmission. Studies with SSRIs have been few and conflicting to this point, but should still be considered for mild or non-violent behaviors in FTD.


Resources and References

For additional information, see:

American Psychiatric Association. Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry 1999 May;156(5 Suppl):1-20. Available from: http://www.guideline.gov/summary/summary.aspx?doc_id=2180&nbr=1406

American Psychiatric Association. (1997). Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life. Am J Psychiatr;154(suppl):1-39

Burlingame, M. B. (1997) Dementia and delirium. Preparatory Program for the Certification Exam in Geriatric Pharmacy. Alexandria, VA: American Society of Consultant Pharmacists.

Burns A. Gallagley A. Byrne J. Delirium. Journal of Neurology, Neurosurgery & Psychiatry. 75(3):362-7, 2004 Mar.

Chapman DP, Williams SM, Strine TW, et al. Dementia and its implications for public health. Prev Chronic Dis, 2006 Available at http://www.cdc.gov/pcd/issues/2006/apr/05_0167.html

Knopman D. S., et al, Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56 (9)

Erkinjuntti T. Kurz A. Gauthier S. Bullock R. Lilienfeld S. Damaraju CV. (2002) Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet. 359(9314):1283-90.

Fick DM. Agostini JV. Inouye SK. Delirium superimposed on dementia: a systematic review. Journal of the American Geriatrics Society. 50(10):1723-32, 2002 Oct.



Folstein MF, Bassett SS, Romanowski AJ, et al (1991) The epidemiology of delirium in the community: the Eastern Baltimore Mental Health Survey; Int Psychogeriatr 3:169-179.

Forette F. Seux ML. Staessen JA. Thijs L. Babarskiene MR. Babeanu S. Bossini A. Fagard R. Gil-Extremera B. Laks T. Kobalava Z. Sarti C. Tuomilehto J. Vanhanen H. Webster J. Yodfat Y. Birkenhager WH. (2002). Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Archives of Internal Medicine; 162(18):2046-52.

Huey ED, Putnam K, Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology 2006; 66: 17-22.

Inouye SK. Delirium in Older Persons. N Engl J Med 2006; 354: 1157-65.

Inouye S. K., et al, A Multicomponent Intervention to Prevent Delirium in Hospitalized Older Patients, N Engl J Med 1999; 340:669-676, Mar 4, 1999

Inouye SK, Van Dyck CH, Alessi CA et al. Clarifying confusion: the Confusion Assessment Method. A new method for detection of delirium. Ann Intern Med 1990; 113: 941-948.

Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry 2003; 36(6): 297-303.

Kanowski S, Herrmann WM, Stephan K, et al. Proof of efficacy of the Ginkgo biloba special extract EGb761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or Multi-Infarct Dementia. Pharmacopsychiatry 1996; 29(2): 47-56.

Le Bars PL, Kieser M, Itil KZ. A 26-week analysis of a double-blind, placebo-controlled trial of Ginkgo biloba EGb 761 extract in dementia. Dement Geriat Cogn Disord. 2000; 11: 230-237.



McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy Bodies. Neurology. 2005; 65: 1863-1872.

Orgogozo JM. Rigaud AS. Stoffler A. Mobius HJ. Forette F. (2002). Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke; 33(7):1834-1839.

Pierre N. Tariot; Martin R. Farlow; George T. Grossberg; et al; Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil, JAMA. 2004;291:317-324.

Pratt RD, Perdomo CA. (2002). Results of clinical studies with donepezil in vascular dementia. Am J Geriatr Psychiatry; 10:88-89.

Rahkoken T, Eloniemi-Sulkava U, Paanila S, et al. (2001). Systematic intervention for supporting community care of elderly people after a delirium episode. Int Psychogeriatr; 13:37-49.

Roman GC. Vascular dementia revisited: Diagnosis, pathogenesis, treatment, and prevention. Medical Clinics of North America, 2002, 86: 477–499.

Roman GC Vascular dementia: distinguishing characteristics, treatment, and prevention. J of the American Geriatrics Society 2003, 51 (5S):S296-304

Schneider LS. Cholinesterase inhibitors for vascular dementia?. Lancet. Neurology. 2(11):658-9, 2003 Nov.

Sha MC. Callahan CM. The efficacy of pentoxifylline in the treatment of vascular dementia: a systematic review. Alzheimer Disease & Associated Disorders. 17(1):46-54, 2003 Jan-Mar.



Delirium Web: http://www.mentalhealth.com/dis/p20-or01.html

http://www.nlm.nih.gov/medlineplus/ency/article/000740.htm

Dementia Web: www.nlm.nih.gov/medlineplus/dementia.html http://www.nia.nih.gov http://www.nimh.nih.gov http://dementia.ion.ucl.ac.uk/

Alzheimer’s Association www.alz.org


Alzheimer's Disease



• Comprehend the incidence of Alzheimer’s disease in the United States.

• Describe the pathophysiology of Alzheimer’s disease.

• List the signs and symptoms of Alzheimer’s disease.

• Comprehend physical exam procedures used to diagnose Alzheimer’s disease.

• Describe dosing, side effects and monitoring guidelines for patients undergoing pharmacological therapy for Alzheimer’s disease.

• Discuss the pharmacological and non-pharmacological management of classic Alzheimer’s disease behavioral symptoms such as agitation, anxiety, sundowning and depression.


Alzheimer’s Disease

• Affects approximately 4.5 million Americans • Affects 3-11% of community dwelling adults = 65 YOA • Prevalence increases to 35-50% in adults = 85 YOA • Alzheimer’s disease (AD) constitutes 50-70% of all dementia cases • Other forms of dementia include: • Mixed dementia ( AD + VD pathology) 25-45% • Vascular dementia (VD)10-20% • Dementia with Lewy bodies (LBD)10-25% • Fronto-temporal dementia (FTD) including Pick's disease 5% -15% • Misc. forms of dementia 5%-10% (Creutzfeldt-Jakob, AIDS, Huntington’s disease, Parkinson’s disease)

Dementia is not a diagnosis, but a collection of symptoms (e.g. syndrome) We now know there are numerous types of dementias. Alzheimer’s disease being the most frequently diagnosed dementia. Alzheimer’s disease is an irreversible form of dementia found in 50 to 70 per cent of all dementia cases. It affects over four million Americans and the incidence increases dramatically as age increases, but it is important to note that AD is not part of the natural aging process. The incidence increases from approximately 6% in those 65 years of age to approximately 35% to 50% in those over 85 years of age. It is not uncommon for AD and vascular dementia to exist concurrently sometimes defined as a “mixed dementia”, which usually is only confirmed at autopsy, Alzheimer’s is a progressive, degenerative disease that impairs memory, cognition, and behavior, eventually leading to an inability to function independently. Life expectancy for an individual diagnosed with AD is approximately eight years, but can be as long as twenty years.


Cascade of Events Postulated as the Pathogenesis of Alzheimer’s Disease

Plaques and tangles, appear to be natural to the aging process and small numbers can be found in the brains of the majority of older adults. Therefore, plaques and tangles per se do not mean you have Alzheimer’s disease.

In Alzheimer’s disease, there is an aggregation of beta amyloid protein, which is toxic to neurons.

Currently two major factors in the development of AD are Beta amyloid and tau pathology. Beta amyloid in the brain is derived from the transmembrane protein, amyloid precursor protein or APP, which in normal brains is processed without the release of beta amyloid. In Alzheimer’s, APP is actively transformed through alternative pathways, resulting in several protein fragments called beta amyloid. One of these,Beta amyloid-42, is thought to a key factor in amyloidosis. These deposits of beta amyloid form the core of neuritic plaques, which are one of the distinctive features of Alzheimer’s disease.

Tau pathology is another hallmark feature of Alzheimer’s disease and is the responsible factor for the presence of tangles of hyperphosphorylated tau in neurons including the dendrites and axon. These tangles prevent transportation of proteins (such as receptors) and communication with other neurons. Another suggested culprit is excessive amounts of the neurotransmitter glutamate resulting in high intracellular calcium levels, excitotoxicity and death of the neuron. This combination of events results in dysfunctional or dying neurons, as well as inflammation and mitrochondrial cell damage. What precipitates this chain of neurological devastation remains an intense area of research.


Cascade of Events Postulated as the Pathogenesis of Alzheimer’s Disease

In AD, plaques develop first in the areas of the brain used for memory and other cognitive functions. the parietal and temporal lobes .These plaques are primarily composed of beta-amyloid, which is a fragment of a protein derived from a larger protein called amyloid precursor protein (APP)- intermingled with portions of neurons and with non neurons cells such as microglia (cells that surround and digest damaged cells for foreign substances that cause inflammation) and astrocytes (cells that serve to support neurons.. It is still not clear whether amyloid plaques themselves cause AD or if they are a by-product of the AD process, but many believe the formation of amyloid plaque is the primary offender.

Brains damaged by AD show numerous clusters of degenerated nerve endings and tangles of fibers in excess of those found in the normal aging process. These findings and an assured diagnosis can only be confirmed after an autopsy. In recent years, we have learned that the patient with AD also suffers from a depletion of certain essential chemicals in the brain called neurotransmitters). Neurotransmitters, such as acetylcholine (ACH), serotonin, norepinephrine and dopamine, are vital to facilitate intercommunication between nerve cells. ACH is noted to be especially reduced in the AD patient's brain as well as Lewy Body dementia, and attempts have been made to increase the concentrations of ACH by either adding more ACH or preventing the normal enzymatic destruction of ACH. The acetylcholine deficit is greater earlier in the course of Lewy Body dementia and later in AD.


Areas of Brain Affected in Alzheimer’s Disease


Areas of Brain Affected in Alzheimer’s Disease

The accumulation of plaques and tangles follow a common pattern in Alzheimer’s disease and result in the progressive loss of memory and cognition. This illustration of the brain delineates the pattern whereby nerve cells are attacked. The area marked "A" is the hippocampus – an area essential to memory and storage. The earliest signs of Alzheimer’s disease are found here. The disease also shows up early in the basal forebrain (marked B in this picture). The basal forebrain contains the nucleus basilis of Meynert a primary source of acetylcholine, a chemical important for learning and memory. Destruction of these neurons is thought to contribute to further decrements in memory. Later the disease attacks the cerebral cortex as well (marked C) which is the area involved in conscious thought and language. As the disease destroys these neurons, marked cognitive decline results. Over time, AD slowly devastates specific areas of the brain, resulting in an over all decline in brain volume.


Symptoms of Alzheimer’s Disease

Cognitive: • Memory loss (first short term, eventually long term memory) • Learning difficulty (especially new information) • Aphasia (impaired language) early in AD difficulty finding words • Apraxia. Several types: Ideomotor: the inability carry out a familiar learned mechanical response, even though cognitively aware of the request. For example “Show me how you might brush your teeth”. Verbal Apraxia, oculomotor etc. • Visual-spatial deficits • Loss of planning and judgment (executive function) • Loss of ability to calculate (often preserved late in individuals trained in calculations, such as accounts.

Emotional: • Apathy (72%) • Agitation (60%) • Anxiety (48%) • Irritability (42%) • Depression (38%) • Delusions (22%) • Hallucinations (10%) • Euphoria (8%) • Paranoia • Emotional liability


Symptoms of Alzheimer’s Disease

Behavioral • Lack of initiative • Socially inappropriate • Insomnia • Nocturnal wandering • Social withdrawal • Incontinence • Aggressiveness

The onset of AD is gradual, frequently first detected by family or friends.

Early cognitive symptoms that result from these neurological changes involve memory loss, commonly starting with short-term memory, especially for new information, and later involve more remote memories. With worsening disease, the patient will experience an increased incidence of learning difficulty, aphasia, and apraxia. Emotional symptoms may include: irritability; agitation; anxiousness; depression; apathy; paranoia and, occasionally emotional labiality—laughing or crying for no apparent reason. Behavioral symptoms include: apathy, disturbed sleep, restlessness/wandering, social withdrawal, and, sometimes aggressiveness. Aggressive behavior, wandering, and/or urinary, fecal incontinence are frequent reasons for long-term care placement. The ability to treat these symptoms, early in the course of the disease, may delay placement in a long-term care facility and reduce caregiver burden. However, this in turn may increase the need for daycare programs, offering new opportunities for pharmacists. In the late stages of the disease, motor skills such as walking may be impaired, the ability to recognize hunger and thirst may be lost, seizures may occur and verbal communication skills may cease altogether. It is important for caregivers to understand that even in the late stages of AD individuals may respond to tone of voice, facial expressions and comforting sounds and/or environment. It is always important to respect “the person within”.


Recognizing AD

It is often difficult to diagnose or even suspect a person of Alzheimer’s disease in the earliest stages, it is estimated that less than 50% of individuals currently afflicted with AD are diagnosed. This is probably due to variety of factors, such as: the continued belief that memory and cognitive decline are part of growing old, professional reluctance to screen for AD, and skepticism by the public and healthcare providers that AD drug therapy is efficacious. One must include in this mix the fact that humans have the ability to compensate for deficiencies, and that spouses/caregivers sometimes seamlessly socially assist the person with AD.

Many neurologists now recognize that it is crucial to diagnosis AD early in the course of the disease. Pharmacotherapy in the earliest stages demonstrates the greatest opportunity to slow the progression of the disease. Early intervention also may improve the quality of life for both the patient and family. Having said that, not all patients will respond positively to AD drug therapy, with some patients demonstrating observable improvement, some declining more slowly and some showing no benefit; unfortunately, all AD patients will decline over time.


Diagnosing Alzheimer’s Disease

• Detailed medical history (from patient and caregiver) • Mini-mental state exam (MMSE) • Physical exam • Neuro-psychological testing (may or may not be necessary) • Laboratory evaluation • Cerebral imaging

In the early stages, Alzheimer’s disease is often unrecognized or misdiagnose. Other brain disorders, such as delirium and other types of dementia, must be ruled out before probable Alzheimer’s disease can be diagnosed. Patients who present with suspicious symptoms should be promptly assessed. A comprehensive medical history is very important and along with a mini-mental status exam can help assess the decline in cognitive functioning. A physical and neurological exam is necessary to rule out other causes of dementia, which may include: B-12 or folate deficiency, and anything that could cause delirium or cognitive impairment, such as infections, thyroid disease, fecal impaction, or drugs. Brain imaging and functioning tests such as MRI may be helpful with the diagnosis to rule out tumors, a subdural hematoma or microvascular disease (which may indicate vascular dementia). The diagnosis of AD is one of exclusion.


Treatment

TREATMENT • Cholinesterase inhibitors • tacrine, Cognex • donepezil, Aricept • rivastigmine Exelon • galantamine Razadyne, Razadyne ER • NMDA antagonists • (memantine Namenda)

Therapeutic options for Alzheimer’s patients include cholinesterase inhibitors and the NMDA (N-methyl-D-aspartic acid) antagonist memantine,. A positive response to cholinesterase inhibitor therapy may include a slight improvement, usually a reduction in apathy or stabilization of the condition with varying decrease in rate of decline for a period of time. Cholinesterase inhibitors prevent acetylcholinesterase from breaking down acetylcholine, which effectively increases the amount of acetylcholine in the brain.

An NMDA antagonist with mid to moderate affinity for NMDA receptor, such as memantine, appears to reduce the excitotoxic activity of gluatmate at the NMDA calcium channel receptor.


Treatment: Donepezil (Aricept®)

Dosing: • 5 mg orally at bedtime or in the morrning • Increase, if no significant side effects, to 10 mg

orally daily after 4-6 weeks • Food does not affect absorption

Adverse Drug Reactions: • Nausea (6-14%) • Vomiting (3% to 8%) • Diarrhea (8% to 15%) • Muscle cramping (7-9%) • Nightmare (6% to 14%) (usually

not a problem if given in AM)

Donepezil was the second cholinesterase inhibitor available for treatment of mild to moderate Alzheimer’s dementia, and is now also FDA approved for the treatment of severe AD. Donepezil reversibly and non-competitively inhibits cholinesterase, and is highly selective for CNS cholinesterase. Studies have repeatedly shown that the optimal benefits of donepezil are achieved if the target dose of 10 milligrams daily is reached. With approximately seventy-hour half-life, donepezil can be given once daily. Donepezil bioavailability after oral administration is complete and food does not affect its absorption; bioavailability is 100% with extensive hepatic metabolism and is excreted primarily renally as inactive metabolites. This allows donepezil to be dosed once daily and without regard to meals. The starting dosage of five milligrams per day should be increased to ten milligrams after four to six weeks. Increasing the dose slowly results in fewer gastrointestinal effects Side effects are generally tolerable and are usually self-limiting with continued therapy. When compared to rivastigmine or galantamine it is generally considered to cause fewer gastrointestinal side effects. Donepezil may cause vivid dreams, and sometimes nightmares, which can be significantly reduced by dosing in the morning. The dilemma of liver toxicity has not been an issue for donepezil, rivastigmine or galantamine ; liver function tests are not required.


Treatment: Rivastigmine (Exelon®)

Dosing: • Initial dose: 1.5 mg BID • Increase to 3 mg BID after two weeks • Increase further to 4.5 mg BID or 6 mg

BID after 2 more weeks • Higher doses correlate with better response • Food decreases peak plasma levels,

but not extent of absorption

Adverse Drug Reactions: • Nausea (29% to 47%) • Diarrhea (7 % to 19%) • Anorexia (6% to 17%) • Dizziness (6% to 21%) • Insomnia (9%) • Headache (4 to 17%) • Abdominal pain (4% to 13%) • Muscle cramping (1%)

Rivastigmine was the third cholinesterase inhibitor to be FDA-approved for the treatment of mild to moderate Alzheimer’s disease. Initial labeling indicated dose titrations every 2 weeks. However, gastrointestinal tolerability is greatly improved if titration occurs every 4 weeks.

Rivastigmine preferentially and irreversibly inhibits the G1 isoform of acetylcholinesterase and butyrylcholinesterase. Since butyrylcholinesterase and the G1 isoform of acetylcholinesterase are preferentially elevated in brains of Alzheimer’s patients, rivastigmine should theoretically improve memory of Alzheimer’s patients more effectively.

However, this has not been substantiated by clinical studies. Butyrylcholinesterase is also found in high levels in the periphery. Gastrointestinal adverse effects are higher with rivastigmine than with either donepezil or galantamine. with up to 47% of patients experiencing nausea and vomiting. Taking rivastigmine with food may decrease the incidence of gastrointestinal problems, perhaps by reducing the peak plasma level Nonetheless, the dose should be titrated up to the maximum dose of 6 milligrams twice daily, or until side effects become intolerable.

Patients who do not tolerate rivastigmine may tolerate donepezil or galantamine. Conversely, some patients who do not tolerate either donepezil or galantamine may tolerate rivastigmine. The titration schedule for treating Parkinson’s disease dementia, for which rivastigmine is FDA approved, is much slower, increasing the dose at monthly increments.


Treatment: Galantamine (Reminyl®)

Dosing: • Initial dose: 4 mg BID • Increase to 8 mg BID after 4 weeks • May increase to 12 mg BID if cognitive decline worsens

Adverse Drug Reactions • Nausea (6% to 24%) • Vomiting (4% to 13%) • Diarrhea (6% to12%) • Anorexia (7% to 9%) • Dizziness (9%) • Headache (8%)

Galantamine is the most recent acetylcholinesterase inhibitor to be approved for mild to moderate Alzheimer’s disease. It reversibly and competitively inhibits acetylcholinesterase and allosterically modulates the nicotinic receptor. The activity of the nicotinic receptor is hypothesized to provide an additional mechanism to improve cognition, decrease behavioral episodes, and/or decrease the cognitive decline associated with Alzheimer’s disease. However, these epidemiological data are tenuous at best, and the data on galantamine has not conclusively supported superiority over the other cholinesterase inhibitors. In fact to date no specific cholinesterase inhibitor has demonstrated superior efficacy. Galantamine is initially dosed at 4 milligrams twice daily and should be increased to 8 milligrams twice daily after 4 weeks of therapy. The dose can be increased further to 12 milligrams twice daily. There does not appear to be a significant increase in efficacy at higher doses (e.g. 32 mg per day) and the incidence of adverse effects increases appreciably. These adverse effects include nausea, vomiting, and diarrhea at a rate between that observed with donepezil (with the lowest incidence) and rivastigmine (with the highest incidence).

Galantamine, first derived from a member of the daffodil family, is available via the Internet as an herbal alternative medication. Therefore, it is important to include herbals and alternative treatments in any comprehensive medication history.


Treatment of Alzheimer’s with Tacrine (Cognex®)

Dosing: • Initial dose: 10 mg QID (40 mg/day) • Titrate: increase by 10 mg QID every 6 wks • Maximum dose: 160 mg/day • Absorption is decreased 30% with food

Adverse Drug Reactions: • Hepatotoxicity • GI distress

Monitor Hepatic Function (esp. ALT): • Start with baseline • Monitor every 2 weeks for 16 weeks after dosage changes • Monitor once every 2 months, then 3 months once dosage is stable • If ALT = 5 X normal, discontinue and rechallenge with drug later • If ALT = 10 X normal, discontinue use of drug permanently

Tacrine was the first acetylcholinesterase inhibitor available. It is no longer prescribed in newly diagnosed patients due to the high incidence of side effects. It was not selective for brain cholinesterase, and so had a low response rate (as compared to the newer agents) and also a higher incidence of adverse effects, including life-threatening hepatotoxicity. Considering that safer and more effective agents are available for treating Alzheimer’s disease, Tacrine is no longer an agent to be considered.


Treatment: Memantine (Namenda®)

• Approved by FDA 10/18/2003 • Only agent approved for moderate to severe stages • Initial dose: 5 mg each morning x 1 week • Week 2: increase to 5 mg twice daily, morning and evening • Week 3: increase to 5 mg each morning & 10 mg in the evening • Week 4: increase to 10 mg twice daily in the morning and evening • Patients with severely impaired renal function (CLcr 5-29 mL/min) the maximum recommended dose is 5 mg twice daily in the AM and PM.

Adverse Drug Reactions

• Hallucinations (3%) • Confusion 6%) • Dizziness (7%) • Headache 6%) • Pain (3%) • Fatigue (2%)

Memantine represents the first in a new class of agents, NMDA receptor antagonists to be approved by the FDA for Alzheimer’s disease, and the first to be approved for moderate to severe stages. Memantine demonstrated only modest effects as monotherapy; two studies with concomitant cholinesterase inhibitors (donepezil or rivastigmine) were more encouraging. Many of the early studies were from Europe and usually were based on case reports or uncontrolled methodology. In more recent controlled studies memantine does demonstrate a modestly significant effect on slowing cognitive loss’s, maintaining or improving some activities of daily living such as feeding and washing and significantly reducing caregiver burden. The best results appear to be accomplished by using a combination of memantiine and a cholinesterase inhibitor for patients diagnosed with moderate to severe AD. Most practitioners start by titrating the cholinesterase inhibitor to an optimal dose and then titrating the memantine to an optimal dose. Memantine is not approved for the treatment of mild AD.


Treatment of Alzheimer’s with Other Agents

• Vitamin E

The possibility that oxidative stress in the brains of AD patients contributes to worsening disease lead to studies of antioxidants such as Vitamin E and others. In one study, Vit E 1000 IU BID (synthetic vitamin E) was shown to delay the time NH placement .Changes in cognition ere not observed in this study. Little evidence exist showing any cognitive benefits from Vit E or other antioxidants when treating patients with AD.

In a recent study in individuals diagnosed with mild cognitive impairment (MCI) vitamin E (2,000 units per day) over a two year period did not reduce the conversion rate to AD.

The safety of dosing vitamin E above 400 IU per day has been questioned, but a more recent study suggests up to 800 IU per day appears not to increase morbidity or mortality. Large doses of vitamin E may adversely affect warfarin anticoagulation therapy.

In general, there appears to be no good medical reason to prescribe vitamin E for AD patients, to do so only increases “ pill burden”.


Proposed Treatment of Alzheimer’s with Other Agents

Estrogen

• Studies to date have substantial methodological problems and have produced conflicting results • Concerns over increased cardiovascular risk with use • Estrogen is not recommended for the prevention or treatment of dementia

Until recently, retrospective and cohort studies indicated that estrogen replacement therapy reduced the risk of developing AD. However, several pivotal trials were recently concluded that shed new light on these data. Specifically, women with mild to moderate AD showed no difference between normal dose CEE (0.625 mg/d) and high dose CEE of 1.25 mg/d verse placebo. Subsequent to this study the WHIMS released their results showing no protective effects for HRT against AD. Together these studies clearly show no benefits from estrogen in either preventing or treating AD.


Proposed Treatment of Alzheimer’s with Other Agents

• NSAIDS • Ergoloid Mesylates (Hydergine) • HMG CoA reducatase inhibitors • Gingko biloba

Epidemilogic studies of rheumatologic disorders patient have shown this population to have a lower incidence of AD. One explanation for this observation is the long-term pattern of antinflammatory use common in this cohort. Patients with AD show inflammation of the brain thought to be related to the presence of Beta amyloid deposits. Therefore, agents that reduce inflammation might be beneficial in AD. Retrospective studies of non-selective COX antagonists for two or more years have shown a decreased relative risk of developing dementia. Other agents such as prednisone have shown no effect in small prospective studies. Given the known serious risks of long term, use of steroids and non-steroidal agents in an older population plus studies that refute the benefit these agents for AD, including new Cox-2 inhibitors they can not be recommended.

Recently, HMG-COA reductase inhibitors, or statins, have shown promise in preventing Alzheimer’s disease. Animal studies of Alzheimer’s disease show that use of statins prevents the aggregation of beta-amyloid into plaques, and therefore may prevent the disease. However, it is not currently known whether the statins will slow the progression of the disease. This class of drugs continues to be studied. Lastly, ginkgo biloba is commonly used due to its availability as an over-the-counter agent. Ginkgo biloba is associated with increased risk of dyspepsia and abdominal cramping and may increase your risk of bleeding if used concurrently with warfarin.and possible bruising with aspirin, given it’s antiplatelet activity. Gingko has not been shown to have a significant impact on learning or memory in Alzheimer’s disease.

Ergoloid mesylates, an ergot derivative, continues to be marketed in most of the world for the treatment of cerebrovascular insfufficiency”. It is not approved for the treatment of AD, but is available in a generic form in the USA and as Hydergine in Canada.


Treatment of Alzheimer’s Psychiatric Behavioral Symptoms

Mild (disruptive, nonaggressive):

• Psychological/Behavioral interventions • Anxiolytics – buspirone, benzodiazepines • Antidepressants – trazodone, citalopram

Severe • (very disruptive, aggressive, with possible harm to self or others

• Acute episodes –antipsychotic agents such as haloperidol, risperidone, ziprasidone, olanzapine, quetiapine and aripriprazole • Long-term – risperidone, olanzapine, quetiapine, divalproex, trazodone

One of the most common symptoms of Alzheimer’s disease, agitation, affects forty to sixty percent of patients at some time during the course of the illness. While agitation and related symptoms such as psychosis may go undetected in the early stages of Alzheimer’s disease, their prevalence increases as the disease progresses. Mild agitation is usually treated with a combination of medical and psychological interventions. More severe agitation usually requires the use of antipsychotics. The criteria for using antipsychotic therapy should always be: 1) is the behavior causing harm to self or others, or 2) is the behavior psychotic in nature. Also, remember the ABC’s of behaviors before trying medications – A is the antecedent of the behavior (in essence, what happened before the behavior was exhibited?), B is the behavior itself (describe the behavior), and C is the consequence of the behavior (is it harmful?). By doing these steps, you can determine whether appropriate steps are being taken to minimize the incidence of behavioral episodes and often will prevent the necessity of pharmacotherapy.

The atypical antipsychotics include: risperidone; olanzapine; quetiapine; ziprasidone; and, aripiprazole. These are favored due to their lower incidence of extrapyramidal syndromes and tardive dyskinesias. However, they are associated with weight gain, diabetes, dyslipidemias, and cardiac disturbances. For patient’s in long-term care facilities, behavior should be documented and attempts at dose reductions should be attempted every 6 months if behaviors are absent.


Treatment of Alzheimer’s Symptoms: Anxiety

Anxiolytics:

• Benzodiazepines without active metabolites - oxazepam, lorazepam,. clonzaepam • Buspirone (Buspar®)

Precautions:

• minimize use to reduce risk of sedation, confusion, delirium, amnesia, falls

Anxiety is a common clinical manifestation of Alzheimer’s disease, occurring in about forty-eight percent of cases. Before beginning any drug therapy for anxiety every attempt should be made to identify precipitating factors. For example, untreated pain which a patient is unable to communicate may lead to anxiety. When a pharmacologic agent is needed, benzodiazepines are frequently prescribed. Recognizing the likelihood that benzodiazepines could impair cognition, this decision should not be made without careful consideration and monitoring of the patient’s cognitive function. The safest benzodiazepines for use in the elderly are those that have no active metabolites and are not metabolized by oxidative pathways. Examples include oxazepam and lorazepam. Another agent, buspirone, is also useful in treating anxiety. These drugs should be used sparingly, however, to minimize the risk of sedation, confusion, amnesia, and falls.


Treatment of Alzheimer’s Symptoms: Insomnia

Nonpharmacological Options: • sleep hygiene

Sedative-hypnotic Drugs: • Benzodiazepines - short half-life; not well studied in geriatric, demented patients • Chloral hydrate (Novochloroalhydrate®) – although data is limited, generally not recommended for use in elderly • Zolpidem (Ambien®) or zaleplon (Sonata®) may be better tolerated • Trazodone (Desyrel®) • Mirtazapine (low dose) (Remeron®) • Antihistamines - avoid in patients with dementia; antihistamines are not generally recommended for use in the elderly • Melatonin • Remeteron (Rozerem)

As AD progresses patients quickly lose track of time perception. In fact they sometimes experience a complete reversal of day and night. More often there is a complete disintegration of their sleep architecture resulting in frequent napping with no consistency as to when or where they sleep. This can lead to tremendous problems for caregivers who can no longer sleep at night because they must watch the patient. In addition to altered sleep, some patients experience worsening cognition during late afternoon or early evening – the so called sundowning.

Because of the frequency of sleep disturbances and the high burden exacted on the pts caregivers, every attempt should be able to treat this condition. That said first line treatments should not include medication, but instead a thorough review of sleep hygiene and ways to support the caregiver – such as aid and attendants, respite care and adult day care.


Treatment of Alzheimer’s Symptoms: Insomnia

When medication must be used, it is important to recognize there is little data in AD patients with sleep problems. A general approach is to use medications that appear to have little or no effects on cognition and little or not drug hang over the next day. When sleep maintenance is desired, ultra short acting agents like zaleplon are less effective than intermediary agents like trazodone, mirtazapine and certain benzodiazepines.

Mirtazapine also has the added benefit of increasing appetite (which is often decreased in AD patients), and the sedative effect is observed at the lower doses Antihistamines and other anticholinergics may increase confusion in patients with dementia, and should be avoided.


Treatment of Alzheimer’s Symptoms: Depression

Goals of Therapy: • diminishing apathy; improving mood, functional status, quality of life, cognitive symptoms

Antidepressants: • SSRIs such as sertraline and citalopram are better tolerated • venlafaxine (EffexorÒ) • mirtazapine (RemeronÒ) • duloxetine (Cymbalta) • treatment must be tailored to individual needs

Depression is a significant problem for thirty-eight percent of Alzheimer’s patients. The goals of treatment for these patients include diminishing apathy and improving mood, functional status, and quality of life.


Resources


American Psychiatric Association. (1997). Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias of late life. Am J Psychiatry, 154 (suppl): 1-39.

Birge, S. J., (Ed.). (May, 1997). The role of estrogen in the treatment and prevention of dementia. Proceedings of a symposium. American Journal of Medicine, 103 (suppl 3A): 1S-50S.

Burlingame, M. B. (1997) Dementia and delirium. Preparatory Program for the Certification Exam in Geriatric Pharmacy. Alexandria, VA: American Society of Consultant Pharmacists.

Costa, P. T., Jr., Williams, T.F., Somerfield, M., et al. (1996). Early identification of Alzheimer’s disease and related dementias. Clinical practice guideline, quick reference guides for clinicians. No. 19. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, AHCPR Publication No. 97-0703.

Cummings, J. L. & Mega, M. (1996). Alzheimer’s disease: etiologies and pathogenesis. Consulting Pharmacist; 11(suppl E): 8-15.

Doody, R.S. (2003). Current treatments for Alzheimer’s disease: cholinesterase inhibitors. J Clin Psychiatry; 64 (Suppl 9):11-17.

Doraiswamy, P. M. (1996, Nov). Current cholinergic therapy for symptoms of Alzheimer’s disease. Prim Psychiat: 56-68.

McNeil, C. (1995, Oct). Alzheimer’s disease: unraveling the mystery. Bethesda, MD: National Institutes on Aging, National Institutes of Health: NIH Publication 95-3782.


Resources

Odenheimer, G. L., (1995). Cognitive dysfunction. In: Delafuente, J. C., Stewart, R.B., (Eds.). Therapeutics in the Elderly. 2nd ed. Cincinnati: Harvey Whitney Books, 307-323.

Paganini-Hill, A., & Henderson, V. W. (1996). Estrogen replacement therapy and risk of Alzheimer’s disease. Arch Intern Med; 156:2213-7.

Reisberg,B., Doody, R., Stˆffler A, et al. (2003). Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med; 348(14):1333-1341.

Sano, M., Ernesto, C., Thomas, R.G. (1997). A controlled trail of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s disease cooperative study. N Engl Journal of Medicine, 336: 1216-1222.

Schmall, V. L. (1996) Dealing with Alzheimer’s disease: caregiver issues. Consulting Pharmacist; 11(suppl E): 25-31.

Scott, H.D., Laake, K. (2003). Statins for the prevention of Alzheimer’s disease. The Cochrane Database of Systematic Reviews, v. 3.

Simonson, W. (1997). Pharmacotherapy of Alzheimer’s disease. Clinical Consult: Suppl 2. Available online at http://www.ascp.com/public/pubs/cc/1997/supp2.html.

Simonson, W. (1996). Alzheimer’s disease: we will cure it someday… soon. Consulting Pharmacist; 11(suppl E): 1.

Simonson, W. (1996). Consult pharmacist involvement with therapy of Alzheimer’s disease. Consulting Pharmacist; 11(suppl E): 4-7.


Resources

Small, G. W., Rabins, P. V., Barry P. P., et al. (1997). Diagnosis and treatment of Alzheimer’s disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA, 278: 1363-1371.

Stewart, W. F., Kawas, C., Corrada, M., Metter, E. J. (1997). Risk of Alzheimer’s disease and duration of NSAID use. Neurology, 48: 626-632.

Tariot, P. N. & Schneider, L. (1996). Contemporary treatment approaches to Alzheimer disease. Consulting Pharmacist; 11(suppl E): 16-24.

Tolbert, S. R., & Fuller, M. A. (1996). Selegiline in treatment of behavioral and cognitive symptoms of Alzheimer disease. Ann Pharmacother; 30: 1122-9.

Watkins, P. B., Zimmerman, H. J., Knapp, J., et al. (1994). Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA; 271: 992-81.


Parkinson's Disease



• Describe the epidemiology and pathophysiology of Parkinson’s disease.

• Identify common agents associated with drug-induced parkinsonism.

• List motor and non-motor signs and symptoms characteristic of Parkinson’s disease.

• Describe pharmacological and nonpharmacological treatment options for patients with Parkinson’s disease.

• Describe side effects and drug interactions associated with antiparkinson agents.

• Describe the management of motor complications associated with levodopa therapy.

• Describe the management of psychiatric complications associated with antiparkinson drug therapy.


