the topical pain relief revolution · 1 the topical pain relief revolution: principles and practice...
TRANSCRIPT
1
THE TOPICAL PAIN RELIEF REVOLUTION:
PRINCIPLES AND PRACTICE OF
COMPOUNDING PHARMACY
●STEPHEN HOLT, MD, PhD, DSc, LLD, DISTINGUISHED PROFESSOR OF MEDICINE (Emeritus),
●UZOMA NWOSU, MD SCIENTIFIC OFFICER, NUMEDCARE LLC, BOCA RATON, FL.
●CLIFFORD B. CARROLL SCIENTIFIC OFFICER, NUMEDCARE LLC, BOCA RATON, FL.
www.numedcare.com
Published by the HOLT INSTITUTE OF MEDICINE, Little Falls, NJ 07424. www.hiom.org
2
BOOK DATA
Copyright 2013 in all languages. Parts of this book can be quoted or reproduced on the understanding that the source of the material is acknowledged. The authors of this book have relied to a variable degree on contemporary information that is published by others in review format (see acknowledgements)
Title: Topical Pain Control: Principles and Practice of Compounding Pharmacy
Authors: Stephen Holt MD, Uzoma Nwosu MD, Clifford B. Carroll
Library in Catalogue
ISBN: 978-0-9830793-4-7
Copyright © Stephen Holt MD, Holt Institute of Medicine
KEY WORDS
1. Pain control, 2. Topical pain control, 3. Topical analgesia, 4. Compounding pharmacy.
3
TABLE OF CONTENTS FOREWORD ..................................................................................................... 5
ACKNOWLEDGEMENTS ................................................................................... 7
NuMedCare: Compounding Excellence ....................................................... 8
INTRODUCTION .......................................................................................... 9
DRUG OVERDOSE EPIDEMIC ....................................................................... 9
ECONOMICS AND COMPOUNDING PHARMACY ....................................... 12
DISADVANTAGES OF ORAL OR PARENTERAL ANALGESICS ....................... 13
ADVANTAGES OF TRANSDERMAL DELIVERY ............................................. 15
ADHERENCE TO MEDICATION REGIMENS (COMPLIANCE) ........................ 19
CONCEPTS OF ADJUVANT ANALGESICS ..................................................... 22
OTC PAIN RELIEF ....................................................................................... 26
TOPICAL DELIVERY OF MEDICATIONS ....................................................... 27
TYPES OF ANALGESICS FOR TOPICAL USE ................................................. 29
NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) ........................ 30
TOPICAL PREPARATIONS OF NSAID FOR TENNIS ELBOW .......................... 35
NEUROMODULATORS ............................................................................... 37
OPIOIDS .................................................................................................... 38
ANESTHETICS ............................................................................................ 41
AMITRIPTYLINE ......................................................................................... 43
CAPSAICIN ................................................................................................. 44
NMDA RECEPTOR ANTAGONISTS .............................................................. 47
AMANTADINE ........................................................................................... 49
KETAMINE ................................................................................................. 50
CLONIDINE ................................................................................................ 57
4
SYNERGY IN PAIN CONTROL ..................................................................... 58
CLINICAL APPLICATIONS ........................................................................... 59
CLINICAL CONCEPTS OF PAIN CONTROL ................................................... 60
Compounded Products: An Overview ...................................................... 62
TOWARDS THE APPLICATION OF TOPICAL AGENTS .................................. 64
Dermatomal Directions ............................................................................ 65
Payment for Compounded Pain Medications ........................................... 67
References ................................................................................................ 68
5
FOREWORD
John Salerno DO This monograph is a very useful guide for all practicing
physicians. It provides a contemporary review of how many different pain medications can be used in the effective induction of topical analgesia. Dr. Holt is an internationally acclaimed expert in Integrative Medicine, and he makes valuable contributions to the important subject of topical pain control.
In this overview, the authors teach us that customized options for pain medication provide alternate dosages in topical forms. These medications can be applied directly to the area to be treated. The use of combined formulae may permit the use of medications in localized topical dosage forms with enhanced safety. Synergistic formulations result in an ability to reduce dosages or apply beneficial strength variations.
To further summarize matters, one can refer to the relative advantages of topical pain control: Topical Versus Oral Benefits
Reduction in side effects.
Lack of gastrointestinal side effects.
Fewer systemic side effects.
Localized relief of pain and inflammation.
Dose reductions.
Reduced addictive potential.
Increased adherence/patient compliance. This book highlights the value of alternatives to oral or
parenteral use of analgesics with the definition of a special role for the compounding pharmacists. This work is timely
6
with the recent calls to limit prescriptions of drugs that have the capability of inducing dependence or addiction.
I recommend this book highly for its role as a basic introduction to the topical pain control revolution that is gaining momentum in clinical practice in the U.S.A.
John Salerno DO, 2013 Salerno Center, Madison Avenue, New York, NY www.salernocenter.com
7
ACKNOWLEDGEMENTS
The authors thank Todd Stephens of NuMedCare LLC, Boca Raton, Florida for his help and support in producing this work. The authors acknowledge the excellent work of several contemporary authors, and they cannot do justice in this short monograph to all current studies in the rapidly expanding literature on this subject which is expanding rapidly. Of special note and reference is the work of Jorge et al., J. Pain Res., 4, 11-24, 2011, Argoff CE, Current Pain and Headache Reports, 7, 34-38, 2003, Current Science, Jamero et al, reference: http://www.uspharmacist.com/content/feature/i/1500/c/2 82821, and Lusser et al, The Oncologist, 2004;9.
8
NuMedCare: Compounding Excellence
NuMedCare LLC is a research and development
corporation that manages and consults with pharmacies
providing synergistic topical compounded drug
formulations for pain control and other conditions. The
company also consults with physicians and other providers
in the development of transdermal medication programs
that can be tailored to a patient’s need (customized
prescriptions).
Physicians and patients using the service of NuMedCare
LLC have access to pain management experts and technical
pharmacy staff who prepare compounded drugs. Many
insurance companies and managed care companies cover
the cost of topical analgesics including: HMO’s, PPO’s,
workers compensation and personal injury coverage.
NuMedCare, LLC has specially trained staff who can work
with third party payers to assist in billing claims.
NuMedCare LLC is located in Boca Raton, Florida but is
able to service patients and physicians in multiple states.
The staff is readily accessible and bilingual (English and
Spanish). Patients can contact [email protected].
9
INTRODUCTION
Compounding pharmacy has revolutionized the topical control of pain with the provision of effective synergistic analgesia. In these circumstances, tailor made combinations of pain-killing medications are presented in unique dosage forms such as creams, gels, ointments, oral lozenges, delayed release formulations, emulsions or suspensions. This practice permits the use of carefully individualized topical preparations that have advantages over standard oral or parenteral forms of analgesic drugs. Topical preparations can replace standard analgesic drug administration, assist in optimal pain control and improve patient compliance. The objective of this review is to guide the physician and pharmacist in a joint approach to efficient systemic and local pain management.
DRUG OVERDOSE EPIDEMIC
At the time of writing, the media was alive with reports of increasing numbers of overdose deaths from drugs. Reports from the Center for Disease Control (CDC) in Atlanta, Georgia indicate that opiate pain-relieving drug deaths increased dramatically from 1999 to 2010. In preceding times, the majority of overdose deaths from drugs occurred in men as a consequence of the consumption of heroin or cocaine. It now appears that overdose deaths in the United States are increasing rapidly among middle-aged women with prescription pain-relieving medication as the main culprit. This alarming increase in overdose death rates is coincidental with an increase in the
10
overall use of prescribed pain-killer drugs. The CDC has reported that the number of prescription pain-killer deaths increased among females by a factor of five times in the period of 1999 to 2010. In contrast, death rates from overdose rose about 3.5 times in men in the same period of time.
It would appear that men may take more risks with drugs than women and they may have a higher prevalence of injuries in the work place which result in the prescription of potent analgesic drugs. In 2010, approximately 23,000 deaths from pain killing drugs were noted in men, compared with 15,300 in women. Drug overdose death rates have risen continuously over the last eleven years and most of these are the result of accidents involving the use of addictive painkillers. Sometimes multiple drugs are involved, with alcohol. There have been a number of initiatives taken to try and control the growing use of painkilling drugs but the problem continues with stubborn persistence. In the year 2010, the CDC reported 38,329 drug overdose deaths nationwide and nearly 60 percent of these deaths were caused by prescription drugs. This circumstance overshadows the number of deaths caused by the use of illicit narcotic drugs, such as heroin or cocaine.
It would appear that opioid drugs (oxycontin and vicodin) are the biggest problem because they contribute to three out of four of all prescription medication overdose deaths. Several reasons are responsible for this serious situation. First, these opioid drugs are prescribed too often and patients may be exposed to “pill mills” where adequate care concerning use of dangerous drugs is absent. Patients
11
may “doctor hop” for drug prescriptions and it is clear that middle-aged women are more likely to have chronic pain which results in the prescription of higher dosages of analgesic, compared with men. This is a dangerous situation because drug toxicity is more likely in women who have a smaller body size than men. There is some evidence that women are more likely to attend multiple doctors and obtain drugs from these physicians. This circumstance of excessive pain-killing drug use persists despite efforts to monitor drug prescriptions. Several solutions have been suggested including counseling on addiction and alternative interventions for chronic pain. Data from drug monitoring programs are available in most states but few physicians avail themselves of this information for patient management. These matters are highly complex because of the need for patient confidentiality.
In January 2013, a federal panel of drug safety specialists recommended that vicodin and many other pain medications be subject to the same restrictions as the narcotic drug, oxycodone. The CDC have focused attention on reporting the dangers of prescription opioids (vicodin and oxycontin), but problems exist with generic forms of these medications, methadone and powerful new drugs such as Opana (oxymorphone). In brief, an alarming finding is the major increase in drug overdose death rates in women ages 45 through 54 and 55 through 64. The rate of deaths for each of these groups of women increased three fold between 1999 and 2010. In response to these problems many hospitals have started to apply appropriate restrictions on the prescription of pain-killing medications.
12
Much information has appeared in popular literature about the progression of patient’s use of pain-killing medications from prescription drugs to illicit narcotics. Many opioid pain-killing drugs are of high addictive potential and the relief of discomfort felt with these drugs is followed by a downside feeling of withdrawal. This vicious cycle of relief or pleasure perpetuates drug habituation. It is estimated that 12 million Americans use non-medically approved opioid analgesics in the year 2010. The opioids act to release dopamine, an excitatory neurotransmitter, which results in secondary sensations of comfort and satisfaction. The saturation of brain opioid receptors makes it necessary for the patient to increase dosages to gain desired effects.
It is clear that there is a serious threat to public health posed by several pain killing drugs, most notably opioids. One important potential approach to this problem is to use topical pain control when possible. Topical pain control will not produce the same circumstances of potential addiction that occur with standard oral dosing. Any intervention that reduces the exposure of patients to the addictive potential of opioid drugs or other neuromodulating agents can make an important impact on public health.
