adjuvant analgesics in palliative and end-of-life care mike harlos md, ccfp, fcfp professor and...
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Adjuvant Analgesics In
Palliative And End-Of-Life
CareMike Harlos MD, CCFP, FCFPProfessor and Section Head, Palliative Medicine, University of ManitobaMedical Director, WRHA Palliative CareMedical Director, Pediatric Symptom Management Service
Case Presentation
55 yo man Metastatic CA lung, large L apical tumour Chemotherapy completed, no response Metastatic disease to bone, liver Presents with worsening L arm pain and
numbness, allodynia, tingling and burning Motor exam normal
Case PresentationCurrent Medications
Morphine 100 mg po q4h
Ibuprofen over the counter
Sennosides, docusate
Adjuvant Analgesics
first developed for non-analgesic indications
subsequently found to have analgesic activity in specific pain scenarios
Common uses: pain poorly-responsive to opioids (eg.
neuropathic pain), or with intentions of lowering the total
opioid dose and thereby mitigate opioid side effects.
Adjuvants Used In Palliative Care
General / Not specific corticosteroids cannabinoids (very uncommonly used)
Neuropathic Pain gabapentin antidepressants topiramate ketamine clonidine
Bone Pain bisphosphonates (calcitonin)
inflammationedema
spontaneous nerve depolarization
tumor mass effects
CORTICOSTEROIDS AS ADJUVANTS
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IMMEDIATE LONG-TERM Psychiatric Hyperglycemia risk of GI bleed
gastritis aggravation of
existing lesion (ulcer, tumor)
Immunosuppression
Proximal myopathy often < 15 days
Cushing’s syndrome
Osteoporosis Aseptic /
avascular necrosis of bone
CORTICOSTEROIDS: ADVERSE EFFECTS
DEXAMETHASONE
• minimal mineralcorticoid effects
• po/iv/sq/?sublingual routes
• perhaps can be given once/day; often given more frequently
• If an acute course is discontinued within 2 wks, adrenal suppression not likely
Cannabinoids
As
Adjuvants
Cannabis sativa
Marijuanadried leaves, flowers
Hashishresin from leaves, buds
Isolated pure compounds (>400)
Noncannabinoids Cannabinoids
Psychoactive• 8-THC• 9-THC• cannabinol
Active, not psychoactive• cannabidiol
Inactive• > 60
Kalant, Pain Res Manage 2001
THC contentapprox. 5%
THC content10 – 20%
Cannabinoid ReceptorsCB1 And CB2
CB1 Central and peripheral nervous system Highest density in globus pallidus, basal
ganglia, substantia nigra, cerebellum, hippocampus, afferent spinal cord pathways
Main effect is neurotransmitter release –dopamine, NE, serotonin
Low levels in cardiorespiratory centres high therapeutic index
CB2 – certain nonneural tissues, eg. immune cells Cannabinoids also bind to NMDA receptors –
possible role in neuropathic pain
Kumar et al, Anaesthesia 2001; 56
The only clinical indication is in chemotherapy-induced nausea
Mixed results in human studies for pain control; animal studies suggest possible role for neuropathic pain
Double-blind, placebo-controlled trials indicate a similar analgesic potency to codeine, however high adverse effects
Cannabinoids
Marijuana Use in Pain
Five RCTs on cancer pain Tetrahydrocannabinol (THC) or nabilone
vs placebo or opioids High rate of side effects 128 pts total, single dose x-over design THC = codeine (60, 120 mg) > placebo Nabilone > placebo Higher doses had unacceptable S/E Poor evidence for pain control
Campbell et al, BMJ 323:13-16, 2001
Marijuana - Acute Effects
Increased pulse, BP unaffected or slight
Conjunctival reddening No effect on pupil size, resp. rate, DTRs Initial euphoria then relaxation Appetite stimulation Slowed reaction time, altered
perception, impaired coordination May cause paranoia, delusions,
hallucinations, depersonalization
Inhaled Marijuana
has all (except one) the same chemical carcinogens found in tobacco
> 400 chemicals High tar content Respiratory epithelium damage Obstruction on PFTs COPD in chronic users H & N, lung cancer reports
What’s A Reasonable Dose Of Inhaled Marijuana For Symptom
Control? Bioavailability of THC in smoked marijuana
ranges from 10 – 27%; significantly influenced by technique/experience
Typical cannabis cigarette has a mass between 0.5 - 1 gm
Informal surveys in US of medicinal cannabis users indicate avg. use of 10 - 20 gm/wk, or 1.42 - 2.86 g/day
Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs 2004; 7(5):464-470.