Epidemiology of Parkinson’s Disease (PD)

• Second most common neurodegenerative disorder among the elderly • Third most common movement disorder • Prevalence increases with age:

• 15% for 65-74 years • 30% for 75-84 years • 50% for 85 years and older

• Men affected slightly more than women • Only 30% diagnosed before age of 55 years • Direct annual cost over 2 billion dollars

Parkinson’s disease is a common neurodegenerative syndrome characterized by progressive deterioration of neurons in subcortical regions of the brain that control or influence movement as well as autonomic body functions and behavior.

The majority of cases are diagnosed in older patients, and as can be seen, disease prevalence increase with age. PD is second only to Alzheimer’s disease as the most common neurodegenerative disorder in the elderly and is the third most common movement disorder (after restless leg syndrome and essential tremor). In the United States, the direct costs associated with this disease are estimated at over $2 billion per year.


Pathophysiology of Parkinson’s Disease

Degeneration of subcortical structures

Hallmark pathology: • Loss of pigmented dopaminergic neurons of substantia nigra and projections to striatum

• At the time PD symptoms are apparent; up to 80% of the neurons in the substantia nigra have been impaired. • Intracellular Lewy bodies found in remaining neurons of substantia nigra or locus ceruleus

Other pathology: • Loss of noradrenergic neurons in the locus ceruleus • Loss of serotonergic neurons in the dorsal raphe nucleus • Altered acetylcholine, GABA, and glutamate activity within the extrapyramidal motor circuit


Pathophysiology of Parkinson’s Disease

The neuropathology of Parkinson’s disease is complex. However, it can be summarized as a progressive and irreversible degeneration of specific subcortical anatomical structures. Such events include: dopamine producing neurons of the substantia nigra, noradrenergic neurons of the locus ceruleus, and serotonergic neurons of the dorsal raphe nucleus. Additionally, acetylcholine, GABA, and glutamate activity within the striato-thalamic-cortical motor circuit are altered. The result is a profound disequilibrium of the extrapyramidal motor circuit as well as disruption of neuronal activity within the mesocortical and mesolimbic regions of the brain. In addition to loss of pigmented neurons, the other hallmark pathologic marker is presence of Lewy bodies found within the remaining substantia nigra neurons, as well as the locus ceruleus.


Etiology of Idiopathic Parkinson’s Disease

•  Unknown triggers for neurodegenerative cascade: • Abnormal protein aggregation • Excitotoxicity • Mitochondrial dysfunction • Oxidant stress • Proteosomal dysfunction

• Pathologic apoptosis and inflammation

• Risk Factors • Age • Genetic susceptibility

• Lifetime environmental toxin exposure

In the majority of cases, the cause of Parkinson’s disease is unknown. This is referred to as idiopathic Parkinson’s disease. Although the etiologic factor or factors responsible for triggering the cascade of events leading to nerve cell degeneration remains unidentified, it is known that multiple mechanisms, such as abnormal protein aggregation, excitotoxicty, mitochondrial dysfunction, oxidant stress, and proteosomal dysfunction are elements of the degenerative cascade. Ultimately, the toxic cascade results in pathologic apoptosis and inflammation accompanied by irreversible nerve cell death.

Risk factors include: advanced age, genetic susceptibility, and possibly lifetime exposure to pesticide and herbicides. Genetic susceptibility appears to play a greater role in younger-onset cases. Several genetic loci have been identified and associated with familial parkinsonism; however, these forms of parkinsonism are relatively rare.


Secondary Parkinsonisms

• Neurovascular (e.g., multi-infarct) • Head trauma • Hepatocerebral degeneration • Normal pressure hydrocephalus

Drugs: • Haloperidol • Methyldopa • Metoclopramide • Phenothiazine antiemetics and antipsychotics

• Atypical antipsychotics may lead to EPS in a dose-related manner. See interpretive guidelines for CMS-directed limits on dosing of these agents. Clozapine and quetiapine are thought to have the lowest potential

for EPS adverse effects. • Reserpine • Valproic acid • Cinnarizine and Flunarizine (Note: although not available in the US, these medications can be purchased via internet providers)

Environmental toxins: • Carbon monoxide • Manganese • Methanol • MPTP exposure • 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine • Pesticides (e.g., organophosphates)


Secondary Parkinsonisms

Several known or inciting factors such as cerebral atherosclerosis, head trauma, hepatocerebral disease, normal pressure hydrocephalus, and a variety of environmental toxins and drugs (such as those listed on your screen) are responsible for secondary parkinsonisms.

Drug-induced parkinsonism is the most common form of secondary parkinsonism. Agents such as haloperidol, metoclopramide, and phenothiazine antipsychotics (like chlorpromazine and fluphenazine) that block dopamine receptors in the striatum are responsible for the majority of drug-induced cases. Other medications, such as valproic acid may be an underappreciated cause of parkinsonism in the elderly. In other parts of the world, cinnarizine and flunarizine (which are not marketed in the United States) commonly induce parkinsonism.

Except for tardive parkinsonism, most cases of drug-induced parkinsonism are reversible upon discontinuation of the offending agent; although, in some cases, improvement may not be observed for several weeks to months. Parkinsonism due to environmental toxin exposure is relatively uncommon and for the most part, irreversible.


Atypical Parkinsonisms

• Corticobasal ganglionic degeneration

• Multiple system atrophy

• Progressive supranuclear palsy

• Dementia-parkinsonism syndromes

• Dementia with Lewy bodies

Although far less common than idiopathic Parkinson’s disease or drug-induced parkinsonism, many types of atypical parkinsonism exist. Clinically, these forms may be difficult to distinguish from idiopathic Parkinson’s disease.

Clues indicating a diagnosis of atypical parkinsonism include: a lack of response, or transient response, to high-dose levodopa therapy; history of falls in early stages; onset of dementia prior to parkinsonism; or dementia in early stages. Vertical gaze paresis and wide-stance gait are characteristic of progressive supranuclear palsy. Limb dystonia and apraxia is characteristic of corticobasal ganglionic degeneration and autonomic abnormalities out of proportion to the motor impairments is characteristic of multiple system atrophy. Examples of autonomic abnormalities include: orthostatic hypotension, erectile dysfunction, and urinary incontinence.


Motor Signs and Symptoms of Parkinson’s Disease

Presence of two (2) or more of the following:

Tremor: • Slow, rhythmic resting tremor • Postural tremor

Rigidity: • “Cogwheel” or “lead pipe” • Resistance to passive joint movement

Bradykinesia: • Slowness of voluntary learned movement

Postural Instability: • Inadequate postural responses • Increased risk of falls

In early stage Parkinson’s disease, the signs and symptoms are rather non-specific and may be misdiagnosed as arthritis, depression, essential tremor, or hypothyroidism. However, as the disease progresses, symptoms begin to cluster and become much more obvious and easier to recognize. Clinical diagnosis is confirmed by presence of two or more of the following: tremor, muscular rigidity, slowness of movement, or postural instability. Other features such as constipation, depression, flat affect, orthostatic hypotension, and sleep abnormalities are also common but not diagnostic.

Although the tremor of Parkinson’s disease is highly visible, it is rather benign compared to the functional impairment and reduction in quality of life caused by the other motor and non-motor symptoms. Two types of tremor are common in Parkinson’s disease: a slow rhythmic rest tremor and a postural tremor. One example is a tremor that emerges when arms are in an outstretched posture.


Motor Signs and Symptoms of Parkinson’s Disease

Muscular rigidity affects the joints in distal extremities as well as axial and proximal joints such as the face, neck, shoulder, and trunk. Passive flexion of the affected joint will reveal a “cog-wheel,” or ratchet-like quality due to superimposed tremor. In the absence of tremor, the rigidity will possess a stiff “lead pipe” quality. A flat facial expression along with reduced blinking is also common and should not be misinterpreted as apathy, cognitive impairment, disinterest, or unfriendliness.

It is important for patients to participate in exercise or stretching activities to maintain flexibility and range of motion. This will minimize muscle contraction and pain.

Bradykinesia or slowness of learned movement along with the rigidity can make daily activities (such as arising from a chair, bathing, dressing, driving, eating and drinking, entering and exiting automobiles, personal hygiene, putting on cosmetics, shaving, turning over in bed, walking, and writing) increasingly time consuming and difficult to accomplish without assistance. Such difficulty results in functional impairment, interference with employment, inability to manage household and business affairs, and psychosocial embarrassment. A slow shuffling gait with reduced arm swing is a very characteristic manifestation of the bradykinetic-rigid symptomatology.

Postural instability, or loss of postural reflexes resulting in imbalance and tendency to fall easily, is more common in advance stages and is a disabling symptom. It results in significant impairment of ambulation and an increased risk of falling. Pharmacotherapy is generally not helpful for this symptom. Non-pharmacological interventions include use of assistive walking devices and wheelchairs.


Manifestations of Motor Symptoms:

• Falls • Functional impairment • Impaired ambulation • Impaired swallowing • Masked facies or flat facial expression • Micrographia • Muscle contraction and reduced range of motion • Reduced frequency of blinking • Slow shuffling gait with reduced arm swing • Somatic pain and discomfort • Stooped posture • Weak vocalization

The motor symptoms of Parkinson’s disease will eventually progress in severity until the ability to perform daily activities is significantly impaired. In addition to functional impairment, the physical symptoms of Parkinson’s disease also contribute to falls, pain, impairment of social activities, as well as many functions listed on the screen. Thus, quality of life is profoundly affected.


Non-Motor Symptoms of Parkinson’s Disease

Behavioral and Neuropsychiatric disorders: • Anxiety • Apathy • Bradyphrenia (slowness of thought processes) • Dementia (late stages) • Depression • Sleep disturbances (e.g., insomnia, hypersomnia)

Autonomic Symptoms: • Bladder incontinence • Constipation • Drooling • Dysphagia • Erectile dysfunction • Orthostatic hypotension • Sweating

Behavioral and cognitive disorders are also very common in Parkinson’s disease. Anxiety, apathy, depression, and sleep disturbances are very common and play a significant role in reducing quality of life for both patients and caregivers alike. All patients should be screened for these symptoms. Dementia is generally a symptom of advanced disease. Bradyphrenia, or slowness in formulating thoughts, should not be mistaken for dementia. Patients with bradyphrenia will require more time to articulate a response during conversations

There are also many autonomic symptoms. The most problematic are bladder incontinence, constipation, dysphagia, and orthostatic hypotension


Diagnosis, Monitoring, and Prognosis of PD

Diagnosis: • Clinical diagnosis dictated by presence of motor symptoms • Levodopa or dopamine agonist response confirmatory • Final diagnosis by autopsy-confirmed presence of nigral Lewy bodies and atrophy of substantia nigra • Rule out secondary causes (e.g., drugs) • Neuroimaging promising • Up to 20% of cases misdiagnosed

Monitoring: • Unified Parkinson’s Disease Rating Scale (UPDRS)

Prognosis: • Increase mortality • Dependence on caregiver • Placement in long-term care facility

The diagnosis of Parkinson’s disease is made by clinical examination and careful history taking to rule out secondary causes such as drugs. A significant and sustained response to levodopa generally validates the diagnosis. But true confirmation of Parkinson’s disease can only be made based on autopsy findings. To date, no laboratory markers are available to diagnose the disease. Neuroimaging techniques such as single-photon emission computerized tomography (SPECT) may someday become widely applicable in clinical settings. Other imaging techniques such as CT and MRI are useful for ruling out secondary causes. Because diagnosis is made by clinical means and there is wide variability in symptom presentation and progression, up to 20% of cases are misdiagnosed.


Diagnosis, Monitoring, and Prognosis of PD

Overall, Parkinson’s disease is associated with an increased risk of death. The combination of functional impairment due to motor symptoms, altered behavior, and dysregulation of autonomic functions eventually results in increased reliance on caregivers or placement in a long-term care facility. Caregivers in turn often experience increased stress due to the added responsibility and activities of providing care.


Nonpharmacological Treatment of Parkinson’s Disease

• Education and support groups • Exercise to keep muscles active and preserve mobility • Stretching to maintain range of motion • Occupational, physical, and / or psychosocial therapy • Surgery: ablation or deep brain stimulation of the thalamus, globus pallidus, or subthalamic nucleus

Reassurance and education appropriate for the level of disability should be provided to both patients and caregivers. Some patients may benefit from attending educational support groups. Parkinson’s disease is a progressive disease and appropriate education will allow patients to make appropriate arrangements for the future (e.g., personal finance and health care).

Exercise, stretching, occupational therapy, and psychosocial therapy are useful and should be viewed as supplements to pharmacological therapy. Exercise and stretching activities are especially important for maintaining range of motion and will minimize muscle contraction and pain.

For patients requiring symptom control beyond that achievable with drugs, surgical techniques involving thermoablation or deep brain stimulation of the thalamus, globus pallidus, or subthalamic nucleus may be an option.


Treatment of Parkinson’s Disease

Pharmacological:

Mild to Moderate Symptoms: • Amantadine • Rasagiline and selegiline (selective MAO-B inhibitors) • Benztropine and trihexyphenidyl (anticholinergics) • Useful for drug-induced parkinsonism

Moderate to Severe Symptoms: • Bromocriptine, pramipexole, ropinirole (dopamine agonists) • Combination levodopa products (carbidopa / levodopa,

carbidopa / levodopa entacapone)

Adjuncts for Motor Fluctuations: • Amantadine • Apomorphine • Entacapone and tolcapone (COMT inhibitors) • Rasagiline and selegiline

To date, no agents have been proven to be preventative or neuroprotective. A recent American Academy of Neurology Practice Parameter highlights the lack of evidence for any neuroprotective agents at this time.

However, various drugs are available for symptomatic treatment of Parkinson’s disease. In general, amantadine, anticholinergics, and the selective monoamine oxidase type B inhibitors are suggested for treating mild to moderate symptoms in early Parkinson’s disease.

Anticholinergics have become less widely prescribed due to limited efficacy, poor tolerability, and availability of other antiparkinsonian agents. However, anticholinergics agents remain a drug of choice for drug-induced extrapyramidal symptoms.

For moderate to severe symptoms, the combination levodopa products and dopamine agonists are very useful.

For the management of motor fluctuations, several drugs listed on your screen are often utilized. As the disease progresses, most patients will require combinations of antiparkinsonian agents for symptomatic management.


Treatment of Parkinson’s with Anticholinergics

Indications: • Mild rest tremor and rigidity • Dystonia • Sialorrhea • Drug-induced EPS

Contraindications: • Prostatic hypertrophy • Bladder or gastrointestinal obstruction • Myasthenia gravis

Mechanism of action: • Unknown

Administration and dosing: • Monotherapy in early disease • Discontinue gradually once dopamine agonists or levodopa is required • Benztropine (Cogentin®) 0.5 – 6 mg QD – QID • Trihexyphenidyl (Artane®) 1 – 10 mg TID – QID

Adverse Reactions:

Aggravation of angle closure glaucoma Blurred vision Dry eyes Confusion and memory impairment Constipation Dry mouth Sedation Tachycardia Urinary retention


Treatment of Parkinson’s with Anticholinergics

Centrally acting anticholinergics such as benztropine and trihexyphenidyl were the first drugs available for Parkinson’s disease and can provide modest benefits in early disease. However, for moderate to severe cases, the benefits generally do not outweigh the disadvantages such as confusion and unwanted sedation.

For patients less than 65 years of age, these agents are good for treating rest tremor, dystonia, sialorrhea, and drug-induced extrapyramidal symptoms. In older patients, these agents should be avoided, if possible. For patients with advanced disease and already receiving levodopa or a dopamine agonist, the need for adjunctive anticholinergic therapy should be reassessed. Anticholinergics should be discontinued gradually, over seven days or more, because sudden withdrawal may precipitate severe agitation and confusion. Side effects to watch for are listed on the screen.

These agents are associated with several adverse effects that can be problematic in the older patient. Also, older patients may have conditions that are relatively contraindicated with anticholinergics.


Treatment of Parkinson’s with Amantadine (Symmetrel®)

Indications: • Mild symptoms of PD

• Benefits of amantadine seem to be limited in duration. Therefore the role of amantadine is largely add-on therapy. Adverse effects may limit its use in older adults.

• Levodopa-induced dyskinesia

Contraindications: • Angle closure glaucoma • Eczematoid dermatitis • Severe renal impairment

Mechanism of Action: • Unknown

Administration and Dosing: • 100 mg BID – TID • Lower dosages in renal impairment • Late afternoon dosing associated with insomnia

Tachyphylaxis: • Effectiveness declines after several weeks to

months • Taper off and restart in 4 weeks

Adverse Reactions: • Ankle edema • Confusion • Hallucinations • Nightmares • Dry skin • Insomnia • Livedo reticularis (reversible reddish – blue mottling of the skin) • Nausea • Orthostatic hypotension • Falls


Treatment of Parkinson’s with Amantadine (Symmetrel®)

Another agent used in treating mild to moderate Parkinson’s symptoms is Amantadine. Amantadine can be used as monotherapy in early disease to alleviate symptoms and delay the need for levodopa or as adjunctive therapy in more advanced disease to manage levodopa-induced dyskinesias.

The initial dose should be 100 mg per day and titrated up to twice or three times a day. Lower dosages are effective in patients with renal impairment, but the drug should be avoided in patients with severe renal impairment. The initial effects of the drug can be seen within two days, but may take up to two weeks for full effects to be determined.

Some patients may experience tachyphylaxis or tolerance to the symptomatic benefits after several weeks to months of therapy. If this occurs, tapering off the drug and restarting after four weeks (also called a drug holiday) is recommended.

Side effects of this drug are listed on the screen. Of note, livedo reticularis, a painless but cosmetically unpleasant mottling of the skin may occur and may be reversible upon drug discontinuation. Drug discontinuation should be gradual so as to avoid withdrawal encephalopathy.


Treatment for PD with Selective MAO-B Inhibitors: Rasagiline and Selegiline

Indications: • Bradykinesia, rigidity, tremors • Motor fluctuations • Early therapy delays need for levodopa therapy

Contraindications: • Concurrent use of meperidine

Mechanism of Action: • Selectively inhibits MAO-B • Increases synaptic dopamine concentrations

Administration and Dosage: • Rasagiline: 1 mg QD • Selegiline (Eldepryl®): 5 mg BID • Best taken with breakfast and lunch

Adverse Reactions: • Dizziness • Insomnia • May be less with rasagiline • Hallucinations and nightmares • Nausea • Orthostatic hypotension

Drug Interactions: • Levodopa

• Results in dystonias or dyskinesias • Meperidine and SSRIs • Rare serotonin syndrome • Tyramine-containing products • Hypertensive effects typically only occur with MAO-A inhibitors • At recommended doses, no problem with tyramine products


Treatment for PD with Selective MAO-B Inhibitors: Rasagiline and Selegiline

The selective monoamine oxidase type B inhibitors, rasagiline and selegiline, have a role in both early and advanced disease. In early disease, monotherapy is effective for mild symptoms and delays the need for levodopa therapy. In more advanced disease, MAO-B inhibitors are useful in combination with carbidopa/levodopa for managing motor fluctuations such as end of dose wearing off.

Rasagiline is dosed 1 mg once per day as monotherapy for early Parkinson disease. It is also approved for adjunctive therapy at 0.5 – 1 mg per day to decrease motor fluctuations in patients already on levodopa therapy. Selegiline should be initiated at 2.5 milligrams daily, building up to five milligrams twice a day, preferably at breakfast and lunch. Dosages of selegiline administered in the late afternoon or in the evening have been known to produce insomnia and nightmares in some patients. Other common side effects include hallucinations, nausea and orthostatic hypotension, which is exacerbated when the drug is combined with levodopa.

Other consequences of levodopa-selegiline interaction include: dystonias or dyskinesias, which occur as and can be alleviated with a reduction in selegiline or levodopa dosage. Rarely, serotonin syndrome occurs when selegiline is combined with either meperidine or selective serotonin reuptake inhibitors. However, in clinical practice, many patients have safely received an SSRI with selegiline.


Treatment: Parkinson’s with Carbidopa/Levodopa (Sinemet®)

Indications: • Early and advanced disease

Contraindications: • Use of non-selective MAO-B inhibitor within 14 days • Melanoma • Narrow angle glaucoma

Mechanism of Action: • Carbidopa combined with levodopa to minimize

• peripheral degradation of levodopa and to • minimize levodopa-induced nausea

• Levodopa converted to dopamine in the brain

Formulations: • Immediate release (IR) and controlled release (CR) • Bioavailability of CR form is less than IR • Need 25% more CR for same effect • CR form requires less frequent dosing • Parcopa®: orally dissolving

Administration and Dosage:

• Start with once daily dosing and titrate rapidly for desired clinical response • Recommended dosages:

• Carbidopa 25 mg / levodopa 100 mg TID – QID • Carbidopa 50 mg / levodopa CR 200 mg BID – TID

• Reduce dosage when patient develops dyskinesia • Discontinue gradually over 3 – 4 days to avoid neuroleptic malignant syndrome (NMS) and abrupt resurgence of Parkinson's symptoms • Avoid “drug holidays”


Treatment: Parkinson’s with Carbidopa/Levodopa (Sinemet®)

The combination of carbidopa and levodopa is the most effective treatment available for Parkinson’s disease. Although patients with mild symptoms may not require carbidopa/levodopa, eventually as the disease progresses, all patients will require it for symptomatic improvement. In the brain, levodopa is converted to dopamine. However, in the periphery, levodopa that is converted to dopamine is unable to cross the blood brain barrier. The addition of carbidopa prevents peripheral conversion of levodopa to dopamine, thus enhancing blood and brain concentrations of levodopa. Carbidopa also reduces dopamine mediated peripheral side effects such as nausea.

Carbidopa/levodopa comes in three formulations: immediate release, controlled release, and orally dissolving. When converting between the immediate release and controlled release formulations, pharmacists should adjust for differences in bioavailability and dosing interval. The controlled release formulation is 25% less bioavailable, and is administered less often. Also, since the CR formulation has a slow onset, some patients may require supplementation with an immediate release dose in the morning. The orally dissolving tablet is available in the same strengths as the immediate release formulation.

Note that the orally dissolving formulation contains phenylalanine. The orally dissolving formulation may be helpful for patients who have swallowing difficulties or find themselves in situations where water is not readily available for consumption. While the tablet dissolves completely in the mouth, the salivate must still be swallowed as this medication is not buccally absorbed.

Carbidopa/levodopa may be initiated with once daily dosing and rapidly titrated for the desired clinical response. If patients develop dyskinesia, the dosage should be reduced. The CR formulation may prolong dyskinesias and should be avoided in patients with pre-existing dyskinesia.

The drug should be discontinued gradually over a period of three to four days to avoid neuroleptic malignant syndrome and abrupt reemergence of severe Parkinson’s symptoms which can be extremely distressing to patients. In general, drug holidays are not recommended.


Adverse Reactions Associated with Carbidopa/Levodopa

• Nausea • Orthostatic hypotension • Motor complications • Psychiatric • Hyperhomocysteinemia

Several side effects are associated with combination of carbidopa/ levodopa therapy. Common acute side effects include nausea and orthostatic hypotension. For the management of nausea, antiemetics such as trimethobenzamide and domperidone (not available in the U.S.) are preferred. Supplementation with carbidopa may also be helpful. Long term side effects include motor complications such as peak-dose dyskinesia and psychiatric reactions such as hallucinations or psychosis. Patients on long-term carbidopa/levodopa may also develop elevated levels of homocysteine and supplementation with folic acid and B vitamins may be considered.


Motor Complications Associated with Carbidopa / Levodopa

Peak-dose Dyskinesia: • Especially choreiform dyskinesias • Dose fragmentation (smaller more frequent dosing) • Add amantadine

“On” Dystonia: • Reduce levodopa dose • Muscle relaxant

Wearing Off: • End of dose phenomenon • Options:

• More frequent levodopa dosing • Add dopamine agonist or selective MAO-B inhibitor • Switch to carbidopa/levodopa CR

Peak-dose dyskinesia and “on” dystonia are associated with peak levels of levodopa and can be alleviated through levodopa dosage reduction. Muscle relaxants may also be helpful in patients with dystonia, but clinicians need to weight the risk-to-benefit ratio of using such an agent in the elderly patient. If dosage reduction improves dyskinesia at the cost of worsening parkinsonism, addition of supplemental amantadine, a dopamine agonist, or a selective MAO-B inhibitor may be required.

“Wearing off phenomenon”, also known as end-of-dose failure occurs towards the end of the dosing interval when levodopa levels are low. Management includes adding additional dosages, that is, more frequent dosing of levodopa, adding a dopamine agonists or a selective MAO-B inhibitor, or switching to controlled release levodopa.


Psychiatric Adverse Effects Associated with Carbidopa / Levodopa

• Hallucinations • Delusions / psychosis

After several years of therapy with levodopa or dopamine agonists, many patients will experience hallucinations. Most are visual hallucinations but can also be auditory, olfactory, or tactile. If non-disruptive, these hallucinations do not require treatment. However, some hallucinations can be alarming and disruptive and some patients may go on to develop delusions, usually involving feelings of jealousy or paranoia. In these instances, treatment is required.


Drug Interactions that Decrease the Effect of Levodopa

Protein: Competes for active transport across the gut wall and blood-brain barrier

FeSO4: Decreases levodopa bioavailability 50% by chelation

Haloperidol, metoclopramide, phenothiazine antiemetics and antipsychotics:

Blocks dopamine receptors

Anticholinergics and tricyclic antidepressants: Slows GI motility, resulting in erratic levodopa absorption

Methyldopa: Inhibits central conversion of levodopa

Reserpine: Central dopamine depletion

Amoxapine and pimozide: Block dopamine receptors

Levodopa has been found to interact with protein and various drugs. The most common interactions are with protein, ferrous sulfate, and drugs that block dopamine receptors. Protein competes with levodopa for active transport across the gut wall and blood and brain barrier. For this reason, levodopa should be given at least a half hour before a high protein meal, especially in patients with end-of-dose failure or in those patients experiencing a delayed onset of action. Low-protein snacks are less of a concern.

Ferrous sulfate should be administered at least one hour apart from carbidopa/levodopa as it reduces the bioavailability of both components by fifty percent. Drugs that block central dopamine receptors such as haloperidol and metoclopramide should also be avoided, as should phenothiazine antipsychotics, such as chlorpromazine & fluphenazine, and phenothiazine antiemetics, such as prochlorperazine.


Treatment: Parkinson’s with COMT Inhibitors

Indications: • Wearing off phenomenon

Contraindications: • Patients not on levodopa • Liver impairment (tolcapone)

Mechanism of Action: • Blocks levodopa conversion to 3-O-methyldopa

and increases levodopa half-life

Administration and Dosing:

• Entacapone (Comtan®): • 200 mg with each dose of carbidopa / levodopa • Max 8 doses per day

• Tolcapone (Tasmar®): • 100 – 200 mg TID • Use restricted due to hepatotoxicity

• Adverse Reactions: • Nausea • Diarrhea • Dyskinesia • Hallucinations • Urine discoloration

Catechol-O-methyltransferase or COMT inhibitors are enzyme inhibitors that extend the half-life of levodopa. Thus, as with carbidopa, COMT inhibitors are only effective if given in conjunction with levodopa.

Tolcapone is associated with hepatic toxicity and is not commonly prescribed. However, hepatotoxicity may not be as common as was once thought. The FDA has recently lightened the intensity of monitoring requirements. A consent or patient waiver for monitoring is still required. Tolcapone is more potent than entacapone and can be given less frequently (three times a day versus with every dose of carbidopa/levodopa). However, entacapone is still more commonly prescribed because it does not require monitoring of liver function tests. These agents are mainly indicated for patients with motor fluctuations, such as “wearing off” or “end of dose” failure.

Entacapone is dosed at 200 mg with each dose of carbidopa/levodopa. It may be administered with the immediate release or controlled release levodopa formulations. The maximum is 8 doses per day. Common adverse effects include: nausea, diarrhea, dyskinesias, hallucinations, and urine discoloration. Nausea, dyskinesias, and hallucinations can be alleviated by reducing the dosage of carbidopa/levodopa.


Treatment of PD with Carbidopa / Levodopa / Entacapone (Stalevo®)

Indications: • Wearing off or end-of-dose failure

Contraindications: • Same as levodopa and entacapone

Mechanism of Action: • Same as carbidopa / levodopa and entacapone

Administration and Dosing: • 12.5 / 50 / 200 mg (carbidopa / levodopa / entacapone) • 50 / 100 / 200 mg • 37.5 / 150 / 200 mg • With each dose of carbidopa / levodopa • Max of 8 doses per day

Adverse Reactions: • Same as carbidopa / levodopa and entacapone

The triple combination product carbidopa/levodopa/entacapone is indicated for patients experiencing the wearing off or end of dose phenomenon. It is available in three fixed-dose combinations, as listed on your screen, and is used in conjunction with an adjusted carbidopa / levodopa regimen for the patient.


Treatment of Parkinson’s with Dopamine Agonists

Indications: • Early and advanced disease

Contraindications: • History of cardiac valvular, retroperitoneal,

or pulmonary fibrosis (bromocriptine only)

Mechanism of action: • Stimulates dopamine receptors

Administration and Dosage:

• Bromocriptine (Parlodel®): • 1.25 mg BID • Increase over several weeks to 10 – 40 mg / day

• Pergolide (Permax®): • Withdrawn from the market March 2007 due to increasing reports of cardiac valve regurgitation.

• Pramipexole (Mirapex®): • 0.125 mg QD

• Increase over several weeks to 3 – 4.5 mg TID

• Ropinirole (Requip®): • 0.25 mg QD • Increase over several weeks to 6 – 9 mg TID

Adverse Reactions: • Lower extremity edema • Nausea • Orthostatic hypotension • Psychosis • Somnolence • Cardiac valvular/retroperitoneal/pleural fibrosis



Dopamine agonists are effective as monotherapy in patients with early disease and are useful in conjunction with levodopa in patients with advance disease. In general, the agonists are associated with a low risk of dyskinesias but a greater risk for hallucinations and delusions. Common side effects include nausea and orthostatic hypotension. Bromocriptine is not commonly prescribed.

The remaining two agonists, pramipexole, and ropinirole are considered equally efficacious and possess similar adverse effect profiles. Fibrosis of cardiac valvular, retroperitoneal, and pleural soft tissue is a serious side effect specific to the dopamine agonists and requires drug discontinuation if it occurs. For all agonists, dosage adjustment requires several weeks of titration.

Adverse effects are common to all agonists and include lower extremity edema, nausea, orthostatic hypotension, hallucinations and psychosis, and somnolence .



• Reduced risk of dyskinesias • Preferred in younger patients



Many clinicians preferentially use dopamine agonists in younger patients and add levodopa at later stages because, as the graph depicts, initiation of therapy with a dopamine agonist reduces the risk of developing dyskinesias. In older patients, the treatment horizon is shorter and the risk of developing dyskinesias less of a concern.

Therefore, levodopa remains the preferential symptomatic agent. As seen in the graphs on your screen, double-blind, randomized studies have demonstrated that patients with early PD initiated on a dopamine agonist, such as pramipexole and ropinirole, are at a lower risk of developing dyskinesias as compared to patients initially treated with levodopa.


Treatment of Parkinson’s with Apomorphine

Indications: • Rescue therapy for on-off fluctuations

Contraindications: • Hypersensitivity to morphine

Mechanism of Action: • Short-acting dopamine agonist

Administration and Dosage: • 2 – 6 mg per rescue dose • Subcutaneous • Calibrated, semi-automatic pen injector device • Trimethobenzamide 250 mg po TID if nausea

Note: trimethobenzamide is on the Beer’s list of potentially inappropriate medications; however, this is the antiemetic least likely to cause EPS.

Adverse Reactions: • Hallucinations • Injection site reactions • Nausea • Orthostatic hypotension • Somnolence • Yawning

Patients with advanced disease may experience an “on – off” response to levodopa therapy. This consists of rapid switches from immobility or “off” states, to mobility, or “on” states. This condition may be alleviated with apomorphine, a dopamine agonist indicated as rescue therapy for episodes of sudden on-offs. A pen injector device is used to administer apomorphine subcutaneously. The patient or a caregiver can be taught to use the pen injector device.

Because nausea is common during initiation of therapy, an antiemetic such as trimethobenzamide is recommended during the first 4 weeks of therapy. After 4 weeks, the antiemetic can be discontinued. Orthostatic hypotension is also a concern and test doses of apomorphine are required prior to initiation of therapy. Other side effects are listed. The apomorphine solution should not come into contact with clothing as staining will occur.


Management of Psychiatric Symptoms Associated with Parkinson’s Disease

Anxiety and Depression • All patients should be screened • Selective serotonin reuptake inhibitors (SSRIs)

Hallucinations and Psychosis • Reduction of antiparkinsonian agents • Addition of atypical antipsychotic • Quetiapine • Clozapine • Addition of cholinesterase inhibitor

Dementia • Cholinesterase inhibitors • Memantine (may worsen hallucinations and delusions) • Agents for concurrent behavioral abnormalities

Anxiety disorders and depression are common in patients with Parkinson’s disease and all patients should be periodically screened. The selective serotonin reuptake inhibitors are well tolerated and effective for both anxiety and depressive symptoms. Hallucinations and psychosis in a patient with Parkinson’s disease is almost always drug-induced.

Any CNS active agent can exacerbate this condition but in most cases, the antiparkinson’s drugs must be tapered down or eliminated. The approach to eliminating antiparkinson drugs is to select the agent that provides the least clinical benefit and to reduce or eliminate the dose. This process may be repeated with until the hallucinations or psychosis improves. In most cases, as antiparkinson drugs are eliminated, patients will experience a worsening of motor symptoms.

However, if the psychiatric symptoms improve and the worsening of parkinsonism is mild, patients and caregivers will view this as a net gain.


Management of Psychiatric Symptoms Associated with Parkinson’s Disease

If parkinsonism significantly deteriorates and psychiatric symptoms remain troublesome, this will be viewed as a net loss. At this point, low doses of an atypical antipsychotic should be added. All the atypical antipsychotics are effective, but olanzapine and risperidone tend to worsen parkinsonism and clozapine and quetiapine may be preferred. In some patients, the addition of a cholinesterase inhibitor may improve delusions. Once the psychiatric symptoms are improved, dosages of antiparkinson agents can be reintroduced and titrated upward to achieve acceptable symptomatic motor benefits.

Dementia may develop in later stages of Parkinson’s disease. Management consists of cholinesterase inhibitors and memantine as well as agents for concurrent psychiatric behaviors. Exelon® (rivastigmine) recently received FDA approval for Parkinson disease patients with dementia symptoms.


Management of Autonomic Symptoms Associated with Parkinson’s Disease

Orthostatic Hypotension • Assess medication profile • Fludrocortisone with salt supplementation • Midodrine • Elastic stockings • Avoid constipation • Avoid hot showers

Orthostatic hypotension is a common autonomic symptom associated with Parkinson’s disease and can interfere with ambulation and increase the risk of falls. Pharmacists should evaluate the patient’s medication profile for any agents that may exacerbate this condition, including antihypertensive agents, diuretics, and tricyclic antidepressants. Antiparkinson agents that can exacerbate this condition include amantadine, dopamine agonists, levodopa, rasagiline, and selegiline.

Pharmacologic management includes dosage reduction or elimination of causative agents, salt supplementation with fludrocortisone, or addition of midodrine. Non-pharmacologic techniques include maintaining proper hydration, avoiding constipation and straining at the toilet, and avoiding hot showers. Elastic stockings may be utilized but are often poorly tolerated and difficult to use by patients.


Management of Sleep Abnormalities Associated with Parkinson’s Disease

Frequent Nocturnal Awakening • Nocturnal akinesia • Add bedtime agonist or levodopa

Excessive daytime somnolence • Reduce dose of dopamine agonist • Methylphenidate

• Studies supporting the use of methylphenidate are limited • Modafinil

• Studies supporting the use of modafinil are limited.

Insomnia • Variety of medical conditions • Short-acting sedative hypnotic (e.g. temazepam, lorazepam, non-benzodiazepines)

• All benzodiazepines increase the risk for falls and risk-benefit should be carefully weighed.