ECONOMICS AND COMPOUNDING PHARMACY
Trevor Stokes (TimesDaily.com, April 2011 and May 2013) reports that drugs delivered through the skin generated revenue of billions of dollars in 2009, according to the independent work of Market Research News. It is
13
estimated that compounding pharmacists make about 1-3% of the prescription topical drug market which is generating high revenue.
This circumstance has contributed to activity in the pharmaceutical industry where “old drugs” are selected and put through an FDA approval process. Stokes (ibid, 2011 and 2013) points out that this circumstance is very lucrative for the pharmaceutical industry; and he quotes the example of Hydroprogesterone use to prevent pre-term labor where costs per injection escalates one hundred fold ($15 per injection to $1,500 per injection) with this proprietary shift in medication. While concerns exist about the expense of compounding pharmacy, in the presence of such economic shifts, compounding pharmacy may benefit cost-containment in several circumstances.
DISADVANTAGES OF ORAL OR PARENTERAL
ANALGESICS
There are many classes of standard oral or parenteral analgesic medications. The most common type of oral analgesics includes acetaminophen or non-steroidal anti- inflammatory drugs (NSAIDs). Acetaminophen preparations may be effective in mild to moderate pain relief, but they have a propensity to cause hepatic toxicity, especially in large dosages.
Acetaminophen overdose is the most common cause of acute liver failure. This has resulted in new warnings on acetaminophen medications with advice to lower daily maximum dosage from 4 grams to 3,250 mg per day. In
14
2005, studies performed in more than 9,000 participants showed that many individuals took over the counter (OTC) pain relievers such as ibuprofen and aspirin in what has been described as an inappropriate and potentially dangerous manner.
It is notable in reviews of the use of NSAID-type analgesics that many subjects are unaware of the potential side effects of gastro-intestinal upset, headache, renal damage and bleeding from the gastro-intestinal tract. More recent studies in 2012 have found that a significant number of individuals are at risk of overdosing on OTC pain medications (e.g. acetaminophen). Furthermore, two dozen or more non-prescription (over the counter, OTC) non-steroidal anti-inflammatory drugs (NSAIDs) have common and potentially onerous side effects to a degree that they are a major public health concern.
To review the status of NSAID usage, it is apparent that many millions of Americans with bone and joint problems are “gobbling” aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). Common side effects of NSAIDs include stomach upset that can herald the onset of peptic ulcer, and the precipitation of life-threatening bleeding from the upper or lower digestive tract. In addition, liver and kidney problems are relatively common with NSAID use. Certain types of NSAIDs are associated with a risk of stroke or heart attack. Unfortunately, the side effects of NSAIDs are sometimes fatal, especially in the elderly, who represent the main target population who take these drugs, and to whom these drugs are often selectively marketed.
For these reasons, many people have sought alternative management strategies for bone and joint health, including
15
the use of dietary supplements. While dietary supplements for bone and joint health are not drugs or considered substitutes for drugs (at law), many doctors and their patients are using dietary supplements to manage simple arthritis, especially osteoarthritis. This approach can occur only with statements that stress the use of “nutritional support for bone and joint structure and/or function.”
More potent pain killing drugs are limited in their use by their ability to produce dependence or frank addiction. For example, opioids are limited in their use by central nervous system effects, respiratory depression and failure to control arthritic pain in some circumstances-vide infra. The relative advantages and disadvantages of several analgesics are reviewed later in this overview.
ADVANTAGES OF TRANSDERMAL DELIVERY
Pain resulting from surgery, traumatic injury, malignant disease, neuropathic diseases (e.g. diabetic, chemotherapy induced, or HIV neuropathy), arthritis, or musculoskeletal pain, are all amenable to the application of topical pain relief compounded preparations. One clear advantage of cutaneous application of analgesia is direct application to the source of the pain. The absorbed pain relief drugs from the topical application can have variable bioavailability, but the cutaneous administration of the drugs tends to produce local pain relief effects. Topical delivery prevents extensive first-pass metabolism that occurs in the liver, most notably when drugs are given by the oral route.
16
There are many drugs that can be placed into specially compounded emulsions that permit absorption of the active moieties through the skin. Classes of drugs that can be compounded in topical formulations include: tricyclic antidepressant drugs, anticonvulsant compounds, NMDA antagonists, NSAID, muscle relaxants, GABA agonists and anesthetic agents. Examples of the successful use of transdermal medications are shown in table 1.
MEDICATION CONCENTRATION (%)
MEDICAL USE
Ketamine 5-20 May combine with Clonidine, 2 and Gabapentin 6
Neuropathic pain, herpetic and myofascial trigger points, neuralgia, by local analgesia.
Magnesium Chloride
10 Fibromyalgia
Ketoprofen 10-20 Anti-inflammatory May combine with effects, low back ketamine 10% pain, arthritis Cyclobenzaprine, and Buvipavcaine 0.5
Amitriptyline 2 May combine with Baclofen or capsaicin
Local analgesia
Gabapentin 6 Local analgesia
17
Clonidine 0.1-0.2 Local analgesia Lidocaine 1-2 Local analgesia
Legend to Table 1. Medications and typical concentrations used for specific disorders, alone or in combination. References:
Chi SC. Jun HW: Anti-inflammatory activities of Ketoprofen gel in carrageenan-induced paw edema in rats. J Pharm sci 79:974-991. 1990.
Lynch ME. Clark AJ. Sawynok J: A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain 19:323-328, 2003.
Carlton SM, Zhou S: Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin. Pain 76:201-207, 1998.
Gammaitoni A. Gallagher RM, Welz-Bossna M: Topical ketamine gel: possible role in treating neuropathic pain. Pain Med 1:97-100,200.
Schwartz SI. Allin D. Kipness MS: Dose ranging and tolerance study of 0.05% clonidine gel in patients with painful diabetic neuropathy. Program and
abstracts of the 19th Annual Scientific Meeting of the American Pain Society: November 2-5, 2000: Atlanta, Georgia. Abstract 671.
Alongside these limited examples of compounded topical pain relief preparations comes information relevant to further advantages of this mode of treatment. Topical pain control appears quite safe except for the occurrence of occasional local reactions (e.g. pain and irritation caused by
18
agents such as capsaicin) or occasional allergic reactions to a variety of drugs.
Topical delivery can result in short-lived stable levels of drugs, but repeated applications, up to four times daily, may be necessary in several circumstances. The use of topical agents in combination can result in synergistic effects, which tend to enhance pain control.
There is clear and substantial evidence that certain combinations of topical agents can effectively block nociceptive and neuropathic pain. Compliance with cutaneously applied analgesia is good as a consequence of a diminished need to take multiple dosages of oral medication and opportunities for the simplification of dosing. Overall, “topical” application of drugs can reduce the central nervous system effects (cognitive impairment) of many drugs (e.g. opioids) and in some cases it can overcome treatment failure with pain-killer drugs or result in reduced dosages that are required for pain control.
While scientists have discussed the placebo effect of local administration of analgesics to the site of the pain, such an effect is quite advantageous. This is the case even in referred pain from distant sources. Placebo effects can alter clinical outcomes of pain control and ancillary adverse effects, such as nausea or digestive upset. In the case of NSAIDs, which are a common cause of dyspepsia when administered orally, topical application can still result in uncommon occurrences of damage to the gastrointestinal tract, but it is much less than that encountered with oral administration of these drugs.
In summary, evidence has accrued that topical analgesics can often be as effective as pain killing drugs when taken
19
orally. While most experience with topical analgesia has been derived from studies in adults, there is increasing success in the use of topical pain control in pediatric populations. However, the pharmacokinetic properties of various drugs may differ between adults and children.
ADHERENCE TO MEDICATION REGIMENS (COMPLIANCE)
Complex factors determine the extent of matching of a prescribed treatment regimen to a patients’ intake of medication (adherence). In other words, “adherence” is a measure of how well the patient “sticks with” the prescribed regimen. Simple conclusions can be inferred about adherence and have been confirmed in clinical studies. For example, simple dosing regimens (once daily) in patients with chronic symptoms indicate that adherence is substantially higher compared with frequent dosing schedules (Claxton et al., Clin.Ther. 23,8,1296-1310, 2001). A number of co-existing factors alter adherence to medication (Jorge et al, J. Pain Res, 4, 11-24, 2011):
- presence of depression or substance abuse history - social support systems - socioeconomic status - patient – clinician relationships - chronicity of disease - symptom burden - mechanisms of healthcare delivery - characteristics of treatment regimens.
20
The above listed circumstances should be optimized to produce good clinical outcome with topical pain treatments. Adjustment of dosing schedules to avoid side effects is important because a principal barrier to compliance is high dosing with attendant side effects. It appears that long half-lives of certain drugs may favor compliance by reducing the complexity or number of dosages required in one day. This knowledge reinforces the value of synergistic topical analgesic programs.
Other factors that can assist in ensuring adherence include consultation with relatives who can assist in the compliance of the patient, and supportive psychotherapy. Furthermore, close patient follow up and telephone or written prompts may be of value, but these latter attempts to improve compliance may result in variable success. More studies are required with the application of topical pain relief to identify important variables in clinical outcome.
Jorge et al (ibid 2011) have summarized a description of different strategies, that vary by disease, to improve patient adherence. Many of these examples of improving adherence can be modified and made portable to circumstances of topical pain control. The following is quoted from Jorge et al 2011.
- Patient awareness of breast cancer has increased and physicians are required to provide information regarding treatment goals and adverse effects of drugs, which are frequent and disabling. These issues influence compliance.
21
- Among patients with cardiac failure, the main predictor for cardiac rehabilitation was the physician’s endorsement of the effectiveness of program. Adherence increase when patients were actively referred, educated, highly self-motivated, and when programs were easily accessible.
- The major barriers for a good glycemic control include low efficacy of oral hypoglycemic drugs, fear of hypoglycemia, issues related to convenience of treatment (subcutaneous route, invasive blood sugar monitoring), poor access to health services, and lifestyle, leading to low adherence.
- Educational sessions, psychotherapeutic interventions, and phone prompts in community psychiatric services increase adherence of psychotic patients.
- Factors associated with poor treatment adherence among patients undergoing renal replacement therapy or under dialysis are frequent dosing, patient’s perception of treatment benefits, poor patient-physician communication, lack of motivation, and low socioeconomic background. Strategies for compliance are not well established, but some are suggested: treatment regimen simplification, establishing a partnership with the patient, and education.
- The most striking barrier to medication adherence in multiple sclerosis is forgetfulness to take pills, coping with adverse effects and perceived lack of efficacy. Validated strategies include good provider-patient
22
relationship, continuous education, and reinforcement regarding the benefit of treatment.
- Non-adherence of chronic obstructive pulmonary disease in 40%-60% as opposed to asthmatic patients, who adhere to inhalers and rescue medication. Economic factors and health beliefs influence device selection.