http://palliative.info
College of Physicians & Surgeons of MB
Oct. 2001 Newsletter
“Physicians who recommend, support the use of, or
prescribe this substance, must be fully
knowledgeable of the risks, benefits, potential
complications, and drug interactions associated
with its use. Based on the available scientific
evidence, the medicinal use of smoked marijuana is
at present generally without valid scientific
foundation and physicians should not feel obliged to
recommend, support, or prescribe this substance”
Oral Cannabinoids
∆9-tetrahydrocannabinol (THC; Marinol; Dronabinol)
Nabilone – synthetic derivative of THC
90 – 95% absorbed, but only 10 – 20% reaches circulation due to hepatic first-pass metabolism
1 hr to peak effect vs. 15 min. if smoked
Available Cannabinoids
Sources: Provincial Drug List; CPS 2002; Marihuana Medical Access Regulations (MMAR), April 2001, Health Canada
Available cannabinoids: Pharmacokinetics
Sources: Néron A, Le medecin du Québec 2001; Product monograph NCesamet ICN Canada 2002; Product monograph NMarinol Sanofi-Synthelabo 2002
Management of Bone Pain
Pharmacologic treatment
Acetaminophen Opioids NSAIDs – be aware of adverse effects! Corticosteroids (not with NSAIDS) Bisphosphonates: pamidronate
(Aredia), clodronate (Bonefos), zoledronate (Zometa)
Bisphosphonates
Osteoclast inhibitors bone metastases: pooled results signif. in all
skeletal morbidity end points except spinal cord compression
signif. time to first skeletal related event, suggesting they should be started when bone metastases are diagnosed
skeletal morbidity and should be continued until no longer clinically relevant
do not affect survival Most evidence supports use of IV
aminobisphosphonates, but further studies needed to determine best drug & route
Ross et al;Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327(7413):469
BisphosphonatesTolerability And Adverse Effects
1. Renal toxicity
2. Flu-like syndrome
3. Hypocalcemia
4. Avascular necrosis of the jaw
BisphosphonatesRenal Implications
Renal toxicity – IV bisphosphonates In rare cases can be life-threatening 9% of patients receiving 4 mg zoledronate and
8% of those receiving 90 mg pamidronate with normal baseline renal function developed increased creatinine levels (Rosen et al; J Clin Oncol 2003)
Should monitor creatinine before each dose, and hold repeat dosing until within 10% of baseline
Make sure patient is well hydrated prior to administration (eg. in hypercalcemia)
Bisphosphonates ctd
Flu-Like Reaction Esp. with intravenous bisphosphonates Up to 36% of patients Usually managed with acetaminophen
Hypocalcemia Usually compensate by increased PTH secretion Hypomagnesemia, previous parathyroid removal,
Vit D deficiency are risk factors Recommendations are to give 500 mg Calcium
and 400 IU Vit. D as daily supplements
BisphosphonatesAvascular Necrosis of Jaw
Robinson NA, Yeo JF. Bisphosphonates--a word of caution. Ann Acad Med Singapore 2004; 33(4 Suppl):48-49.
Greenberg MS. Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 98(3):259-260.
Schwartz HC. Osteonecrosis and bisphosphonates: correlation versus causation. J Oral Maxillofac Surg 2004; 62(6):763-764.
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62(5):527-534.
Pogrel MA. Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 2004; 62(3):391-392. Carter GD, Goss AN. Bisphosphonates and avascular necrosis of the jaws. Aust Dent J 2003;
48(4):268. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003;
21(22):4253-4254. Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer
patients. J Oral Maxillofac Surg 2003; 61(10):1238-1239. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the
jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61(9):1115-1117.