Parasomnias • Reduction of bedtime dopamimetic dose • Bedtime atypical antipsychotic

REM sleep behavior disorder • Clonazepam

Restless leg syndrome • Bedtime dopamimetic • Gabapentin


Management of Sleep Abnormalities Associated with Parkinson’s Disease

Sleep disorders are common in Parkinson’s disease. Frequent nighttime awakenings or sleep fragmentation may occur as a result of nocturnal akinesia. In such cases, a bedtime dose of controlled release carbidopa / levodopa or dopamine agonist may help.

Excessive daytime somnolence can be exacerbated by antiparkinson agents, especially dopamine agonists, and dosage reduction may be helpful as well as a trial of modafinil or methylphenidate.

Insomnia can be due to a variety of reasons including depression, drugs, and reversal of the sleep-wake cycle. If a sedative is required, a short acting agent maybe preferred.

Parasomnias are characterized by disruptive nocturnal behavior including hallucinations, nightmares, nocturnal vocalizations, panic attacks and night terrors. A reduction in nighttime dopamimetics is often helpful or the addition of a bedtime atypical antipsychotic such as quetiapine.

REM sleep behavior disorder predominantly affects male patients and is characterized by excessive movement and thrashing about during REM sleep. Low dose clonazepam at bedtime is often helpful.

Patients may also experience restless leg syndrome which can be managed by bedtime dopamine agonist, gabapentin, or levodopa.


Surgical Treatment: Parkinson’s Disease

Ablative Procedures: • Thalamotomy • Pallidectomy

Electrical Deep Brain Stimulation Procedures: • Chronic thalamic stimulation • Chronic pallidal stimulation • Chronic subthalamic nucleus stimulation

Experimental Restorative Procedures: • Fetal tissue transplantation

Surgical techniques are available for treatment of Parkinson’s disease but are generally reserved for non-demented patients requiring symptom control beyond that achievable with drugs. Patients with severe tremor may benefit from thalamotomy or thalamic deep brain stimulation, which is successful in controlling symptoms in the majority of cases. Other ablative procedures include pallidectomy, in which lesions are created in the globus pallidus, or pallidal deep brain stimulation. These procedures are helpful for relieving severe, disabling dyskinesias, as well as bradykinesia and rigidity, as is chronic electrical stimulation of the subthalamic nucleus. In the hands of an experience neurosurgery team, these procedures are highly successful and safe. Fetal tissue transplantation has been performed successfully to restore mobility but this procedure is considered experimental.




American Parkinson Disease Association: www.apdaparkinson.com

National Parkinson Foundation: www.parkinson.org

Several Parkinson Disease guidelines can be found at: http://www.aan.com/professionals/practice/guideline/index.cfm

http://tasmar.com/fileRepository/en-US/consent_form.doc

Chen JJ. “Parkinson's Disease and Essential Tremor.” In: American College of Clinical Pharmacy. Ed. Pharmacotherapy Self-Assessment Program, 4th edition. Book 7:Neurology/Psychiatry.Kansas City, MO:American College of Clinical Pharmacy, 2002:1-41.

Chen JJ and Shimomura SK. “Parkinsonism.”In: Herfindal ET, Gourley DR, (eds).The Textbook of Therapeutics: Drug and Disease Management.Baltimore:Williams & Wilkins, 7th edition, 2000;1139-1155.

Fernandez HH, Trieschmann ME, Friedman JH. “Treatment of psychosis in Parkinson’s disease – safety considerations.” Drug Safety.2003;26:643-59.

Friedman JH, Factor SA. “Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson’s disease.” Mov Disord.2000;15:201-11.

Hauser R and Zesiewicz T.Parkinson’s Disease - Questions and Answers.Coral Springs, FL: Merit Publishing International, 2nd edition, 1999.

Lang AE, Lozano AM.” Parkinson’s disease.”N Eng J Med. 1998;339:1130-43.



Lang AE, Lozano AM.” Parkinson’s disease.”N Eng J Med. 1998;339:1044-53.

Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. “Practice parameters: initiation of treatment for Parkinson’s disease: an evidence-based review.” Neurology. 2002;58:11-17.

Miyasaki JM, Shannon K, Voon V, et al. Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review). Neurology 2006; 66: 996-1002.

Pahwa R, Factor SA, Lyons KE, et al. Practice Parameter: Treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review). Neurology. 2006; 66: 983-995.

Poewe W, Luessi F. Clinical studies with transdermal rotigotine in early Parkinson's disease. Neurology. 2005 Jul 26;65(2 Suppl 1):S11-4. Review. No abstract available. Erratum in: Neurology. 2005 Oct 25;65(8):1328.

Suchowersky O, Reich S, Perlmutter J, et al. Practice parameter: Diagnosis and prognosis of new onset Parkinson disease (an evidence-based review). Neurology 2006; 66: 968-975.

Suchowersky O, Gronseth G, Perlmutter J, et al. Practice parameter: Neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review). Neurology 2006; 66: 976-982.

The Parkinson Study Group. A controlled trial of rotigotine monotherapy in early Parkinson's disease. Arch Neurol. 2003 Dec;60(12):1721-8


Spinal Cord Syndromes and Neuropathies



• Identify the basic neurologic differential diagnosis of central verses peripheral disorders.

• List spinal and peripheral nerve syndromes that can afflict adults later in life.

• Describe the etiology and clinical presentation of vascular, neoplastic and degenerative diseases that affect the spinal cord.

• Describe the etiology and clinical presentation of degenerative diseases that affect the spinal cord and peripheral nerves.

• List common causes and presenting signs and symptoms characteristic of the class of disorders known as polyneuropathies.

• Compare and contrast etiology and clinical presentation of specific types of polynneuropathies.

• Describe treatment options for patients with polyneuropathy.


Spinal Cord Syndromes and Neuropathies

Current Content Expert:

Mitchell R. Emerson, Ph.D. Assistant Professor of Pharmaceutical Sciences College of Pharmacy-Glendale Midwestern University


• Understand the basic concept of the neurologic differential diagnosis of central versu s peripheral disorders. • List spinal and peripheral nerve syndromes that can afflict adults later in life. • Describe the etiology and clinical presentation of vascular, neoplastic and degenerative diseases that affect the spinal cord. • Describe the etiology and clinical presentation of degenerative diseases that affect the spinal cord and peripheral nerves. • List common causes and presenting signs and symptoms characteristic of the class of disorders known as polyneuropathies. • Compare and contrast etiology and clinical presentation of specific types of polyneuropathies . • Describe treatment options for patients with polyneuropathy


The Basic Neurologic Examination

This exam helps to delineate central versus peripheral lesions by assessing the patient’s presenting signs and symptoms, history of illness and physical exam findings. The physical exam focuses on the following:

• Motor function • Sensory function • Reflexes • Skin examination

Diseases of the nerve, muscle and neuromuscular junction may present with varying degrees of sensory loss and weakness. Clinicians therefore must look for specific patterns of the sensory and motor disturbance to help differentiate between these disorders.

A neurologic examination considers the patient’s complaints, history of the illness as well as specific limitations. For example, the complaint of sensory loss in a patient’s legs could suggest either a lesion in the central nervous system or that the problem is coming from somewhere along the length of the nerve fibers, between the nerve root and the most distal nerve fibers.

Assessing motor function and in particular the degree and distribution of muscle weakness through a motor examination helps to determine if single nerve roots or multiple nerve territories are involved.


The Basic Neurologic Examination

Sensory function assessment identifies the pattern of feeling the patient is or is not experiencing. For example, weakness is a difficult symptom for patients to quantify and localize. Frequently patients will complain of both pain and muscle weakness. Since pain may limit the action and mobility of a joint, the finding of weakness in the setting of pain may not indicate true neurologic dysfunction. However if a patient with long-standing diabetes mellitus presents with classic “stocking-glove” sensory loss, the diagnosis of diabetic neuropathy is relatively easy to make.

A loss of reflexes suggests a neuropathic lesion, generally affecting either sensory or motor fibers. In muscle disease, reflexes are generally preserved. Guillain-Barre Syndrome is an example of a disorder with globally depressed or absent reflexes.

Finally, a skin examination may further help when differentiating neurologic disorders. For example, polyneuropathies frequently result in loss of distal hair over the feet. Dermatomal rashes may indicate recent herpes zoster infection. Patients with Reflex Sympathetic Dystrophy Syndrome (Complex Regional Pain Syndrome I) experience vasomotor disturbances with variable intensity, producing altered skin color and temperature. Finally, the loss of sensation associated with diabetic peripheral neuropathy leads to diabetic foot ulcers, the most common cause of amputations in the United States.


Spinal Cord and Peripheral Nerve Syndromes

• Spinal cord trauma • Spinal cord infarction • Malignancy • Cervical spondylosis • Lumbar stenosis • Subacute combined degeneration • Amyotrophic lateral sclerosis (ALS) • Multiple sclerosis • Polyneuropathies

Spinal cord dysfunction and neuropathies can occur as a result of trauma, ischemia, nutritional, malignant or degenerative conditions. In the elderly, they are often complications of age-related skeletal or systemic syndromes. For example, more than eighty percent of individuals over the age of fifty-five show evidence of cervical disc degeneration, and half of them are asymptomatic. These conditions are frequently disabling, impairing voluntary movement, primary sensory perception, bowel and bladder function, ventilatory capacity and sexual activity. The next series of screens will review spinal cord syndromes and neuropathies which occur more commonly in the elderly.


Spinal Cord Infarction, Malignancies and Other Syndromes

Spinal cord infarction – ischemia of anterior spinal artery Malignancies – cord compression caused by intra- or extra-medullary, intra- or extradural tumors; metastatic tumors Cervical spondylosis – “arthritis of the neck”, narrowing of the cervical canal, intervertebral foramina caused by degenerative changes Lumbar stenosis - narrowing of the spinal canal, intervertebral foramina caused by degenerative changes

Spinal cord infarction occurs in the vascular distribution of the anterior spinal artery. Ischemia of this artery produces corticospinal signs and dissociated sensory loss.

Malignancies of the spine frequently cause spinal cord compression as the tumors grow. Tumors may be located intramedullary, intradural, extramedullary, or extradural. Metastatic tumors, which occur with greater frequency in the elderly, can cause extradural compression. One type of cancer with frequent metastases to the spine is advanced prostate cancer. Occasionally, the first presenting signs of cancer occur as local or radicular pain associated with rapidly progressive metastatic lesions.

Cervical spondylosis is characterized by extensive degeneration of intervertebral bodies with narrowing of disc spaces, thickening of ligaments, and osteoarthritic changes in posterior vertebral joints. The result of these changes are generalized or focal narrowing of the cervical canal and intervertebral foramina.

Lumbar stenosis, which also tends to affect older adults, is caused by similar pathological changes and also results in narrowed disc spaces which may result in neurologic impairment and pain. This may progress to cauda equina syndrome resulting in neuromuscular dysfunction and nerve damage.


Degenerative Diseases of the Spinal and Peripheral Nerves

Subacute Combined Degeneration – demyelination produced by non-dietary vitamin B12 deficiency usually associated with pernicious anemia

Amyotrophic Lateral Sclerosis - progressive dysfunction of the corticospinal pathways, brainstem motor nuclei, and anterior horns of the spinal cord

Multiple Sclerosis (MS) - progressive dysfunction of the distal motor nerves secondary to demyelination and plaque formation in the central nervous system.

The spinal cord and peripheral nerves are also subject to a variety of degenerative diseases such as subacute combined degeneration, amyotrophic lateral sclerosis and multiple sclerosis.

Subacute combined degeneration is produced by a vitamin B-12 deficiency and is almost always associated with long-standing pernicious anemia in the elderly. The deficiency is not caused by diet, but by impaired intestinal absorption of B-12 secondary to autoimmune or surgical loss of gastric parietal cells. Demyelination can occur in the brain, optic nerves, or peripheral nerves, leading to paresthesias and loss of vibratory sensation, spasticity and weakness, mental status changes, and visual impairment. Patients may display a high-stepped gait as they attempt to compensate for the loss of vibratory sensation and foot drop in their lower extremities.

Multiple sclerosis also results in demyelination of axonal pathways leading to increasing motor dysfunction. MS occurs more often in younger women between the ages of 20 – 40 and typically presents with visual or motor changes. MS has variable clinical presentations and can be relapsing or progressive.

Another degenerative disease, amyotrophic lateral sclerosis, is characterized by progressive dysfunction of the corticospinal pathways, brainstem motor nuclei, and anterior horns of the spinal cord. The mean age of onset is fifty-six, culminating in death within an average of two-point-five years. Symptoms include limb paresis, spasticity, dysphagia, inappropriate emotional reactions and atrophy of the limbs.


Polyneuropathy, Peripheral Neuropathy and Neuropathy

All characterized by noninflammatory degeneration of nerves.

Chronic axonal polyneuropathies: • Most common form of polyneuropathy • Secondary to diabetes mellitus, malignancy or uremia • Longer axons affected first • Sensory symptoms precede motor symptoms • Slowly progressive sensory loss

Acute axonal polyneuropathies: • Produced by toxic exposure or porphyria • More fulminant symptoms • Pain is often predominant • Worsens over 2 – 3 weeks, plateaus, then recovery over months

Acute demyelinating polyneuropathies: • Affects predominately motor nerve fibers • Weakness occurs early and before sensory loss

Nutritional polyneuropathies • Associated with alcoholism

Entrapment neuropathy • Associated with trauma, structural abnormalities (e.g., spinal stenosis, carpal tunnel)


Polyneuropathy, Peripheral Neuropathy and Neuropathy

Hereditary polyneuropathies (Charcot-Marie Tooth disease) • Chronic demyelinating disorder • Leads to distal muscle atrophy and “stork leg deformity”

The terms polyneuropathy, peripheral neuropathy and neuropathy are frequently used interchangeably, but are distinct.

Polyneuropathy is a specific term that refers to a generalized, relatively homogeneous process affecting many peripheral nerves, with the distal nerves usually affected most prominently. Polyneuropathy is typically characterized by symmetric distal sensory loss, burning or weakness. It often occurs as a side effect of medications such as chemotherapeutic agents or as a manifestation of systemic disease.

Peripheral neuropathy is a less precise term that is frequently used synonymously with polyneuropathy, but can also refer to any disorder of the peripheral nervous system including radiculopathies and mononeuropathies.

Neuropathy, which again is frequently used synonymously with peripheral neuropathy and/or polyneuropathy, can refer even more generally to disorders of the central and peripheral nervous system.

Neuropathies are a class of disorders characterized by a noninflammatory degeneration of nerves. There are many types of neuropathies, each resulting from a different medical condition. The most common neuropathy in the elderly is the polyneuropathy associated with diabetes or malignancy. Entrapment neuropathies are soft tissue rheumatic pain syndromes that are caused by focal peripheral nerve damage secondary to traumatic injury or spinal stenosis. Finally nutritional neuropathy is sometimes seen in the presence of alcoholism.


Etiology of Neuropathies

It is important to distinguish between neuropathies and myopathies – both can present with muscle weakness but one is due to impaired nerve function and the other due to impaired muscle function.

Heredity • Charcot-Marie Tooth

Alcoholism

Diabetes • Ulnar neuropathy • Gastrointestinal autonomic neuropathy • Genitourinary autonomic neuropathy • Peripheral autonomic neuropathy • Cardiovascular autonomic neuropathy

Thyroid dysfunction

Malignancies

Uremia

Heavy metal exposure (arsenic, mercury, lead)

Infectious diseases (tick paralysis, polio)

Nutritional vitamin deficiency

Pharmacological agents: • Amiodarone • Chloramphenicol • Cisplatin • Dapsone • Phenytoin • Disulfiram • Gold • Isoniazid • Lithium • Nitrous oxide • Nitrofurantoin • Pyridoxine • Vincristine


Etiology of Neuropathies

Neuropathies in the elderly are often insidious in nature and difficult to diagnose. In the case of malignancies, both cancer and chemotherapy are associated with causing neuropathies. Many medications result in nerve damage or altered nerve conduction. Drugs that are known to cause nerve damage and induce neuropathy include amiodarone, phenytoin, isoniazid and lithium, among others.

Some diseases like diabetes are associated with multiple neuropathies. Other common systemic illnesses that can lead to neuropathy in the elderly include thyroid dysfunction and uremia.


Common Signs and Symptoms of Neuropathy

• Tingling sensation (pin-prick) • Loss of sensation –“stocking glove” • Pain • Loss of motor function in hands or feet • Weakness in hand grip • Abnormal gait

The clinical presentation of neuropathy is dependent on the extent to which sensory, motor, and/or autonomic nerves are affected. A loss of sensory fibers causes loss of feeling, while the loss of motor nerve fibers can cause muscular weakness. If autonomic nerve fibers are damaged, functions not normally under conscious control, such as digestion and blood pressure, may be disrupted. Neuropathy symptoms can also be caused by increased nerve activity in damaged or healing nerves. These symptoms include prickling, tingling, burning, aching, or sharp jabs of needle-like pain. Peripheral neuropathies are all characterized by subacute axonopathy with sensorimotor features such as the ones listed on your screen.


Nutritional Neuropathies: Clinical Presentation

• Lesions are axonal, with secondary demyelination • Symptoms include distal limb pain, tingling, sensory loss, weakness, areflexia

While nutritional neuropathy is usually associated with alcoholism, it has also been described as sequelae of unintentional weight loss. The underlying deficiency may be thiamin, pyridoxine, pantothenic acid or folate. Lesions are axonal, with secondary demyelination. Symptoms include distal limb pain, tingling, sensory loss, weakness and areflexia.


Acquired Toxic Neuropathies: Clinical Presentation

• Symptoms tend to appear first in lower extremities • Weakness, numbness, and paresthesias are common • Rapid onset suggest acute intoxication; slow progression is associated with chronic exposure • Diagnosis is based on history and toxicology screening

Acquired toxic neuropathies are caused by exposure to neurotoxic drugs or chemicals such as arsenic, mercury or lead. Since the majority of these neuropathies are axonal, symptoms usually develop in the lower extremities first because the longer axons are more vulnerable. These symptoms include weakness, numbness, and paresthesias in a stocking-glove pattern. While rapid onset is more characteristic of acute intoxication, insidious progression is more common with chronic exposure. Differential diagnosis of acquired toxic neuropathy requires a rigorous history review and toxicology screening.


Diabetic Polyneuropathy: Clinical Presentation

• Numbness, prickling and tingling are early symptoms • Patients may present with pain in toes or feet • As the disease progresses, level of pain and disability increases • Although some symptoms may disappear with treatment, loss of sensation is usually irreversible • Loss of sensation and inappropriate foot care can lead to diabetic foot ulcers, and potentially amputation


Diabetic Polyneuropathy: Clinical Presentation

In diabetes mellitus, a complex array of metabolic, vascular and perhaps hormonal factors shift the balance between nerve fiber damage and nerve fiber repair in favor of the former. One popular theory involves altered sorbitol metabolism. Glucose that enters cells is metabolized in part to sorbitol via the enzyme aldose reductase. Aldose reductase has a low affinity for glucose, and under physiologic conditions little substrate is processed. However, glucose conversion to sorbitol is more pronounced with chronic hyperglycemia. The accumulation of sorbitol within the cells results in a rise in cell osmolality and a decrease in intracellular myoinositol; these changes in turn lead to a decrease in Na-K-ATPase activity and a possible shift in the redox potential within cells. Hyperglycemia may also contribute directly to the decline in cell myoinositol levels by competitively interfering with myoinositol uptake from the extracellular fluid via a sodium-myoinositol cotransporter. The potential value of blocking aldose reductase is suggested by the observation that Brazilian natural medicines for diabetes, named myrciacitrin 1 and myrciaphenone B (made from the leaves of Myrcia multi flora DC), are potent inhibitors of both aldose reductase and alpha glucosidase.

Clinically, diabetic polyneuropathy tends to develop only after many years of diabetes and poor blood sugar control. Patients with diabetic polyneuropathy present with numbness and prickling sensations or tingling. Some patients feel pain in the toes or feet. During a neurological examination, patients with this form of neuropathy may show a marked inability to feel a pinprick or a vibration, especially against the toe. While some of the symptoms of diabetic polyneuropathy may go away after several months, others, such as loss of sensation in the feet, are irreversible. Appropriate management includes tight control of the patient’s diabetes with reduction in their hemoglobin A1c to less than 7.0. If left untreated, diabetic polyneuropathy can become painful and may lead to amputation secondary to poorly healing diabetic foot ulcers.


Charcot-Marie-Tooth Disease: Clinical Presentation

• Motor and sensory axonopathy evolve slowly • Mild numbness, tingling in feet indicate early onset • Foot drop is the most prominent sign • As the disease progresses, loss of muscle mass below the knee produces “stork leg” appearance • Diagnosis based on family history, electrophysiologic testing


Charcot-Marie-Tooth Disease: Clinical Presentation

Charcot-Marie-Tooth is a demyelinating disorder of peripheral nerves. Charcot-Marie-Tooth disease or Charcot’s Joint is characterized by joint impairment secondary to peripheral nerve damage in the foot. The person with Charcot's joint loses most sensation in the foot, including the ability to feel pain and sense the position of the foot. As the muscles lose their ability to support the foot properly, the foot becomes unstable, predisposing the person to ankle sprains. Early complaints may include frequent sprained ankles or difficulty running and keeping up with peers. The only obvious physical findings may be loss of reflexes, pes cavus foot deformity, and hammer toes. Joints grind on bone, leading to inflammation, further instability and possible dislocation.

As the disease progresses, loss of muscle mass below the knee produces a “stork leg” appearance. Eventually, the bone structure of the foot collapses, and as it heals on its own, deformity may result. Elderly at risk of Charcot's joint are those who already have some other form of neuropathy. Patients who present with symptoms such as swelling, redness, heat, strong pulse, and insensitivity of the foot should be evaluated for Charcot’s joint as soon as possible, as early treatment can stop bone destruction and aid healing. Diagnosis is based on family history and electrophysiologic testing. Life expectancy is not affected.


Diagnostic Aids

• Electromyography • Nerve conduction studies • Blood tests • Genetic testing • Muscle biopsy • Nerve biopsy • Skin biopsy

Electromyography and nerve conduction studies are the two most common diagnostic tests for establishing a diagnosis of nerve and muscle disease after the history and examination. They involve electrical stimulation of nerve fibers and as such are uncomfortable tests and occasionally patients are unable to complete a study. Additionally these tests are often hampered by technical factors that can affect the accuracy and legitimacy of the results.

Blood tests may be ordered to rule out myopathies such as rhabdomyopathy where initial presenting signs and symptoms could be easily confused with a neuropathy. Additionally, muscle biopsies may help provide the definitive diagnosis in cases of uncertain etiology. Muscle biopsies are also useful in patients evaluated for vasculitic polyneuropathy where inflammatory changes may be present in blood vessel wall of the muscle.

Nerve biopsies are not as definitive as muscle biopsy. They may provide additional answers to why myelin is being destroyed as well as clarify EMG/NCS findings that are unclear.

Skin biopsy allows terminal nerve twigs to be studied which are diagnostic in patients with idiopathic painful distal sensory polyneuropathies.

Genetic testing is available for several neurologic disorders including Charcot-Marie-Tooth, ALS and certain forms of myotonic dystrophy.


Treatment of Neuropathies

Treatment of Underlying Cause:

• Nutritional – vitamin and mineral supplements • Diabetic polyneuropathy – tight blood sugar control • Acquired toxic neuropathy- removal of offending agent • Charcot-Marie-Tooth disease – immobilization of foot

The treatment of axonal polyneuropathies depends on the type of neuropathy involved, its underlying cause, and severity of symptoms. Reducing exposure to endogenous or exogenous toxins that may be causing the polyneuropathy is the single most important step in treating and preventing the progression of axonal polyneuropathies. As an example, in patients with axonal polyneuropathy secondary to alcohol or drugs, avoidance of the offending agent is extremely important.

Patients with diabetic polyneuropathy may prevent or delay the disorder with tight blood sugar control. Angiotensin Converting Enzyme Inhibitors or ACE inhibitors may also confer additional benefit in preventing or delaying the onset of peripheral neuropathy. There is a lot of interest in using aldose reductase inhibitors to interrupt the flawed sorbitol metabolism thought to result in neuropathy. However current aldose reductase inhibitors have produced inconsistent benefits in diabetic neuropathy.

Although the effects were not uniform, nerve growth factor and aldose reductase inhibitors have shown initial promise in treating diabetic neuropathy as well as cis-platinum induced polyneuropathy.

The treatment priority for patients with Charcot’s joint is prevention of joint damage, usually with the aid of a cast or special shoes. In most cases if the underlying condition is not addressed the result is an irreversible neuropathy. If treatment is initiated early then recovery can occur gradually and often incompletely over a period of many months to years.


Treatment of Symptoms and Prevention of Complications

Diabetic Peripheral Neuropathic Pain

• Duloxetine (Cymbalta®) • Pregabalin (Lyrica®) • Phenytoin (Dilantin®) • Carbamazepine (Tegretol®) • Amitriptyline (Elavil®)/Nortriptyline (Pamelor®) • Gabapentin (Neurontin®) • Capsaicin creams • Muscle relaxants • Stretching

Since diabetic neuropathy produces chronic pain it is perceived as a model for other neuropathic pain syndromes. Many different agents have been studied with mixed results. Review concept 12.8 will discuss neuropathic pain in greater detail. However it is appropriate to discuss the general treatment strategy at this point.

To begin, numerous placebo-controlled studies were conducted in diabetic neuropathy with carbamazepine, phenytoin and amitriptyline and others. The results with anticonvulsants are conflicting with a negative result in the longest study using phenytoin for 46 weeks balanced by positive studies of shorter duration. Antidepressants such as TCAs have been useful therapy while other agents like SSRI’s have shown limited efficacy. Recently, duloxetine, a dual inhibitor of neuronal serotonin and norepinephrine reuptake has been approved for treatment of painful diabetic neuropathy. While several studies have shown improvement in pain the results are tempered by the side effects these agents produce in an older population.


Treatment of Symptoms and Prevention of Complications

Gabapentin is useful in diabetic peripheral neuropathy. This is in part due to its more favorable tolerability in the elderly and also to several trials showing benefit. However, current data suggests gabapentin is equivalent to other available agents for neuropathic pain, but not superior. Backonja reported a 60% improvement on a global scale for patients on gabapentin (up to 3.6 grams per day) after four weeks' treatment in a study of 165 participants. The NNT for effectiveness compared to placebo was 3.8 (CI 2.4-8.7). It should be noted that this study used doses significantly higher than the maximum licensed dose of 2.4 grams. Morello compared gabapentin 1800 mg/d to amitriptyline 75 mg/d over a 6 week period. Patients received both therapies in this randomized, double dummy, cross-over trial. Both agents were shown to be equally effective in reducing pain. Recently, pregabalin, an anticonvulsant that inhibits calcium-mediated neurotransmitter release has also been approved for neuropathic pain associated with diabetic peripheral neuropathy.

The usual clinical decision is a choice between antidepressants and anticonvulsants as first-line treatment. Systematic reviews of the literature show that gabapentin is effective in post-herpetic neuralgia and diabetic neuropathy but does not appear to be superior to carbamazepine or amitriptyline, both cheaper alternatives in many countries. However, as mentioned above gabapentin is often better tolerated and therefore an appropriate option when side-effects are a concern. Therefore, one approach is to attempt treatment initially with tricyclic antidepressants for example, a secondary amine like nortriptyline 25 – 50 mg at bedtime. If ineffective or not tolerated, duloxetine, pregabalin, or gabapentin may be considered, with carbamazepine, phenytoin and others as third line agents.

Other symptomatic treatments of pain include the use of capsaicin creams, which contain hot pepper extract. Capsaicin is a naturally occurring component of many hot peppers, and causes analgesia through local depletion of substance P. It is available in a cream for topical application. In randomized trials in patients with diabetic neuropathy, capsaicin has been associated with moderate, but statistically significant improvement in symptoms, the ability to do daily tasks, and in physician global assessment compared with placebo.

Finally, physical therapy is important in patients with significant weakness. Ankle-foot-orthotics, also known as AFO braces will assist in walking and can greatly improve functionality. Muscle relaxants and stretching may relieve pain in the muscles caused by neuropathy.




Aisen, M. (1994).Spinal and peripheral nerve syndromes: Back pain and weakness. In Hazzard, W. R., Bierman, E.L., Blass, J. P., Ettinger, W. H. & Halter, J. B. (Eds.). Geriatric Medicine and Gerontology, 3rd ed.New York:McGraw-Hill: 1285-1296.

Bockonja M, Betdoun A, Edwards KR, Schwarz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E. Gabapentin for the symptomatic treatment of painful neuropathy in patients with Diabetes Mellitus. JAMA 1998;280(21):1831-6.

Candis M. Morello; Susan G. Leckband; Carol P. Stoner; David F. Moorhouse; Gregory A. Sahagian. Randomized Double-blind Study Comparing the Efficacy of Gabapentin With Amitriptyline on Diabetic Peripheral Neuropathy Pain Arch Intern Med. 1999;159:1931-1937.

Chadda VS, Mathur MS. Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy. Journal of the Association of Physicians of India 1978;26:403-6.

Cruse RP. Overview of hereditary neuropathies. www.uptodateonline.com Version 14.3 accessed 12/21/06.

Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003; 60(11):1524-1534.

Feldman EL and McCulloch DK. Treatment of Diabetic Neuropathy. www.uptodateonline.com Version 14.3 accessed 12/21/06.

Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain 2005; 116(1-2):109-118.



Gomez-Perez F, Choza R, Rios JM, Reza A, Huerta E, Aquilar CA, Rull JA. Nortriptyline-Fluphenazine vs Carbamazepine in the symptomatic treatment of diabetic neuropathy. Archives of Medical Research 1996;27(4):525-9.

Gorson, K. C. & Ropper, A. H. (1995). Idiopathic distal small fiber neuropathy. Acta Neurol Scand; 92:376–382.

Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004; 63(11):2104-2110. Notermans, N. C., Wokke, J. H. J., Franssen,H., et al. (1993). Chronic idiopathic polyneuropathy presenting in middle or old age: a clinical and electrophysiological study of 75 patients. J Neurol Neurosurg Psychiatry; 56:1066–1071.

Rull J, Quibrera R, Gonzalez-Millan H, Lozano Castenada O. Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine: double-blind crossover study. Diabetologia 1969;5:215-20

Saudek CD, Werns S, Reidenberg MM. Phenytoin in the treatment of diabetic symmetrical polyneuropathy. Clin Pharmacol Ther 1977;22:196-9.

The management of persistent pain in older persons. J Am Geriatr Soc 2002 Jun;50(6 Suppl):S205-24.

Rutkove SB: Overview of polyneuropathy. www.uptodate.com Version 11.3 accessed 10/03

Veterans Health Administration, Department of Defense. Clinical practice guideline for the management of low back pain or sciatica in the primary care setting. Washington (DC): Department of Veterans Affairs (U.S.); 1999 May.

Washington State Department of Labor and Industries. Antiepileptic drugs guideline for chronic pain. Provider Bull 2005; PB 05-10:1-3.



Neurosciences on the Internet – Neuropathy

Neurosciences on the Internet – Spinal Cord Injury

The Neuromuscular Disease Center

Charcot-Marie-Tooth Association


Essential Tremor

Learning Objectives


• Describe the epidemiology and pathophysiology of essential tremor.

• Identify common agents associated with drug-induced tremor.

• Differentiate the clinical presentation of essential tremor from tremor of Parkinson’s disease.

• List disabilities experienced by patients with essential tremor.

• Describe nonpharmacological and pharmacological treatment options for patients with essential tremor.


Epidemiology of Essential Tremor


• Prevalence ranges from 0.4% to 5% • 10 to 20 times more prevalent than Parkinson’s Disease • Affects 1 in 25 people > 70 years old • Autosomal dominant inheritance in 50% • Bimodal age of onset:15 – 20 years and 55 – 65 years

Pathophysiology

• Cerebellum – abnormal oscillatory activity • Thalamus – abnormal GABA receptor activity • Locus ceruleus and dentate nucleus – increased norepinephrine • Genetic in 50% of cases

Patient Presentation

Essential tremor is characterized by bilateral action tremors which are involuntary rhythmic oscillations. These tremors are postural, occurring while maintaining posture against gravity, and kinetic, occurring during movement. Upper limbs are affected in 95% of patients with essential tremor. Other areas are less likely affected: head in 35% of patients with essential tremor, lower limbs in 30%, voice in 12%, tongue, face or trunk in < 10% each.



Essential tremor is the most common movement disorder in the United States. Essential tremor is 10 to 20 times more prevalent than Parkinson’s disease and affects one in 25 people over the age of 70.In about 50% of patients, an autosomal dominant mode of inheritance can be found. Essential tremor also occurs in younger patients, typically with onset occurring between the ages of 15 – 20 years. Incidence and prevalence increase with age. Tremor amplitude gradually increases over time.

Because mortality is not affected, essential tremor has been referred to as benign essential tremor. This terminology is misleading, as patients can experience significant functional and psychosocial impairment, and the term “benign” is inappropriate.

To date, no specific neuroanatomic pathology is associated with essential tremor except that abnormal neurochemical and synaptic activity occur in the cerebellum, thalamus, locus ceruleus, and dentate nucleus. It is also known that in 50% of patients, genetic predisposition plays a role but the exact pathology remains unknown.Overall, much work remains to determine the pathophysiology of essential tremor.


Common Secondary Causes of Tremor in the Elderly

Parkinson’s disease

This chart lists some of the clinical distinctions between essential tremor and Parkinsonian tremor. If the patient demonstrates resting tremor, bradykinesia, or rigidity, then it is most likely Parkinson’s disease. If there is a head tremor, a family history of tremor, and positive response to alcohol, then it is likely essential tremor.

Essen*al Tremor Parkinsonian Tremor

Tremor Type Postural / kine8c Res8ng /postural

Symmetry Bilateral Unilateral or bilateral

Loca*on Hands / head / voice Hands / legs

Family History Posi8ve Nega8ve

Response to Alcohol Posi8ve Nega8ve

Bradykinesia Absent Present

Rigidity Absent Present


Common Secondary Causes of Tremor in the Elderly

Drugs: • Alcohol withdrawal / chronic alcoholism • Amiodarone • Beta-agonists (albuterol) • Corticosteroids • Cyclosporine • Lithium • Methylxanthines (e.g., caffeine, theophylline) • Selective serotonin reuptake inhibitors (SSRIs) • Thyroid hormone • Tricyclic antidepressants (TCAs) • Valproic acid

Besides essential tremor, the most common causes of pathologic tremor in the older adult are Parkinson’s disease and medications. The tremor of Parkinson’s disease may precede the onset of other parkinsonian symptoms such as bradykinesia and rigidity. Therefore, patients with essential tremor may be misdiagnosed as having early Parkinson’s disease.

In the older adult, cerebellar degeneration due to chronic alcoholism can cause tremor. Additionally, tremor associated with alcohol or drug withdrawal syndrome should also be considered. Commonly prescribed tremor-inducing drugs include: albuterol, lithium, SSRIs, TCAs, thyroid hormones, and valproic acid.


Clinical Diagnosis of Essential Tremor

• Review medication profile • Rule out hypoglycemia and hyperthyroidism • Absence of parkinsonian symptoms (e.g., bradykinesia, rigidity) • Bilateral postural and kinetic tremor of arms • Rarely exhibit resting tremor • Family history in 50% • Alcohol benefit in 50%

Diagnosis of essential tremor is clinical and dependent on ruling out other causes of tremor, such as drugs, hypoglycemia, hyperthyroidism, and Parkinson’s disease.

Essential tremor is most commonly characterized by a postural or kinetic tremor affecting both upper extremities.