- Long-term adherence for asymptomatic conditions such as arterial hypertension is 50%. For these patients, adverse effects related to antihypertensive therapies and costs threaten treatment adherence. The most commonly used method to increase compliance in dyslipidemia and hypertension is dosing schedule modification from twice to once a day dosing.
DIFFERENT STRATEGIES IMPROVE PATIENT ADHERENCE IN A VARIETY OF DISEASES
CONCEPTS OF ADJUVANT ANALGESICS
In an excellent reviewed article, Lussier et al discussed
the characteristics and use of adjuvant analgesics in cancer
23
pain management. The term “adjuvant analgesic” refers to
drugs that have a primary indication other than pain
treatment, but they have analgesic properties in some
painful disorders. While they can be used alone to manage
pain, they are usually administered with other pain killing
medications e.g. acetaminophen, NSAID and Opioids. In
this circumstance, the use of adjuvant analgesics is referred
to as “co-analgesics”. This use of co-analgesia may result in
the reduction of the dosage of a pain killer and improve
pain that has not responded to the primary analgesic drug.
Sparing the dosage of opioids is particularly valuable in
reducing drug side effects.
Many different types of drugs can be used as adjuvant
analgesics and some are multi-purpose in their function.
Types of adjuvant analgesics include: antidepressants,
corticosteroids, a2-adrenergic agonists, neuroleptics,
whereas others are specific for neuropathic pain (anti-
convulsants, local anesthetics, N-methyl-D-aspartate
receptor antagonists), bone pain (calcitonin,
bisphosphonates, radio-pharmaceuticals), musculoskeletal
pain (muscle relaxants), or pain from bowel obstruction
(octreotide, anti-cholinergics).
There have been few direct comparisons of the relative
benefits of adjuvant analgesics. The clinician should
attempt to select the optimal adjuvant analgesic by
consideration of the underlying diagnosis and satisfaction
24
so that the drug addition is compatible with the patient’s
status. Certain types of pain match individual categories of
adjuvant analgesic and sometimes other disorders
associated with the painful addition may benefit from the
use of a specific drug. For example, the drug Cymbalta® is
an antidepressant with specific benefit in patients with pain
from diabetic peripheral neuropathy. This drug not only
affords pain relief but it also exerts antidepressant effects.
Chronic pain is often associated with depression.
There is general agreement that it is advantageous to
start treatment with one drug at a time so that additive
toxicity can be avoided (Lussier et al (ibid, 2004). Factors
that guide the use of adjuvant analgesic in the management
of cancer pain are listed below and taken verbatim from the
review article by Lussier et al (ibid), 2004.
1. Consider optimizing the opioid regimen before
introducing an adjuvant analgesic.
2. Consider the burdens and potential benefits in
comparison with other techniques used for pain that
is poorly responsive to an opioid, including: A) opioid
rotation. B) more aggressive side-effect
management. C) a trial of spinal drug administration,
and D) trials of varied non-pharmacologic approaches
for pain control (e.g. nerve blocks, rehabilitative
therapies, and psychological treatments).
25
3. Select the most appropriate adjuvant analgesic based
on a comprehensive assessment of the patient,
including inference about the predominating type of
pain and associated factors (co-morbidities) or
symptoms.
4. Prescribe an adjuvant analgesic based on knowledge
of its pharmacological characteristics, actions,
approved indications, unapproved indications
accepted in medical practice, likely side effects,
potential serious adverse effects, and interactions
with other drugs.
5. The adjuvant analgesics with the best risk-benefit
ratios should be administered as first-line treatment.
6. Avoid initiating several adjuvant analgesics
concurrently.
7. In most cases, initiate treatment with low doses and
titrate gradually according to analgesic response and
adverse effects.
8. Reassess the efficacy and tolerability of the
therapeutic regimen on a regular basis, and taper or
discontinue medications that do not provide
additional pain relief.
9. Consider combination therapy with multiple adjuvant
analgesics in selected patients.
26
OTC PAIN RELIEF
Before reviewing prescribed compounded topical analgesics, it is relevant to briefly review over-the-counter (OTC) pain relief products. These products are not as potent as prescription medication and often have limited absorption of certain ingredients, thus nullifying their effect.
Unlike topical compounded pain products, few of these OTC products have delivery mechanisms that would drive an analgesic through the skin. That said, some products have temporary pain relief actions with potential effects on mild to moderate local pain. The most common effects of OTC pain relievers is to mask pain by producing a heating or cooling effect that may also be achieved variably by hot or cold-pack treatments.
Ingredients in over-the-counter (OTC) topical pain medications include capsaicin (from hot peppers), salicylates (aspirin-like compounds) and essential oils (camphor or menthol). Capsaicin has special uses in compounded pain creams. It is derived from hot peppers and produces a burning sensation when eaten or applied on a topical basis. It will be described in more detail later in this review. Examples of commercially available, low dose capsaicin topical products include Capzaisin ® and Zostrix®.
Salicylates are the prime example of NSAIDs and are available as Aspercreme ® and Biofreeze®. It is important not to mix OTC analgesic products with compounded pharmacy preparations for fear of interaction.
27
TOPICAL DELIVERY OF MEDICATIONS
The stratum corneum of the skin provides a barrier that limits the cutaneous absorption of many compounds. In topical pain control substances, the pharmacist may add agents that facilitate the transport of drugs through the skin. Physico-chemical factors of additives to pain creams work in different ways including: increasing absorption, diluting drug concentrations, retaining the drug at the target site, decreasing drug clearance and enhancing permeation, with attempts to decrease drug toxicity. One overriding objective is to reduce systemic absorption, in comparison to oral or parenteral administration, without interfering with analgesic effects. As mentioned earlier, the compounded preparation, when applied topically, can reduce first pass hepatic metabolism and sometimes contribute to stable blood concentrations of the administered drug. However, topical analgesia is capable of being produced by many agents that have negligible systemic bioavailability.
The effects of topical drug administration are altered by many factors, other than the relatively impenetrable barrier of the stratum corneum. These factors include: inter- individual (and some degree of intra-individual) difference in absorption (drug penetration amounts and rates), the degree of penetration into the subcutaneous areas and toxic or allergic properties of delivered drugs. Factors such as blood flow, lymphatic flow, the presence of carrier substances and ambient conditions can all affect transdermal transfer of drugs.
28
The site of application of the topical drug can affect absorption amounts and rates, as can specific factors such as pH, temperature, lipophilic or hydrophilic properties of the drug etc. As noted earlier, differences in response can be expected in children versus adults, and special caution should be applied in pediatric care.
Physical factors have been variably applied to modulate the transdermal uptake of drugs using electricity (iontophoresis), sound waves (phonophoresis) and even simple massage. Massage is to be avoided because of inconsistent effects. Special combinations of cooling (hypothermia) with iontophoresis have shown to increase levels of topically applied sodium diclofenac and prednisone in synovial fluids (Sammeta et al, Pharm. Res, 26, (11), 2535-40, 2009). Many studies in animals have confirmed the ability of physical methods to enhance drug concentrations in joints.
Innovations in the delivery of analgesic drugs include the use of biodegradable, implantable, controlled- drug delivery systems, and the addition of novel agents to topical preparations. Specially compounded emulsions can help in drug absorption. Pure powdered medications are obtained by pharmacies from licensed vendors which can be blended and placed into a gel or cream base. Milling of the preparations to a small particle size is an important step in enhancing transdermal bio-availability of drugs.
For example, lecithin or ganogel provides a suitable matrix for transdermal drug absorption, and pluronic lecithin ganogel (PLO) mixed with isopropyl palmitate acts as a surfactant with low toxicity and little irritation to the skin (Brown S, Tech. Reg. Anes and Pain Mgmt., 12, 199-
29
121, 2008). Other valuable additives to topical pain preparations include wetting agents, (e.g. ethoxy diglycol), which assist in the deposition and holding of medication within the skin (Ritschel et al, Skin Pharmacol, 4, 235-245, 1991, cited by Brown S, ibid, 2008).
A number of different patches have been developed for the topical delivery of a variety of analgesics. Some may cause minor irritation with occasional severe local inflammatory reactions. In general, the use of single agents is most common, and they are produced with a variety of additives to improve transdermal transfer, but the “power of synergy” in analgesic combinations is most advantageous – vide infra.
TYPES OF ANALGESICS FOR TOPICAL USE
Different properties of analgesics permit the selection of combination creams, gels or lotions which may possess different carrier mechanisms. The main classes of medication used in compounded pharmacy preparations are summarized below (Table 2).
CLASS OF MEDICATION
EXAMPLES
Non-Steroidal Anti Inflammatory Drugs (NSAID
Diclofenac, Ibuprofen, Ketoprofen, Piroxicam, Baclofen, Ketorolac (Tromethamine), Naproxen Flurbiprofen
Opioids Buprenorphine, Fentanyl
30
Anesthetics Lidocaine, Prilocaine, Tetracaine Capsaicin Zostrix®Qutenza® Capzasin P®
Zostrix HP®
Nitroglycerin Organic nitrate, Nitro Dur®, Nitrodisc®, Transderm - Nitro®Glyceryl Trinitrate
Ketamine Kealar®, Ketanest®, Ketaset® (with hydrogel or ganogel, Pluronic®, PLO)
Clonidine Catapres TTS®
Legend to Table 2. Examples of classes of drugs that are
used in topical analgesic preparations produced in a
compounding pharmacy.
NON STEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDs)
Direct comparisons of the safety and effectiveness of
topical NSAIDs have not occurred in a systematic manner.
Each NSAID has unique pharmacokinetic and
pharmacodynamic properties when given orally, but topical
dosages of NSAIDs (creams, gels or sprays) are designed to
31
produce peripheral (local) effects on pain without
significant systemic absorption and bio distribution.
The application of topical NSAIDs is to improve patient
tolerance, especially with reduction of gastrointestinal side
effects. As tolerance improves, compliance should
improve. In one systematic review of 3455 individuals with
musculoskeletal disorders (mainly sprains) good levels of
pain control were encountered without the adverse
systemic effects of orally administered NSAIDs ( Massey et
al, Cochrane Database Syst Rev. June 16, 6, CD 607402,
2010, cited by Jorge et al; ibid 2011).
The topical application of NSAIDs results in the
development of high concentrations of the administered
drug in subcutaneous tissues and local muscles, with
considerable reduction in gastrointestinal side effects. In
addition, there is a reduction in blood levels of the drug to a
level of 5-15% of the levels encountered with a systemically
administered drug. It is noted that synovial levels of NSAIDs
increase when topical application occurs. This assists in
producing prolonged analgesic effects.