BisphosphonatesAvascular Necrosis of Jaw ctd
Retrospective chart review Feb. 2001 – Nov. 2003
63 patients with chronic osteonecrosis of jaw while on bisphosphonates; 7 for osteoporosis
4 patients during that time period with similar presentation while not on bisphosphonates; 3 of them had prior local radiation for sq. cell CA
Localized vascular insufficiency, similar to osteoradionecrosis
Correlation with dental procedures - suggest a complete dental exam prior to long-term bisphosphonate treatment, and any dental pathology addressed
Adjuvants in
Neuropathic Pain
Gabapentin
a second line anticonvulsant shown to be effective in neuropathic pain;
has become a first-line agent in neuropathic pain
structural analog of GABA, but does not bind to GABA receptors
increases concentration and synthesis of GABA in the brain
GABA receptors have been shown to mediate pre- and postsynaptic inhibition in sensory afferent fibers
Gabapentin
Common Starting Regimen 300 mg hs Day 1, 300 mg bid
Day2, 300 mg tid Day 3, then gradually titrate to effect up to 1200 mg tid
Frail patients 100 mg hs Day 1, 100 mg bid Day
2, 100 mg tid Day 3, then gradually titrate to effect
TCAs
increase in monoamine activity in descending pain modulating pathways
inhibition of reuptake of NE and serotonin at spinal dorsal horn synapses
alt. mechanisms include blockade of Na+ channels, GABA effects, K+ channel blockade, adenosine
neuropathic pain, esp. continuous dysaesthesia anticholinergic adverse effects; amitriptyline >
nortriptyline > desipramine lower doses and earlier response than
depression
SSRIs And Newer Antidepressants
less convincing evidence for independent analgesic effects; those affecting both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs
newer meds with mixed neurotransmitter effects:1. Serotonin and Noradrenergic Reuptake Inhibitors
(SNaRI) – eg. Venlafaxine (Effexor), nefazodone (Serzone), duloxetine
2. Noradrenergic and Specific Serotoninergic Antidepressants (NaSSA) – eg. mirtazapine (Remeron)
3. Noradrenaline Reuptake Inhibitors (NaRI) – eg. reboxetine
Topiramate
Multiple neurostabilizing actions: anti-glutamate effects at AMPA receptors;
blockade of voltage activated Na+ channels; enhancement of GABA-mediated neuroinhibition; inhibition of L-type high voltage-activated Ca++ currents; activation of potassium conductance
Neuropathic Pain Consider if gabapentin failed Typically start with 25 mg/day Effectiveness demonstrated in diabetic neuropathy Ocular adverse effects include secondary angle-
closure glaucoma, transient myopia, and uveal effusions
Decreased serum bicarbonate in up to 67%
Ketamine Disassociative anesthetic Analgesic in subanesthetic doses Most potent NMDA receptor antagonist available
for clinical use NMDA-receptor activation is associated with
windup, hyperalgesia and reduced opioid sensitivity.
Ketamine is widely used in cancer pain to improve opioid analgesia when tolerance has developed or the pain is considered to be opioid resistant.
Randomised and controlled trials are rare; data from two of these trials suggest potential benefit of ketamine as adjuvant to morphine in cancer pain (Bell et al., 2003).
Ketamine
Often use oral dosing of intravenous preparation
A common starting dose is 10 mg qid po (low dose)
Concomitant benzodiazepine administration may attenuate adverse CNS effects (eg. Lorazepam 0.5 – 1 mg sl bid – tid)
Decrease concurrent opioid dose by 25 – 50%
Clonidine
alpha-2 agonist decrease sympathetic transmitter release
through pre and post-synaptic inhibition Considered in refractory neuropathic pain Literature predominantly regarding spinal
administration Recent literature suggests possible
topical role
Calcitonin
Osteoclast inhibition Cochrane review 2003: “The limited
evidence currently available for systematic review does not support the use of calcitonin to control pain from bone metastases. Until new studies provide additional information on this treatment, other therapeutic approaches should be considered ”
Case Presentation ctd
Rule out opioid-induced neurotoxicity d/c NSAID Add gabapentin and dexamethasone Consider:
CT to determine anatomy; ? Radiation Methadone Ketamine TCA Topiramate Spinal analgesia
Opioid-Induced Neurotoxicity (OIN)
Potentially fatal neuropsychiatric syndrome of:
Cognitive dysfunction Delirium Hallucinations Myoclonus/seizures Hyperalgesia / allodynia
Increasing incidence – practitioners more comfortable and aggressive with opioids
NMDA receptor involved Early recognition is critical
Seizures,Death
Opioidtolerance
Mild myoclonus(eg. with sleeping)
Severe myoclonus
Delirium
Agitation
Misinterpretedas Pain
OpioidsIncreased
Hyperalgesia
Misinterpretedas Disease-Related Pain
OpioidsIncreased
Spectrum of Opioid-Induced Neurotoxicity
OIN: Recognition
Myoclonus – twitching of large muscle
groups
Delirium
Rapidly escalating dose requirement
Pain “doesn’t make sense”; not
consistent with recent pattern or known
disease
OIN: Treatment
Switch opioid (rotation) or reduce opioid dose; usually much lower than expected doses of alternate opioid required… often use prn initially
Hydration
Benzodiazepines for neuromuscular excitation