Postural tremor can be observed in a standing or sitting patient by instructing them to extend their arms and hands forward, parallel to the floor. With the arms and hands in this posture, the tremor will emerge.

Kinetic tremor can be observed by having the patient touch the examiners fingertip and then the patient’s nose or chin. This is called the finger to nose test. A kinetic tremor will emerge as the patients hand and arms move back and forth between finger and nose.

If patients report a family history of tremor or if alcohol alleviates the tremor, then it further confirms the diagnosis of essential tremor. If tremor occurs at rest, if onset is sudden, if leg tremor is present, or if the tremor is only unilateral, then it is less likely to be essential tremor.


Disabilities Associated with Essential Tremor

Functional Disability:

• Drinking liquids and eating • Dressing and shaving • Fine manipulations • Handwriting and typing • Interference with home and job tasks • Premature termination of employment

Psychosocial:

• Depression • Embarrassment • Withdrawal from public speaking • Social withdrawal

Patients with disabilities are more likely to seek treatment. Depending on the location and severity of the disorder, persons with essential tremor experience a variety of functional limitations. These limitations may affect eating and drinking, handwriting, typing, and other fine motor manipulations. In more severe cases, the tremor will significantly interfere with the performance of job tasks and result in early retirement or loss of job function. Of patients who seek medical attentions for essential tremor, 25% will retire or change jobs due to tremor associated with disability.

For most patients, the psychosocial disability is much more significant than the functional disability. Patients often gradually withdraw from social activities due to embarrassment and inability to perform normal tasks without attracting attention. Head tremor is particularly embarrassing. Depression is common and patients should be periodically screened.


Non-Pharmacological Treatment of Essential Tremor

Adaptive Techniques • Performing tasks with unaffected arm and hand • Blunt-tip safety scissors • Plastic dinnerware and cups • Relaxation techniques • Wrist weights • Plate guards

Drug Therapy • Decrease amplitude of the tremor and disability • Unlikely to eliminate the tremor • Used alone or in combination

There is not a cure for essential tremor or medications that slow progression of the disease. Drugs decrease the amplitude of the tremor and disability, but do not affect tremor frequency. Completely eliminating the tremor with drug therapy is unlikely. Overall, tremor of the hand respond more favorably than does a tremor affecting the head of voice. The drugs are given as maintenance therapy and may be utilized as monotherapy or in combination. Propranolol and primidone comprise the mainstays of symptomatic therapy for essential tremor.

All patients with essential tremor who utilize some form of non-pharmacological means to minimize disruption and hazards associated with the performance of daily tasks. The types of adaptive techniques are numerous, and often very creative and unique. Some are listed on the screen.


Pharmacological Treatment of Essential Tremor

Three drugs comprise the mainstays of symptomatic therapy for essential tremor:propranolol, primidone, and gabapentin. Overall, tremor of the hand responds more favorably then does a tremor affecting the head or voice. All three are given as maintenance therapy and may be utilized as monotherapy, or in combination. Immediate-release propranolol can also be administered on an as needed basis prior to events that may exacerbate tremors. Adjunctive agents include alcohol and benzodiazepines.

In the absence of contraindications, propranolol is considered the first line agent. Both immediate-release and sustained-release formulations of propranolol are effective. Common side effects include:bradycardia, dizziness, and fatigue.ß1-receptor-selective agents (e.g., atenolol and metoprolol) are also effective, but ß2-receptor blockade appears to be required and the efficacy of selective ß1-receptor blockers may be due to spillover ß2-receptor antagonism. Of the ß-blockers, propranolol appears to be the most effective and a lack of response to propranolol generally predicts lack of response to other ß-blockers.

In patients intolerant of propranolol or other beta-blockers, primidone or gabapentin are the drugs of choice. Initiation of primidone is associated with acute side effects of nausea, ataxia, dizziness, sedation, confusion, and malaise that can result in discontinuation or refusal of therapy by patients. To minimize these side effects, primidone should be initiated at low doses (e.g. 12.5 mg) and given at bedtime. These side effects generally abate after the first week. Blood dyscrasias are an idiosyncratic side effect and CBC should be periodically monitored. Since primidone is metabolized to phenobarbital, a P450 enzyme inducer, this must be considered as a potential for drug-drug interactions. Additionally, serum concentrations of primidone and/or phenobarbital are not useful for monitoring efficacy.

Gabapentin is well tolerated in both young and elderly patients and has few drug interactions associated with it. Dose-dependent side effects include ataxia and sedation. Weight gain may occur with chronic therapy. In patients with reduced renal clearance, lower doses of gabapentin are required.



Maintenance Therapy:

• Beta Blockers • Propranolol Immediate Release :60 mg BID – TID, or as needed

• 12 studies shoe efficacy • Reduced tremor magnitude by 50% • Side effects occurred in 12-66% of patients

• Propranolol Long Acting:120 – 240 mg QD • 2 studies show comparable benefit to short acting propranolol • 87% of patients preferred propranolol LA to propranolol



Maintenance Therapy:

Primidone:12.5 – 250 mg qHS – BID • Monitor CBC • Drug-drug interactions since it is a P450 enzyme inducer • 12 studies in a total of 218 patients

• Mean reduction in tremor magnitude was 50%

Primidone is an anticonvulsant that is metabolized to phenylethlmalonamide (PEMA) and phenobarbital. Primidone has similar or slightly better efficacy than propranolol.



Other Maintenance Agents:

• Gabapentin (Neurontin®) • Topiramate (Topamax®) • Botulinum toxin A (Botox®) • Levetiracetam (Keppra®) • Zonisamide (Zonegran®)

Topiramate is an anticonvulsant which shows clinical improvement in essential tremor. Side effects are significant and include appetite suppression, weight loss, anorexia, paresthesias and concentration difficulties.

Adjunctive Therapy:

• Alcohol • Associated with less missteps and improvement in ataxia

• Benzodiazepines

Other drugs that are less commonly used for maintenance therapy include: botulinum toxin, levetiracetam, topiramate, and zonisamide. Botulinum toxin may be more useful for treatment refractory head or voice tremor.

Alcohol and benzodiazepines should be used sparingly for relief of tremor symptoms. The symptomatic effect of alcohol (e.g., a glass of wine) lasts for about one hour and many patients will have a glass of wine with dinner. Benzodiazepines may be helpful in some patients; however, routine and chronic use can result in an increased risk of falls and dependence.


Surgical Treatment of Essential Tremor

• Thalamotomy – ablative surgery • Lesions are created in the thalamus to clock electrical impulses

• Chronic thalamic deep brain stimulation (DBS) • Electrical impulses block abnormal thalamic impulses

Surgical techniques are available for treatment of essential tremor but are generally reserved for non-demented patients requiring symptom control beyond that achievable with drugs. Patients with severe tremor may benefit from thalamotomy or thalamic deep brain stimulation. These procedures are successful in controlling symptoms in the majority of cases and in the hands of an experience neurosurgery team are very safe.

Stereotactic thalamotomy is a procedure in which permanent lesions are created in the thalamus to block electrical impulses.

Thalamic deep brain stimulation is often preferred over thalamotomy and involves implantation of a battery powered electrical pulse generator in the chest cavity with a lead that runs to the thalamus. Electrical impulses block abnormal thalamic impulses that contribute to tremor.


Treatment Outline for Essential Tremor

Initial Treatment • Propranolol or primidone • 3 studies compared efficacy • Both significantly reduce tremor compared to baseline and

placebo

Other Treatment Options • Anticonvulsants: gabapentin, topiramate • Botulinum toxin A • Surgery: Chronic thalamic DBS, thalamotomy

Combination Therapy

Drug treatment is initiated to decrease the disability associated with the tremor. Treatment of older patients with essential tremor should begin with propranolol or primidone. Both drugs are supported by well done prospective randomized controlled clinical trials for essential tremor. Studies have compared propranolo to primidone, but these have low numbers of patients. Side effect profiles and contraindications may guide the choice of initial therapy between propranolol and primidone.

Gabapentin and topiramate, anticonvulsants, have limited data supporting their use in essential trmor. Botulinum toxin is generally reserved for refractory, disabling head tremor. Combination therapy may be considered for patients who do not respond to monotherapy. The combination of primidone and propranolol is more effective that either drug alone without worsening of side effects.

For patients with suboptimal response despite maximally tolerated doses of drugs, neurosurgical procedures may be an option.


References and Resources

For further information, see:

Benito-Leon J, Bermejo-Pareja F, Morales JM, et al. Prevalence of essential tremor in here elderly populations of central Spain. Mov Disord. 2003;18:389-394.

Brin MF, Koller WC. Epidemiology and genetics of essential tremor. Mov Disorder 1998;13(suppl 3):55-63.

Chen JJ and Swope DM. Essential tremor: diagnosis and treatment. Pharmacotherapy 2003;23:1105-22.

Cleeves L, Findley LJ. Propranolol and propranolol-LA in essential tremor: a double blind comparative study. J Neurosurg Psychaitry 1988;51:379-84.

Gorman WP, Cooper R, Pocock P, et al. A compa4rison of primidone, propranolol, and placebo in essential tremor, using quantitative analysis. J Neurol Neurosurg Psychiatry 1986;49:64-8.

Gunal DI, Afsar N, Bekiroglu N, et al. New alternative agents in essential tremor: a study based on quantitative tremor recording and plasma anticonvulsant levels. Acta Neurol Scand 1987;75:332-40.

Klebe S, Stolze H, Grensing K, et al. Influence of alcohol on gait in patients with essential tremor. Neurology 2005;65(1):96-101.

Koller WC. Long-acting propranolol in essential tremor. Neurology 1985;35:108-10.

Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol and primidone in essential tremor. Neurology 1989;39:1587-8.

Louis ED. Essential tremor. N Eng J Med 2001;345:887-91.



Louis ED, Marder K, Cote L, et al. Differences in the prevalence of essential tremor amoung elderly African Americans, whites, and Hispanics in northern Manhattan, NY. Arch Neurol 1995;52:1201-5.

Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder: estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13:5-10. Zesiewicz TA, Elble R, Louis ED, et al. Practice Parameter: Therapies for essential tremor: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2005;64(12):2008-20.

International Tremor Foundation


Seizure Disorders

Learning Objectives


• Describe the incidence and etiology of seizure disorders in the geriatric population.

• Differentiate among the following kinds of seizures based on clinical presentation:partial seizures, generalized seizures, status epilepticus and acute repetitive seizures.

• List the common signs and symptoms of seizure disorders.

• Describe procedures for evaluating and diagnosing patients with seizure disorders.

• Describe in general terms the advantages, limitations, side effects and administration of drugs used to treat seizure disorders.

• Discuss dosing, half-life, toxicities and interactions of specific antiepileptic agents.

• List agents recommended as initial and adjunct therapy for specific types of seizure disorders.


Epidemiology of Seizure Disorders

• 3rd most common neurological disorder • Incidence highest in elderly over 80 years of age • Affects more older men than women • Most common cases caused by strokes, brain tumors and head trauma

Incidence increases with progression of Alzheimer’s disease. Seizures occur when there is an imbalance in the electrical activity of the brain. Seizures result from transient abnormal, excessive and synchronous activity of predominantly cortical neurons. This imbalance results from an increase in excitatory activity from the glutamatergic system, or from a decrease in inhibitory activity from the GABAergic pathway.

Seizure disorders are the third most common neurological disorder in the elderly following stroke and dementia. The incidence of seizure increases with age, especially for males as a result of the higher rate of strokes in males. Seizures are more frequent in older adults. Their causes are unique to this age group; there is a higher frequency of other medical conditions, normal age related changes in hepatic and renal metabolism impact dosing and administration of medications and seizures all have a unique impact on seniors.

For instance, the incidence of seizures increases to 127 per 100,000 by 60 years of age and exceeds that of young children at 80 years of age, affecting 140 per 100,000 individuals. In nursing homes, 15-18% of residents have exhibited seizure activity. Older adults are the fastest growing segment of the population and also have an increased risk of underlying disease such as stroke, trauma, head injury, brain tumors, toxic encephalopathy, metabolic disorders and dementia. Half of all seizure cases are caused by stroke, brain tumors or head trauma. Additionally, the incidence of seizures increases with progression of neurodegenerative disorders such as Alzheimer’s disease. It has been determined that 20% of Alzheimer’s patients have seizure activity after 6-8 years post-diagnosis.

Of further importance, geriatric patients are at an increased risk of injury secondary to seizure activity due to increased co-morbidities such as osteoporosis.


Incidence of Seizure Disorders

This graph represents the incidence of acute symptomatic and unprovoked seizures (epilepsy) based on age. There is a progressive increase in the incidence of seizures and epilepsy for each decade after age 60, with the highest incidence among those 80+ years. The incidence of epilepsy in older adults (65+ yrs) exceeds that of any other age group including children. About 30% of new cases now occur in people over age 65.


Classification of Seizure Disorders

Partial Seizures (focal cerebrovascular lesions): • Simple partial: consciousness not impaired • Complex partial: consciousness impaired

Generalized Seizures (cerebral hemispheres involved at onset): • Myoclonic • Tonic-clonic • Tonic • Clonic • Absence seizure - brief periods of

unawareness and staring • Atonic

Status Epilepticus: • Repeated generalized convulsions

for 30 minutes • Consciousness impaired


Classification of Seizure Disorders

There are two main classes of partial seizures; complex partial seizures resulting from focal cerebrovascular lesions and associated with a loss of consciousness and simple partial seizures where consciousness is not impaired. Complex partial seizures are more common in older adults than in younger adults and represent the most common type of seizure activity in the older adult. Simple partial seizures may involve motor, sensory, autonomic, or psychiatric symptoms and are the second most common type of seizure in the older adult.

When most people think of seizures they picture a generalized tonic-clonic seizure characterized by rhythmic contractions and relaxations of muscles. These generalized seizures, historically called Grand Mal seizures, involve the cerebral hemispheres bilaterally and symmetrically at the onset and result in loss of consciousness. They can present in several different forms as shown on your screen. Generalized tonic-clonic seizures are characterized by rhythmic contraction and relaxation of muscles. The third most common type of seizure in the elderly is the secondary generalized tonic-clonic seizure, whereby the seizure is generated from either a partial seizure or from a medical condition.

One additional type of generalized seizure, absence seizure, is characterized by brief periods of unawareness and staring without loss of posture.

Status epilepticus involves either continuous seizure activity for thirty minutes or more, or two or more sequential seizures without full recovery of consciousness between seizures.

Most older patients have no prior history of seizure disorder or status epilepticus.

Mortality and morbidity rates are significantly higher in the older adult. Status epilepticus can occur with any of the seizure types and should be treated as a medical emergency.


Etiology of Seizure Disorders

• Neurodegenerative disorders • Cerebral infarction and abnormality • Brain tumors • Intracranial CNS infections and/or bleeding • Head trauma • Autoimmune disease • Idiopathic or genetic factors • Metabolic abnormalities (infections, hypoglycemia, hyponatremia, uremia) • Adverse drug reactions • Drug and alcohol intoxication • Abrupt withdrawal of antiepileptic drugs • Abrupt withdrawal of alcohol or drugs

Different medical conditions can induce seizures. Examples include cerebral infarction, central nervous system infections and intracranial bleeding. It appears that genetic factors play a role in increasing susceptibility to some types of epilepsy. Medical or drug-induced metabolic abnormalities, such as hypoglycemia, hyponatremia, hypocalcemia, and uremia, may also contribute to seizure disorders. In the older adult, most new seizures are attributable to strokes, brain tumors, or head trauma.


Signs and Symptoms of Seizure Disorders

• Mood changes and intense feelings of fear or déjà vu • Fatigue • Aura – e.g., sense of flashing lights, noises • Jerking or twitching of arms and legs

During the onset of a seizure and prior to impairment of consciousness the patient may report mood changes, fatigue and an aura. Patients often have no symptoms of the disorder between seizures. Older patients often have alterations in awareness, increase in sensation, and/or increase in motor activity, such as jerking and twitching of limbs. Older patients with seizure disorders often have prolonged postictal states which can result in confusion, aphasia, and memory impairments. It may take up to several days for recovery from a seizure. Fortunately most symptoms will improve over time.


Evaluation of Seizure Disorders

• Confirm seizure • Rule out alternative neurological diagnoses – (e.g., syncope, migraine, TIA) • Obtain history of event with precipitating factors • Classify seizure using historical data and lab studies • Obtain medical history during childhood, as well as family history • Determine head trauma history • Physical exam

Evaluation of a seizure disorder begins with a confirmation of the seizure event. A diagnosis of syncope, migraine or transient ischemic attack should be ruled out immediately. A history of the event is the most important component in evaluating seizure disorders. The patient and any witness should be interviewed regarding the time immediately preceding the event and the patient’s mental and physical behavior and cognitive status pre- and post- event. Assessment should also include family history, history of diseases that can precipitate seizures, time of occurrence, and history of diseases that can mimic seizure activity, such as stroke, transient ischemic attack, essential tremor, Huntington’s disease, and restless leg syndrome. Conditions that can cause seizures, such as drug intoxication or withdrawal, brain tumor, and metabolic disease, should be treated first and further seizure activity should be followed. Medication history is also important to assess and if offending agents have recently been started, such as the selective serotonin reuptake inhibitors or bupropion, they should be slowly tapered so as not to induce further seizure activity. Also, evaluation of withdrawal of certain medications including but not limited to benzodiazepines, opioids, and alcohol, should be assessed and medication should be reintroduced with slow taper initiated after 4-6 weeks of reintroduction.


Treatment of Seizure Disorders with Antiepileptic Drugs (AEDs)

Advantages: • Can be used as monotherapy or polytherapy • More effective with older than with younger patients

Disadvantages: • Decline in kidney and liver function can increase serum concentrations • Alterations in distribution affects activity of drug • Adverse drug interactions • Increased incidence and severity of adverse events • Use cautiously in patients with:

• liver disease • malnutrition/underweight patients • narrow-angle glaucoma • allergy to tricyclic antidepressants • bone marrow depression, blood dyscrasias • severe respiratory depression • porphyria

Antiepileptic drugs prescribed as monotherapy or polytherapy will effectively treat the majority of seizures. However, few studies have evaluated the use of AEDs in those > 85 years of age and given AEDs’ high potential for drug interactions. caution is warranted when either starting therapy or changing any medications in a patient on AEDs. Additionally, there are growing concerns over drug-nutrient depletions, such as those resulting from enzyme induction and increased metabolism of 1, 25 dihydroxy vitamin D caused by phenytoin, which can lead to decreased calcium absorption from the gut, as well as osteoporosis.


Antiepileptic Drugs: Administration Guidelines

Dosing: • Start with lowest and least frequent dose • Titrate slowly • Change dose based on clinical response • Monotherapy is preferred

Use with Other Medications: • If monotherapy unsuccessful, consider using adjunctive therapy

Monitoring: • Seizure counts • Documentation of event • Adverse drug reactions and interactions • Quality of life • Compliance

Treatment with antiepileptic drugs should begin with the lowest starting dose possible, and be titrated slowly, as with all drug use in the older adult. Dosage changes should be guided by the patient’s clinical response by evaluating incidence of seizures and appearance of drug toxicity rather than by therapeutic drug monitoring. Monotherapy is always preferred but, if monotherapy with higher doses is unsuccessful, adjunctive therapy with a different agent should be attempted. Patients on antiepileptic drug therapy should be monitored closely using seizure counts, adverse drug reactions, and interactions. A seizure event should be documented in the clinical record of the patient with a detailed summary of events of the entire seizure. Quality of life should be periodically assessed, and compliance with different regimens noted. Unfortunately, it frequently happens that patients were started on an AED 20 or more years ago for a seizure and then kept on that drug without experiencing any further seizure activity. Therefore it is very important to continually monitor these patients and clearly identify endpoints in therapy.


Examples of Antiepileptic Drugs

Older Agents:

• Phenytoin • Carbamazepine • Barbiturates • Benzodiazepines • Valproic acid • Ethosuxamide

Newer Agents:

• Gabapentin (Neurontin®) • Lamotrigine (Lamictal®) • Topiramate (Topamax®) • Tiagabine (Gabitril®) • Vigabatrin (Sabril®) • Levetiracetam (Keppra®) • Zonisamide (Zonegran®) • Oxcarbazepine (Trileptal®) • Pregabalin (Lyrica®)

Antiepileptic drugs that have been in use for several years are termed standard antiepileptic drugs and include phenytoin, carbamazepine, barbiturates, benzodiazepines, valproic acid, and ethosuxamide. Newer antiepileptic drugs include, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, zonisamide, oxcarbazepine and pregabalin. Additionally, some of the older medications have been released in new dosage forms such as rectal diazepam gel, parenteral valproic acid, and extended release carbamazepine. These agents have improved side effect profiles, fewer drug-drug interactions, decreased protein-binding effects and improved dosing regimens. These advantages suggest that newer AEDs may be better medications for long-term treatment of seizure disorders in the older adult. Nonetheless, many newer AEDs have complex titration schedules and require several weeks of therapy to achieve therapeutic control. In the presence of frequent seizures, standard AEDs should be initiated and changed to newer AEDs after seizure activity is controlled. To switch therapies, the new AED should be started at a low dose and titrated normally. At the first dose titration, the standard AED should be titrated down by no more than 25% of the total dose. When the new AED is tapered up again, the standard AED should be tapered until discontinued, but with no greater frequency than weekly reductions.


Treatment of Seizure Disorders

Treatment of Seizure Disorders with Phenytoin

Dosing: 200-400 mg daily or 2 divided doses BID

Half-life: 15-24 h or longer, depending on concentration

Zero order kinetics

Dose-related Neurotoxicity (20-30 µg/ml): • Nystagmus • Ataxia • Lethargy

Adverse Effects: • Osteomalacia • Gum hypertrophy • Rash

Treatment of Seizure Disorders with Fosphenytoin

The dose, concentration in solutions, and infusion rates for fosphenytoin are expressed as phenytoin sodium equivalents; fosphenytoin should always be prescribed and dispensed in phenytoin sodium equivalents.

Dilute fosphenytoin in 5% Dextrose or 0.9% Saline Solution for Injection to a concentration ranging from 1.5 to 25 mg PE/ml.

Status epilepticus:

The loading dose 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.

Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for control of status epilepticus.



Nonemergent and maintenance dosing:

Loading dose: 10 to 20 mg PE/kg given IV or IM.

Maintenance dose: 4 to 6 mg PE/kg/day.

Because of the risk of hypotension, administer at a rate of = 150 mg PE/min.

Continuously monitor the electrocardiogram, blood pressure and respiratory function and observe the patient throughout the period of maximal serum phenytoin concentrations, »10 to 20 min after the end of the infusion.

Renal/Hepatic function impairment:

Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, interpret total phenytoin plasma concentrations with caution. Unbound phenytoin concentrations may be more useful in these patients. After IV administration, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events.

Older Adults: Age does not have a significant impact on the pharmacokinetics of fosphenytoin following administration. Phenytoin clearance is decreased slightly in older patients and lower or less frequent dosing may be required.

Storage / Stability: Refrigerate at 2° to 8°C (36° to 46°F). Do not store at room temperature for more than 48 hours.



Phenytoin is effective for partial and generalized tonic-clonic seizures and is the most frequently prescribed AED in older adults for seizures. It should be dosed at 200 to 400 milligrams daily. Doses greater than 300 mg should be provided in two divided doses to reduce gastric irritation. If the patient is receiving the suspension, always make sure that it is properly shaken before administration to ensure uniform doses.

At lower serum concentrations, the half-life of phenytoin is fifteen to twenty-four hours. Longer half-lives can be expected with higher concentrations. Dose-related neurotoxicity begins at levels of twenty to thirty microgram per milliliter resulting in nystagmus, ataxia, and lethargy. It should be noted that ataxia is the most common side effect of phenytoin and can be observed with serum levels < 20 mg/ml.

Phenytoin is 95% protein bound. Thus, patients with decreased albumin may experience adverse events at lower total serum levels due to higher free fraction of phenytoin. To estimate the impact of hypoalbuminemia on phenytoin, divide the patient’s serum phenytoin level by the sum of 0.2 times serum albumin level plus 0.1. This concentration is the theoretical phenytoin level in that patient and may suggest hidden phenytoin toxicity. Phenytoin should be reduced in these patients. Understand that this calculation is theoretical and treat the patient instead of the lab test. As an example, if you have a patient who has a serum phenytoin level of 16 mg/ml and a serum albumin level of 2.4 g/dL, the theoretical corrected phenytoin level would be 28 mg/ml. A much more expensive but reliable method would be to obtain a free phenytoin level.

Patients treated with phenytoin may experience osteomalacia, gum hypertrophy, or rash, regardless of serum level. The gum hypertrophy may be especially significant in denture wearers. Emphasis should be placed on good oral hygiene and consultant pharmacists should suggest biannual dental visits. It should also be noted that phenytoin toxicity can lead to coma and death if left untreated and total or corrected phenytoin level is greater than 25 mg/ml in the older adult.

Many drugs commonly prescribed in older patients interact with phenytoin via protein binding or enzyme induction. Due to phenytoin’s interaction profile, risk for bone mineral density loss and adverse drug profile, the newer antiepileptic agents may offer safer alternatives.


Treatment of Seizure Disorders with Carbamazepine

Dosing: 100 mg once to twice daily, slow titration to effective dose

Half-life: 8-36 hours

Adverse Drug Reactions: • Dose-dependent neutropenia (common) • Idiosyncratic aplastic anemia (rare) • Diplopia, ataxia (dose-related)

Precautions: • Discontinue or reduce dose if neutrophil count < 1200/mcL • Carbamazepine exhibits cytochrome p450 induction, including autoinduction

Carbamazepine is effective for generalized tonic-clonic seizures and complex partial seizures. Indeed, carbamazepine is considered by some to be the drug of choice in treating complex partial seizures in older patients. In the older adult, carbamazepine is dosed at 100 mg one to two times daily and increased by 100 mg per day at weekly intervals until a serum level of 4 to 12 mg/ml is achieved or until seizures are controlled. Maintenance dose is usually 600 to 800 mg daily in divided doses. The half-life of carbamazepine is eight to thirty-six hours, depending on concentration.

Neurotoxic symptoms include diplopia, ataxia, and lethargy. Carbamazepine can also cause hepatic failure so liver function should be monitored routinely. The most common side effect of carbamazepine is dose-dependent neutropenia, which is usually self-limiting. Idiosyncratic aplastic anemia is rare. Discontinue carbamazepine or reduce dose if the neutrophil count is 1200 or less.



Carbamazepine is a strong inducer of cytochrome P450 isoenzymes 1A2, 2C8/9, 2C19, and 3A4. Thus, it may be necessary to increase doses of other medications that are metabolized by these isoenzymes, such as thyroid hormones, valproic acid, amiodarone, SSRIs, calcium channel blockers, and phenytoin. Furthermore, carbamazepine can induce its own metabolism. Therefore, serum levels of carbamazepine should be obtained after 1-2 months and the dose increased accordingly to minimize the impact of this phenomenon. Carbamazepine saturates the enzyme system at 1-2 months and the patient should not experience further autoinduction.



Dosing: • Phenobarbital 1-4 mg/kg daily • Primidone 10-20 mcg/kg qid or bid

Barbiturates such as phenobarbital and primidone may be prescribed for seizures. Both are effective for partial and generalized tonic-clonic seizures. Primidone is ultimately metabolized to phenobarbital and phenylethylmalonamide. It is dosed at ten to twenty micrograms per kilogram, twice or four times daily. The most common adverse effect of the barbiturates is sedation. Phenobarbital is a potent inducer of the cytochrome P450 isoenzymes 1A2, 2C8/9, and 3A4. Medications that are metabolized by these enzymes may need to be increased. The half-life of phenobarbital is approximately 140 hours in the older adult. Phenobarbital also decreases absorption of vitamin D which increases risk and/or severity of osteoporosis. With the high incidence of sedation, decrease in vitamin D absorption, dizziness, and confusion, phenobarbital is not recommended for use in the older adult.


Treatment of Seizure Disorders with Valproate

Forms: Valproic Acid and Divalproex Sodium • Divalproex sodium Delayed Release (Depakote DR®) • Divalproex sodium Extended Release (Depakote ER®) • Valproic acid (Depakene IR ®) • Valproate sodium injection (Depacon®)

Dosing: 10-15 mg/kg, 3 -4 divided doses, taper up weekly, Depakote ER® is not bioequivalent to the Depakote DR dosage form. The Depakote ER formulation can be dosed once daily.


Adverse Drug Reactions: • GI upset • Increased appetite • Weight gain • Alopecia • Hepatic failure (rare) • Sedation • Tremor (dose-related)

Valproic acid, or valproate, is best for generalized seizures, complex partial seizures, and may be the drug of choice for absence seizures. The enteric-coated slow release form of sodium divalproex should be dosed initially at ten to fifteen milligrams per kilogram in two to four divided doses and increased by 5 to 10 mg/kg/day at weekly intervals until therapeutic level of 50 to 100 mg/ml is achieved.

The extended release formulation can be dosed once daily. In hepatic failure or insufficiency, the dose should be reduced. Sedation, dizziness, increased levels of liver enzymes, and tremor are the most common symptoms of toxicity.

Other side effects include gastrointestinal upset, increased appetite, thrombocytopenia, weight gain, and alopecia. Hepatic failure can occur but is rare. Nonetheless, liver function should be monitored routinely. Parenteral valproate is currently indicated for replacement of oral valproate doses when the patient is unable to take oral medications.


Treatment of Seizure Disorders with Gabapentin

Dosing: 400-3600 mg in divided doses 3 to 4 times a day


Drug-Drug Interactions: • Cimetidine decreases renal clearance by 10% • Antacids decrease bioavailability by 20%

Gabapentin is an antiepileptic agent for adjunctive treatment of partial seizures. The dosing starts at 300 mg daily usually at bedtime and can be increased by 300 mg daily, every 3 to 5 days until seizures are controlled, up to a maximum of 3600 milligrams per day. Gabapentin has a half-life of five to seven hours. Gabapentin is useful as adjunct therapy because no interactions have been found with phenytoin, carbamazepine, valproic acid, or phenobarbital. However, cimetidine decreases renal clearance of gabapentin by ten percent and antacids decrease its bioavailability by twenty percent. Nonetheless, no significant drug interactions have been found. This medication is not considered as effective monotherapy for seizure disorders. However, it is often used to treat neuropathic pain so it may be a perfect adjunctive therapy in patients with diabetic neuropathies and post-herpetic neuralgias. Side effect profile is favorable and includes somnolence, dizziness, and ataxia. Gabapentin is excreted unchanged in urine. Thus, dose reductions should be made at initial dose in renal insufficiency but dose should be tapered up until seizures are controlled or until adverse effects emerge.


Treatment of Seizure Disorders with Pregabalin

Dosing: 150-600 mg in divided doses 2 to 3 times a day

Half-life: 6 hours

Drug-Drug Interactions: No drug interactions of clinical significance in published clinical trails

Pregabalin is an antiepileptic agent for adjunctive treatment of partial seizures. The dosing starts at 150 mg daily divided as 75mg, two times daily or 50mg, three times daily. Based on individual patient response and tolerability, the dose may be increased until seizures are controlled, up to a maximum of 600mg milligrams per day. Pregabalin has a half-life of six hours. Pregabalin is useful as adjunct therapy because no interactions have been found with phenytoin, carbamazepine, valproic acid, or phenobarbital. No other significant drug interactions have been found. Pregabalin is indicated as an adjunctive treatment for partial seizures and for the management of diabetic neuropathies and post-herpetic neuralgias. Side effect profile is favorable and includes somnolence, dizziness, and ataxia. Pregabalin is excreted unchanged in urine. Thus, dose reductions should be made at initial dose in renal insufficiency but dose should be tapered up until seizures are controlled or until adverse effects emerge.


Treatment of Seizure Disorders with Lamotrigine

Dosing: 100-500 mg daily in 2 divided doses must be titrated slowly

Half-life: 24 hours (monotherapy), 15 hours with concurrent phenytoin/carbamazepine, 59 hours with valproic acid

Adverse effects: • Rash (which can lead to Stevens-Johnson syndrome)

• Approximately 10% of patients develop erythema and a maculopapular rash; however, rashes associated with lamotrigine do not have specific identifying characteristics. Approximately 1% of the patients develop Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema or pruritis.

• Sedation

Drug-Drug Interactions: • Decreases valproic acid concentration by 25% • Valproic acid increases lamotrigine concentrations • May increase carbamazepine epoxide • Phenytoin, carbamazepine, phenobarbital increase dosage requirements 50-100%


Treatment of Seizure Disorders with Lamotrigine

Lamotrigine, may be used in monotherapy or polytherapy for partial seizures. Lamotrigine should be initiated at 25 mg twice daily for 2 weeks then increased to 50 mg twice daily for two weeks. Dose can then be increased by 100 mg daily every 2 weeks until effective dose is achieved. It is important that tablets are not crushed or cut. Half-life varies depending on concurrent medications, ranging from 15 to 59 hours. This agent does interact with other epileptic drugs, decreasing valproic acid concentration by twenty-five percent and producing carbamazepine epoxide, which is a toxic metabolite of carbamazepine.

When used in combination with phenytoin, carbamazepine and phenobarbital, dosage requirements for lamotrigine increase by fifty to one hundred percent. It is very important to note that valproic acid increases concentrations of lamotrigine significantly. When lamotrigine is given with valproic acid, titration must be slowed. The most significant adverse effect is a severe and life-threatening rash which usually occurs within the first 8 weeks of therapy initiation. Lamotrigine should be discontinued at the first sign of a rash.

The risk of this rash increases significantly with concomitant valproic acid and with rapid dose titration. Thus, valproic acid is not recommended as adjunctive therapy with lamotrigine. Other common side effects include headache, dizziness, ataxia, lethargy, nausea, and diplopia.


Treatment of Seizure Disorders with Topiramate

Dosing: 200 mg daily in two divided doses (adjunct therapy); start at 50 mg/day

Half-life: 20 hours (monotherapy)

Adverse effects: • Psychomotor slowing • Kidney stones (1.5%)

Drug/Drug Interactions: • Increases phenytoin steady state concentration by 25%, • Decreases valproic acid by 10%, • Decreases ethinyl estradiol and digoxin • Topiramate decreased approximately 50% by concurrent phenytoin/carbamazepine

Topiramate is indicated as adjunct therapy of partial seizure and generalized tonic-clonic seizures. The drug should be initiated in the older adult at 25 mg daily with a taper of 25 to 50 mg every week until seizure activity is controlled to a maximum dose of 1600 mg per day. Topiramate inhibits carbonic anhydrase and increases bicarbonate excretion in the kidney, resulting in a decreased serum bicarbonate level in 67% of patients. In some individuals, metabolic acidosis can result. Thus, serum bicarbonate should be monitored initially and every 6 months. Other side effects include dizziness, psychomotor slowing, memory impairments, tremor, psychosis, and kidney stones. Interactions associated with this agent include an increase in phenytoin concentration and decreases in valproic acid, ethinyl estradiol, and digoxin. Phenytoin and carbamazepine have been shown to reduce topiramate levels by 48 and 40%, respectively.


Treatment of Seizure Disorders with Tiagabine

Dosing: 4mg daily, tapering up to maximum of 48 mg daily

Half-life: 5-8 hours (monotherapy)

Adverse effects: Sedation

Drug-Drug Interactions: • Not an inducer or inhibitor • Reduced 50% by other inducing AEDs

Tiagabine is another new antiepileptic with a half-life of five to eight hours when used as monotherapy. It is indicated as adjunct therapy for partial seizures. However, adjunct therapy with carbamazepine can result in toxicity. It should be initiated at 4 mg daily for 1 week and increased by 4 to 8 mg/day every week. Tiagabine should be administered with food. Adverse effects include somnolence, muscle weakness, dizziness, and hostility. Tiagabine is extensively metabolized by cytochrome P450 3A4 so should be used cautiously with inducers and inhibitors of this isoenzyme. While tiagabine is 97% protein bound, drug interactions involving protein displacement have not been observed. Tiagabine does not induce or inhibit other drugs, but it is reduced by fifty percent when used with other inducing antiepileptic drugs.