Topical NSAIDs provide valuable relief in chronic pain
of osteoarthritis (Jorge et al ibid 2011). Jorge et al (ibid
2011) quote the opinions of the European League Against
Rheumatism and the International Osteoarthritis Research
Society that topical NSAID for mild to moderate knee and
32
hand arthritis are preferred over oral NSAIDs, in patients
with “sensitivity” to oral compounds. Other guidelines
concur with those opinions. For example, in Great Britain,
guidelines (NICE) suggest a preference for the use of
acetaminophen alone or in combination with topical
NSAIDs, compared with opioids or oral Cox-2 inhibitor drugs
or oral NSAID (Conaghan et al, BMJ, 336, 502-3, 2008).
The effects of various topical NSAIDs on the induction of
analgesia have been pieced together from a variety of
animal experiments, with controlled observations mainly of
single agents (NSAIDs) in humans. For example, in an in
vitro inflammatory/pain model, Ketorolac Tromethamine
gel, delivered by phonophoresis, had a lower permeability
coefficient than Ibuprofen, Piroxicam and Diclofenac,
delivered in the same way (Yang et al, Arch. Pharm Res. 31,
511-7, 2008). More studies of this type are required to
compare absorption of topical NSAIDs, but extrapolation of
the results from animal experiments to humans are
sometimes problematic.
Evidence has accumulated that NSAIDs work by a local
action. For example, a patch containing diclofenac epolaine
(DE) (Flector ®) was able to provide analgesia for
musculoskeletal disorders within one hour, at a time when
no drug would be expected to have systemic distribution.
Studies of diclofenac confirm efficacy in the management of
joint stiffness and pain in osteoarthritis (OA) of the knee
33
and other musculoskeletal disorders (e.g. Voltaren Gel®,
Pennsaid®) (Barthel et al, Sem Arth Rheum 39,203-12, 2009,
Altman et al, J. Rheumatol, 36, 1991-9, 2009, Toweeh RJ J.,
Rheumatol, 33, 567-73, 2001, Rainsford et al, Curr Med Res
Opin, 24, 2967-92, 2008).
Ketoprofen works by stabilizing the membranes of
lysosomes, antagonizing bradykin and cox inhibition.
Placebo controlled trials show its benefits when applied
topically in cases of traumatic injury and rheumatic
diseases. It can cause skin irritation when administered in
patch form (Mazieres B, Drugs RD, 6,337-44, 2005). In a
multi-center randomized controlled trial, Ketoprofen in
topical patch format was equivalent in actions, in OA of the
knee, to 100mg of oral celecoxib (Rother et al, Ann Rheum
Dis, 66, 1178-83, 2007).
Ibuprofen is a popular NSAID that penetrates well into
synovial fluid and, as mentioned earlier, it is believed that
this results in a prolonged action on joints. It is often used
in chronic arthritis and post-exercise pain; and it has less
adverse effects than aspirin or indomethacin at equivalent
pain-control dosages. Two types of ibuprofen topical
preparations (Dolgit® cream and Nurofen® gel) are of
demonstrated value in acute pain following injury and knee
osteoarthritis (OA).
34
To reiterate, the objective of using topical NSAIDs is to
provide analgesic and anti-inflammatory effects without
systemic side effects. In a review of 47 studies (Massey et al
Cochrane Database syst. Rev. Jun 16, 6, CD 007402, 2010)
that mainly compared topical NSAIDs (creams, gels and
sprays) with placebo, it was observed that, in 3455 patients,
topical NSAIDs produced overall good pain relief in a
mixture of different musculo-skeletal disorders. In brief, it
was found that topical application of diclofenac, ibuprofen,
ketoprofen and piroxicam were of equivalent effectiveness
at pain control but indomethacin and benzydamine were
not superior to placebo. There were few side-effects, but
the data could not result in a reliable comparison of efficacy
of each topical NSAID with each other, or with the same
NSAID, administered by the oral route.
Moore and Rabbie (Cochrane Data Base Syst Rev, Sep 12,
CD 007400, 2012), of the University of Oxford, England,
performed a detailed analysis of chronic musculoskeletal
pain, using information from 7688 individuals in 34 studies,
derived from 32 publications. It was concluded that topical
NSAIDs provided good pain relief and topical diclofenac
solution was found to be equivalent in efficacy to oral
NSAID in the treatment of knee and hand osteoarthritis
(OA). An important finding was that changes in formulation
were found to influence levels of topical analgesia. While
the occurrence of local side effects of topical NSAID
35
application occurred, gastrointestinal complaints and
events were significantly reduced compared with the
application of oral NSAIDs.
This short review of NSAID applications in topical pain
relief shows efficacy of several preparations, but
comparisons are difficult due to difference in study design,
variable controlled observations and several other factors.
TOPICAL PREPARATIONS OF NSAID FOR TENNIS ELBOW
Lateral epicondylitis (or tennis elbow) is one of the most
common overuse injuries in clinical practice. In this
condition there is inflammation of adjacent tendons and
soft tissues which often results in its treatment by NSAIDs.
Gastrointestinal (GI) intolerance of NSAIDs and other side
effects limit the oral use of these drugs and GI upset occurs
in up to one in three users (Polisson R, JAMA, 100, suppl 2A,
315-36, 1996 cited by Burnham et al, Clin J. Sports Med, 8,
78-81, 1998).
Burnham et al (ibid, 1998) studied the effectiveness of
topical diclofenac 2% in a liposomal delivery system
(pluronic-lecithin liposomal organogel, PLO) in 14 subjects
with chronic lateral epicondylitis. The gel (2% diclofenac)
provided effective reduction in elbow pain during the time
of its administration and improved elbow discomfort and
wrist extensor weakness that was due to the chronic
epicondylitis (tennis elbow). Other studies have confirmed
36
the benefit of selected topical NSAIDs in the treatment of
epicondylitis.
One of the most frequently asked questions about the
use of topical drugs is how far they penetrate tissues to
achieve maximal effects. Until recently, no studies have
measured NSAID concentrations in tendon, bone,
periarticular, and periosteal tissues after both topical and
oral administration.
In excellent studies, Shuken Kai et al (British J. Clin.
Pharmacol, 75: 3, 799-804, 2012) compared the tissue
concentrations of flurbiprofen (an NSAID) as a consequence
of oral and topical administration (according to standard
and approved dosing schedules). In these studies, 16
patients were randomly assigned to the topical application
or oral administration of flurbiprofen by tape or tablet,
respectively.
There were no adverse effects experienced with the test
drug, and specific laboratory testing remained normal
throughout the studies. Flurbiprofen concentrations were
higher in the tissues examined after topical versus oral
administration, but systemic levels of the drug were
predictably higher following oral administration. Thus, the
flurbiprofen concentrations were significantly higher
following cutaneous (tape) application in fat, muscle,
tendon and periosteum. Concentrations of flurbiprofen
37
were higher in bone after oral administration compared
with topical application. Flurbiprofen tapes for topical pain
relief are available in Japan as Zepolos ® Tape (Mikasa
Seiyaku, Tokyo).
Calculations of the topical to plasma drug concentration
ratios were much higher in topical treated groups, but
measures of pain control were not assessed in this study.
These findings indicate that flurbiprofen was delivered to
the tissues by blood and other transport systems. Recent
research implies that both dermal blood flow and lymphatic
vessel flow play a significant role greater than simple direct
diffusion of NSAID into deeper tissue (Anirmov and Roberts,
Pharm Res., 28, 2119-29, 2011 and Sammeta et al Pharm.
Res, 26, 2535-40, 2009). These data offers strong support
for the use of flurbiprofen, and perhaps other NSAID, in the
effective topical delivery to multiple tissues adjacent to the
body surface.
NEUROMODULATORS
Richards et al (Cochrane Database Syst Rev, Jan 18, 1,
CD008921, 2012) examined, in a literature review, the
ability of neuromodulators to control pain in rheumatoid
arthritis. Several drugs were included in the review process
including: anticonvulsants (gabapentin, pregabalin,
phenytoin, sodium valproate, lamotrigine, carbamazepine,
levetiracetam, oxcarbazepine, tiagabine and topiramate),
ketamine, bupriopion, methylphenidate, nefopam, and
38
capsaicin. Following a computer-assisted search of several
databases, four trials were included (Richards et al, ibid,
2012). The four selected trials were considered to have a
high degree of potential bias. Two of the four trials studied
oral nefopam, and one studied topical capsaicin.
Oral nefopam was superior to placebo, but there were
side-effects of the medication (nausea and sweating).
Topical Capsaicin was also superior to placebo in pain
control, but local burning reactions were common and 2%
withdrew because of this troublesome side effect. Overall,
the benefits of the investigated neuromodulators were
perceived to be modest.
OPIOIDS
The two opioids that have received most use and
research attention in topical analgesia are buprenorphine
and fentanyl. Buprenorphine and fentanyl are synthetic
opioids. While the effects of these drugs are largely on the
central nervous system, there are peripheral receptors
involved in pain control that interact with these opioids.
Observations in humans on the effects of topical opioids on
pain have produced mixed results, but support for their
potential actions comes from the recent discovery of mu
and delta opioid receptors at the endings of sensory
afferent neurons.
39
Morphine administered topically may relieve mucositis
related pain in individuals undergoing chemotherapy for
head and neck cancer (Hassan et al Neuroscience, 55, 185-
95, 1993), but topical opioids may have limited effects on
pain from skin ulcers, bladder pain and pain from dental
procedures (cited by Jorge et al ibid 2011, Cerchietti et al,
Pain, 105, 265-73, 2003).
Fentanyl interacts with mu opioid receptors. It is lipid
soluble and of low molecular weight which makes it ideal
for transdermal use. Fentanyl has most use in the
treatment of chronic malignancy-related pain but it has
been used in more general forms of pain control (e.g. post-
operative pain) following major abdominal surgery. In
contrast, buprenorphine has a long half-life and potent
anti-hyperalgesic effects. It is available as Butrans® and it is
used most often for musculoskeletal and chronic cancer
pain. (Jorge et al, ibid, 2011).
Buprenorphine is a partial agonist of mu, delta and
kappa receptors and it is an efficient agonist of opioid
receptor-like receptor 1 (ORL1). Thus, it differs in its
pharmacological action from other opioids. The success
achieved with Buprenorphine in neuropathic pain is
explained by its effect as an agonist of Kappa receptors.
Overall, clinical trials show improved pain control outcome
with general benefits of better sleep and less need for extra
pain control interventions, especially when Buprenorphine
40
is used for the management of cancer pain. (Jorge et al,
ibid, 2011).
Both Buprenorphine and Fentanyl can cause onerous
side effects in high dosages. Respiratory depression can be
a problem with both medications, but Buprenorphine can
cause renal impairment. In fact, Buprenorphine has a
greater propensity to cause respiratory depression and
renal dysfunction than other opioids, such as methadone,
hydromorphone, morphine and fentanyl. The key to
controlling side effects is dosage adjustment, but topical
administration generally limits the side effect profile of
opioids, compared with oral or parenteral administration.
In common with Buprenorphine, the most frequent
adverse effects of fentanyl are nausea, vomiting,
headaches, skin irritation and occasional flushing. Fentanyl
carries a modest risk of respiratory depression. The side
effect profile of the use of Buprenorphine and Fentanyl are
substantially similar in several respects, but arguably
Fentanyl has less adverse effects.
There is a considerable amount of research on
transdermal patch matrix compositions for delivering
opioids. Fentanyl has been administered by patient-
controlled iontophoretic (electricity) transdermal systems
(Fentanyl ITS®). This system is approved by the Food and
drug Administration (FDA) for the treatment of
41
postoperative pain (induced by surgery) (Jorge et al, ibid,
2011).
This system of self-controlled treatment differs from a
standard Fentanyl patch which is fabricated mainly to
produce a controlled release of the drug over a 72 hour
period. This patch design is more suitable for chronic pain
than the acute fluctuating pain suffered by the post-surgical
patient (Jorge et al, ibid, 2011). In brief, much more
research is required on the use of Fentanyl which has been
increasingly applied for pain control in a topical form in
FDA-off label usage.
Whittle et al (J. Rheumatol. Suppl, Sep, 90, 40-6, 2012)
performed an analysis of 11 studies of patients with
rheumatoid arthritis (RA). These studies were all of short
duration and had a high risk of outcome bias. In brief, these
studies showed the marginal benefit of the use of opioids,
administered by any route, in Rheumatoid Arthritis (RA);
and adverse events were quite common. Adverse events
were considered to reduce overall benefits after short term
use in RA and long term risks of the use of opioids in RA are
not well defined.
ANESTHETICS
Topical anesthetics in common topical use include
lidocaine, prilocaine and tetracaine. These anesthetics are
available in gel, cream and patch preparations, with the
42
most popular combination use of prilocaine 2.5% and
lidocaine 2.5% (EMLA cream-2).
EMLA can be applied to the skin prior to invasive
procedures (most notably minor surgical interventions) and
it has been used (FDA – off-label) for the treatment of
neuropathic pain (post-herpetic neuralgia). Anesthetic
‘topicals’ can all cause skin irritations and some cause
significant allergic skin eruptions, perhaps from both the
anesthetic content and additives, such as parabens or
propylene glycol (Jorge et al, ibid, 2011).
The topical analgesic Ametop® is a tetracaine base
product which is widely used for cutaneous pain relief in
both children and adults. It has been applied successfully in
skin needle insertion in children. While topical anesthetics
are useful in reducing pain of intravenous catheter insertion
or needle puncture of blood vessels, they have not been
used routinely, largely because of the time taken for their
onset of analgesia (Jorge et al, ibid, 2011).
The patch Rapydan®, containing 70 mg of Lidocaine with
70 mg of Tetracaine, has been used with a heat delivery
system for rapid onset of action. This system of topical
pain control is approved in Europe for pain relief during
blood vessel cannulations and minor surgical procedures.
Lidocaine is often available in 5% patches (Lidoderm®)
and it is approved for the treatment of post-herpetic
43
neuralgia and other neuropathic conditions. It is
recommended for use when other treatment are
ineffective, such as failure of antidepressants or
anticonvulsants e.g. Lyrica®, Cymbalta ® or opioids. These
suggestions for the use of expensive drugs, with common
attendant side effects as first line options, may be
misguided.
Lidocaine patches (5%) have been shown to be valuable
in the management of sub-acute or chronic low backache
when administered on a daily basis for six weeks. Overall,
lidocaine patches have a low incidence of adverse effects
and they are unlikely to cause drug interactions. They have
a high degree of tolerance and adherence (Jorge et al, ibid,
2011).
AMITRIPTYLINE
Amitriptyline is a more potent topical local analgesic
than Bupivacaine and Lignocaine. It has a longer action
after cutaneous infiltration than bupivacaine and both
drugs are enhanced in their action by the co-administration
of Epinephrine (Mohammed et al, Anesthesiology, Jan, 96,
1, 109-116, 2002). Furthermore, prolonged cutaneous
analgesia is achieved with the topical application of
Amitriptyline and Capsaicin in a manner that is superior to
Amitriptyline alone.
44
In several studies, the co-administered Capsaicin
prolongs cutaneous analgesia by facilitating the passage of
Amitriptyline into pain receptor locations (nociceptors) and
the co-applied capsaicin could theoretically counteract the
vaso-constrictive effects of topically applied Amitriptyline
(Calvin et al, Regional Anesthesia and Pain Medicine, 36, 3,
236-40, 2005).
CAPSAICIN
Capsaicin is a derivative of hot pepper plants. Capsaicin
interacts with sensory nerve afferents via vanilloid
receptors (VRI). These receptors are cation channels that
are part of the transient receptor potential family (Jorge et
al ibid, 20110). In addition, capsaicin can deplete substance
P at nervous afferent endings and it decreases the density
of nervous fibers in the skin. Chronic topical use of
Capsaicin both stimulates and desensitizes cation channels
thereby interfering with sensory nerve afferents.
Several reviews confirm the benefit of topical Capsaicin
in different strengths of 0.75% and 8%. In one overview of
1566 subjects with neuropathic or musculoskeletal pain,
improvements in neuropathic pain occurred in 57%,
whereas 42% relief of pain occurred in the placebo group.
In the study group with musculoskeletal pain, 38%
improvement was observed with a Capsaicin patch (0.25%)
with only a 25% improvement in the placebo group (cited
by Jorge et al ibid, 2011).
45
Overall, improvement in neuropathic pain can be
expected with 0.75% strength of Capsaicin cream or single
patch application of 8% Capsaicin. Improvements have
been noted in several disorders including: post-surgical
pain, post-herpetic neuralgia, diabetic neuropathy, HIV
neuropathy and Guillain-Barre syndrome (Mason et al, BMJ,
328, 991-5, 2004, Derry et al, Cochrane Data Base Review,
CD007393,4,2009, Ellison et al, J. Clin Oncol, 15,6,2974-
80,1997).
Common side effects of Capsaicin include a burning
sensation at the site of application with redness of the skin
and an occasional rash. There are uncommon severe
reactions, especially when there is a need for the use of
capsaicin on a frequent basis (4 x per day). Frequent use of
Capsaicin affects compliance in an adverse manner. One
can expect to see some local irritation in 33% of patients
and 10% may have to withdraw from capsaicin therapy due
to considerable discomfort.
Moore DS (Cochrane Database Syst. Rev, Sep 12,
CD010111, 2012) investigated the use of low dose (<1%)
topical Capsaicin creams in the management of chronic
neuropathic pain. Six studies were found to have compared
low dose 0.075% Capsaicin cream with placebo. In these
studies, there was much variation in outcome with different
measures of beneficial outcome. Only two studies reported
at least 50% pain relief. The outcome of this research
46
review did not permit conclusions to be made about the
efficacy of low dose Capsaicin cream, but apart from local
irritation there were few systemic side effects (Moore DS,
ibid, 2012).
Derry et al (Cochrane Database Syst Rev, Feb 28, 2,
CD007393, 2013) have produced a recent review of the
safety and effectiveness of high concentration (8%) topical
Capsaicin for the management of chronic neuropathic pain.
These authors reviewed six studies which examined 2073
participants in comparisons of 8% topical Capsaicin versus a
control of 0.04% topical Capsaicin. As anticipated, mild to
moderate local adverse effects were common, but serious
side effects were not significantly greater in the high
capsaicin concentration versus low concentration treated
individuals.
The authors Derry et al (ibid, 2013) concluded that high
concentration topical capsaicin (8%) was effective in
inducing pain relief in patients with post-herpetic neuralgia
and Human Immunodeficiency Virus (HIV) induced
peripheral neuropathy. There were added benefits in the
responsive group including: better sleep, reduced fatigue,
lightening of depression and improvements in quality of life
(QOL). The authors commented that unknown risks of
chronic application of high dose Capsaicin exist, most
notably a risk of disruption and damage to cutaneous
innervation.
47
NMDA RECEPTOR ANTAGONISTS
A noxious stimulus to the peripheral parts of the body
releases glutamate. Glutamate is a neurotransmitter that
interacts with the N-methyl-d-aspartate (NMDA) receptor
and serves to antagonize its actions. The stimulation of
NMDA receptors produces three main effects. First, it
causes hyperalgesia and, second it contributes to
neuropathic pain. The third effect is to reduce the actions
of opioid receptors. Neuropathic pain and hyperalgesia
result from spinal neuron sensitization. The reduction in
the function of opioid receptors contributes to opioid
tolerance. This tolerance to opioids results in a need to use
higher dosages of opioids to induce adequate pain control.
A number of NMDA receptor antagonists are available
for use in topical or systemic dosing. These antagonists
include ketamine, methadone, memantine, amantadine,
and dextromethorphan. Table 4 gives examples of NMDA
receptor antagonists and their recommended dosages and
potential side effects. It is apparent that ketamine is the
most potent NMDA antagonist, but it is more likely to
induce central nervous system side effects which may
include dizziness, fatigue, headache, nightmares and
sensory changes. These circumstances have led to a
preference for the use of amantadine.
48
Table 4. NMDA Antagonists for Pain Management
DRUG Analgesic Dosing Side Effects Ketamine IM: 2-4 mg/kg
IV: 0.2-0.75mg/kg
Continuous iv infusion: 2-7
Mcg/kg/min
CNS effects: Hallucinations,
confusion, dreamlike state,
irrational behavior. Other
effects: Respiratory
depression, increased CSF
pressure, hypertension,
Tachycardia, tremor,
nystagmus, myocardial
Depression
Methadone Opioid naive: Initial dose: 2.5-10
mg q8-12th
(interval may range from 4-12 h as analgesic duration is short during initial therapy, although it increases with prolonged therapy). Opioid-tolerant: Oral morphine to oral methadone conversion is variable
CNS depression, respiratory depression, QTc prolongation, constipation, nausea and vomiting, dizziness, disorientation
Memantine PO: 10-30 mg/day Hypertension, dizziness, drowsiness, confusion, anxiety, hallucinations, cataract
Amantadine IV:200 mg infused over
3h PO: 100-200 mg/day
Orthostatic hypotension, dry mouth, drowsiness, agitation, confusion, hallucinations, dyskinesia.
Dextromethor Phan
PO:45-400 mg/day Light-headedness, drowsiness, confusion, nervousness, visual disturbances, serotonin syndrome
Reproduced from:
http://www.uspharmacist.com/content/d/feature/i/1500/c
/28282
49
AMANTADINE
Amantadine is an anti-viral drug which is sometimes used
in the treatment of Parkinson’s disease. It is a non-
competitive NMDA antagonist that is used on a chronic
basis in humans because of its relative safety. Case studies
and preliminary trials show that amantadine can result in
significant reduction of surgical-induced neuropathic pain in
cancer patients (Macres SM, Understanding Neuropathic
Pain) http://www.spineuniverse.com/conditions/chronic-
pain/udnerstandign-neuropathic-pain.