Treatment of Seizure Disorders with Levetiracetam

Dosing: 500-1500 mg BID; must adjust in renal failure

Half-life: 7 hours

Adverse effects: • Somnolence • Coordination difficulties • Behavioral abnormalities

Drug/Drug Interactions: • None known

Levetiracetam has been approved as adjunctive therapy for treatment of partial seizures. Dosing begins at 500 mg twice daily and is increased every two weeks as needed. Common adverse effects include somnolence, weakness, psychosis, agitation, hostility, depression, and coordination difficulties. Levetiracetam has not been found to interact with other medications. A recent subanalysis of the KEEPER trial, suggested that levetiracetam reduced seizure activity by 80% and was well-tolerated in the older adult. Thus, it may be used safely and effectively in older patients as add-on therapy.


Treatment of Seizure Disorders with Zonisamide

Dosing: 100-400 mg daily

Half-life: 63 hours

Contraindications: sulfonamide therapy

Adverse effects: • Psychiatric symptoms • Psychomotor slowing • Somnolence • Rash • Agranulocytosis (rare) • Decreased sweating (rare) • Kidney stones

Drug/Drug Interactions: • Inducing AEDs • Increased clearance when combined

with drugs that induce CYP 3A4

Zonisamide is indicated as adjunct therapy for partial seizures and is given at a starting dose of 100 mg a day and may be increased. Because of its long half-life, the dose is given once daily, but it may take two weeks to get to steady-state serum concentrations.

Patients with sulfonamide allergies should not take zonisamide since reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis can occur, usually within 2 to 16 weeks of initiation of therapy. Adverse effects include somnolence, dizziness, anorexia, psychosis, agitation, memory impairments, and kidney stones.

Rare cases of agranulocytosis have been reported. There are limited studies using zonisamide in patients greater than 65 years of age.

Thus, this medication should be reserved after failure of other therapies. It is metabolized by the cytochrome P450 enzyme system. Its metabolism is also increased by inducers of this system.


Treatment of Seizure Disorders with Oxcarbazepine

Dosing: 300 mg BID, increased by 300 mg/day every third day to 1200 mg/day. Usual dose is 1200-2400 mg/day

Pharmacokinetics: metabolized to 10-monohydroxyoxcarbazepine, the active medication

Adverse effects: • Somnolence • Diplopia • Hyponatremia

Drug/Drug Interactions: • No autoinduction • Increases concentrations of phenobarbital and phenytoin • Phenobarbital, phenytoin, and valproic acid decrease oxcarbazepine concentrations

Oxcarbazepine is a derivative of carbamazepine with a metabolite as the active component of the medication. It is indicated for treatment of partial seizures. It is considered to be a safer alternative to carbamazepine but it is significantly more expensive. Adverse effects include dizziness, somnolence, ataxia, diplopia, and hyponatremia. A recent study by Kutluay et al demonstrated that older patients have similar rates of adverse effects from oxcarbazepine as younger patients, with the exception of a higher incidence of hyponatremia. It is known to inhibit 2C19 and induce 3A4 isoenzymes of the cytochrome P450 system. This activity leads to an increased concentration of phenytoin and phenobarbital. Oxcarbazepine levels are reduced by phenytoin, phenobarbital, valproic acid, and verapamil.


Treatment of Specific Seizure Disorders

Treatment** Seizure Disorder**

Carbamazepine par8al, tonic, clonic, tonic-‐clonic

Clonazepam absence, myoclonic, atonic, Lennox-‐Gastaut syndrome

Ethosuxamide absence

Fosphenytoin par8al, clonic, tonic, tonic-‐clonic, status epilep8cus

Gabapen*n par8al

Lamotrigine par8al, tonic, clonic, tonic-‐clonic, absence, Lennox-‐Gestaut syndrome

Leve*racetam Par8al, myoclonic

Oxcarbazepine Par8al

Pregabalin par8al

Phenobarbital par8al, tonic, clonic, tonic-‐clonic, myoclonic

Phenytoin par8al, tonic, clonic, tonic-‐clonic, status epilep8cus

Primidone par8al, tonic, clonic, tonic-‐clonic


Treatment of Specific Seizure Disorders

** This chart reflects FDA indications only.

Agents recommended for treatment of specific types of seizure disorders are listed in the chart. Prompt treatment is required for status epilepticus, which is considered a medical emergency. Intravenous lorazepam or diazepam should be used to initially stop the seizure. Then intravenous or intramuscular fosphenytoin or intravenous phenytoin, phenobarbital, or valproic acid should be given to treat this type of seizure and changed to oral therapy after seizure activity is controlled.

Treatment** Seizure Disorder**

Tiagabine partial

Topiramate Partial, tonic-clonic, atonic, Lennox-Gastaut syndrome

Valproic acid partial, absence, myoclonic, clonic, tonic, tonic-clonic, atonic

Zonisamide Partial


Discontinuing AED Therapy

• No history of seizures • No seizure activity > 2 years with normal EEG • Taper med by 25% of dose every 4 – 6 weeks.

Often, AED therapy continues indefinitely once it is started. This is often due to fear of patients having subsequent seizure activity. However, the adverse effects of these medications, even in the newer AEDs, support the need to re-evaluate the need for therapy, especially in the older adult. Older patients are often placed on AED therapy after a brief episode of seizure activity following a stroke and many are often placed on AED therapy as precaution after a stroke and have not exhibited any seizure activity.

Many of these patients will remain on these medications indefinitely. Thus, pharmacists can and should play a key role in determining whether therapy is warranted. The rule of thumb is that if a patient has not had any seizure activity in greater than two years, an EEG should be obtained. If the EEG is normal, AED therapy should be reduced slowly until seizure activity returns or until the medication is discontinued. This slow reduction should encompass no greater than 25% of the total dose every 4 to 6 weeks. Quick withdrawal of any antiepileptic drug can result in seizure activity so it should be actively discouraged.




Annegers, J. F. (1994). Epidemiology and genetics of epilepsy. Neurol Clin; 12: 15-29.

Cloyd J., et al (2006). Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res. 68S:39-48.

Garcia, P. A., Alldredge, B. K. (1994). Drug-induced seizures. Neurol Clin; 12: 85-99.

Gidal B.E. (2006). Drug absorption in the elderly: Biopharmaceutical considerations for the antiepileptic drugs. Epilepsy Res. 68S:65-69.

Hartshorn, J. C. (1996). Seizures and the elderly. Crit Care Nurs Clin North Am; 8(1): 71-8.

Hauser, W. A. (1992). Seizure disorders: the changes with age. Epilepsia; 33(suppl 4): S6-14.

Kutluay E. McCague K. D'Souza J. Beydoun A. (2003). Safety and tolerability of oxcarbazepine in elderly patients with epilepsy. Epilepsy & Behavior. 4(2):175-80.

Lackner TE. (2002)Strategies for optimizing antiepileptic drug therapy in elderly people. Pharmacotherapy. 22(3):329-64.

Leppik I.E., et al (2006). Outcomes research: Clinical trials in the elderly. Epilepsy Res. 68S:71-76.

Rowan AJ. (2000).Management of seizures in the elderly. Pharmacotherapy. 20(8 Pt 2):178S-184S.

Rowan AJ. (1998). Reflections on the treatment of seizures in the elderly population. Neurology. 51(5 Suppl 4):S28-33.



Ruggles KH. Haessly SM. Berg RL. (2001). Prospective study of seizures in the elderly in the Marshfield Epidemiologic Study Area (MESA). Epilepsia. 42(12):1594-1599.

Perucca E., et al. (2006). Pharmacological and clinical aspects of antiepileptic drug use in the elderly. Epilepsy Res. 68S: 49-63.

Scheuer, M. L., & Cohen, J. (1993). Seizures and epilepsy in the elderly. Neurolog Clin; 11(4):787-804.

So, N. K. (1993). Recurrence, remission, and relapse of seizures. Cleve Clin J Med.; 60(6): 439-44.

Stephen LJ, Brodie MJ. (2000).Epilepsy in elderly people. Lancet 355:1441-6.

Traeger, S.M., et al. (1995).. Seizures associated with ofloxacin therapy. Clin Infect Dis; 21(6): 1504-06.

Treiman, D. M. (1993). Current treatment strategies in selected situations in epilepsy. Epilepsia, 34 (suppl 5): S17-S23.

Velez L. Selwa LM. (2003). Seizure disorders in the elderly. American Family Physician. 67(2):325-32.

Walsh, G. O. & Delgado-Escueta, A. V. (1993). Status epilepticus. Neurol Clin; 11:835-851.

Willmore LJ. (1998). Antiepileptic drug therapy in the elderly. Pharmacology & Therapeutics. 78(1):9-16.

Neurosciences on the Internet – Epilepsy and Seizures

PharmInfo Net – Epilepsy


Cerebrovascular Disease



• State the overall incidence of cerebrovascular disease, and the incidence of various types of stroke among the elderly

• Identify the risk factors that contribute to the progression of cerebrovascular disease

• Classify and describe the various types of strokes among the elderly

• List possible etiologies for hemorrhagic stroke and ischemic stroke

• Describe the pathophysiology behind acute stroke

• Define transient ischemic attack (TIA) and explain how symptoms of TIA can confound a differential diagnosis of impending

stroke

• Describe the signs and symptoms of a patient presenting during and after a TIA or a stroke

• Compare and contrast the therapeutic regimens recommended for patients with a TIA, acute ischemic stroke or

cardioembolic stroke

• Describe the role of thrombolytics in the treatment of an acute ischemic stroke including dosing, indications, and

contraindications

• Describe the pharmacological agents used in secondary stroke prevention

• Describe the therapeutic recommendations for the prevention of cerebral vasospasms and seizures secondary to a

subarachnoid hemorrhage


What is a Stroke?

• Sudden onset focal neurological deficit • Abrupt interruption of focal cerebral blood flow • Escape of blood from vessels into the brain at its surrounding structures causing neurologic dysfunction

Stroke is a major manifestation of cerebrovascular disease where there is a sudden onset of focal neurologic deficit due to an acute blockage of blood circulation in an area of the brain, called ischemic stroke or due to leakage of blood called hemorrhagic stroke.


Introduction to Stroke

Ischemic Stroke: • 87% of all strokes • caused by an embolic or thrombotic clot

• Thrombotic: located in the vicinity of the infarction • Embolic: formed elsewhere in the body and migrated to the brain

Hemorrhagic Stroke: • 13% of all strokes • Caused by a breakage or "blowout" of a blood vessel in the brain

• Intracerebral: bleeding occurring from vessels within the brain itself • Subarachnoid: aneurysm bursting in a large artery on or near the • membrane surrounding the brain


Introduction to Stroke

Strokes are either “ischemic” or “hemorrhagic”. Eighty-seven percent of all strokes are ischemic. Ischemic strokes are usually caused by an embolic or thrombotic clot. If the clot is located in the vicinity of the infarction, it is considered to be a thrombus. If the clot was formed elsewhere in the body and migrated to the brain, it is considered to be an embolus. Once in the brain, the clot lodges in a blood vessel small enough to block its passage, causing the stroke. Thirteen percent of strokes are “hemorrhagic strokes”, caused by the breakage or “blowout” of a blood vessel in the brain. Hemorrhagic stroke may be intracerebral, which involves bleeding within the brain, or subarachnoid, which involves bleeding into the cerebrospinal fluid (CSF) that surrounds the brain.


Overall Incidence and Epidemiology of Stroke

• 3rd leading cause of death in the USA • 1 of every 16 deaths is due to stroke (Heart Disease and Stroke • Statistic 2007 update) • 700,000 new and recurrent strokes annually

• 500,000 are first attacks • 200,000 are recurrent attacks

• 50,000 deaths annually • Women account for approximately 61% of stroke deaths per year

• Estimated direct and indirect cost for stroke for 2007 is $ 62.7 billion

• Most common debilitating neurologic disorder

• Of all those surviving a stroke for 3 months: • 50% will live for 5 years and 30% will live for 10 years • 60% recover with self care and 20% require institutional care

• About 33% of people who have had a stroke and survived will have another stroke within five years


Overall Incidence and Epidemiology of Stroke

• The risk of having a stroke increases with age • People over age 55: the incidence of stroke more than doubles in • each successive decade • Seventy-two percent of all strokes occur in people over the age of 65 • Mortality risk is 7 times higher in > 65 y/o vs. younger adults • Stroke survivors who were > 65 y/o, 26% admitted to nursing home

• African-Americans are twice as likely to experience stroke as Caucasian-Americans

• Asians, Hispanics, and Native Americans have a higher prevalence of stroke then Caucasian-Americans

While stroke is catastrophic at any age, elderly patients are especially vulnerable to its effects due to concurrent medical conditions and their greater overall physical and psychological debilitation. According to the National Stroke Association, two thirds of all strokes occur in individuals over the age of sixty-five, and the risk doubles with each decade after age fifty-five. The stroke rate in African Americans is greater than that of other racial groups. In terms of mortality, the risk of an elderly person dying from stroke is seven times that for the population overall.


Risk Factors for Stroke

Disease-Induced: • Cardiovascular:

• Hypertension (Systolic > diastolic) • Hyperlipidemia (total cholesterol >240 mg/dL) • Atrial fibrillation (increase risk 5-fold) • Mitral stenosis or mitral annular calcification • Left arterial or ventricular hypertrophy • History of myocardial infarction (MI), heart failure (HF), endocarditis, carotid bruits, or prosthetic cardiac valves

• Diabetes Mellitus (esp. women) • Sickle cell disease • Increased hematocrit • Increased platelets • Hyperhomocysteinemia (level > 10 µmol/L) • Migraines • Obesity • Sedentary lifestyle



• Drug-Induced: • Phenylpropanolamine • Herbal supplements for weight control/loss

• Ephedrine, Ma Huang, Hoodia Gordonii, Zhi Chi • Cigarette Smoking: risk for women > men • Hormone replacement therapy for menopausal symptoms • Oral contraceptives: estrogen > 50 mcg/day (Demulen 1/50®, Ortho • Novum 1/50®, Ovcon-50®, Nelova 1/50®) • Grapefruit juice increases the serum levels of estrogen by 25% • Illicit drugs: cocaine & crack (esp. men < 45yo), heroin, • amphetamines, LSD (lysergic acid diethylamide), PCP (phencyclidine) • Alcohol: habitual (greater than 2 beverages daily) or binge drinking • COX-2 selective NSAIDs (celecoxib) and non-selective NSAIDS • Atypical antipsychotics used to treat behavioral and psychological • symptoms of dementia (BPSD) in those with established risk factors • for stroke



Medications Altering Lipid Profile: • Thiazide diuretics: increase LDL, VLDL • Loop diuretics: lower HDL

• Beta-Blockers: increase VLDL; lower HDL • More pronounced with selective agents • Favorable: Alpha-1 Antagonists (5-15% decrease in

LDL, VLDL, and increase in HDL) • Neutral: ACEIs, ARBs, CCBs, alpha-2 Agonists, Indapamide • Neuroleptics: especially typicals, due to 5HT2c blockade

• Weight gain • Clozapine, olanzapine > risperidone > haloperidol, quetiapine • Lithium, valproic acid and gabapentin

Non-modifiable risk factors • Family History of Stroke • Age • Race (Black > Caucasians) • Male • Ethnicity

Conditions such as heart disease and hypertension increase the risk of stroke significantly, but may be modified, reducing this risk. For example, studies have shown that a decrease in diastolic or systolic blood pressure can reduce the risk of stroke by as much as forty percent. Smoking, alcohol abuse, elevated cholesterol, and hyperhomocysteinemia also increase the risk of cerebrovascular disease. Although obesity is not directly related to an increased stroke risk, it increases the likelihood of stroke through secondary mechanisms such as high cholesterol, high blood pressure, and diabetes. Other risk factors are considered non-modifiable, which include black race, male sex, and being elderly.

Use of certain medications can also increase risk for stoke. Over-the-counter drugs and herbals used to promote weight loss have been associated with increasing the risk for stroke. Recently, medications such as rofecoxib (Vioxx®) and valdecoxib (Bextra®) have been withdrawn from the market due to increase risk for vascular events. The mechanism may be related to cyclooxygenase 2 substrate inhibition resulting to decrease prostaglandin I2, which is a vasodilator and inhibitor of platelet aggregation. Atypical antipsychotics revised their package inserts to indicate the increase risk of cerebrovascular accidents when used in the elderly to treat behavioral symptoms associated with dementia (BPSD).


Classification of Stroke

STROKE

87% Ischemic Stroke

20% Atherosclerotic

Cerebrovascular Disease

25% Penetrating Artery

Disease (“Lacunes”)

20% Cardiogenic Embolism •Atrial fibrillation

•Valve disease •Ventricular Thrombosis •Many other

30% Cryptogenic Stroke

5% Other, Unusual

Causes •Prothrombic states

•Dissections •Arteritis

•Migraine/Vasospasm •Drug Abuse

• Hypoperfusion Artenogeneric Emboli

13% Primary Hemorrhage

•Intracerebral •Subarachnoid

Cerebrovascular disease is actually a group of related conditions, each with its own unique etiology. The chart on your screen shows how these conditions are related, and the percentage of cases attributable to each. Stroke is classified as either ischemic or hemorrhagic in nature. Ischemic stroke is classified to 5 subtypes based upon clinical features.


Etiology of Hemorrhagic Strokes

Causes of ICH (Intracerebral hemorrhage) • Hypertension (most common) • Trauma • Bleeding diathesis • Illicit drug use • Vascular malformation • Tumor, aneurysmal rupture and valculitis (least common)

Causes of SAH (subarachnoid hemorrhage) • Rupture of arterial aneurysm (most common) • Bleeding diathesis, trauma, amyloid angiopathy, illicit drug use (least common)

Other Causes • Bleeding from a congenital vascular malformation • Septic aneurysm • Bleeding into a neoplasm • Anticoagulant/bone marrow suppression therapy

The most common causes of hemorrhagic stroke include hypertensive intraparenchymal bleeding, bleeding from a congenital vascular malformation and subarachnoid hemorrhage from a ruptured berry aneurysm In the elderly, another cause that assumes increased importance is amyloid angiopathy. Strokes of this latter etiology present as lobar rather than deep cerebral hemorrhage, and multiple hemorrhages. An iatrogenic cause of hemorrhagic stroke comes from anticoagulant usage, particularly when the INR exceeds the therapeutic range, or from Aspirin, adenosine diphosphate inhibitors (clopidogrel and ticlopidine), heparin, low molecular heparins, direct thrombin inhibitors, glycoprotein IIB/IIIA receptor antagonists, and thrombolytics. Selective serotonin reuptake inhibitors (SSRI) may have antiplatelet effects and increase the risk of bleeding disorders, gastropathy, and hemorrhagic stroke, however, studies have shown the risk for hemorrhagic stroke is not affected by its use.


Etiology of Hemorrhagic Strokes

Type of Aneurysms

An aneurysm is a localized widening (dilation) of artery or vein due to a weakened vessel wall, which may rupture causing hemorrhage.


Etiology of Ischemic Strokes

•  Atherosclerotic disease • Cardiogenic embolism • Cryptogenic • Prothrombic states

• Sickle Cell Anemia • Polycythemia vera • Protein C or S deficiency (acquired/congenital) • Factor V Leiden mutation • Hyperhomocysteinemia • Antithrombin III deficiency

• Migraine/vasospasm • Drug abuse • Decreased cerebral blood flow due to:

• Penetrating artery disease, arteritis, arterial dissection, venous • occlusion, profound anemia, hyperviscosity

• 

Ischemic strokes may be caused by atherosclerotic disease, penetrating artery disease, or cardiogenic embolism. Some strokes are cryptogenic in nature. All of these conditions may directly or indirectly lead to decreased blood flow in the brain, which may then trigger the acute event.


Stroke Rates in High-Risk Patients

Ischemic Stroke Rates (% per year)

General Popula8on, are 70 yr 0.6

Asymptoma8c Bruit 1.5

Prior myocardial infarc8on 1.5

Asymptoma8c Caro8d Stenosis 2.0

Nonvalvular atrial fibrilla8on 5.0

Transient Ischemic ATack 6.0

Prior Ischemic Stroke 10.0

Sherman DG, et al.

According to the Chest Guidelines, presence of existing ischemic disease or prior history of transient ischemic attack or stroke significantly increases the risk of recurrent stroke.


Pathophysiology of Acute Stroke

• Embolic or thrombotic occlusions constitute approximately 70 – 80% of stroke etiology

• Atherosclerosis --> plaque formation --> arterial narrowing --> arteriocranial stenosis

• ICH • Bleeding occurs from arterioles or small arteries bleed directly to the brain forming localized hematoma blood accumulates and hematoma enlarges increase intracranial pressure blood irritates the brain neurologic deficits

• SAH • Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) increase intracranial pressure death/coma if bleeding continues

• Molecular events: decreased energy production, over-stimulation of excitatory glutamate receptors, excessive intraneuronal accumulation of sodium, chloride, and calcium ions, mitochondrial injury --> eventual cell death


Pathophysiology of Acute Stroke

Atherosclerosis initially presents as fatty streaks, which are lipid deposits in the endothelial cells of a vessel wall. As the process continues, fibrous plaques are formed, which stimulate platelet aggregation. When the endothelium is injured, the resulting exposed vessel collagen acts as a stimulant for platelet activation. Platelet aggregation and activation play a pivotal role in the generation of a thrombus.

A thrombus or clot occurs in those areas where plaque formation causes the greatest narrowing of the blood vessel. Even if the initial plaque formation is minor, the resulting platelet activation may lead to the formation of a clot. When a clot, plaque, or platelet aggregate ruptures and enters the circulation (embolus), it may produce a stroke by blocking an artery in the brain.


Hemorrhagic Stroke

A, B, and C, CT scans showing subarachnoid hemorrhage Subarachnoid blood is recognized by visualizing the high density of blood outing the cerebral sulci and subarachnoid cisterns.

A B C

Hemorrhage is the third most frequent cause of stroke. Bleeding usually occurs in the brain after an artery ruptures, for example, due to significant increases in blood pressure. Blood entering into the brain tissue forms a mass, damages and displaces the brain tissue, which leads to impairment of many brain functions.


Cardioembolic Stroke

The figure depicts the molecular events that are generated in the brain due to cerebral ischemia. When cerebral blood flow is interrupted, it results in a cascade of events leading to decreased energy production, mitochondrial injury, release of free radicals, and excitotoxins. Increased levels of ions, prostaglandins, leukotrienes, eventually lead to the breakdown of DNA/cytoskeleton and result in membrane cell death. Clinical outcome is dependent on the severity and duration of the decrease in cerebral blood flow.


Transient Ischemic Attack (TIA)

• Temporary focal cerebral dysfunction • Rapid onset • Symptoms last 2 – 20 minutes • Duration: minutes to < 24 hours • Rapid recovery • Annual incidence: 200,000 – 500,000 events • Males and blacks have higher rate of TIA

Most recently, the definition of TIA has changed, due to advances in modern brain imaging. The conventional clinical definition for TIA was focal neurological deficit lasting <24 hours, without permanent sequela. However, it was found that many patient with symptoms lasting <24 hour were found to have an infarction. Therefore the proposed new definition for TIA is a brief episode of neurological dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical symptoms lasting less than 1 hour, and without evidence of infection.

Atherosclerotic processes involving platelet aggregation and thrombus generation plays an important role in the process of transient ischemic attack. Microemboli, such as platelet aggregates or cholesterol particles, traveling and lodging in smaller arteries lead to this phenomenon. Although the ischemia is temporary and duration is less than 24 hours, TIAs are extremely important because they act as warning signs of an impending stroke. The cumulative risk of stroke after a TIA is ~ 5% 30 days after the event, 12 – 13% one year after a TIA, and increases to ~30% five years post TIA.

Diagnosis of TIA is problematic as it largely hinges upon the memory of the afflicted patient, who was neurologically impaired at the time of the event. Migraines, seizures, anxiety, syncope, and cardiac dysrhythmias may present with a similar clinical scenario, rendering a diagnosis of TIA difficult. There may be no neurologic deficits between attacks.


Signs and Symptoms of Stroke

• Sudden numbness or weakness of face, arm or leg, especially on one side of the body • Hemiparesis • Sudden confusion, trouble speaking or understanding • Sudden trouble seeing in one or both eyes, • Loss of hearing • Sudden trouble walking, dizziness, loss of balance or coordination • Sudden severe headache with no known cause • Nausea or vomiting • Photophobia • Seizures

The most common signs and symptoms of stroke include sudden numbness or weakness of the face, arm or leg, especially on one side of the body. The patient may exhibit sudden confusion, speech or vision problems, or loss of balance and coordination. Severe headache with no known cause is also common. When accompanied by symptoms such as hemiparesis or aphasia, the differential diagnosis of ischemic stroke is relatively straightforward. However, when symptoms are limited to weakness or numbness in a specific body part, the diagnosis is less clear. Other symptoms that tend to confound the differential diagnosis of ischemic stroke include syncope, vertigo, and transient global amnesia.


Diagnosis of Stroke

• CT scan shows area of decreased attenuation or hypodense lesion in the infarcted area • CT scan maybe normal in the first 48 hours after a thrombotic infarction • CT scan useful in detecting tumors and intracranial hemorrhage • MRI can detect small infarcts on cortical surface usually within 1 hour of stroke occurrence • MRI takes longer to perform than CT scan • MRI take 30 – 90 minutes • CT takes 20 min – 1 hour • Recommendations for brain imaging for a suspected TIA: • CT scan of the head without contrast to exclude other lesions, such as

• tumors, that may present with similar clinical manifestation • MRI not routinely recommended unless CT is a failure • Recommendations for brain imaging during acute stroke: • CT scan of the head without contrast • Repeat CT 2 – 7 days after acute event if initial CT was negative • MRI is not recommended for routine evaluation of acute stroke

The diagnosis of a stroke or TIA is based on the evaluation of the clinical presentation and laboratory findings. Brain imaging is the most important test once acute stroke has occurred. According to the American Stroke Association guideline, diagnostic computed tomography (CT) remains the gold standard brain imaging test. CT without contrast dye should be conducted immediately to detect signs of intracerebral and subarachnoid hemorrhage and differentiate from ischemic stroke. Other diagnostic tests that may be utilized in addition to CT scans include magnetic resonance imaging (MRI), magnetic resonance angiography, transcranial and extra-cranial Doppler ultrasonography, cerebral arteriography, etc. The choice of diagnostic test is made based on the anatomical regions involved and the etiology of the infarction. Although MRI may be more accurate in diagnosing a stroke, it often fails in detecting or excluding intracerebral hemorrhage in an acute setting, which is crucial in determining the course of therapy. MRI may be necessary if there is suspicion that CT studies may have missed certain conditions such as sub-dural hematomas or small-vessel disease infarction (e.g., lacunar infarcts).


General Principles for Treating Stroke

Goals:

1. Rapid Recognition Of Stroke Symptoms 2. Differential Diagnosis Of Stroke Type 3. Prompt Treatment Of Condition 4. Prevent Rebleeding (If Hemorrhagic) 5. Prevent Damage Due To Delayed Ischemia

Successful treatment of stroke depends on rapid recognition of stroke symptoms and prompt treatment. It is also critical to determine whether the stroke is ischemic or hemorrhagic in nature. Misdiagnosing the type of stroke can have devastating consequences, such as prescribing a thrombolytic for hemorrhagic stroke.

Ensuring the patient’s airway, breathing and circulation (ABC’s) is the primary step in providing initial supportive care. The clinical exam includes a thorough patient history, physical exam, and neurological exam. Laboratory tests routinely ordered include chemistry, hematology, and coagulation panels, an ECG, chest radiography and diagnostic computed tomography (CT).


Treatment of Acute Stroke

In-patient hospital admission • Assess criteria and consider for thrombolytic therapy • Evaluate for neurologic complications: new cerebral infarction or cerebral edema

Immediate Treatment of Neurological Complications:

• Fever: Antipyretic agent, Acetaminophen 650 mg (avoid opioids, NSAIDs/COX-2 inhibitors) + cooling blanket • Risk of arrhythmia: Increased cardiac monitoring • Seizures: Anticonvulsant therapy – may initiate prophylactically if seizures on presentation • Life-threatening cerebral edema: Mannitol plus furosemide

• Avoid corticosteroids if suspect cerebral edema or increased intracranial pressure

Early Supportive Care: • Elevate head at 30 degree angle, do not allow oral intake until swallowing evaluation has been conducted, and mobilize early to prevent aspiration • Treat or prevent malnutrition, pneumonia, pulmonary embolism (PE), deep vein thrombosis (DVT), decubitus ulcers, stress ulcer, and contractures • Prophylactic heparin 5,000 units Q8h or low molecular weight heparin (LMWH) to prevent DVT. If patient receives tPA, delay therapy until 24 hours after tPA. Important to rule out hemorrhagic stroke prior to initiation. Otherwise, consider the use of sequential pneumatic compression devices. • Antibiotics for infection


Treatment of Acute Stroke

Acute Therapy with Antithrombotics or Antiplatelets if thrombolytic not given (must rule out hemorrhagic stroke first):

• Aspirin 160 – 325 mg/day • Administer within 48 hours of acute event • Moderate benefit in preventing new ischemic events

• Data is conflicting and controversial regarding full dose intravenous heparin (must rule out bleed) • Low dose subcutaneous heparin for DVT prophylaxis may be administered

• Associated with small risk of bleed

Treatment for acute ischemic stroke includes pharmacologic agents that address both the vascular and neurologic complications of cerebrovascular disease. Patients with an acute vascular stroke event may be observed in an intensive care unit for complications, such as increased intracranial pressure or cerebral edema. Complications may also occur in the form of febrile episodes, arrhythmias, or seizures. Opioids may exacerbate respiratory depression and NSAIDs may increase the risk of bleeding in patients with a hemorrhagic stroke; hence, both classes of agents should be avoided in febrile episodes during acute stroke. Corticosteroids should be avoided when treating cerebral edema and increased intracranial pressure following a stroke.

If seizures are part of the clinical presentation, anticonvulsants can be given to prevent recurrence. Phenytoin, a broad-spectrum anticonvulsant, has been used in this setting. A parenteral loading dose at 18 mg/kg, followed by a maintenance dose to maintain serum concentrations between 10 – 20 mcg/mL should be initiated. Although seizures may manifest in up to 5% of stroke patients, routine prophylaxis is not recommended. If phenytoin is contraindicated, carbamazepine may be used as an alternative, however, a parenteral dosage form is not available. Oral carbamazepine may be initiated with a loading dose of 8 – 10 mg/kg administered as a suspension. Early supportive care is critical to avoid other complications such as aspiration, malnutrition, pneumonia, pulmonary embolism, pressure ulcers and contractures. Prophylactic heparin or low molecular weight heparin is recommended to prevent deep venous thrombosis. Antibiotics should also be given if infection is present. As for antithrombotic or antiplatelet therapy for acute ischemic stroke, there is data that low doses of Aspirin (160 – 325 mg/day) may decrease the incidence of recurrent events.


Treatment of Acute Cardioembolic Stroke

Heparin (target aPTT 1.5 – 2 times control) and warfarin (target INR 2 – 3) within 48 hrs of stroke, provided that:

1. The patient is not hypertensive due to increase risk of intracerebral bleeding 2. The embolus is small to moderate in size 3. CT scans show no bleed

If large cardioembolic stroke or patient is hypertensive, postpone anticoagulant for 5 – 14 days

For patients with atrial fibrillation or thrombus due to cardioembolic stroke, heparin and warfarin therapy are begun forty-eight hours after the stroke, provided that CT scans do not reveal a bleed and the patient is not hypertensive. If the embolism is large or the patient is hypertensive, postpone anticoagulation therapy for five to fourteen days to avoid hemorrhage.


Management of High Blood Pressure During Acute Stroke

• Lowering blood pressure during first few hours can be harmful • Acceptable BP threshold:

• SBP < 220 mm Hg • DBP < 120 mm Hg • Mean Arterial Pressure (MAP) < 130 mm Hg

• Antihypertensive therapy is indicated only in hypertensive emergency: • Aortic dissection • Myocardial Infarction • Heart failure • Acute renal failure • Hypertensive encephalopathy

• Antihypertensive agents used to control blood pressure in patients with an acute stroke treatment include: • Labetalol 10 – 20 mg IVP over 1 – 2 minutes, and may repeat every 10 minutes (maximum of 300 mg) or • Nicardipine IV infusion at an initial dose of 5 mg/hour, titrated to desired efficacy by increasing the rate at 2.5 mg/hour every 15 minutes to a maximum of 15 mg/hour • Nitroprusside sodium 0.25 – 0.5 mcg/kg/minute and increase by 0.5 mcg/kg/minute every 3-5 minutes until blood pressure is controlled; average dose is 3 mcg/kg/minute, range is 0.5-10 mcg/kg/minute

• Lower BP gradually, aim for 10% - 20% BP reduction • Decrease MAP by a max 20 mm Hg • Mean arterial pressure can be calculated by:

• MAP = [Systolic BP + 2 (Diastolic BP)] ÷ 3 • MAP = (Cardiac output x Systemic Vascular Resistance) + Central Venous Pressure

• Normal MAP is 70 – 100 mm Hg


Management of High Blood Pressure During Acute Stroke

During the first hours of a stroke, treatment of hypertension may be detrimental to the patient because an acute decrease in blood pressure may decrease perfusion and lead to further complications. Currently, there is a paucity of compelling data to show that treating hypertension in patients with acute stroke yields any benefit. Even treatment of BP ranges as high as SBP 200 – 220 mm Hg and DBP from 100 – 120 mm Hg have not proven beneficial in acute events. However, antihypertensive therapy is indicated in those patients with stroke who develop aortic dissection, acute myocardial infarction, heart failure, acute renal failure, or hypertensive encephalopathy.

For patients who are candidates for thrombolytic therapy, treatment for hypertension may be initiated when SBP ≥180 mm Hg or DBP ≥105 mm Hg. When lowering blood pressure, the process should be done gradually. Mean arterial pressure should not be reduced by more than 20 mm Hg.


Role of Thrombolytics in Acute Stroke

Candidates: • >18 years of age with clinically apparent neurologic deficiency with stroke • Within 3 hours of symptom onset • Not indicated for stroke upon awakening • Baseline CT shows no evidence of intracranial hemorrhage • No antithrombotics/antiplatelets used in past 24 hours

Dose: • Tissue Plasminogen Activator (tPA): 0.9 mg/kg (maximum of 90 mg) • 10% as initial bolus IV push • 90% administered by IV infusion over 60 minutes mixed in normal saline • Available as Intravenous Powder for Solution: 2 mg, 20 mg, 50 mg, 100 mg

Tissue plasminogen activator (tPA) is effective in treating acute ischemic stroke provided it is administered within three hours of the onset of symptoms. However, studies demonstrate the greatest benefit when tPA is used within 90 minutes from the stroke occurrence, and no harm if used within 6 hours. Patients should also have a clinically meaningful neurologic deficit and a baseline CT showing no evidence of intracranial hemorrhage.

Nine-tenths of a milligram per kilogram is the recommended dose. tPA may not be recommended in those patients who have been taking Aspirin or other antiplatelet agents if the last dose was within 24 hours of the acute event. Patients on current anticoagulation therapy may be at increased risk for hemorrhage and should not receive tPA if they are receiving heparin or warfarin. Administration of these drugs, as well as Aspirin and ticlopidine, should be withheld until at least twenty-four hours following tPA. Due to its excess hemorrhage in clinical trials, streptokinase is contraindicated for stroke patients.