Pud et al (Pain, 1998, 75,349-354) performed a
randomized placebo-control trial of amantadine in cancer
patients who were experiencing surgical neuropathic pain.
The amantadine was given by infusion, and there was an 85
percent reduction in pain with the administration of
amantadine compared with 45 percent following the
administration of placebo. In this study, pain intensity at
two days prior and two days following treatment resulted in
a 31 percent reduction in pain compared with only 6
percent reduction in pain in the placebo group.
Amin P and Sturrock NDC (Diabetic Medicine, 20,: 114-
118. Doil: 10.1046/j.1464-5491.2003.00882.x) studied the
effects of amantadine in the treatment of painful diabetic
peripheral neuropathy. Amantadine was given by
intravenous infusion to 17 patients and it resulted in
reduction of the pain experienced from diabetic
50
neuropathy. Favorable pain relief was present for at least
one week following the infusion of amantadine. In this
study, perception of pain relief was 10-fold greater
following amantadine administration compared with
placebo.
Not all studies with amantadine have shown positive
outcome in pain control. For example, Fukui et al
(J.Anesth,2001,15,179-181) studied the use of oral
amantadine in patients who had failed to respond to
several conventional treatment for neuropathic pain. In
this study, only 2 of the 19 patients experienced significant
pain reduction and side effects were experienced in 52.6
percent of the patients. Side effects consist of drowsiness,
hallucinations, irritation, dizziness and dyskinesia.
KETAMINE
Ketamine is a glutamate receptor antagonist that causes
analgesic effects in doses less than those used for
anesthesia. This drug works as a non-competitive, N-
methyl – aspartate (NMDA) receptor antagonist with some
degree of opioid activity. The analgesic effects of Ketamine
are complex and they are dependent on: calcium channel
blockage, actions on opioid receptors, cholinergic or
monoaminergic effects and glutamate receptor activity.
Glutamate receptors are present on afferent nerve
terminals in the peripheral nervous system and on
membranes of unmyelinated peripheral axons.
51
Table 4 summarizes four topical (alone or in
combination) Ketamine studies:
Author Design Patient
population
and numbers
Design/
Methodology
Outcomes Withdraw
al/Side
Effects
Barton
(2011)
DB RCT
PLC
N-208:
Chemo-
therapy
associated
peripheral
neuropathy
for 1 month
Topical Gel
of 10 mg
baclofen, 40 mg
amitriptyline
and 20 ug
ketamine vs
placebo 10ml
applied daily x
4 weeks
Statistically
significant
improvement
in motor
neuropathy
symptoms on
CIPN-20
questionnaire
; trend towards
improvement
in sensory
neuropathy
symptoms
No
significant
difference in
adverse
events
between
placebo and
treatment
Lynch
(2003)
DB RCT
PLC:
subsequent
open label
prospective
in “ketamine
responder s”
subgroup
N=20;
Chronic
neuropathic
pain
Topical
ketamine
cream
(0.5%) vs.
topical
amitriptyline
cream
(0.1%) vs.
combination
cream vs.
placebo 5ml
daily x 2 days:
subsequent 7
day open
No difference
on McGill Pain
Questionnaire
or VAS
between
treatment
arms in 2 day
trial; open
label arm
showed
significant
decrease in
pain by day
2 patients
Experienced
“minor” side
effects
52
label trial of
combination
cream
3-7
Lynch
(2005)
DB RCT
PLC
N=92:
Diabetic
neuropathy,
Post- Herpetic
neuralgia or
Post traumatic
neuralgia
Topical
ketamine
cream (0.1%
vs. Topical
amitriptyline
cream (0.2%)
vs.
combination
cream vs.
Placebo
(emulsant
only); all
creams 4 ml
TID x 3
Weeks
No
statistically
significant
difference in
pain reduction
on NRS- PI scale
between 1-
1.5 decrease in
spontaneous
pain
1 episode
of local skin
irritation; 1
swollen
feet; 2
episodes of
drowsiness
Vranken
(2005)
DB RCT
PLC
N=33
Central
Neuropathic
Pain
Iontopatch
administered
50 mg
ketamine vs. 75
mg ketamine
vs. placebo
(NS) over 24hr
x 5 days
No significant
difference
between any
groups in change
of VAS scores
after 7 days;
significant
improvement in
PDI, EQ-5D
and SF-6 scores
in the 75 mg
ketamine group
3 patients
in ketamine
arms
reported
sedation, 1
each of
nausea/
vomiting,
confusion,
dizziness,
vivid dreams
53
Table 5. A summary of four controlled observations of topical ketamine effects when given alone or in combination. Reproduced from Presentation by Horsha Shanthanna, Assistant Professor, Anesthesiology and Pain Medicine, St. Joseph’s Hospital, McMaster University: 2013 accessed.
In summary, the value of topical ketamine for pain control
can be summarized (Shanthanna H, 2013), verbatim.
- “There is some evidence to argue for peripheral
NMDA activation via glutamate.
- The potency of local anesthetic action needs more
investigation
- Animal studies have shown the decreased pain
behaviors with peripheral ketamine, can it still be
systemic?
- Human studies have not been conclusive.
- The topical application is not used on its own in any
study (in any RCT’s).
- It is difficult to say that there is any good evidence for
topical ketamine application (Class III).Proper well
designed studies with adequate patients are
needed.” (Shanthanna H, McMaster University,
2013).
54
Ketamine (Ketalar®, Ketanest®, Ketaset®) comes in
intravenous and intramuscular preparations, but studies
have been undertaken with intranasal, transdermal and
rectal administration to evaluate its analgesic effects.
Ketamine is a phencyclidine analogue and it is not routinely
used as an anesthetic. Transdermal varieties of the drug
include complexes with PLO (Pluronic® lecithin organogel).
These preparations come in liposomal (phospholipid)
emulsions, oil and water base 0.5% or a 1% cream or basic
emulsion. The most efficient delivery system appears to be
the PLO form (Jorge et al, ibid, 2011).
Complementary trials to those listed in Table 4 include
the use of 0.5 – 1% Ketamine cream for postoperative pain
and cancer pain. In this context, limited observations have
shown synergistic benefits of ketamine 0.5% with
amitriptyline 2.5% in treating rectal pain of unknown cause
(cited by Jorge et al, ibid, 2011).
The resistance of neuropathic pain to opioids has led to
the application of other analgesic agents for neuropathic
pain e.g. antidepressants, anticonvulsants and local
anesthetics (Gammaitoni et al, J. Pain, Oct 6, (10), 644-9,
2005). These latter authors describe the role of central
sensitization or pain “wind up” that may contribute to the
continuity of chronic neuropathic pain, even in the absence
55
of peripheral neuropathy (Gammaitoni et al, ibid, 2005).
The phenomenon of “wind up” is considered to be a cause
of allodynia, hyperpathia and hyperalgesia, as a
consequence of action through various receptors e.g.
NMDA, AMPA.
The ability of Ketamine to interact with NMDA receptors
has led to its use for the treatment of neuropathic pain. It is
suggested that Ketamine has an action on peripheral
receptors in opioid and Na⁺ K⁺ channels. In a small study of
five patients with neuropathic pain, Ketamine was shown to
substantially reduce numerical pain scores (range 53-100%)
with patient reports of significant pain relief accompanied
by relaxation, altered temperature sensation and
“decreased tension” at the site of application. Other more
recent studies have confirmed these findings on the benefit
of ketamine gel in chronic neuropathic pain.
The “power of synergy”, involving the combined use of
Ketamine and Amitriptyline, is apparent in a study by Lynch
et al (J. Pain, Oct 6, (10), 644-9, 2005). In this latter study,
28 individuals with moderate-severe but refractory pain
from peripheral neuropathy received topical Amitriptyline
2% containing Ketamine 1%. There was no significant
absorption of the drugs and regular use of the topical
cream resulted in up to 12 months of perceived analgesic
effects. At the termination of the study 89% of the
56
participants rated their level of satisfaction at 3 out of 5 or
greater and 2 subjects were pain free.
This study combines two medications with multiple
pharmacological effects that variably contributed to the
successful outcome. Together these drugs exert the
following actions blocking peripheral N-methyl-D-aspartate
receptors, local anesthetic effects and interactions with
adenosine systems. This and other studies suggest that
synergy among drugs with different actions, can be used to
amplify benefits of combination topical formulations that
are produced by principles of compounding pharmacy.
Topical ketamine has been found useful in the
management of neuropathic pain as a consequence of
multiple causes including: complex regional pain syndrome
CRPS, lumbar radiculopathy, post-surgical neuropathic pain,
post herpetic neuralgia and idiopathic proctodynia.
It has been suggested that Ketamine works by a
mechanism of central sensitization but its action is most
likely due to local causes (Finch et al, Pain, Nov, 146, (1-2),
18-25, 2009). Ketamine even when applied at a
concentration of 10% is not detectable in the systemic
circulation and when applied to healthy limbs it has no
effect on separate painful limbs. These findings provide
support for the valuable local effects of ketamine which
blocks N-methyl-D-aspartate receptors and Na⁺ and Ca⁺
57
channels. In addition, ketamine blocks tissue edema
response of inflammation. Ketamine applied topically is
ideal for delivering pain relief without significant side
effects.
CLONIDINE
When administered in a topical format clonidine (creams
or patches, Catapres TTS®) produces central and peripheral
analgesic effects. It works by blocking the emerging pain
signals at peripheral terminals (via alpha – 2
adrenoceptors).
This blocking circumstance avoids the central adverse
effects of clonidine which when given orally can produce
sedation, hypotension and rebound hypertension. While
the effect of clonidine is generally analgesia, in the
presence of peripheral nerve damage, hyperalgesia may
occur or worsen. That said, topical clonidine has been
applied for the control of hyperalgesia in complex regional
pain syndromes (CRPS) (cited by Jorge et al, ibid, 2011).
The effects of clonidine in topical analgesia appears to be
localized and it can be administered in a transdermal
therapeutic system consisting of a multilayered film of the
drug that is designed for slow and continuous release, over
a seven day period (Jorge et al ibid, 2011).
58
SYNERGY IN PAIN CONTROL
According to the Webster Unabridged Dictionary: Synergy, [Gr. Synergia, joint work, from synergein, to work together.] is combined or co-operative action or force: specifically, in medicine, (a) the combined or correlated action of different organs or parts of the body, as in performing complex movements; (b) the combined or correlated action of two or more drugs.” Synergy is a very important concept in compounded topical pain control agents.
Who said that a ‘little bit’ of this combined with a “bit” of that provided a better treatment outcome than a lot of this or that alone? An acknowledgment of the therapeutic power of synergy may answer this “gobbledygook” question. The power of synergy is apparent when one considers the common therapeutic failure of single receptor drug interventions and the complex biochemistry or physiology of the “harmony of life” (Claude Bernard, circa 1860). All body functions and structure rely upon carefully coordinated cascades of biological or physiological events. These “cascades” cannot be completely responsive to a unitary intervention such as single drug, nutrient or botanical compound. These notions form the basis of the “completeness” of treatment approaches (holism) that must be present in the practice of Integrative Medicine. Welcome to the domains of “synergy”.