Contraindications for Thrombolytic Therapy

Absolute Contraindication

• INR > 1.7 • Prolonged aPTT • Received heparin in last 48 hours and elevated prothrombin (PT) of >15 seconds • Platelets < 100,000/mm3 • SBP > 185 mm Hg, DBP > 110 mm Hg • Glucose < 50 mg/dL or > 400 mg/dL • Within 3 months of CVA, intracranial surgery, or head injury • Prior intracranial bleed • Recent myocardial infarction • Seizure at onset of stroke • Gastrointestinal or genitourinary bleeding within last 21 days • Major surgery or trauma within last 14 days • Rapidly improving neurological signs • Isolated mild neurologic deficits • CT reveals signs of intracranial hemorrhage • Aggressive treatment required to lower blood pressure • Arterial puncture at a noncompressible site within past 7 days • Lumbar puncture within past 7 days • Pregnant or lactating women • Clinical presentation suggesting post-MI pericarditis • Suspected subacute bacterial endocarditis or vasculitis • Suspected aortic dissection associated with stroke


Contraindications for Thrombolytic Therapy

Relative Contraindication • Large stroke with NIH scale score >22 • CT scan show evidence of large middle cerebral artery (MCA) territory infarction (sulcal effacement or blurrying of gray-white junction in greater than 1/3 of MCA territory)

Thrombolytic therapy is contraindicated in patients who have prolonged prothrombin time, low platelet counts, and uncontrolled elevated blood pressure. tPA should also be avoided in patients with prior head injury, intracranial bleed, or recent myocardial infarction. Thrombolytic therapy is unnecessary in cases where neurologic deficits are isolated or mild, or where symptoms are showing rapid improvement such as a TIA.


Secondary Stroke Prophylaxis

• Aspirin • Clopidogrel/Ticlopidine • Aspirin/Extended Release Dipyridamole (Aggrenox®) • Warfarin

Antiplatelet agents have unique mechanisms through which they inhibit platelet activation and aggregation. Antiplatelet medications are recommended for TIAs or strokes of non-cardiac origin. The usual first choice is Aspirin; however, for secondary prophylaxis Aspirin, clopidogrel, or Aspirin/extended release dipyridamole may be initiated. Aspirin inhibits cyclooxygenase and thromboxane A2 synthesis. Clopidogrel and ticlopidine inhibit adenosine diphosphate (ADP) receptors. Dipyridamole is a potent vasodilator; it increases plasma adenosine and inhibits plasma phosphodiesterase. Long-term warfarin therapy is recommended after an acute MI in patients with an increased embolic risk, such as presence of atrial fibrillation.


Pharmacology of Anti-Platelet Agents

Aspirin – Irreversible inhibitor of cyclooxygenase, preventing conversion of arachidonic acid to thromboxaneA2

Dosing: Doses ranging from 50 mg – 1500 mg have been found to be effective in the prophylaxis against ischemic events. However, higher doses increase the risk of bleeding as well as worsening hypertension. Dosage recommendation for Aspirin in stroke prophylaxis ranges from 50 mg – 325 mg/day. For those who require chronic Aspirin therapy and have risk factors for NSAID gastropathy, a proton-pump inhibitor should be initiated and administered for as long as the patient remains on Aspirin. NSAID gastropathy risk factors include age greater than 65 years, history of peptic ulcer disease, warfarin, steroids, and SSRIs.

Contraindications: Aspirin should not be given to those who had a known allergic reaction to NSAIDs. It is also contraindicated in those who have a recent history of GI bleed or bleeding disorders.

Adverse effects: side effects of Aspirin include dizziness, tinnitus, bronchospasm, gastrointestinal ulceration, anemia, increased transaminases, hypoglycemia, and renal failure.

Drug interactions: Concomitant administration of Aspirin and ibuprofen may decrease the anti-platelet effects of Aspirin. Ibuprofen prevents Aspirin from irreversibly binding platelet cyclooxygenase by competitively blocking the same target site known as serine residue at position 530. It is unknown if other NSAIDs will interact similarly. For occasional use of ibuprofen, the interaction can be circumvented by administering Aspirin 2 hours prior to ibuprofen. Unlike ibuprofen, Diclofenac (Voltaren®) and Celecoxib (Celebrex®) do not interact with Aspirin, and may be a safer alternative than other NSAIDs.



Antiplatelet agents selectively inhibit one or more of the aggregating pathways that promote thrombus formation to decrease the risk of ischemic events. Thromboxane A2 is synthesized and released by platelets in response to a variety of stimuli and in turn induces irreversible platelet aggregation. Aspirin blocks platelet cyclooxygenase by irreversible acetylation of a serine residue at position 530 (s530), thus preventing the formation of thromboxane A2. By inhibiting cyclooxygenase, Aspirin also inhibits the synthesis of vasodilatory prostaglandins. However, its effects are limited against other pro-aggregatory agents such as ADP, thrombin, collagen, etc.



Clopidogrel (Plavix®): Thienopyridine drugs that are inhibitors of the adenosine diphosphate pathway to platelet activation

Dosing: 75 mg once daily with food to minimize gastrointestinal discomfort. If existing liver disease is present, clopidogrel may be used with caution. No adjustment is needed in renal disease.

Availability: 75 mg tablets

Elimination: 50% Kidney, 50% Feces

Contraindications: Clopidogrel is contraindicated in those with active pathological bleeding such as bleeding peptic ulcer or intracranial bleed.

Adverse effects: Abdominal pain, dyspepsia, gastritis, elevated transaminases, rash which can progress to erythema multiforme, bleeding disorders, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP). Patients should be trained to inspect their skin daily for signs of bleeding such as petechiae, purpura, ecchymosis, and monitor for epistaxis, hematuria, hematochezia, hemoptysis, and bleeding gums.

TTP is characterized by a constellation of signs and symptoms that can include thrombocytopenia, purpura, microangiopathic hemolytic anemia, mental status changes, renal failure, hepatic failure, and fever. Often TTP may present very similar to a stroke. The incidence of clopidogrel-associated TTP is approximately (<0.1%). Schistocytes on smear are considered diagnostic for TTP. If TTP is suspected, a peripheral blood smear should be obtained. TTP requires prompt treatment, often with plasmapheresis, and may recur.



Drug interactions: Clopidogrel is a pro-drug that needs to be activated by the CYP3A4 system to its active metabolite. The concomitant use of CYP450-3A4 substrate HMG-CoA reductase inhibitors such as atorvastatin (Lipitor®), Simvastatin, and Lovastatin, with clopidogrel may decrease clopidogrel’s efficacy via competitive inhibition of CYP3A4 enzyme. HMG-CoA reductase inhibitors that are not CYP3A4 substrates such as pravastatin (Pravachol®), fluvastatin (Lescol®), and rosuvastatin (Crestor®) may circumvent an interaction with clopidogrel.

Ticlopidine (Ticlid®): Thienopyridine drugs that are inhibitors of the adenosine diphosphate pathway to platelet activation

Dosing: 250 mg twice daily with food to minimize gastrointestinal discomfort. No dosage adjustments required for patients with renal or hepatic disease.

Availability: 250 mg tablets

Elimination: 60% Kidney, 23% Feces, 17% Other

Contraindications: Ticlopidine is contraindicated in patients with hematopoietic disorders such as neutropenia or thrombocytopenia, severe liver disease, hemostatic disorder or active pathological bleeding.

Adverse effects: Neutropenia, thrombocytopenia, TTP, aplastic anemia, elevated total cholesterol (mean total increase is ~9%), elevated triglycerides, increase in liver transaminases, cholestatic jaundice, nausea, vomiting, diarrhea, abdominal pain, and rash which can progress to erythema multiforme.

Monitoring parameters: Baseline CBC with differential, repeat CBC with differential every 2 weeks for 3 months. If discontinuation of therapy is warranted, CBC with differential should be obtained 2 weeks after discontinuation due to ticlopidine’s long half-life. Baseline LETs and LFTs, repeat monthly. Monitor for signs and symptoms of TTP, neutropenia, bleeding, and hepatotoxicity.



Clopidogrel is a pro-drug thienopyridine derivative; it blocks the ADP receptor to prevent the binding of fibrinogen to that site. Clopidogrel also decreases the number of functional ADP receptors.

Ticlopidine is also a pro-drug thienopyridine derivative that affects the ADP-dependent activation of the glycoprotein IIb/IIIa complex and effectively inhibits platelet aggregation by inhibiting fibrinogen activation. It has been shown to be effective as an adjunct to Aspirin to prevent restenosis after intra-coronary stent placement.



Aspirin/Extended-release dipyridamole (Aggrenox®): Aspirin inhibits cyclooxygenase and extended-release dipyridamole inhibits phosphodiesterase and increases in plasma adenosine due to its potent vasodilatory activity

Dosing: 1 capsule daily for 1 to 2 days, then increase to (25 mg Aspirin/200 mg Extended-release Dipyridamole) twice daily, in order to decrease the incidence of transient headaches associated with vasodilatory property of dipyridamole.

Availability: 25 mg Aspirin/200 mg extended-release dipyridamole capsules. Extended-release dipyridamole is not available in the United States. Dipyridamole requires an acidic media for absorption, the extended release pellets contain tartaric acid to ensure absorption in the often hypochlorhydric elderly. The Aggrenox product cannot be crushed, chewed, or administered via a feeding tube. Dipyridamole alone is available as 25 mg, 50 mg, and 75 mg immediate release tablets, and 5 mg/mL intravenous. Intravenous used for pharmacologic stress test.

Contraindications: This medication should not be used in those who have a known contraindication to Aspirin or NSAIDs.

Adverse effects: Headache, nausea, vomiting, diarrhea, and abdominal pain

Caution: Aspirin in this product (50 mg) may not be sufficient for coronary heart disease prophylaxis – doses of 75 mg or greater are required. This product cannot be interchanged with individual components of Aspirin and immediate-release dipyridamole (Persantine®).

Drug Interactions: Concomitant administration of Aspirin and Ibuprofen may decrease the anti-platelet effects of Aspirin.



Dipyridamole inhibits the uptake of adenosine into platelets, which increases local concentrations of adenosine, and inhibits platelet aggregation. Dipyridamole also inhibits platelet phosphodiesterase, increasing cGMP in various tissues and increasing nitric oxide concentrations.



Warfarin (Coumadin®) – Racemic compound that inhibits the formation of Vitamin K dependent clotting factors II, VII, IX, and X

Dosing: Warfarin dosing is individualized to PT/INR goals and individual response of the patient. The initial dosing regimen in a 70 kg patient is 5 mg/day.

Contraindication: Any condition where the benefits of anticoagulation are outweighed by the risk of hemorrhage.

Adverse effects: Purple toe syndrome, skin necrosis, hemorrhage, hypersensitivity reactions, and rarely hepatotoxicity.

Drug interactions: Warfarin undergoes extensive metabolism via CYP2C9 (major) and CYP3A4 (minor) pathways. Inducers of the CYP3A4 system such as phenytoin (Dilantin®), carbamazepine (Tegretol®), Phenobarbital (Luminal®), rifabutin (Mycobutin®), primidone (Mysoline®), and rifampin (Rifadin®) may increase the metabolism of warfarin and result in subtherapeutic INRs. Inhibitors of CYP2C9 such as isoniazid (Nydrazid®), fluoxetine (Prozac®), and omeprazole (Prilosec®), inhibitors of 3A4 such as clarithromycin (Biaxin®), diltiazem (Dilacor®), fluconazole (Diflucan®), and grapefruit juice may increase INR and risk of bleeding episodes.

Warfarin inhibits the synthesis and activation of vitamin K dependent clotting factors. This inhibition of Vitamin K-dependent clotting factors is achieved due to warfarin interference with the regeneration of Vitamin K epoxide.


Evidence Behind Recommendations for Stroke Prophylaxis

CAPRIE trial:

• Clopidogrel 75mg vs. ASPIRIN 325 mg vs. placebo • Primary endpoint: incidence of first occurrence of ischemic stroke, myocardial infarct, or vascular death • Randomized, double-blind placebo-controlled trial in 19,000 patients with CV disease • Clopidogrel similar to ASPIRIN in treatment of ischemic events • Clopidogrel efficacy > ASPIRIN in patients with peripheral arterial disease (p=0.0028)

CURE trial:

• Clopidogrel loading dose plus ASPIRIN vs. ASPIRIN vs. placebo • Primary endpoint: composite of death from cardiovascular causes, non-fatal MI, or stroke • Randomized, double-blind placebo-controlled trial in 12,562 patients with acute coronary syndrome • Clopidogrel 300 mg once, then 75 mg/day plus ASPIRIN 75 mg - 325 mg/day vs. ASPIRIN 75 - 325 mg/day vs. placebo • Clopidogrel plus Aspirin achieved a 20% relative risk reduction for ischemic events compared to ASPIRIN alone (p<0.001)

ESPS-2 trial:

• Extended-release Dipyridamole (ER-DP) 200 mg bid vs. ER-DP plus Aspirin (ASPIRIN) 25 mg bid vs. ASPIRIN 25 mg bid vs. placebo

• Primary endpoint: stroke, death, stroke and/or death • Double-blind, placebo-controlled, multi-center trial evaluating efficacy of agents after TIA/stroke • 2 year follow-up • Relative risk reduction for stroke greatest with ER-DP plus ASPIRIN is 37% when compared to placebo • ASPIRIN alone 18.1% vs. placebo (p=0.013) • ER-DP alone 16.3% vs. placebo (p=0.039)



MATCH trial:

• Addition of Aspirin 75 mg /day to high risk patients already receiving clopidogrel 75 mg/day • Randomized, double-blind, placebo-controlled trial • Primary endpoint: composite of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia • No statistically significant difference in rate of primary endpoint between groups (p=0.244) • Addition of aspirin resulted in significantly higher bleeding complications

• Life-threatening bleed (p<0.0001) • Major bleeding (p<0.0001) • Minor bleeding (p<0.0001)

Several trials have been conducted to evaluate the efficacy of anti-platelet agents in the prevention of ischemic events. The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared the relative efficacy of clopidogrel 75 mg once daily vs. ASPIRIN 325 mg once daily in >19,000 patients with atherosclerotic vascular disease, recent ischemic stroke, recent MI, or peripheral arterial disease. This study was a prospective, randomized, double blind study that followed patients for up to 3 years. The study showed overall risk reduction of 8.7% due to MI, ischemic stroke or vascular death in the clopidogrel group compared to Aspirin.

However, a subanalysis of the study results revealed that the patients that benefited the most, with decreased composite endpoints from clopidogrel were only those with peripheral arterial disease. All the other subgroups experienced similar risk reduction in stroke or composite endpoints with Aspirin as with clopidogrel. The number of GI bleeding events in the ASPIRIN group was also statistically significant (Aspirin 2.7% vs clopidogrel 2%).



The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial compared the combination of ASPIRIN plus clopidogrel to ASPIRIN alone in 12,562 patients diagnosed with acute coronary syndrome and evaluated both groups based on recurrent MI, stroke or cardiovascular death. Patients in the combination group received a load of clopidogrel 300 mg once and then, received clopidogrel 75 mg plus ASPIRIN 325 mg once daily. The other group received placebo plus ASPIRIN 325 mg once daily. Patients were treated for 3 months and followed for a period of 12 months. The study showed that patients that received clopidogrel plus Aspirin achieved ~20% relative risk reduction in the first primary endpoint of stroke, myocardial infarction and cardiovascular death when compared to ASPIRIN alone.

The European Stroke Prevention Study (ESPS-2) published in 1997 was a multicenter, randomized, double-blind, placebo-controlled trial that compared placebo to Aspirin (25 mg twice daily), ER-DP (200 mg twice daily) [not marketed in the USA], and the combined effect of ASPIRIN/ER-DP (25 mg / 200 mg, respectively, twice daily) in a total 6,602 patients randomized within 3 months of a qualifying event (TIA or stroke). The study group followed patients for a period of 2 years. The overall relative risk reduction for all strokes was greatest in the ER-DP/ASPIRIN group (36.8%), followed by ASPIRIN (18.9%), and ER-DP (16.5%). All results were statistically significant when compared to placebo.



Major side effects reported in all treatment arms were headache, nausea, vomiting, diarrhea, dizziness, and bleeding episodes. Headache and GI disturbances were significantly greater in the ER-DP and ASPIRIN/ER-DP groups. However, bleeding events were significantly higher in ASPIRIN and ASPIRIN/ER-DP group than ER-DP alone and placebo. The study concluded that ASPIRIN/ER-DP reduces stroke risk by 37% and is about twice as effective as either ASPIRIN or ER-DP alone. Both low-dose ASPIRIN (50 mg/day) and ER-DP (400 mg/day) are independently effective and have similar efficacy.

The Management of Atherothrombosis With Clopidogrel in High-Risk Patients With TIA or Stroke (MATCH) trail was conducted to determine whether the addition of Aspirin would further reduce the risk of recurrent ischemic vascular event in high-risk patients receiving clopidogrel after TIA or ischemic stroke. It is a randomized, double-blind, placebo controlled trial comparing clopidogrel 75 mg/day (placebo group) to combination clopidogrel 75 mg/day and Aspirin 75 mg/day (Aspirin group). A total of 7599 patient were randomized: 3802 in placebo group, and 3797 in Aspirin group. The study group followed patients for 18 months. Primary endpoint is composite of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia. After 18 months, intention to treat analysis revealed no statistically significant reduction in absolute risk and relative risk of primary outcome (1% [95% CI -0.6 to 2.7] and 6.4% [95% CI -4.6 to 16.3], respectively) (p=0.244). Addition of Aspirin to clopidogrel however, resulted in significantly more bleeding complications (p<0.0001). In conclusion, there was no significant benefit with combination therapy compared with clopidogrel alone in reducing primary outcome.


Prevention of Stroke

Risk Factor Control: • Hypertension, diabetes, hyperlipidemia, cigarette smoking, alcohol consumption, obesity, and physical inactivity

Prevention of Stoke Caused by Cardiogenic Embolism:

• Persistent or paroxysmal atrial fibrillation (AF) • Warfarin (target INR 2-3) or • Aspirin 325 mg/day if patient cannot take anticoagulant

• Acute MI with left ventricular mural thrombus • Warfarin (target INR 2-3) at least 3 months up to 1 year • Aspirin should be used concurrently for ischemic coronary artery disease during oral anticoagulant up to dose of 162 mg/day

• Dilated cardiomyopathy • Warfarin (target INR 2-3) or • Antiplatelet therapy of either ASPIRIN (50 – 325 mg/day), ASPIRIN/ER-dipyridamole (25 mg/200 mg twice a day)

• Rheumatic mitral valve disease • With or without presence of atrial fibrillation treated with long-term warfarin (target INR 2-3) • With or without presence of atrial fibrillation and with recurrent embolism while receiving warfarin, recommended to add Aspirin 81 mg/day



• Mitral valve prolapse • Long term antiplatelet therapy

• Mitral annular calcification (MAC) • Not documented to be calcific, antiplatelet therapy may be considered • With mitral regurgitation cause by MAC, without atrial fibrillation, antiplatelet or warfarin therapy may be considered

• Aortic valve disease • No atrial fibrillation, treat with antiplatelet

• Prosthetic heart valves • Modern mechanical prosthetic valve, treat with warfarin (INR 2.5-3.5) • Ischemic stroke or systemic embolism despite adequate anticoagulants, recommended to add Aspirin 75 mg – 100 mg/day and continue maintaining adequate anticoagulation (INR 2.5-3.5) • Bioprosthetic heart valves without other sources of thromboembolism, treat with Aspirin with warfarin (INR 2-3)



Asymptomatic Carotid Stenosis: • Aspirin (ASPIRIN)

Symptomatic Carotid Stenosis (prior TIA or minor stroke): • With >70% blockage, consider carotid endarterectomy • With 50 – 69% blockage, consider carotid endarterectomy if surgeon has a good rate of successful procedures • Always initiate and stabilize antiplatelet therapy before performing a carotid endarterectomy procedure

Prevention of Non-cardioembolic TIA or Stroke: • ASPIRIN 50 - 325 mg/day or • Clopidogrel 75 mg QD, or • ASPIRIN 25 mg plus extended release dipyridamole 200 mg BID • Ticlopidine 250 mg bid is a second-line agent due to its side effect profile



In addition to modifying risk factors arising to lifestyle habits and disease, patients with predisposing conditions can help prevent stroke through the use of certain pharmacologic agents and surgical techniques. Patients with asymptomatic carotid stenosis, for example, may reduce their risk slightly by taking antiplatelet agents such as Aspirin. For patients with symptomatic carotid stenosis and seventy to ninety percent blockage, carotid endarterectomy can reduce the risk of stroke by sixty percent. Patients with nonvalvular atrial fibrillation may benefit from warfarin therapy or Aspirin as seen in the chart.


Summary of Recommendations for Antiplatelet Use

For primary stroke prophylaxis, Aspirin 50 – 325 mg is recommended • All patients with noncardioembolic stroke or TIA should receive antiplatelet agent • Initial choice for Secondary Prophylaxis

• ASPIRIN 50 – 325 mg/day or • Clopidogrel 75 mg QD, or • ASPIRIN 25 mg plus extended release dipyridamole 200 mg BID

• Clopidogrel has greater safety profile than ticlopidine • Clopidogrel not more effective than ASPIRIN • ER-DP + ASPIRIN > efficacy vs. ASPIRIN alone • Ticlopidine 250 mg bid is a second-line agent due to its side effect profile

Patients who have a history of TIA or non-cardioembolic stroke should receive antiplatelet therapy. Initial standard of therapy is Aspirin 50 – 325 mg daily, or clopidogrel 75 mg daily, or Aspirin/extended release dipyridamole twice daily. Ticlopidine has also been studied in secondary prophylaxis. Although studies show it is more efficacious than Aspirin, its side effect profile makes it a second line agent. Clopidogrel is not superior to Aspirin in the prophylaxis against stroke. The addition of Aspirin to clopidogrel therapy in high risk patients does not confer additional benefit. Extended-release dipyridamole/Aspirin (Aggrenox®) has been proven to have greater efficacy than Aspirin alone. This agent may be preferred in patients who have increased risk factors for multiple ischemic events or in whom Aspirin resistance may be suspected.


Treatment of Subarachnoid Hemorrhage (SAH)

• Administer nimodipine 60 mg (two 30 mg capsules) po q4h x 21 days, within 96 hours of onset • Improves neurologic outcome by reducing the incidence and severity of ischemic deficits • Four randomized, double blind, placebo-controlled trials demonstrated improvement of neurologic outcome at 3 months • Reduce dose with hepatic impairment to 30 mg q4h • May cause hypotension and reflex tachycardia • Monitor heart rate and blood pressure throughout therapy • No intravenous dosage form is available, if the contents of the capsule are administered intravenously, cardiac collapse may occur • The capsule may be opened with an 18-gauge needle and administered via a feeding tube

Control of Risk Factors: • Hypertension, smoking • Neurosurgery to remove unruptured aneurysms, 5 – 7 mm • Clinical evidence for risk reduction insufficient

Sixty milligrams of oral nimodipine every four hours for twenty-one days has been found to be effective in reducing the incidence and severity of ischemic deficits caused by cerebral vasospasm that follow a subarachnoid hemorrhage, provided it is administered within four days of onset. The improvement of neurologic outcome was noted in clinical trials at 3 months. Patients with hepatic impairment have significantly reduced clearance, thus warranting a dosage reduction to 30 mg every four hours.


Treatment of Subarachnoid Hemorrhage (SAH)

Nimodipine is a central calcium channel blocker, however, it may have peripheral effects and cause hypotension and reflex tachycardia. Cardiac monitoring for blood pressure and heart rate throughout therapy with nimodipine is essential. There is no intravenous dosage form of nimodipine available. If the contents of the capsules are opened and administered intravenously, severe decreases in blood pressure may occur ensuing in cardiac arrest.

For patients who cannot swallow the capsule (unconscious), a hole in both ends of the nimodipine capsule with an 18-gauge needle may be made, extracting the contents into the syringe, and administering the liquid nimodipine via a feeding tube. Washings with 30 mL of normal saline are recommended. While the control of risk factors such as hypertension and smoking, as well as the clipping of unruptured aneurysms, may reduce the likelihood of subarachnoid hemorrhage, there is insufficient clinical evidence to support such claims.


Treatment of Post-Stroke Depression

• Common, serious condition after stroke • Impedes rate and extent of stroke rehabilitation • Increased risk of recurrent ischemic events if not treated • Concurrent psychotherapy, counseling, and pharmacotherapy of depression vital for effective rehabilitation

Depression is a common aftermath of stroke, especially in elderly patients who have little to look forward to beyond a life compromised by physical and cognitive debility. Untreated depression impairs the rehabilitation process after stroke and places the patient at increased risk for further ischemic events. Whether depression is a psychic reaction to a devastating illness or a consequence of the cerebral lesion itself is controversial. In either case, a combination of concerned caregivers, psychiatric consultation, and pharmacotherapy may be necessary to manage this consequence of stroke.


Resources


Adams H, Adams R, Del Zoppo G, et al. “Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the stroke council of the American Heart Association/American Stroke Association.” 2005;36:916-923.

Adams HP, Jr., Adams RJ, Brott T, et al. “Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association.” Stroke. 2003; 34(4): 1056–83.

Adams RJ, Chimowitz MI, Alpert JS, et al. “Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association. Circulation. 2003; 108(10): 1278-90.

Albers GW, Amarenco P, Easton JD, et al. “Antithrombotic and thrombolytic therapy for ischemic stroke: the seventh ACCP conference on antithrombotic and thrombolytic therapy.” Chest. 2004;126:483-512.

Albers GW, Amarenco P, Easton JD, Sacco L, & Teal P.“Antithrombotic and thrombolytic therapy for ischemic stroke.”Chest.2001;119(1):300S-320S.

American Heart Association. Heart Disease and Stroke Statistics – 206 Update. Dallas, Texas: American Heart Association;2006.

Bak S, Tsiropoulos I, Kjaersgaard JO. “Selective Serotonin Reuptake Inhibitors and Risk of Stroke: A population-based case-control study.” Stroke. 2002;33:1465-1473.


Resources

Barnett HJM, Eliasziw M, Meldrum HE.” Drugs and surgery in the prevention of ischemic stroke.” N Engl J Med.1995;332:238-247.

Bath P, Chalmers J, Powers W, et al.” International Society of Hypertension (ISH): statement of management of hypertension in acute stroke.” J Hypertens. 2003; 21($): 665-72.

Bradbury JC and Fagan SC.(2002).“Stroke.” IN: Pharmacotherapy: A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill. Ch 20.

Brott T and Bogousslavsky J.” Treatment of Acute Ischemic Stroke.” N Engl J Med.2000;343:710-722.

Cairns JA, Therous P, Lewis HD, Ezekowitz M, MeadeTW, Sutton GC.“Antithrombotic agents in coronary artery disease.”Chest.1998;114(Suppl 5):611S-633S.

Coull BM, Williams LS, Goldstein LB, et al. “Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association). Neurology. 2002; 59(1): 13-22.

Delafuente JC and Stewart RB.Therapeutics in the elderly, 2nd ed.Cincinnati: Harvey Whitney Books. Chapter 15.

Diener HC, Bogousslavsky J, Brass LM, et al. “Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomized, double-blind, placebo-controlled trial.” Lancet. 2004;364:331-37.

Gill S, Rochon PA, Herrmann N, et al. “Atypical antipsychotic drugs and risk of ischaemic stoke: population based retrospective cohort study.” BMJ. 2005;330:445-450.


Resources

Hack W, Kaste M, Bogousslavsky J, et al. “European Stroke Initiative Recommendations for Stroke Management – update 2003. Cerebrovasc Dis. 2003; 16(4): 311-37.

Hankey GJ. “Secondary Prevention of Recurrent Stroke.” Stroke. 2005;36:218-221.

Hart RG & Harrison MJ.“Aspirin wars: the optimal dose of Aspirin to prevent stroke.”Stroke.1996;27(4):585-587.

Johnston SC.“Transient Ischemic Attack.”N Engl J Med.2002;347:1687-1692.

MacMahon S & Rodgers A.“Primary and secondary prevention of stroke.”Clin Experi Hyperten.1996;18(3-4):537-46.

McPherson ML (2001). Neurology review: Parkinson's disease and stroke.Preparatory Program for the Certification Exam in Geriatric Pharmacy. Alexandria, VA:American Society of Consultant Pharmacists.

Morley J, Marinchak R, Rials SJ & Kowey P.“Atrial fibrillation, anticoagulation, and stroke.”Am J Cardiol.1996;77(3):38A-44A.

Mukherjee D, Nissen S, Topol E. “Risk of cardiovascular events associated with selective COX-2 inhibitors.” JAMA. 2001;286:954-959.

Pearson TA, Blair SN, Daniels SR, et al. “AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation. 2002; 106(3): 388-91.


Resources

Sacco RL, Adams R, Albers G, et al. “Guidelines for Prevention of Stoke in Patients with Ischemic Stroke of Transient Ischemic Attack: A statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.” Stoke. 2006;37:577-617.

Websites:

Brain Disorders Network – Stroke:


Pain Management and End of Life Care



• Value the incidence and prevalence of pain complaints in the elderly population.

• Realize why pain management is a complex problem for geriatric clinicians.

• Summarize the differences between the most common types of pain experienced by the elderly.

• Explain the different intervention modalities for the management of pain in the elderly patient.

• Describe adverse effects to watch for in patients undergoing drug therapy for pain.

• Identify the clinical dilemmas in end-of-life care and the role of the pharmacist in managing the symptoms.


What is Pain?

McCaffery, 1968: “…whatever the experiencing person says it is, existing whenever s/he says it does…”

International Association for the Study of Pain (IASP), 1979: “…unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

American Geriatrics Society, 1998 and 2002: “ any persistent pain that has an impact on physical function, psychosocial function, or other

aspects of quality of life should be recognized as a significant problem.”

McCaffery’s definition emphasizes that pain is a subjective experience with no objective measures. What’s more, it stresses that the patient, not the clinician, is the authority on the pain and that his or her self-report is the most reliable indicator of pain. The similarities with the widely-used International Association for the Study of Pain (IASP) are seen in that the IASP definition emphasizes that pain is a complex experience that includes multiple dimensions (www.ampainsoc.org).


Incidence of Pain

• 9 in 10 Americans regularly suffer from pain • Most common reason individuals seek health care • 25 million Americans experience acute pain annually • 50 million Americans suffer from chronic/persistent pain annually • Only 1 in 4 individuals with pain receive appropriate therapy • More frequent in oldest-old and women • Most frequently reported by community-dwelling elderly • Frequently reported in nursing home patients

As the population ages, the number of people who will need treatment for pain from back disorders, degenerative joint diseases, rheumatologic conditions, visceral diseases, and cancer is expected to rise. Data from a 1999 Gallop survey suggested that only 1 in 4 individuals with pain receive appropriate therapy. Undertreated pain has significant physical, psychological, and financial consequences. Undertreated pain leaves patients unable to accomplish activities of daily living, which adds significant suffering for patients and families. Many patients may experience anxiety, fear, anger, or depression.


Trends and Consequences of Pain in the Elderly

Trends in Pain Therapy:

• 25-50% of community dwelling elderly suffer important pain problems • 45-80% of nursing home residents have substantial pain that is undertreated

• Of residents with daily pain, 26% do not receive analgesic therapy • Elderly at greatest risk for lack of pain therapy include:

• Very old (> 85 years) • Minorities • Elderly with low cognitive performance • Elderly taking several concurrent medications

Barriers to Recognizing Pain in the Elderly:

• Patients and caregivers falsely believe that pain is a part of aging. • Pain is not adequately assessed and treated. • Patients have fear of bothering or annoying medical staff or family members. • Patient’s perception that having pain means that they are really sick or imminently dying. • Concerns regarding side effects of medicines • Communication problems (aphasia & hearing) • Cognitive impairment • Addiction fears


Trends and Consequences of Pain in the Elderly

Consequences of Persistent Pain:

• Depression • Anxiety • Decreased mobility • Difficulty performing activities of daily living • Decreased socialization • Sleep disturbance • Impaired ambulation • Increased healthcare utilization and costs

Management of pain in the elderly is a complex and challenging problem for the clinicians. Studies show that pain is a common experience in at least twenty-five to fifty percent of all adults over age sixty. In the nursing home, approximately seventy-five percent of patients have at least one pain complaint, and a third of these patients describe their pain as continuous. Between twenty-four and thirty-eight percent of cancer patients in nursing homes report daily pain.

Of these, more than a quarter do not receive any analgesic agent. Many barriers exist that hamper optimal pain treatment in the older individual. Personal beliefs, cultural beliefs, and concerns over adverse effects and addiction are just a few reasons why pain is underrecognized and undertreated in this population. Elderly at the greatest risk for lack of pain treatment included the very old, those of minority race or low cognitive performance, and patients receiving several concurrent medications. The consequences of persistent pain among older adults are numerous and include depression, decreased socialization, sleep disturbance, impaired ambulation, and increased healthcare utilization and costs.


Consequences of Undertreatment

Physiological:

Berry et al.


Consequences of Undertreatment

Financial:

• Costs Americans $100 billion annually • Patients with chronic/persistent pain are 5 times more likely to use healthcare services than those without • Unrelieved pain can lengthen hospital stays, increase rehospitalization rates, and increase outpatient visit • Loss of productivity and income for society and patients alike

The “stress” responses triggered by a person’s body to PROTECT the body sometimes have negative effects, especially if allowed to persist. The table on your screen summarizes some of the adverse physiological consequences of under treating pain. Very young, very old, and very frail patients are at greatest risk for such complications. Clinical manifestations that could evolve from such “stress responses” include: weight loss, unstable angina, myocardial infarction, anxiety, depression, constipation, and hypertension.

According to Becker and colleagues, patients who suffer from undertreated pain are more likely to seek healthcare services than those without. Fox and colleagues found that undertreated pain levies a huge financial burden on society through work absenteeism, causes of underemployment, and a major reason for unemployment.


Common Causes of Pain in LTC Facilities

Sources of pain in the nursing home:

• Low back pain: 40% • Arthritis: 37% • Previous fractures: 14% • Neuropathies 11% • Leg cramps 9% • Claudication 8% • Headache 6% • Generalized pain 3% • Neoplasm 3%

Source: Stein et al, 1996

Osteoarthritis, rheumatism, and angina are just some of the physical conditions that cause pain more frequently among older adults. Other sources include back pain, cancer, postherpetic neuralgia, temporal arteritis, polymyalgia rheumatica, and atherosclerotic peripheral vascular disease. Additionally, comorbid conditions such as gait disturbances, slow rehabilitation, and drug-induced adverse effects may worsen the experience of pain.

Although treatment of the cause of pain is always the first priority, some underlying disorders are not amenable to therapy because the cause of pain cannot always be completely eliminated. An additional complication is that drug therapy, the mainstay of pain management, has both desirable and undesirable effects.


Terminology

Tolerance

“A state of adaptation in which exposure to drug induces changes that result in a diminution of one or more of the drug’s effects over time”

Physical Dependence

“…a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist”

Addiction

“A primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations”

• Characterized by one or more of the following: • Impaired control over drug use • Compulsive use • Continued use despite harm • Craving


Terminology

Pseudoaddiction

• Used to describe patients whose pain is undertreated / unrelieved • Characterized by one or more of the following:

• “Clock watching” • Inappropriate “drug seekers” • Illicit drug use or deception

Savage and colleagues use the definitions shown on your screen to describe tolerance and physical dependence. Tolerance is something that can be expected with long-term usage of pain treatments. Tolerance may occur to both desired and undesired effects of medication. In the case of opioids, tolerance develops more slowly to analgesia than to respiratory depression, and tolerance to constipating effects may not occur at all.

A patient who is physically dependent on an opioid may sometimes continue to use these agents despite resolution of pain only to avoid withdrawal. Use of opioids in this manner does not necessarily reflect addiction to the agent.