Synergy (synergism) may be best understood as the addition or reinforcing actions of separate agents that can
59
produce a greater overall effect than when such agents are used in a single manner (singly). While I focus on the notion of using therapeutic agents in a synergistic manner, the principles under discussion apply specifically to drug use or even the interactions of organs in the coordinated harmony of body functions.
Proposals about “the power of synergy” are neither novel nor new. They are well known to scholars of “classic” therapeutics. The power of synergy in therapeutics is “crystal clear”, but it is often forgotten. An extension of the concepts of synergy underlies the practice of Topical Pain Relief. Pain is a complex cascade of bio-physiological events that require multipronged (synergistic) interventions.
CLINICAL APPLICATIONS
Charles Argoff (Argoff CE, Current Pain and Headache
Reports 7, 34-38, 2003, Current Science) has provided a
valuable review of the clinical applications of topical
analgesics in a variety of circumstances. Argoff (ibid, 2003)
has coined the useful term “targeted peripheral analgesics”
which he defines as “the use of analgesics whose
mechanisms of action appears to be primarily through
reducing pain transmission within the peripheral nervous
system”.
The terms used by Argoff (ibid, 2003) are not redundant because in addition to differentiating the actions of targeted peripheral and systemic analgesics, Argoff (ibid, 2003) distinguishes topical and transdermal analgesics. For example, some transdermal preparations are used as a way
60
of delivering systemic concentrations of analgesics (eg. fentanyl patch), whereas targeted peripheral analgesics are used only for the accumulation of local concentrations of pain killing or anti-inflammatory drugs.
One clear advantage of the use of targeted peripheral analgesics is to avoid systemic side effects and potentially eliminate drug-drug interactions. Many patients have necessary polypharmacy and lack of drug interactions is sometimes important for the induction of optimal pain control without the development of adverse drug events (Gammaitoni AR and Davis MW, Ann. Pharmacother. 36, 236-240, 2002).
CLINICAL CONCEPTS OF PAIN CONTROL
Table 6 gives a list of common clinical pain disorders that are amenable to treatment by topical analgesics.
- Acute sports injuries. - Allodynia - Arthritis - Chemotherapy-Induced Peripheral Neuropathy. - Complex regional pain syndrome (CRPS). - Diabetic Neuropathy. - Epicondylitis (Tennis Elbow). - Failed back syndrome. - Fibromyalgia. - Idiopathic Proctodynia. - Musculoskeletal pain. - Osteoarthritis. - Lumbar radiculopathy. - Phantom limb pain.
61
- Plantar fasciitis. - Post herpetic neuralgia. - Prior to minor surgery. - Post-surgical pain. - Trigeminal neuralgia. - Tendonitis (Tennis elbow). - Tendinosis.
Legend to Table 6. Clinical circumstances in which compounded topical pain creams are advantageous for management.
It is valuable to reiterate earlier concepts on the value of topical pain management which is generally applied to the following clinical circumstances:
Neuropathic pain
Soft tissue injuries
Low back pain
Myofascial pain
Osteoarthritis pain
Surgical pain
Pain from inflamed tissue (e.g. RA)
The use of topical peripheral analgesics carries few risks of adverse effects and it is possible to avoid significant blood levels of the applied substances. Also, even with continuous use, there tends to be little systemic accumulation of the administered drug (Argoff, ibid, 2005). Local anesthetics, e.g. lignocaine, (lidocaine) 5% patches can be expected to benefit pain without delivering systemic levels of the drug that may alter cardiac function.
62
Compounded Products: An Overview
The compounding pharmacy can create synergistic combinations of several agents that can be effective in pain control by a mechanism of targeted topical delivery. Table 7 gives examples of several substances that can be used in variable combinations.
Medication Mode of action.
Amantadine NMDA receptor antagonist
Amitriptyline Sympatholytic
Baclofen GABA(p) agonist Bupivacaine Anesthetic
Clonidine Alpha 2 agonist
Gabapentin Glutamate antagonist
Ketamine NMDA receptor antagonist Lidocaine Anesthetic
Nifedipine L type calcium channel Antagonist
Orphenadrine NMDA receptor antagonist
Pentoxiphylline TNF 1 alpha antagonist
Tetracaine Anesthetics
Table 7. Medications that can be used for effective topical pain control. Some of these agents can be used together. In view of different modes of actions it is possible to use them in a synergistic manner. The prescribing physician should always check compatibility and drug interaction potential with the compounding pharmacist.
In Table 8 a number of combination creams and lotions
used by NuMedCare LLC are shown in example format.
Information in Table 8 displays only examples. Ingredients
and dosages can vary depending on the Physicians
requirements.
63
SPORTS INJURIES OVERUSE
SYNDROMES Plantar Fasciitis
Tendonitis Bursitis
Epicondylitis Osteoarthritis
Standard
Flurbiprofen 20%, Tramadol 5%, Clonidine 0.2%,
Cyclobenzaprine 4%, Bupivacaine 1%
Advanced
Flurbiprofen 20%, Tramadol 5%, Clonidine 0.2%,
Cyclobenzaprine 4%, Bupivacaine 1%
Advanced with
Neuropathic
Flurbiprofen 10%, Gabapentin 6%, Nifedipine 7%, Pentoxifylline 5%, Lidocaine 3%, Clonidine 0.2%
Chemo-induced Neuropathy RSD/CRPS General
Neuropathy Post-Herpetic
Neuralgia Diabetic
Neuropathy
Chemo Neuropathic
(Ketamine (C-III) 10% or Amantadine 15%),
Gabapentin 6%, Tramadol 8%, Amitriptyline 4%, Cyclobenzaprine 4%, Clonidine 0.2%
Flurbiprofen 20%, Baclofen 4%, Cyclobenzaprine 2%, Gabapentin 6%, Lidocaine 5%
Standard Neuropathic
Flurbiprofen 10%, Gabapentin 6%, Nifedipine 7%, Pentoxifylline 5%, Lidocaine 3%, Clonidine 0.2%
(Ketamine (C-III) 10% or Amantadine 15%),
Gabapentin 6%, Nifedipine 7%, Pentoxifylline 5%, Lidocaine 3%, Clonidine 0.2%
Diabetic Neuropathic
(Ketamine (C-III) 10% or Amantadine 15%),
Gabapentin 6%, Tramadol 8%, Amitriptyline 4%, Cyclobenzaprine 4%, Clonidine 0.2%
Flurbiprofen 20%, Baclofen 4%, Cyclobenzaprine 2%, Gabapentin 6%, Lidocaine 5%
Back Pain Myofascial Pain
Fibromyalgia Post
Laminectomy Pain
Standard with anti-muscle
spasm
Flurbiprofen 20%, Tramadol 5%, Clonidine 0.2%, Cyclobenzaprine 4%, Bupivacaine 1%
Flurbiprofen 20%, Baclofen 4%, Cyclobenzaprine 2%, Gabapentin 6%, Lidocaine 5%
Advanced Formulation
(Ketamine (C-III) 10% or Amantadine 15%),
Gabapentin 6%, Tramadol 8%, Amitriptyline 4%, Cyclobenzaprine 4%, Clonidine 0.2%
Flurbiprofen 20%, Baclofen 4%, Cyclobenzaprine 2%, Gabapentin 6%, Lidocaine 5%
Table 8. Numedcare formulations.
64
TOWARDS THE APPLICATION OF TOPICAL AGENTS
Most custom compounding pharmacies focus attention
on the development of combination topical agents. Lotions
or creams or gels are applied to clean dry areas of the skin
and it is important that the person administering the topical
wash their hands both before and after applications. It is
important not to touch the eyes, mouth or other sensitive
areas of the body especially if capsaicin is used. Intense
burning and itching with skin rashes can occur as a
consequence of capsaicin applied to sensitive areas of the
integument. It is important to educate the patient in the
correct application of topical analgesics otherwise
compliance and adherence with medication will not occur.
Under no circumstances whatsoever should a topical
analgesic be applied to an open wound. Most compounded
creams (or lotions or emulsions) come with a way of
measuring applications e.g. by a syringe or by the use of a
pump device that will allow metered dispensation. For
example, there are pump applicators that will deliver one
gram of cream for every manual pump. For optimal
outcome the preparation should be rubbed into the skin, in
a thorough manner, for one to two minutes. Optimal
application will have occurred when the sensation of
friction is felt after rubbing. It is important to check with
65
your physician on the best site of application for
each specific type of pain.
Dermatomal Directions
A dermatome is an area of skin that is mainly
supplied by a single spinal nerve. These nerves relay
pain from the skin and adjacent tissues directly to the
brain. Figure 1 shows examples of dermatomes.
It is important to cover the area of pain and the area
innervated in each dermatome in cases of referred
pain. This will result in maximum effects, but pain
can cross over a dermatome segment.
For example, inspecting figure 1 shows the extent
of dermatome e.g. L2 and L3. These dermatomes are
located on the inner and front aspect of each thigh
and covering much of the area of the dermatome is
ideal. However, one can see that the dermatome L2
and L3 is close to the scrotum (or vagina) in its upper
reaches and it is important to avoid these sensitive
areas of skin. Equally the trigeminal nerve area of
innervations is close to the eye and mouth and these
areas are to be avoided. The prescribing physician
should take care to explain optimal site of
administration of topical pain control agents,
preferably by using a dermatome chart.
66
Fig 1 Examples of dermatomes
67
Payment for Compounded Pain Medications.
In many cases, medical insurance will pay for the cost
of the medication but the amounts of co-payments
required vary from one prescription plan to the other.
The staff of NuMedCare, LLC is dedicated to assisting you
and your physician to obtain reimbursement. Sometimes
insurance companies hold the opinion that all standard
forms of therapy e.g. oral NSAID should be used in place
of topical NSAID, but many people have stubborn pain
that has not responded to standard treatments and
decisions by insurance companies can be appealed.
68
References
Airaksinen O, Venãlãinen J, Pietilãinen T. Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries. Int J Clin Pharmacol Ther Toxicol. 1993 Nov; 31(11): 561-3.
Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer RA,
Campbell JN. Intradermal injection of norepinephrine
evokes pain in patients with sympathetically maintained
pain. Pain. 2000; 88(2): 161–168.
Altman R, Barkin RL. Topical therapy for osteoarthritis:
clinical and pharmacologic perspectives. Postgrad Med.
2009; 121(2):139–147.
Altman RD, Dreiser RL, Fisher CL, Chase WF, Dreher DS, Zacher J. Diclofenac sodium gel in patients with primary hand osteoarthritis: a randomized, double-blind, placebo- controlled trial. J Rheumatol. 2009;36(9):1991–1999.