Opioid-naïve patients that receive an opioid for the treatment of pain have less than 1% chance of addiction when used and monitored appropriately. Pseudoaddiction can be distinguished from true addiction in that the behaviors resolve when pain is effectively treated. Once this pattern initiates, it is often difficult to break, encouraging vigilance in adequate assessment and proper pain management up front.

Pseudoaddicted patients will clock watch between doses as they wait until the next dose can be taken. Some of these patients may begin to seek alternatives for alleviating their pain. Alternatives may include illicit drugs, or may simply be through deception and ‘doctor shopping’ for other providers of pain medications for relief.


The ABC’s of Pain Assessment

• Ask and Assess • Believe • Choose appropriately • Deliver interventions in a timely manner • Empower and Enable patients and families • Follow up

Jacox et al.

For comprehensive pain assessment in any patient, ASK about pain regularly and be sure to do a “head-to-toe” interview. ASSESS any indication from the patient systematically by probing for information about the pain such as: quality, description, location, intensity or severity, aggravating and ameliorating factors, and cognitive responses. Be sure to then ASK the patient about their goals and desires for pain control. BELIEVE the patient and family reports of pain and what relieves it.

Once appropriate diagnostic tests have been completed, they must be reviewed to determine the extent of any underlying disease. Analgesic treatment of pain may be needed initially to facilitate the patient’s participation in further diagnostic studies. Then, CHOOSE appropriate pain control measures for each individual patient, family, and setting. Make sure to CONSIDER drug type, dosage, route, contraindications, and side effects. Also CONSIDER non-drug interventions. DELIVER the interventions in a timely, logical, coordinated manner to the patient, family, and other healthcare providers involved. EMPOWER patients and their families—perhaps the patient or caregiver is cognitively capable of adjusting the dose or timing interval according to the symptoms experienced at the present time. ENABLE patients to control their course to the greatest extent possible. Finally, FOLLOW-UP with the patient and caregiver to reassess the persistence of pain, changes in the pain pattern, or development of new pain.


Obtaining a History of the Pain Complaint

• Precipitating events: "What brings the pain on?" • Palliative events: "What makes the pain better?" • Quality: "Can you describe the pain in your own words?” • (e.g., burning, stabbing, shooting, aching, gnawing, etc.) • Region / radiation: "Where is the pain and does it move anywhere?" • Severity: "Can you tell me how bad the pain is on a ten point scale?” • (e.g., 0 = no pain and 10 = worst possible pain) • Temporal: "How long have you been having this pain? How many times per day? How long does it last?" • Associated symptoms: "Does the pain cause any other problems?” • (e.g., insomnia, loss of appetite, mood alterations, etc.) • Previous treatment or therapy: "What have you used to try to treat the pain?"

When obtaining a history of the pain complaint, it may be helpful to use terms synonymous with pain in the patient interview. Terms such as “burning”, “discomfort”, “aching”, “soreness”, “heaviness”, or “tightness” define the nature of the pain more clearly. When interviewing patients who cannot verbalize pain complaints, observe for changes in function or gait, withdrawn or agitated behavior, moaning, groaning, grimacing, guarding or crying.


Pain Assessment Tools

One of many tools used by clinicians for pain assessment is the simple faces across the top portion of your screen. Such an assessment tool is good for those of all ages, from age 3 and up. The facial expressions are easily related to, even for patients with difficulty verbalizing. However, clinicians must be cautious of the limitations of using just this type of assessment tool. First and foremost, the faces are one-dimensional. They do not provide whether the pain is burning or stabbing, or if it is localized or diffuse, among other items of concern necessary for a complete assessment.

Perhaps a better approach to pain assessment is one that is multi-faceted. By combining the facial assessment with the example questionnaire on the lower portion of the screen, clinicians are better able to assess specific areas directly. Patients may also keep a pain diary, or fill out a self-assessment known as a “Brief Pain Inventory.” The clinician may also want to include a full physical and neurological assessment, and even get a toxicology screen. Such measures will allow for a complete assessment.


Assessment of Pain in the Cognitively Impaired Patient

Non-Verbal Pain Cues:

• Frowning, grimacing, fearful look • Grinding of teeth • Bracing, guarding, rubbing • Fidgeting, agitation, increasing restlessness • Poor eating or sleeping habits • Sighing, groaning, crying, heavy breathing • Decreasing activity levels • Resisting care • Change in gait • Change in behavior AGS Panel

For the older adult with moderate to severe dementia, or one who is nonverbal, the practitioner should attempt to assess pain via direct observation or history from caregivers. Patients should be observed for evidence of pain-related behaviors during movements like walking, morning care, and transfers.

Unusual behavior in a patient with severe dementia should trigger assessment for pain as a potential cause. Of note, some patients demonstrate little or no specific behavior associated with severe pain.

Common pain behaviors in cognitively impaired elderly persons can be helpful in distinguishing the extent of the patient’s pain. For instance, facial expressions may include grimacing or rapid blinking; there may be grunting or calling out as verbalizations of the pain. Furthermore, there may be constant fidgeting or other changes in body movements such as tense posture or increased pacing. Changes in interpersonal interactions should always clue the clinician in to something abnormal. Such changes might include aggressive or combative behavior, or even resisting care or becoming socially withdrawn. Routines have been known to vary, with changes in sleep patterns being most common and changes in eating habits also being frequent.


Pain Assessment: Acute Pain vs. Persistent Pain

Acute • Related to identified event or condition • Resolution within days or weeks • Examples: surgery, sprain, laceration

Persistent • Continues for a prolonged period of time (i.e. 3 to 6 months beyond onset) • May or may not be related to a condition • May be present for an indeterminate period • The term “chronic pain” is no longer recommended due to negative connotation (e.g. chronic whiner, chronic complainer)

Generally speaking, pain that lasts for more than three months is considered persistent. Persistent pain may be associated with cancer as well as non-cancer diagnoses. Differentiating patients with acute or persistent pain is useful to clinicians, since the response to treatment is often different between these groups. Patients with persistent pain may have already failed to respond to acute pain therapy, and over time may experience significant changes in personality, lifestyle and functional ability. Treatment for these patients is often multifaceted, designed to manage not only the discomfort of the pain itself, but any physical and psychosocial complications as well.


Types of Pain: Nociceptive vs. Neuropathic

Nociceptive • Ongoing activation of nociceptors in response to a noxious stimulus • Somatic or visceral

Neuropathic • Reflects nervous system injury or impairment • Protopathic (pertaining to a general, nondiscriminating responsiveness to pain or temperature stimuli) or epicritic (pertaining to a discriminating responsiveness to small variations in pain or temperature stimuli)

Elderly patients typically experience one of several types of pain. Somatic pain and visceral pain are examples of nociceptive pain. Other types of pain include neuropathic pain, mixed or undetermined pain, and psychologically based pain syndromes (such as somatization disorders and hysterical reactions). Although the pathophysiology of each type of pain is poorly understood, proper differentiation is important for diagnosis and therapy.

Because many patients will have more than one type of pain present at any given time, it is vital that the clinician identify and assess each and every pain complaint. Not all pains respond equally to similar analgesic drugs. For example, somatic and visceral pain responds well to traditional analgesics, while neuropathic pain may not.


Types of Pain: Somatic

• Mechanism: • Activation of nociceptors in cutaneous and deep tissue

• Sensation: • Sharp, localized “gnawing” or aching

• Common causes: • Joint pain, arthritis, myofascial and musculoskeletal pain, bone metastases

Somatic pain occurs when the peripheral nociceptors in cutaneous and deep tissues are activated. This type of pain is localized and frequently described as a “gnawing” or aching sensation. Joint pain, myofascial and musculoskeletal pain, and bone metastases produce this kind of pain.


Types of Pain: Visceral

Mechanism: Activation of nociceptors due to infiltration, compression, distension, or stretching of viscera

Sensation: Throbbing, deep, squeezing and pressure-like, diffuse / poorly localized

Common Causes: Primary & metastatic tumors, gallstones, kidney stones, GI ulceration

Visceral pain results from infiltration, compression, distention, or stretching of thoracic or abdominal viscera, with resulting activation of nociceptors. Visceral pain is described as deep, squeezing and pressure-like. It tends to be poorly localized and associated with nausea, vomiting, and diaphoresis. Disorders that produce this kind of pain include primary and metastatic tumors, gallstones or kidney stones, and gastrointestinal ulceration.


Treatment Options

Pharmacotherapy: • Non-opioid analgesics • Opioid analgesics • Adjuvant medications

Anesthetic Therapy: • Trigger joint injections • Joint capsule injections • Nerve / autonomic blocks

Neurosurgical Therapy: • Neuroablative • Neurostimulatory • Neuropharmacologic

Physical Therapy: • Bracing or splinting • Transcutaneous electrical nerve stimulation (TENS) • Range of motion (ROM) exercises to minimize

pain and facilitate activity

Behavioral Therapy: • Relaxation • Biofeedback • Hypnosis to manage the psychological consequences of pain

Alternative methods of pain control should be considered during the initial evaluation of the elderly patient. Drug therapy consists of opioid, non-opioid and adjuvant medications.

Local anesthetics may be used to treat myofascial and inflammatory joint pain, postoperative pain, and other pain syndromes.

Neurosurgical approaches include neuroablative, neurostimulatory, and neuropharmacologic treatment. Physical therapy and behavioral modalities should also be considered.


Guidelines for the Pharmacologic Management of Pain

World Health Organization Pain Treatment Ladder

Source: World Health Organization

• Manage tolerance by switching to an alternative analgesic, or starting with half dose and titrating to pain relief

• Prevent acute withdrawal by tapering drugs slowly

• Do not use placebos to assess the nature of the pain


Guidelines for the Pharmacologic Management of Pain

It is rare that any two patients respond with exactly the same degree of relief or side effects to the same pain relieving medications. Thus, individually tailored pain regimens are the hallmark of effective pharmacotherapy for pain.

Analgesic therapy is the mainstay of pain management; however, the use of analgesic medications must take into account age-related changes in drug absorption, distribution, metabolism, and excretion. The presence of concurrent medications and underlying diseases must also be considered.

In determining the appropriate analgesic agent for a patient presenting with pain, factors that should be taken into consideration include the patient’s pain intensity, the patient’s prior exposure to any analgesic agent, the patient’s concomitant disease state or organ function that may affect the effectiveness of the analgesic agent, and the pharmacokinetic properties and available formulations of the analgesic agent.

If a patient presents with mild pain, nonopioid analgesics include acetaminophen, non-acetylated salicylates, and NSAIDs. In choosing these agents, the clinician should be aware of their limitations as discussed previously under the section of treating pain with non-opioid analgesics.

When a patient presents with mild to moderate pain the combination products that include acetaminophen or aspirin along with hydrocodone, codeine, or oxycodone are usually the agents of choice. Again, the clinician should be aware that these products have a ceiling dose due to the non-opioid component of the combination and the side effects for the NSAIDs have to be monitored.

In a patient who presents with severe pain, it is appropriate to start the patient off with an opioid analgesic agent to control the pain.


Principles of Opioid Therapy

Dose-Response Relationship

• There is no ceiling dose for pure opioid agonists • As the dose is increased, the analgesic effect is increased in a log-linear function • The dose of the opioid analgesics may be increased until the patient achieves pain relief or the patient develops dose-

limiting side effects

Equianalgesic Dose Ratio

• The “Equianalgesic Dose Ratio” is the ratio of the dose of two analgesic agents required to produce the same analgesic effect

• Principles for using the “Equinalgesic Dose Ratio” table • The ratio does not reflect variability observed between single dose and multidose cross- • over study • Does not take into account the phenomenon of incomplete cross-tolerance in switching • from one agent to another • For most opioid agonists, the equianalgesic relationship with morphine is linear • For methadone, the relationship is curvilinear and the equianalgesic dose ratio

increases as the dose of morphine increases.

For example: • At oral morphine doses between 30-300 mg the equianagesic ratio to oral methadone is 4:1 to 6:1 • At oral morphine doses > than 300 mg the equianalgesic ratio to oral methadone is 10:1 to 12:1



Drug A Equivalent Dose (mg)

Parenteral Oral

Morphine 10 30

Oxycodone NA 30

Hydromorphone 1 – 1.5 6

Fentanyl inj. 0.1 NA

Methadone B 2.5 5

Meperidine*** 75 – 100 300

Codeine 120 – 130 200

Hydrocodone NA 30

A Equianalgesic dose to 10 mg IM morphine .B The Food and Drug Administration (FDA) has issued a Public Health Advisory alerting healthcare providers to reports of death and life-threatening adverse events (eg, respiratory depression, cardiac arrhythmias) in patients receiving methadone for pain control. These events may be the result of unintentional overdoses, drug interactions, and cardiac toxicities associated with methadone (QT prolongations, torsade de pointes). Particular vigilance is necessary during treatment initiation (including conversion from another opioid), and dose titration. Methadone’s duration of analgesic action (single-dose studies) is approximately the same as morphine’s, but it’s elimination half-life is significantly longer. The respiratory depressant effects of methadone occur later and persist longer than its peak analgesic effects. *** should be avoided in the older adult (see discussion below)



In considering an opioid analgesic for the management of a patient’s pain, it is important to realize that there is no ceiling dose and that the effective dose is individualized for each patient. The most appropriate dose is the one that achieves the goal of relieving pain without causing intolerable, dose-limiting side effects.

There is not complete tolerance across individual opioids. For example, if a patient has good pain relief with 60 mg of oral morphine but is not able to tolerate the CNS side effects, the patient may be switched to oxycodone 30 mg, which is half the dose. Because of the non-cross tolerance property of the opioids, the patient should experience analgesia with fewer side effects.

When using opioid analgesics for pain control, it is crucial for the clinician to be knowledgeable of the relative potency between parenteral and oral routes and between different agents to ensure proper dosing. The table on the screen provides an equianalgesic conversion ratio guideline of the most commonly used opioid agents. The clinician should recognize that it is not a precise conversion factor and prudence should be used in switching opioids to prevent intolerable side effects.


Principles of Choosing an Appropriate Opioid Agent

• Choose an agent that the patient has had prior experience with and tolerated well • Consider a parenteral route initially if the patient is in severe pain and requires rapid analgesic effect. • Otherwise, the oral route is preferred • Start with a low dose and gradually increase the dose • Consider alternate routes such as parenteral, rectal, or transdermal if the patient has difficulty swallowing or GI dysfunction • The potency of the rectal route is approximately the same as the oral route for opioids • Switching to an alternative opioid should be considered if the patient experiences dose-limiting side effects that precludes dose increment to relieve pain • Doses for breakthrough pain (i.e., rescue doses) are commonly 5% to 15% of the 24-hour opioid dose, and may be administered on an as-needed basis.

• Opioids to avoid in the elderly include: • Meperidine- metabolite accumulation/questionable efficacy • Propoxyphene- metabolite accumulation/questionable efficacy • Methadone- difficulty to titrate, variability in half-life • Pentazocine- increased CNS adverse effects in the elderly



Dose Selection and Titration

• For a patient who is relatively opioid-naïve or non-tolerant dosing should begin at a dose equivalent to 2.5-5 mg parenteral morphine every 4 hours for severe pain • If pain relief is not adequate at the initial dose, repeated doses can be increased in strength by small increments (1-4mg) • Severe pain patient

• Titrate the parenteral opioid every 15 to 30 minutes until the pain is partially relieved • Patient on chronic immediate-release oral opioids

• Titrate the dose twice a day as needed • Patient on chronic, sustained-release oral or transdermal opioids

• Titrate the dose every 24 to 48 hours as needed

Adverse Effects: • Cognitive impairment* • Respiratory depression • Sedation* • Nausea* • Vertigo* • Constipation • Urinary retention

* Some tolerance to these effects can develop



In determining the appropriate analgesic agent for a patient presenting with pain, factors that should be taken into consideration include the patient’s pain intensity, the patient’s prior exposure to any analgesic agent, the patient’s concomitant disease state or organ function that may affect the effectiveness of the analgesic agent, and the pharmacokinetic properties and available formulations of the analgesic agent.

If a patient presents with mild pain, nonopioid analgesics include acetaminophen, non-acetylated salicylates, and NSAIDs. In choosing these agents, the clinician should be aware of their limitations as discussed previously under the section of treating pain with non-opioid analgesics.

When a patient presents with mild to moderate pain the combination products that include acetaminophen or aspirin along with hydrocodone, codeine, or oxycodone, or are usually the agents of choice. Again, the clinician should be aware that these products have a ceiling dose due to the non-opioid component of the combination and the side effects for the NSAIDs have to be monitored.

In a patient who presents with severe pain, it is appropriate to start the patient off with an opioid analgesic agent to control the pain. When considering the initial opioid dose for a patient who has only received the equivalent of a combination opioid analgesic from Step Two of the World Health Organization Ladder, the clinician should start at a dose equivalent to 2.5-5 mg of parenteral morphine for the geriatric patient.

If at any time a patient is not receiving adequate pain relief, the dose should be increased by at least 30 to 50% in order to achieve analgesic effect. An incremental any less than that will most likely not provide significant improvement because of the log linear relationship between response and the dose increase.

For the patient receiving a parenteral opioid for rapid relief of severe pain, the dose may be titrated every 15 to 30 minutes to achieve pain relief.

For the patient who is on chronic immediate-release oral opioids, the dose may be titrated twice a day and for the patient on the sustained-release formulation, the dose should be titrated every 1 to 2 days.


Continuous Infusion Opioid Analgesics

• For patients who may not be able to swallow or absorb oral opioids • For patients who require extremely high doses of opioids and oral or parenteral dosing is impractical • Long term continuous infusion of the opioid dose may be administered IV or SC on an hourly rate (e.g. this is also known as the “basal rate”)

Common opioid agents used in continuous infusions: • Morphine • Hydromorphone • Fentanyl

Patient Control Analgesia (PCA)

Use: Bolus doses of opioids controlled by the patient in addition to continuous infusion of the basal rate of pain medication Both acute and chronic pain Typically when oral cannot be taken or has failed

Dosing: The PCA dose is normally 50 to 100% of the hourly basal dose and may be programmed to be administered every 10 to 15 minutes from the time the patient last demanded the dose Lockout period limits total dose allotted per hour Can revise bolus allotment by evaluating previous 24-hour usage

Outcomes: Improved patient response and satisfaction with pain management Short and long-term management of cancer pain by PCA has been shown to be safe and effective



Opioid Dosing Principles

Chronic pain:

• “Around-the-clock dosing” • Controlled release formulations • Provide “rescue doses” or “prn” doses

• Available every 2 hours • Dose is 5 to 15% of the 24 hour around-the-clock dose

Continuous infusions of opioids via intravenous or subcutaneous routes are commonly employed for patients who are not able to swallow, absorb oral drugs, or require such high doses of opioids that it is impractical to administer so many oral tablets.

Morphine, hydromorphone, and fentanyl are the agents most commonly used for this purpose.

In addition to the continuous, hourly administration of the opioid drug, some patients may also have the option of controlling a device that allows bolus doses of the opioid “on demand” as set by predetermined parameters by the physician. This is known as patient controlled analgesia (PCA). PCA enables the patient and provider to adjust for variations in response to therapy that result from differences between patients and their responses to pain medications. Studies show that PCAs produce an overall improvement in analgesia without significantly increasing sedation.



Initializing PCA therapy on a patient can prove to be challenging. However, the American Pain Society provides guidelines for loading doses and projected hourly usage for starting patients on opioid therapy for severe pain.

When treating patients with chronic pain the pain medication dosing should be around-the-clock to provide continuous pain relief and prevent the pain from recurring. In order to help facilitate convenient dosing for the patient, sustained release medications such as morphine and oxycodone, which can be dosed every 8 to 12 hours, should be used as first line therapy. For the patient who can not swallow, the transdermal patch or the continuous opioid infusions are also viable alternatives.

Additionally, despite receiving scheduled pain medications, patients may still experience breakthrough pain. Thus, rescue pain medications should also be provided. The rescue pain medication dose should be 50-100% of the dose administered every 4 hours, or alternatively, the rescue dose may be calculated by taking 5 to 15% of the 24 hour around-the-clock dose. The rescue dose should be available every 2 hours for breakthrough pain. Patients who require more than 4 to 6 doses of breakthrough pain med should have their around-the-clock dose increased accordingly.


Treatment of Pain with Non-Opioid Analgesics: Acetaminophen

Indications: • Drug of choice for relieving mild to moderate musculoskeletal pain

Dosing: • Maximum daily dose: 4000 mg, given in divided doses TID – QID

• Reduce in patients with hepatic impairment or alcohol abuse

Adverse Drug Reactions: • Hepatotoxicity

Precautions: • Avoid exceeding maximum recommended dose • Multiple products/preparations contain APAP • Does not have any anti-inflammatory properties

Both opioid and non-opioid analgesics play an important role in the management of pain. Of the non-opioids, acetaminophen is the drug of choice for relieving mild to moderate musculoskeletal pain. When prescribing acetaminophen, do not exceed maximum daily dose of four thousand milligrams, and some even suggest that 3000 mg is a more appropriate ceiling dose in the elderly. Be prepared to adjust the dosage in patients with hepatic impairment.


Treatment of Pain with Non-Opioid Analgesics: NSAIDs

Aspirin:

• Maximum adult dose: 3200 – 4000 mg, given in divided doses TID – QID • Adverse drug reactions: gastric bleeding, abnormal platelet function, tinnitus, confusion • Precautions: avoid high doses for prolonged periods • Tinnitus may be a difficult and unreliable indication of toxicity due to age-related hearing loss or eighth cranial nerve damage •  CNS adverse effects such as confusion, agitation, and hallucination are generally seen in overdose or high-dose situations, but older adults may demonstrate these adverse effects at lower doses than younger adults.

Ibuprofen:

• Maximum adult dose: 2400 mg given in divided doses TID – QID • Adverse drug reactions: gastric bleeding, renal dysfunction,edema, hypertension, abnormal platelet function (may be dose-dependent), constipation, confusion, headaches • Precautions: avoid high doses for prolonged periods • Ibuprofen may interfere with aspirin’s antiplatelet effect depending upon when it is administered. Ibuprofen should be taken 30-120 minutes after aspirin ingestion or at least 8 hours should elapse after ibuprofen dosing before giving aspirin.

Naproxen:

• Maximum adult dose: 1250 mg given in divided doses TID – QID • Adverse drug reactions: same as for ibuprofen • Precautions: avoid high doses for prolonged periods


Treatment of Pain with Non-Opioid Analgesics: NSAIDs

Choline Magnesium Trisalicylate:

• Maximum adult dose: 5500 mg given in divided doses TID – QID • Adverse drug reactions: same as for ibuprofen AND salicylate toxicity at high doses • Precautions: test for salicylate levels to avoid toxicity

U.S. Boxed Warning on Labeling for all NSAIDs: • NSAIDs may increase risk of gastrointestinal irritation, ulceration, bleeding, and perforation • NSAIDs are associated with an increased risk of adverse cardiovascular events, including MI, stroke, and new onset or worsening of pre-existing hypertension

Nonsteroidal anti-inflammatory agents frequently used in pain management include: aspirin, ibuprofen, naproxen, and choline magnesium trisalicylate. These agents should all be used with caution in any patient, and most certainly in the elderly patient. Short-acting agents are best, and should be taken on an as needed basis rather than daily or around-the-clock. High-dose long-term therapy should be avoided.

Adverse reactions to nonsteroidal anti-inflammatory agents include gastric and renal disturbances, abnormal platelet function, constipation and headaches. These agents are contraindicated in patients with abnormal renal function, peptic ulcer disease or bleeding diathesis. The elderly are at increased risk for adverse effects (especially peptic ulceration, CNS effects, and renal toxicity) from NSAIDs, even at low doses. The lowest effective doses should be used.


Treatment of Pain with Opioid Analgesics: Short-Acting Agents

Morphine Sulfate: • Oral equivalent: 30 mg • Starting dose: 10mg q3- 4h for opioid-naïve patients; variable based on patient response. • Dosing adjustment in renal impairment:

• Clcr 10-50 mL/minute: Administer at 75% of normal dose • Clcr <10 mL/minute: Administer at 50% of normal dose

• Adverse drug reactions: constipation, sedation, impaired cognition, nausea • Precautions: start low and titrate slowly • Start bowel regimen early

Codeine: • Oral equivalent: 120 mg • Starting dose: 15 – 60 mg q4–6h; variable depending on patient response. • Adverse drug reactions & interactions: constipation, sedation, impaired cognition, acetaminophen-NSAID combinations limit dose • Precautions: start low and titrate slowly • Start bowel program early

Hydrocodone: • Oral equivalent: 20 – 30 mg • Starting dose: 2.5-5 mg of the hydrocodone component every 4-6 hours. • Adverse drug reactions & interactions: similar to morphine, acetaminophen-NSAID combinations limit dose • Precautions: start low and titrate slowly • Start bowel program early


Treatment of Pain with Opioid Analgesics: Short-Acting Agents

Hydromorphone: • Oral equivalent: 7.5 mg • Starting dose: 1.5 mg q3–4h • Adverse drug reactions & interactions: similar to morphine • Precautions: start low and titrate slowly • Start bowel regimen early • Hydromorphone may be confused with morphine

• Significant overdoses have occurred when hydromorphone products have been inadvertently administered instead of morphine sulfate

Opioid analgesics are useful for relieving moderate to severe pain, especially nociceptive pain. When used to treat episodic pain, they should be prescribed only as needed. Short-acting or immediate-release opioid analgesics such as morphine sulfate, codeine and hydrocodone are useful for the kind of "break-through" pain associated with end-of-dose pain, incidental pain, or spontaneous pain. Staring doses of these agents are shown on your screen; for many older patients, these starting doses may need to be reduced. Dosages should be titrated carefully and the patient monitored for adverse effects such as constipation, sedation, impaired cognitive performance, and nausea. Dosages of opioid analgesics are more limited when used in combination with acetaminophen. When used as monotherapy, most morphine-like agonists do not have a ceiling dose.


Treatment of Pain with Opioid Analgesics: Long-Acting Agents

SR Morphine:

• Available strengths: 15, 30, 60, 100, 200 mg • Oral equivalent: 30 mg • Starting dose: 15 – 30 mg q12h or q24h equivalent of total prior analgesics in divided doses q12h

• Once daily morphine is the total daily dose (TDD) as a single dose • Adverse drug reaction & interactions: constipation, sedation, impaired cognition, nausea • Precautions:

•  Titrate slowly to avoid accumulation • Use immediate release (IR) opioids for breakthrough pain • Extended/sustained release products: [U.S. Boxed Label Warning]: Extended or sustained release dosage forms should not be crushed or chewed • Avinza®: [U.S. Boxed Label Warning]: Do not administer with alcoholic beverages or ethanol-containing products, which may disrupt extended-release characteristic of product. • Start bowel regimen early



SR Oxycodone:

• Available strengths: 10, 20, 40, 80, 160 mg • Oral equivalent: 20 – 30 mg • Starting dose:

• Dependent upon the equianalgesic dose of the opioid agent the patient is receiving • prior to switching to the patch • 10 – 20 mg q12h or 24 h equivalent of total prior analgesics in divided doses q12h

• Adverse drug reactions & interactions: similar to sustained release (SR) morphine • Precautions:

•  Titrate slowly • Use immediate release (IR) opioids for breakthrough pain • Extended/sustained release products: [U.S. Boxed Label Warning]: Extended or sustained release dosage forms should not be crushed or chewed • Start bowel regimen early



Transdermal Fentanyl:

• Available strengths: 25, 50, 75, 100 mcg/hour • Starting dose: > 25 mcg/h • Peak effects of first dose may take 18 – 24 hours • Contraindications: opioid-naïve patients • Adverse drug reactions & interactions: similar to sustained release (SR) morphine; hypoventilation, sedation, respiratory depression • Precautions:

• Effective activity may exceed 72 hours in elderly patients • Patches should not be cut • Avoid exposure of applied patch to heat (i.e. heating pads, hot tub, high fever) • Start bowel regimen early • Do not use soap, alcohol, or other solvents to remove transdermal gel if it accidentally touches skin as they may increase transdermal absorption

When the pain is continuous, long-acting or sustained-release analgesic preparations should be prescribed with short-acting formulations of the same medication provided for as needed relief or breakthrough pain. Morphine and oxycodone are both available in sustained0-release and immediate release form. Again, dosages should be titrated slowly to avoid accumulation, and patients observed for adverse reactions. Stimulant laxatives may be needed in patients who become constipated. Stool softeners are generally ineffective alone and offer no help for immotility. Bulk laxatives in the absence of adequate fluid intake can worsen constipation and potentially lead to fecal impaction. Patients who experience nausea may also require treatment.



• In 1985, Foley developed an equianalgesic dose conversion based on morphine. Foley used an intramuscular dose of each drug listed and compared it with morphine to establish the relative potency. Although controlled studies are not available, in clinical practice it is customary to consider doses of opioids given as intramuscular, intravenous, or subcutaneous to be equivalent, recognizing that there may be some difference in pharmacokinetic parameters such as Cmax and Tmax.

Ten mg of parenteral morphine is equivalent to 30 mg of oral morphine based upon studies in chronic/persistent pain patients. In acute pain patients perhaps as much as 10 mg of parenteral morphine is equivalent to 60 mg of oral morphine.

Clinically, patients receiving more than 100 mg a day of sustained release morphine or oxycodone may take these agents on an every 8 hours dosing interval to prevent end-of-dose failure.

Transdermal fentanyl can also be converted to or from an oral or parenteral dose of any medication, as long as you first convert the equivalent dose to parenteral morphine. As a generally accepted rule, 1 microgram per hour of transdermal fentanyl is considered equivalent to 2 mg per 24 hours of oral morphine. The makers of the drug consider the conversion to be conservative and to take that into consideration when making conversion recommendations.

The transdermal fentanyl patch should not be initiated in an opioid naïve patient. This route of administration is usually considered for the patient who is no longer able to swallow and needs to switch to an alternative opioid agent. The table provides some guidelines in determining the equivalent patch dose based upon the equianalgesic 24 hour oral or parenteral morphine dose.

After application of the patch it takes at least 24 hours before the drug attains steady state, thus it is important to overlap with a parenteral opioid agent during this time period before the effect of the fentanyl patch kicks in. It should be kept in mind that patients still need an immediate release agent for breakthrough pain while on the patch.


Management of Opioid Adverse Effects

Managing Constipation in Patients Receiving Opioid Therapy:

• Encourage the patient to drink ample fluids, including fruit juices. • Increase daily fiber (e.g., bran or equivalent) as tolerated • Help the patient to remain as mobile as possible. • Prescribe a regular dose of a stimulant laxative (e.g. senna) plus a stool softener in combination with lactulose or sorbitol as indicated, increasing the dose until the desired effect is achieved. • Reduce the analgesic dosage if feasible or reduce the dosages of other medications that affect bowel motility, such as calcium channel blockers and drugs with significant anticholinergic properties.

All patients on a standing dose of an opioid, or those that are using regular PRN doses, should be put on a standing bowel regimen. Constipation is the most common opioid side effect and should be aggressively managed and prevented. Constipation should be anticipated, and a bowel regimen started with every pain regimen that could potentiate constipation. Simply put, opioids block bowels as they block pain. Stimulant laxatives are the preferred agents as stool softeners do nothing to increase motility. In the absence of adequate fluid intake, bulk laxatives such as psyllium can cause fecal impaction and obstruction and should be avoided.

Binding of mu agonist opioids to receptors results in both therapeutic effects and adverse effects. Side effects of opioids as a class include sedation, mental clouding or confusion, respiratory depression, urinary retention, and more. According to Berry and colleagues, with the exception of constipation, these side effects tend to resolve with time.

Most opioids should be used with caution in patients with impaired ventilation or bronchial asthma. Opioid-induced respiratory depression is usually short-lived, antagonized by pain, and most common in the opioid naïve patient. What’s more, since the relation between opioids and respiratory depression was first identified in 1954, less than 1% of all appropriately managed patients have experienced opioid-related respiratory depression.


Management of Opioid Adverse Effects

The use of methylphenidate in patients with incident cancer pain receiving regular opiates was studied by Berrera and colleagues. In 50 patients receiving a mean daily equivalent dose of morphine of 165 mg per day methylphenidate was initiated at 15 mg per day for narcotic-induced sedation. Forty-four of the patients reported improvement after 48 hours of treatment, and continued on methylphenidate for an average of 39 days. The mean maximal dose of the psychostimulant in the study was 42 mg per day. Two patients had acute toxicity (namely, hallucinations and paranoid-aggressive reactions), and required discontinuation of the drug. The authors did note that significant tolerance developed to the methylphenidate over the period of a month. The American Pain Society suggests using dextroamphetamine 2.5 – 10 mg by mouth or methylphenidate 5 – 10 mg by mouth, and titrate to effect.


Agents Contraindicated for Use in the Elderly

Propxyphene (Darvon®): • Few, if any benefits as compared to acetaminophen • Accumulating metabolites cause CNS side effects

Pentazocine (Talwin®): • Mixed agonist/antagonist • Causes psychotomimetic reactions

Indomethacin (Indocin®): • NSAID with highest incidence of CNS effects (esp. headaches)

Meperidine (Demerol®): • Seldom dosed appropriately • Causes CNS excitation, including seizures • Accumulates with chronic dosing, particularly in older adults and patients with renal dysfunction

Despite the efforts of many in the pain management community there continues to be wide-spread use of agents with significant potential for adverse effects in the elderly.

Propoxyphene, indomethacin, and meperidine cause significant central nervous system effects. Thus, their use should be restricted and avoided in the elderly.


Types of Pain: Neuropathic

Definition: International Association for the Study of Pain (IASP): “A pain initiated or caused by a primary lesion or dysfunction of the nervous system.”

Etiology of Nerve Damage that Causes Neuropathic Pain: • Infections • Trauma • Surgery • Radiation • Inflammation • Chemotherapy • Tumor Infiltration • Nerve Compression • Metabolic Abnormalities • Neurotoxins

Conditions Commonly Associated with Peripheral Neuropathic Pain: • HIV Infections or AIDS • Diabetes • Herpes zoster • Trigeminal neuralgia • Tumor Infiltration • Cancer chemotherapy • Post-mastectomy • Phantom limb pain


Types of Pain: Neuropathic

Conditions Commonly Associated with Central Neuropathic Pain:

• Multiple sclerosis • Parkinson Disease • Central post-stroke pain • Spinal cord Injury

In the coming years, the incidence of neuropathic pain is expected to rise. The reasons for this are due in part to the aging of our population, where neuropathic pain syndromes such as post-herpetic neuralgia, post diabetic neuropathy, and central post-stroke pain are very common. Furthermore, with the advance of medical technology, we have patients surviving longer from disease states such as cancer, HIV-infection, and diabetes, and these patients often have neuropathic pain associated with their disease.

Neuropathic pain is defined by the International Association for the Study of Pain as: “a pain initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system.” The pain results from compression, infiltration, or degeneration of the central or peripheral nerve pathways due to injury, disease, or medical treatment. In contrast to nociceptive pain, which serves as a warning signal for potential or actual damage to a tissue, neuropathic pain is considered to be pathologic, as it serves no adaptive purpose and it causes suffering and distress.

The etiologies for the nerve damage and associated pain are diverse. Some examples include postherpetic neuralgia as a consequence of a shingles outbreak or polyneuropathies associated with diabetes, HIV, or patients receiving chemotherapy agents such as vincristine or paclitaxel.

Neuropathic pain may also be associated with stroke, trigeminal neuralgia, or compression of a nerve by a tumor.


Mechanisms of Neuropathic Pain

Direct stimulation • Automatic firing of nerve fibers • Deafferentation • Sympathetically Mediated Pain • Other possible Mechanisms:

• Increased sodium channels in nociceptor neurons • Up regulation of substance P receptors in the dorsal horn • Increased numbers of receptors for glutamate • Increased spinal cord levels of pain-producing cytokines • Decreased CNS levels of gamma-aminobutyric acid, opioid peptides or their receptors

There are many proposed mechanisms for the pathology of neuropathic pain. The four most common types are direct stimulation of pain sensitive neurons, automatic firing of damaged nerves, deafferentation, and sympathetically mediated pain.

Direct stimulation pain is a result of compression, mechanical stretching, or chemical irritation to the peripheral nerve. Automatic firing is defined as a spontaneous firing of the nerves at the site of the nerve injury or at ectopic foci along the damaged nerve, whereas deafferentation is the abnormal production of impulses by neural tissue that is independent from the afferent input. Sympathetically mediated pain ectopic discharges are generated at the site of the injured peripheral nerve and the respective dorsal root ganglion. These damaged peripheral nerve fibers are mechanosensitive, spontaneously active, and responsive to adrenergic agonists and sympathethic chain stimulation.

Other possible mechanisms of neuropathic pain are listed on the screen.


Signs and Symptoms of Neuropathic Pain

Spontaneous Pain

• Continuous Pain • Intermittent Pain

Stimulus Evoked Pain

• Dysesthesia • Allodynia • Hyperalgesia • Paresthesias • Hyperpathia

Pain Descriptors

• Shooting, burning, aching or a combination • Electric like, lancinating, stabbing • Shock, cold, prickling, tingling

Patients with neuropathic pain have abnormal pain qualities and the distribution of their pain is consistent with neural damage. The abnormal pain sensation may be spontaneous or evoked, and is defined by the term dysesthesia. The forms of dysesthesia include: allodynia, hyperalgesia, hyperpathia, and paresthesias.

Allodynia refers to experiencing pain in response to a stimulus that is usually not considered to be painful. For example, the light movement of a cotton swab or the sensation of the wind over the skin can elicit a pain response. Hyperalgesia is experiencing a disproportionate increase in pain intensity to a normally painful stimulus. On the other hand, paresthesia is an abnormal sensation that is not unpleasant. Hyperpathia is an exaggerated reaction to a stimulus, especially a repetitive stimulus. Hyperpathia is notable for the unique characteristics of delay, radiation after sensation, and faulty identification and localization of the stimulus.

In trying to distinguish between neuropathic pain and nociceptive pain, it is important to recognize that patients commonly describe their pain as electric shock-like, burning, cold, prickling, tingling, lancinating, and itching sensations.


Pharmacologic Management of Neuropathic Pain: Overview

Opioids

• NSAIDs

• Antidepressants Tricyclic Antidepressants SSRIs (selective serotonin reuptake inhibitors) SNRIs (serotonin/norepinephine reuptake inhibitors)

• Anticonvulsants Gabapentin Phenytoin Valproic Acid Carbamazepine Lamotrigine Pregabalin Topiramate Tiagabine

• Topical Lidocaine Capsaicin

When treating patients with neuropathic pain, the ideal method is to identify the specific pathophysiologic mechanism that causes the pain. The next step is to tailor the treatment regimen to the specific mechanism. The rationale for this approach is because patients with the same disease state may have different mechanisms of pain, thus accounting for the difference in their response to the same therapy regimen.

Unfortunately, we are not at the point clinically where we are able to accurately identify the specific mechanisms based upon the patient’s neuropathic pain signs and symptoms.

Furthermore, neuropathic pain is challenging to treat because conventional analgesics such as opioids and nonsteroidal anti-inflammatory agents are generally ineffective for this pain diagnosis.


Pharmacologic Management of Neuropathic Pain: Antidepressants

Tricyclic Antidepressants (starting dose – max geriatric dose):

Amitriptyline (10 – 150 mg) Nortriptyline (10 – 75 mg) Desipramine (10 – 150 mg) Imipramine (10 – 150 mg) Doxepin (10 – 150 mg) Clomipramine (25 – 200 mg)

• Principles for Therapy Initiation: • Start with the lowest oral dosage strength • Titrate only one drug at a time • Increase dose if pain relief is not adequate • Titrate until patient experiences pain relief, complains of side effects, reaches toxic serum concentration, or is at the maximum recommended dose • Titrate dose up every 3 to 7 days • May require up to three weeks for an adequate trial for managing neuropathic pain.

• Side Effects: • Dry mouth • Constipation • Blurred vision • Tachycardia • Urinary retention • Sedation • Agitation/confusion



• Special Precautions in the Elderly • Heart block • Orthostatic hypotension • Cardiac Arrhythmias

• Contraindicated: • Narrow angle glaucoma • Prostatism

SSRIs

• SSRIs are better tolerated than TCAs but have not consistently been shown to effectively manage neuropathic pain symptoms in nondepressed patients.

SNRIs

• Duloxetine • Shown to effectively manage painful diabetic neuropathy; may be useful in other types of chronic pain • Adverse drug reactions: somnolence, constipation, urinary hesitancy, dry mouth • May cause hepatotoxicity; avoid use in patients with substantial alcohol intake, evidence of chronic liver disease, or hepatic impairment. • May require up to 1 week of therapy to achieve pain relief

• Venlafaxine: •  Adverse effects :insomnia/anxiety, somnolence, anorexia, constipation • .Venlafaxine may be considered for neuropathic pain that does not respond to TCAs, duloxetine, or anticonvulsants. •  May require 1-3 weeks to achieve pain relief.



Tricyclic antidepressants have been extensively studied for the relief of neuropathic pain, particularly diabetic neuropathy and postherpetic neuralgia. They block the reuptake of serotonin and noradrenaline, and it is thought that they relieve pain by inhibiting sodium channels.

Controlled trials with various tricyclic antidepressants in patients with diabetic neuropathy show that one-third to one-half of patients achieves a 50% reduction in neuropathic pain.

When initiating TCAs the lowest oral dose available given at bedtime should be the starting point. For elderly, frail patients start at the lowest dose possible, then increase dose slowly every 3 to 7 days until pain relief is achieved, intolerable side effects occur, or the patient has reached the maximum recommended dose.

The major side effects with the TCAs are due to antimuscarinic effects and include dry mouth, constipation, blurred vision, tachycardia, and urinary hesitancy. Nortriptyline and desipramine are typically less sedating than doxepin and amitriptyline.

In addition to the listed side effects, the elderly should also be monitored for symptoms of heart block, arrthytmias and orthostatic hypotension. TCAs should not be administered if the patient has a history of narrow angle glaucoma, prostatism, or heart block.

The Selective Serotonin Reuptake Inhibitor antidepressants currently available have not been proven to be effective in relieving neuropathic pain in non-depressed patients, and therefore are not commonly used for this indication. However, SNRIs are increasingly being used for neuropathic pain, due to their more tolerable side effect profile. Any patient taking an antidepressant should be monitored for serotonin syndrome (symptoms of agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia), especially if taking multiple proserotonergic drugs (other antidepressants, triptans, etc.)


Pharmacologic Management of Neuropathic Pain: Anticonvulsants (Pt 1)

Gabapentin

• Initiate at a dose of 100mg TID • Titrate the dose up by 100 – 300 mg every 3 to 5 days

• Maximum dose = 3600 mg a day • Short half-life; three times a day dosing or 4 times a day for higher doses is recommended

Gabapen*n Dosing Adjustments in Renal Impairment

Crea*nine Clearance (mL/min) Daily Dose Range

≥60 300-‐1200 mg 8d

>30-‐59 200-‐700 mg bid

>15-‐29 200-‐700 mg daily

15 100-‐300 mg daily

Adverse drug reactions: • Somnolence, fatigue • Dizziness • Nausea • Edema • Ataxia



Pregabalin

• Initial adult dosing: 150 mg a day in 2- 3 divided doses • Increase dose within 1 week based on tolerability and effect •  Maximum dose: 300 mg/day (600mg for post-herpetic neuralgia)

Pregalabin Dosing Adjustments in Renal Impairment

Crea*nine Clearance (mL/min) Total Max Daily Dose

≥60 150-‐300 mg

>30-‐59 75mg

>15-‐29 25-‐50mg

15 25mg

Adverse drug reactions: • Somnolence, fatigue • Dizziness • Nausea • Edema/fluid accumulation • Ataxia



Carbamazepine

• Start at 100 mg twice a day in elderly patients • Increase dose gradually by 100 mg a week • Effective dose range is between 800 – 1200 mg total daily dose • Drug interactions: (numerous!) diltiazem, azole antifungals, clarithromycin, verapamil, phenytoin, valproic acid, etc.

• Adverse drug reactions: • COMMON: drowsiness, dizziness, ataxia, diplopia, nausea, vomiting • ELDERLY: SIADH, hyponatremia, cardiac conduction defects • LESS COMMON (<10%):leukopenia, thrombocytopenia, aplastic anemia, • Hepatitis

• Monitor: • CBC with platelets, LFT and repeat every 6 months

Oxacarbazepine

• Start at 300 mg a day • Increase by 300 mg a week • Usual dose range 1200 – 2400 mg a day • Renal Impairment Clcr <30 mL/minute: Therapy should be initiated at one-half the usual starting dose and increased slowly to achieve the desired clinical response • Adverse drug reactions: dizziness, somnolence, ataxia, hyponatremia, nausea, vomiting. • Drug interactions: (numerous!) diltiazem, azole antifungals, clarithromycin, verapamil, phenytoin, valproic acid, etc



Anticonvulsants have been shown to be effective in the treatment of neuropathic pain and are generally first line agents for this diagnosis. Gabapentin is the anticonvulsant used most frequently for this indication.

Gabapentin was developed as a gamma-aminobutyric acid (GABA) analog. It is postulated that it increases levels of GABA in the nervous system and it binds to alpha-2-delta subunit voltage-gated calcium channels; however, the precise mechanism by which gabapentin exerts its action is not known. Pregabalin, cousin to gabapentin, exhibits basically the same therapeutic and adverse effects as gabapentin.

Large clinical, randomized, placebo controlled trials in patients with diabetic neuropathy and post-herpetic neuralgia have shown that gabapentin is effective in relieving neuropathic pain. The patients mean reduction in pain scores was 33 to 41% in the treatment group compared to 8 to 19% in patients receiving placebo. The most common adverse effects reported were dizziness and somnolence.

Elderly patients are generally initiated at 100 mg a day, with 300 mg a day for being the starting point for most other patients. The dose may be titrated up every 3 to 5 days by 100 to 300 mg until there is pain relief or the patient experiences intolerable side effects. The maximum dose a day is 3600 mg. Since gabapentin has a short half life it should be dosed 3 to 4 times a day.

Carbamazepine stabilizes membranes by inhibiting sodium channels, thus reducing neuronal excitability. It has mainly been evaluated in patients with trigeminal neuralgia and results showed there is significant pain score improvement in patients receiving carbamazepine versus placebo. In clinical practice, the side effect profile of carbamazepine, especially in the elderly, greatly contributes to its limited use. Oxacarbazepine is a keto acid analog of carbamazepine and is better tolerated. It has efficacy for trigeminal neuralgia similar to carbamazepine, making it a suitable alternative.



Lamotrigine

• Should be started at a dose of 25 mg per day in the elderly • May be titrated weekly by 25 – 50 mg • The effective dose is usually 200 – 400 mg a day, administered in divided dose twice daily

• Adverse drug reactions: • Dizziness, unsteadiness • Nausea • Drowsiness • Rash-

• Severe and potentially life-threatening skin rashes requiring hospitalization have been reported • Risk may be increased by coadministration with valproic acid, higher than recommended starting doses, and rapid dose titration.

Phenytoin

• Limited use due to side effects • Complicated pharmacokinetic profile • Availability of other agents



Topiramate

• No pain relief in patients with diabetic neuropathy • Under evaluation for other neuropathic pain states • May be helpful for trigeminal neuralgia in some cases.

Valproic Acid

• No controlled trials for neuropathic pain

Lamotrigine is an anticonvulsant that works by stabilizing sodium channels and suppressing the release of glutamate from presynaptic neurons. It is effective as add-on therapy for trigeminal neuralgia and for patients with post-stroke pain.

Lamotrigine should be initiated at the lowest dose of 25 mg, although in clinical trials the minimum effective dose was 200 mg a day. However, it is important to start low and go slow with titration because high dose and fast titration significantly increases the likelihood of rash.

The role of phenytoin in the treatment of neuropathic pain, is limited because of its side effects profile, complicated pharmacokinetics, and the availability of other agents such as gabapentin, which may be prescribed with better ease.

Topiramate is an anticonvulsant that modulates sodium channels, potentiates GABA-ergic inhibition, blocks excitatory glutamate activity, and blocks voltage gated calcium channels. Currently, this agent has failed to show pain-relieving effect in patients with diabetic neuropathy. Studies are reviewing whether it has any effect on any other neuropathic pain states.

There are currently no controlled trials to document the efficacy of valproic acid in neuropathic pain.



Lamotrigine is an anticonvulsant that works by stabilizing sodium channels and suppressing the release of glutamate from presynaptic neurons. It is effective as add-on therapy for trigeminal neuralgia and for patients with post-stroke pain.

Lamotrigine should be initiated at the lowest dose of 25 mg, although in clinical trials the minimum effective dose was 200 mg a day. However, it is important to start low and go slow with titration because high dose and fast titration significantly increases the likelihood of rash.

The role of phenytoin in the treatment of neuropathic pain, is limited because of its side effects profile, complicated pharmacokinetics, and the availability of other agents such as gabapentin, which may be prescribed with better ease.

Topiramate is an anticonvulsant that modulates sodium channels, potentiates GABA-ergic inhibition, blocks excitatory glutamate activity, and blocks voltage gated calcium channels. Currently, this agent has failed to show pain-relieving effect in patients with diabetic neuropathy. Studies are reviewing whether it has any effect on any other neuropathic pain states.

There are currently no controlled trials to document the efficacy of valproic acid in neuropathic pain.


Topical Analgesics for Neuropathic Pain Management: Capsaicin

Capsaicin

• 0.025% and 0.075% topical cream • Apply 3 – 5 times a day to the affected pain area • Should be used for a minimum of 4 – 6 weeks before its therapeutic effects can be assessed adequately

• Adverse Drug Reaction: Initial transient burning and erythema at site of application

• Clinical pearls: Use gloves when applying the capsaicin Avoid application near open wounds, and especially avoid rubbing near the eyes and mucus membranes since severe burning pain results when this occurs

Capsaicin is an alkaloid extracted from the chili pepper. Capsaicin can selectively activate, desensitize, or exert neurotoxic effect on small sensory afferent nerves due to its agonist activity at the vanilloid receptors. Initial stimulation of the vanilloid receptor enhances pain, produces hyperalgesia in the affected tissue, and causes the release of pro-inflammatory peptides such as substance P from terminals of unmyelinated C fibers, causing the sensation of pain or itch. However, with repeated exposure to capsaicin, the neurotransmitters responsible for pain transmission are depleted and desensitization occurs with the end result of producing prolonged analgesic effect.


Topical Analgesics for Neuropathic Pain Management: Capsaicin

Studies utilizing 0.075% topical capsaicin have shown that it modestly reduces pain in patients with postherpetic neuralgia and diabetic neuropathy when compared to placebo cream vehicle. Topical capsaicin should not be used as the primary therapy for chronic neuropathic pain, but instead should be used as an adjuvant in conjunction with other analgesic agents.

On initial application, capsaicin produces a sensation of burning pain and hyperalgesia, especially in the first week of therapy. However, with repeated applications, the receptive terminals of pain sensors are desensitized and the pain lessens with time. Nevertheless, patient compliance is affected because most patients may not like the exacerbation of pain with initial application. Additionally, it may take a week or longer before a therapeutic effect is observed. Despite its side effect profile, there are no drug interactions with capsaicin, making it a useful adjunctive agent for neuropathic pain in the elderly.


Topical Analgesics for Neuropathic Pain Management: Lidocaine

Topical 5% Lidocaine Patch

Indication: FDA approved for the treatment of postherpetic neuralgia

Dose/Administration: • Apply to intact skin only • Cover most painful area • May apply up to 3 patches for 12 of 24 hours • Patches may be cut into smaller sizes

Adverse Drug Reactions: • Local erythema or edema • Allergic reaction to lidocaine • Systemic reactions unlikely

Caution: Monitor closely in patients receiving concomitant class I antiarrythmics or in patients with hepatic disease


Topical Analgesics for Neuropathic Pain Management: Lidocaine

Topical lidocaine provides postherpetic neuralgia pain relief with low incidence of systemic adverse effects. It works by blocking voltage gated sodium channels thus blocking nerve conduction and has been shown to be effective in reducing the intensity of common neuropathic pain qualities such as “hot”, “sharp”, “itchy”, “cold” or “cold” sensations.

The patch should be applied over intact skin in the most painful area on the body. The FDA approval is for the application of up to 3 patches for 12 hours on and 12 hours off in a 24-hour period. The patches may be cut into smaller sizes to fit the area of pain sensation. However, studies have shown that for off-label use, up to 4 patches may be applied for a 24-hour period safely with effective relief of pain.

The topical application of the lidocaine patch may be tried as first line therapy in elderly patients with neuropathic pain who are susceptible to systemic side effects of other agents or are at risk for significant drug-drug interactions with other therapies. While the topical lidocaine patch achieves clinically insignificant lidocaine serum concentrations, it should be used with caution in patients receiving concomitant class I antiarrythmic agents such as mexiletine or patients with severe hepatic disease.


Other Agents for Neuropathic Pain Management

Tramadol • 25-50mg every 4-6 hours; titrating dose slowly upwards to achieve optimal pain relief • Maximum daily dose= 300mg daily • Maximum daily dose if CrCl<30ml/min= 200mg daily

• Extended release tablets should not be used with CrCl<30ml/min

• Drug Interactions: • Increased risk of serotonin syndrome with monoamine oxidase inhibitors, SSRIs, tricyclic agents

• Adverse Drug Reactions: • Nausea • Constipation • Headache • Dry mouth • Dyspepsia • Dizziness • Somnolence

N-Methyl-D-Aspartate (NMDA) Glutamate Antagonists

• Dextromethorphan


Other Agents for Neuropathic Pain Management

• Adverse Drug Reactions: • Sedation • Dizziness • Ataxia • Motor incoordination • Dizziness • Impairment of memory

Tramadol has opioid analgesic activity but has low affinity binding to mu-opioid receptors. It has been shown to be effective in relieving neuropathic pain caused by either diabetic neuropathy or polyneuropathies associated with paresthesias and touch-evoked pain when compared with placebo. The most common adverse effects reported by patients are nausea and constipation in 20% of patients. Other side effects include headache, dyspepsia, tiredness, dizziness, and dry mouth.

Dextromethorphan is a partial antagonist of the N-Methyl-D-Aspartate, or N-M-D-A receptor. The few controlled studies with a small number of diabetic neuropathy patients suggest that dextromethorphan reduces neuropathic pain when compared to placebo. There are multiple intolerable side effects experienced by all patients with this agent that precludes its use clinically, including sedation, impairment of memory, ataxia, motor incoordination, and dizziness.


Interventional Strategies for Neuropathic Pain

• Peripheral nerve block • Chemical and Physical Neurolysis

• Alcohol, 5% lidocaine, phenol • Cryoanalgesia, radiofrequency lesioning

• Central neural blockade • Epidural, intrathecal

• Neuraxial drug delivery • Opioids, local anesthetics, adrenergic antagonists

• Neuroaugmentation • Spinal cord stimulation • Peripheral nerve stimulation

• Neurosurgical techniques • Decompression laminectomy • Microvascular decompression • Foraminotomy

Interventional therapy in the treatment of neuropathic pain may reduce or eliminate the need for systemic therapy. Examples of the different types of interventional strategies are provided on the screen.

Peripheral nerve block provides temporary relief of neuropathic pain and is used as an indicator to predict success with neurolysis.

Neuraxial therapy delivers the drug locally to the presumed site of involvement. This allows for the drug to be delivered almost directly to the receptors in the central nervous system, enabling a dose reduction of as much as 100 times less than that of oral dosing. Morphine is the most commonly used intrathecal opioid. Studies of this mode of administration are primarily in the cancer patient population and suggest good to excellent pain relief.


Non-Pharmacologic Management of Neuropathic Pain

• Cognitive and Behavioral Strategies • Biofeedback • Guided imagery • Meditation • Relaxation therapy

• Physical and occupational therapy • Electrostimulation

• Transcutaneous electrical nerve stimulation (TENS) • Percutaneous electrical nerve stimulation (PENS) • Acupuncture

Practitioners need to be aware that treatment modalities such as cognitive and behavioral strategies, and physical and occupational therapies might be useful in helping patients to cope with their debilitating symptoms. The key is to incorporate these treatment interventions early on in the management of the patient’s pain with other interventional or medical treatment and not wait to use these non-pharmacological approaches as a last resort.

Electrostimulation is thought to induce the release of endogenous opioid-like chemicals. Studies of TENS and PENS therapy in patients with diabetic neuropathy have shown temporary relief of pain over placebo therapy. However, the results are not yet convincing enough to establish these treatment modalities as first-line therapy.


Adjuvant Analgesics

Corticosteroids (e.g., dexamethasone, prednisone)

• Painful conditions that respond to corticosteroids: • Metatastic bone pain in cancer patients • Acute spinal cord compression • Superior vena cava syndrome • Symptomatic lymphedema • Raised intracranial pressure headache • Hepatic capsular distention • Neuropathic pain due to compression or infiltration by a tumor

• Starting dose: dexamethasone: • From 1 – 2 mg a day to as high as 96 mg per day in divided doses for spinal cord compression • Adverse drug reactions: • Increased risk of hyperglycemia • Osteopenia • Cushing phenomena • Oral candidiasis • Dyspepsia • Neurologic changes • Myopathy • Dyspepsia • Immunosuppression

• Use lowest possible dose for geriatric patients.


Adjuvant Analgesics

Bisphosphonates (risidronate, alendronate, ibandronate, pamidronate, zoledronic acid)

• Adjuvant agent for bone pain • Risidronate/alendronate/ibandronate/pamidronate:

• Generally given for 6-month treatment duration • Adverse drug reactions:

• Bone pain • Hypocalcemia • Hypomagnesemia • Hypokalemia • Hypophosphatemia • Nausea

• Zoledronic Acid: • Very potent bisphosphonate • Usual dose is 4 mg infused over 15 minutes every 3 to 4 weeks

• Calcitonin • Can be used for modest pain control of vertebral fractures and bone pain • Adverse drug reactions:

• Nasal irritation • Flushing • Back/joint pain


Adjuvant Analgesics

Adjuvant analgesics are agents that may be added on with the primary analgesics in any of the 3 steps in the World Health Organization Ladder approach for pain management.

The determination of which adjuvant agent to use is based largely upon the specific characteristic of the pain the patient is experiencing and the properties of the agent that may contribute to pain relief due to its non-analgesic effect.

The different classes of agents that are used for neuropathic pain, the anticonvulsants, the antidepressants, are great examples of adjuvant analgesics.

Other adjuvant analgesics include the corticosteroids and bisphosphonates. The corticosteroids work in relieving pain by its anti-inflammatory, anti-edema effect. The most commonly used corticosteroid agent in clinical practice is dexamethasone.

The use of the corticosteroids are associated with many side effects and patients should be monitored carefully, especially the patients who have active peptic ulcer disease, diabetes, or immunosuppression.

The bisphosphonates work by inhibiting osteoclast activity and reduces bone resorption. One of their main indications is for the treatment of hypercalcemia. Additionally, they have been found to be effective in reducing bone pain in patients with advanced metastatic cancer. Zoledronic acid is another bisphosphonate that is approximately 100 times more potent than pamidronate. It has the same indication as pamidronate, which is for patients with multiple myeloma or other solid tumors with metastasis to the bones.

The purpose of the bisphosphonates is to decrease skeletal related events such as pathologic fractures or spinal cord compression or increase the time to when these events may occur. They are an option for decreasing bone pain due to their effect in decreasing the skeletal related events. Calcitonin is mildly effective for treating bone pain, particularly for those with Paget’s disease or vertebral fractures.


End-Of-Life Symptoms

Palliative care is the focus on optimizing comfort and reducing physical suffering through management of bothersome symptoms. Palliative care clinicians recognize the existence of an extensive list of possible symptoms to address, including common ailments like pain and dyspnea.

Incidence of conditions in patients in palliative care: • Dyspnea – 62% • Pain – 44% • Noisy breathing – 39% • Delirium – 29% • Fever – 24%

Interventional Hall and colleagues report the top five symptoms on your screen as those that occur when patients enter into the end-of-life. Patients may have more than one of the symptoms listed, and possibly others that are not.

Noisy breathing is defined as wheezing, gasping, and the death rattle. Most patients have a noticeable change in breathing as they near death. Patients commonly have Cheyne-Stokes respirations, which are characterized by periods of shallow and deep breathing where the deep breath can last as long as 20 seconds and appear or sound outwardly as if the patient has stopped breathing. Kussmaul respirations, or many short, rapid respirations (similar to those seen in diabetic ketoacidosis patients), typically follow Cheyne-Stokes patterns. Finally, many patients will exhibit the death rattle, best described by the sound of a baby’s rattle in the patient’s throat, with minimal respirations and diaphragm movement.


Pain at the End-Of-Life

A key aspect of palliative care is focusing on optimizing comfort and reducing physical suffering through management of bothersome symptoms.

• Pain is present in up to 87% of patients • Terminal cancer patients have pain via several mechanisms and at many sites

• Direct tumor involvement (67%) • Tumor invasion of bone (50%)

• Pain control starts with routine screening and assessment for pain

Drug selection:

Mild pain (1–3 out of 10 on a 10-point scale): Begin acetaminophen or a nonsteroidal anti-inflammatory agent (consider opioids in older adults).

Moderate pain (4–7 out of 10 on a 10-point scale): Begin an opioid combination product.

Severe pain (8–10 out of 10): Begin a strong standing opioid (hydromorphone, morphine sulfate, oxycodone) and titrate until pain relief is obtained or intolerable side effects develop.

•  Long-acting opioids (sustained-release morphine or oxycodone, transdermal fentanyl) should be started after pain is well controlled and steady state is achieved.

• Methadone should only be used by clinicians experienced in its use.

Rescue doses using immediate-release opioids should be 10% of the 24-hour total opioid dose and given every hour (oral) and every 30 min (parenteral) as needed.

Adjuvant agents (corticosteroids, anticonvulsants, tricyclic antidepressants, bisphosphonates) should be used for specific pain syndromes when applicable (eg, neuropathic pain).


Pain at the End-Of-Life

Dosing pain medications at the end of life: • Pain medications should be administered on a standing or scheduled basis. • PRN or rescue doses should be available for breakthrough pain or pain not controlled by the standing regimen. • All patients on opioids should be started on a bowel regimen.

Please refer to previous sections for dosing, titration, and adverse effects of the various pain medications

Prevention and relief of suffering is the chief goal of palliative care. In current practice, palliative care is the interdisciplinary specialty that focuses on improving quality of life for persons with advanced illness and their families. It is aggressive care that is offered simultaneously with all other appropriate medical treatments. Pain management is an integral part of palliative care at the end of life. Fortunately, when pain is recognized, more than 80% of patients with pain can be brought under control with a basic approach.


Additional End-of-Life Interventions

Dyspnea

• Dyspnea is a subjective discomfort around breathing. • May vary with activity • Described as:

• Shortness of breath, • Trouble catching one’s breath • Chest tightness • Sensation of smothering or suffocation.

Interventions:

• Oxygen • Cool air to the face

• Window or fan • Benzodiazepines

• Start with low dose and titrate up slowly • Morphine

• 2–5 mg intravenously or subcutaneously every 10 to 15 minutes until improvement

Dyspnea is another very common symptom for patients with chronic progressive illnesses, especially those with advanced lung disease. Similar to pain, dyspnea is often unrecognized and underreported, and identification and assessment depends on patient perception and self-report.

Oxygen offers relief to the dyspnea, and can possibly help reduce anxiety associated with both pain and the feeling of breathlessness. Schwartzstein and colleagues found that cool air to the face provides significant relief of breathlessness symptoms. Patients will commonly find relief from either a fan or window or doorway with a draft.

Benzodiazepines also have a role in end-of-life care in providing added relief of the anxiety directly associated with constant pain and dysnpeic symptoms. But, we must be still be age-cautious in choosing an agent, and use a benzodiazepine that has a short half-life and no active metabolites. Commonly, lorazepam is used because of its multiple formulations for administration that allows for ease of dose interchangeability. Opioid medications, typically morphine sulfate , are very effective for some patients with dyspnea and work by decreasing the central perception of air hunger. Be aware that benzodiazepines and concurrent opioid therapy can increase the likeliness of sedation and perceptual disturbances, which may be disturbing to the patient and family.


Key Points for End-of-Life Care

Primary goal: Get patient to where they are comfortable

• Don’t forget the “whole patient” • Don’t forget the family • Don’t be afraid, but be aware • End of life care requires more than just medications:

• Flow of communication (family, patient, health care team) • Symptom management • Coordination of care (including hospice and community resources) • Psychosocial and spiritual realms • Grief and bereavement • Legal and ethical concerns

• Palliative care team may include: • Physician • Nurse • Pharmacist • Social worker • Chaplain • Bereavement counselor • Volunteers and others

All too often, as patients enter into the end-of-life, providers forget the idea of treating the “whole patient.” This is why common interventions such as an appropriate bowel regimen with the pain therapy are often forgotten. What’s more, we need to be vigilant to comorbid diseases and polypharmacy in these patients so that we do not make matters worse for the patient, the families, or ourselves.

Do not fear the symptoms or the inability to meet the needs of every patient. No two patients present the same, nor do they respond the same. Be aware of what can occur if the patient is under- or over-treated, but do not let it hinder your ability to provide optimal patient care.


Barriers to Adequate Pain Treatment and End-Of-Life Care

Pa*ent Provider

Denial Limited formal training

Fear of addic8on Knowledge deficits

Fear of side effects Fear of addic8on

Pain is ‘inevitable’ Fear of legal ramifica8ons

Misconcep8on of the common terms used

Finding the ‘happy medium’ between comfort and sedation also seems to pose a significant problem, both for families, patients, and providers. Often, the patient wants to be cognitively intact during the day and pain free and heavily sedated at night in order to sleep comfortably. Erasing the stigma associated with ‘morphine’ and dealing with its close association with death continues to be an issue. The term ‘narcotic’ provides similar anxieties for patients and families alike.

Breakthrough or PRN doses provide an opportunity for pharmacists to become directly involved by providing appropriate recommendations for dose adjustments. Many physicians fail to recognize the need for coverage between scheduled dosing. Most PRN doses are 10 – 20% of a scheduled dose. PRN doses plus the total daily dose of scheduled doses is helpful in determining an appropriate increase, or decrease, in dosage from day – to – day to help meet patients’ wishes of comfort versus alertness.

Commonly, many healthcare providers are uneasy about increasing doses to meet the pain and breathing discomfort needs of the patient. The providers are uncertain of where the ceiling is and when a dose increase will cause respiratory depression. While we should remain cautious of the potential ability for this to occur, remember that less than 1% of all appropriately managed patients will experience opioid-related respiratory depression.

Addressing the desires of the patient while also trying to accommodate the wants of the family is reportedly one of the most difficult dilemmas to address. Advanced Illness Coordinated Care, or AICC, helps to accomplish this easier by instituting palliative care and transitioning the patient gradually from acute intervention to full supportive measures when time allows.

Ferris et al.




AGS Panel on Persistent Pain in Older Persons. “The Management of Persistent Pain in Older Persons.”JAGS.2002;50(6):S205-S224.

Ballantyne JC, Mao J. “Opioid Therapy for Chronic Pain.”NEJM.2003;349(20):1943-1953.

Barry PH et al. “Pain: Current Understanding of Assessment, Management, and Treatments.”A Collaboration of the National Pharmaceutical Council, Inc. and the Joint Commission on Accreditation of Healthcare Organizations, December 2001.

Becker N et al. “Pain epidemiology and health related quality of life in chronic non-malignant pain patients referred to a Danish multidisciplinary pain center.”Pain.1997;73:393-400.

Bernabei R, Gambassi G, Lapane K, et al.“Management of pain in elderly patients with cancer.”JAMA.1998;279(23):1877-1882.

Bruera E, Brenneis C, Paterson AH, MacDonald RN. “Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer.” Journal of Pain and Symptom Management.1989;4(1):3-6.

Bruera E, Chadwick S, Brenneis C, Hanson J, MacDonald RN. “Methylphenidate associated with narcotics for the treatment of cancer pain.” Cancer Treat Rep.1987;71:67-70.

Bruera E, Fainsinger R, MacEachern T, Hanson J. “The use of methylphenidate in patients with incident cancer pain receiving regular opiates: a preliminary report.”Pain.1992;50(1):75-77.

Chevlen E.“Opioids: A Review.” Current Pain and Headache Reports.2003;7:15-23.



Cleary JF, Carbone PP. “Palliative medicine in the elderly.”Cancer.1998;80(7):1335-1347.

Fick DM, Cooper JW, Wade WE, et al. “Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.” Archives of Internal Medicine.2003;163:2716-2724.

Ferris FD et al. “Ensuring competency in end-of-life care: controlling symptoms.”BMC Palliative Care.2002;1(5).

Foley K. “Chapter 28: Pain Management.”In: Hazzard WR, Bierman EL, Blass JP, Ettinger WH, Halter JB (Eds.). Geriatric Medicine and Gerontology, 3rd ed.New York: McGraw-Hill, 1994.

Fox CD et al. “Pain assessment and treatment in the managed care environment. A position statement from the American Pain Society.” Glenview, IL: American Pain Society; 2000.

Gagliese L, Melzack R. “Chronic pain in elderly people.” Pain.1997;70:3-14.

Hall P, Schroder C, and Weaver L. “The Last 48 Hours of Life in Long-Term Care: A Focused Chart Audit.” Journal of the American Geriatrics Society.2002;50(3):501-506.

Jacox A, Carr DB, Payne R et al. “Management of Cancer Pain.” Clinical Practice Guideline No. 9. AHCPR Publication No. 94-0592.Rockville, MD:Agency for Health Care Policy and Research, U.S. Department of Health and Human Service, Public Health Service, March 1994.

McCaffery M.Nursing practice theories related to cognition, bodily pain, and man-environmental interactions. Los Angeles, CA: 1968.UCLA Students Store.



Merskey H and Bugduk N. “Classification of Chronic Pain.” Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd edition. Seattle, WA:IASP Press, 1994.

MacFarlane BV, Wright A, O'Callaghan J, Benson HAE. “Chronic neuropathic pain and its control by drugs.”Pharmacol Ther.1997;75(1):1-19.

Morrison LJ, Morrison RS. “Palliative Care and Pain Management”. Med Clin N Am 90 (2006) 983–1004.

Savage S et al. “Definitions Related to the Use of Opioids for the Treatment of Pain.” American Academy of Pain Medicine, American Pain Society, and American Society of Addiction Medicine, 2001.

Schwartzstein RM, Lahive R, Pope A, et al. “Cold facial stimulation reduces breathlessness in normal subjects.” American Review of Respiratory Diseases.1987;136:58-61.

Sellick SM, Zaza C. “Critical Review of 5 Non-Pharmacologic Strategies for Managing Cancer Pain.” Cancer Prevention and Control.1998;2(1):7-14.

Sutton LM, Wahnefried W, and Clipp EC. “Management of terminal cancer in elderly patients.” The Lancet Oncology.2003;4:149-157.

Shimp LA. “Safety issues in the pharmacologic management of chronic pain in the elderly.”Pharmacotherapy.1998;18(6):1313-1322.

Source: Stein et al, Clinics in Geriatric Medicine 1996

Wong DL et al.Wong’s Essentials of Pediatric Nursing, 6th edition.St. Louis:2001; p. 1301.



Web Sites:

American Geriatrics Society:

American Pain Society

Lexicomp Online Drug Information Handbook.

Neurosciences on the Internet – Pain

Partners Against Pain

module 12 - pharmacotherapy for neurological disorders

Documents