Aniimov YG, Roberts MS. Modeling dermal drug distribution after topical application in human. Pharm Res 2011; 28: 2119–29.
Argoff CE. Targeted peripheral analgesics therapy for neuropathic pain. Curr Pain Headache Rep. 2004;8(3): 199- 204.
69
Argoff CE. Targeted topical peripheral analgesics in the management of pain. Curr Pain Headache Rep. 2003 Feb; 7(1):34-8.
Argoff CE. New analgesics for neuropathic pain: the lidocaine patch. Clin J Pain. 2000 Jun;16(2 Suppl):S62-6.
Aronson JK, editor. Meyler’s Side Effects of Drugs – The
International Encyclopedia of Adverse Drug Reactions and
Interactions. 15th ed. Amsterdam, The Netherlands:
Elsevier Science; 2005.
Attal N, Brasseur L, Chauvin M, Bouhassira D. Effects of single and repeated applications of a eutectic mixture of local anesthetics (EMLA) cream on spontaneous and evoked pain in post-herpetic neuralgia. Pain. 1999 May;81(1-2):203-9.
Baskurt F, Ozcan A, Algun C. Comparison of effects of
phonophoresis and iontophoresis of naproxen in the
treatment of lateral epicondylitis. Clin Rehabil. 2003; 17(1):
96-100.
Barnett AH. Treating to goal: challenges of current
management. Eur J Endocrinol. 2004; 151 (Suppl 2):T3–T7.
Barthel HR, Haselwood D, Longley S, 3rd, Gold MS, Altman
RD. Randomized controlled trial of diclofenac sodium gel in
knee osteoarthritis. Semin Arthritis Rheum. 2009;39(3):203–
212.
70
Bolten W. The pharmacokinetics, pharmacodynamics and comparative efficacy of flurbiprofen LAT. Br J Clin Pract 1994; 48: 190–5.
Briggs M, Nelson EA. Topical agents or dressings for pain in
venous leg ulcers. Cochrane Database Syst Rev. 2010;4:
CD001177.
Brogden RN, Heel RC, Speight TM, Avery GS. Flurbiprofen: a review of its pharmacological properties and therapeutic use in rheumatic diseases. Drugs 1979; 18: 417–38.
Brown BG, Bardsley J, Poulin D, et al. Moderate dose, three-
drug therapy with niacin, lovastatin, and colestipol to
reduce low-density lipoprotein cholesterol <100 mg/dl in
patients with hyperlipidemia and coronary artery disease.
Am J Cardiol. 1997; 80(2):111–115.
Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006.
Buchanan WW, Kassam YB. European experience with flurbiprofen. A new analgesic/anti-inflammatory agent. Am J Med 1986; 80: 145–52.
Buckwalter JA, Stanish WD, Rosier RN, Schenck RC Jr,
Dennis DA, Coutts RD. The increasing need for
nonoperative treatment of patients with osteoarthritis. Clin
Orthop Relat Res 2001; 385:3645.
71
Byl NN. The use of ultrasound as an enhancer for transcutaneous drug delivery: phonophoresis. Phys Ther. 1995;75(6):539-553.
Cairns BE, Sessle BJ, Hu JW: Evidence that excitatory amino acid receptors within the temporomandibular joint region are involved in the reflex activation of the jaw muscles. J Neurosci 18:8056-8064, 1998.
Capell HA, Konetschnik B, Glass RC. Anti-inflammatory analgesic drug responders and non-responders: a clinicopharmacological strudy of flurbiprofen. Br J Clin Pharmacol 1977; 4: 623–4.
Cardoe N, de Silva M, Glass RC, Risdall PC. Serum concentrations of flurbiprofen in rheumatoid patients receiving flurbiprofen over long periods of time. Curr Med Res Opin 1977; 5: 21–5.
Carlton SM, Zhou S: Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin. Pain 76:201-207, 1998.
Cerchietti LC, Navigante AH, Korte M W, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain. 2003;105(1- 2):265-273.
Chi SC, Jun HW: Anti-inflammatory activities of ketoprofen gel carrageenan-induced paw edema in rats. J Pharm Sci 79:974-991, 1990.
72
Conaghan PG, Dickson J, Grant RL. Guideline Development
Group. Care and management of osteoarthritis in adults:
summary of NICE guidance. BMJ. 2008;336(7642):502–503.
Costello K, Kennedy P, Scanzillo J. Recognizing non-
adherence in patients with multiple sclerosis and
maintaining treatment adherence in the long term.
Medscape J Med. 2008;10(9):225.
Cumpston M, Johnston RV, Wengier L, Buchbinder R.
Topical glyceryl trinitrate for rotator cuff disease. Cochrane
Database Syst Rev. 2009;3:CD006355.
Davies NM. Clinical pharmacokinetics of flurbiprofen and its enantiomers. Clin Pharmacokinet 1995; 28: 100–14. Davies PS, Galer BS. Review of lidocaine patch 5% studies in
the treatment of post-herpetic neuralgia. Drugs.
2004;64(9):937–947.
Davis KD, Treede RD, Raja SN, Meyer RA, Campbell JN.
Topical application of clonidine relieves hyperalgesia in
patients with sympathetically maintained pain. Pain.
1991;47(3):309–317.
De Paula E, Cereda CM, Tofoli GR, Franz-Montan LF, de
Araujo DR. Drug delivery systems for local anesthetics.
Recent Pat Drug Deliv Formul. 2010;4(1):23-34.
73
Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin
for chronic neuropathic pain in adults. Cochrane Database
Syst Rev. 2009;(4):CD007393.
Devers A, Galer BS. Topical lidocaine patch relieves a variety
of neuropathic pain conditions: an open-label study. Clin J
Pain. 2000;16(3):205–208.
DHEP plasters as a topical treatment of knee osteoarthritis-- a double-blind placebo-controlled study. Drugs Exp Clin Res. 1993;19(3):117-23.
Drummond PD, Skipworth S, Finch PM: Alpha-a- adrenoceptors in normal and hyperalgesic human skin. Clin Sci 91:73-77, 1996.
Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-
controlled trial of capsaicin cream in the management of
surgical neuropathic pain in cancer patients. J Clin Oncol.
1997;15(8):2974–2980.
Epstein JB, Grushka M, Le N. Topical clonidine for orofacial
pain: a pilot study. J Orofac Pain. 1997;11(4):346–352.
Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains. J Accid Emerg Med. 1994 Sep;11(3):178-82.
Faymonville ME, Libbrecht D. Transdermal buprenorphine:
a current overview of pharmacological and clinical data. Rev
Med Liege. 2008;63(11):671–676.
74
Fleming JA, O’Connor BD. Use of lidocaine patches for
neuropathic pain in a comprehensive cancer centre. Pain
Res Manag. 2009;14(5):381–388.
Galeazzi M, Marcolongo R. A placebo-controlled study of the efficacy and tolerability of a nonsteroidal anti-inflammatory drug, DHEP plaster, in inflammatory peri- and extra-articular rheumatological diseases. Drugs Exp Clin Res. 993;19(3):107-15.
Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain. 1999;80(3):533–538.
Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini
A, Ghelardini C. Menthol: a natural analgesic
compound. Neurosci Lett. 2002 Apr 12;322(3):145-8.
Galer BS: Topical medications. In Bonica’s Management of
Pain. Edited by Loeser JD. Philadelphia: Lippincott Williams
&Willkins; 2001: 1736-1741 Galer BS, Jensen MP Development and preliminary validation of a pain measure specific to neuropathic pain: the
75
Neuropathic Pain Scale. Neurology. 1997 Feb;48(2):332- 8.
Gammaitoni A G, Galer BS,Rowbotham MC, Perander J, et
al.: Topical diclofenac patch significantly reduces pain
associated with minor sports injuries: results of a
randomized, double-blind, placebo-controlled, multicenter
study. J Pain Symptom Manage 2000, 19:287-294.
Gallacchi G, Marcolongo R. Pharmacokinetics of diclofenac hydroxyethylpyrrolidine (DHEP) plasters in patients with monolateral knee joint effusion. Drugs Exp Clin Res. 1993;19(3):95-7.
Gallagher RM, Welz-Bossna M: Topical ketamine gel:
possible role in treating neuropathic pain. Pain Med 1:97-
100, 2000.
Gammaitoni AR, Davis MW. Pharmacokinetics and tolerability of lidocaine patch 5% with extended dosing. Ann Pharmacother. 2002 Feb;36(2):236-40.
Gani F, Pozzi E, Crivellaro MA, et al. The role of patient
training in the management of seasonal rhinitis and
asthma: clinical implications. Allergy. 2001;56(1):65–68.
76
Gibbs M. The role of transdermal fentanyl patches in the
effective management of cancer pain. Int J Palliat Nurs.
2009;15(7):354–359.
Geisslinger G, Lotsch J,Menzel S, Kobal G, Brune K. Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers. Br J Clin Pharmacol 1994; 37: 392–4. Gimbel J, Linn R, Hale M, Nicholson B. Lidocaine patch
treatment in patients with low back pain: results of an
open-label, nonrandomized pilot study. Am J Ther.
2005;12(4):311–319.
Hair PI, Keating GM, McKeage K. Transdermal matrix
fentanyl membrane patch (matrifen): in severe cancer-
related chronic pain. Drugs. 2008;68(14):2001–2009.
Hans G, Robert D. Transdermal buprenorphine – a critical
appraisal of its role in pain management. J Pain Res.
2009;2:117–134.
Harbeck N, Haidinger R. The patient experience. Breast
Cancer Res Treat. 2007;105 (Suppl 1):91–103.
Hassan AH, Ableitner A, Stein C, Herz A. Inflammation of
the rat paw enhances axonal transport of opioid receptors
in the sciatic nerve and increases their density in the
inflamed tissue. Neuroscience. 1993;55(1):185-195.
77
Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X.
Interventions for enhancing medication adherence.
Cochrane Database Syst Rev. 2008;2:CD000011.
Hedayati H, Parsons J, Crowther CA. Topically applied
anaesthetics for treating perineal pain after childbirth.
Cochrane Database Syst Rev. 2005;2:CD004223.
Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice
AS. Analgesic therapy in post-herpetic neuralgia: a
quantitative systematic review. PLoS Med. 2005;2(7):e164.
Henry A, Batey RG. Enhancing compliance not a
prerequisite for effective eradication of Helicobacter pylori:
the HelP study. Am J Gastroenterol. 1999;94(3):811–815.
Henry D, Lim LL, Garcia Rodriguez LA, Perez Gutthann S,
Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey
C, Hill S, Fries JT. Variability in risk of gastrointestinal
complications with individual non-steroidal anti-
inflammatory drugs: results of a collaborative meta-
analysis. BMJ 1996; 312:1563-6.
Herndon CM. Iontophoretic drug delivery system: focus on
fentanyl. Pharmacotherapy. 2007;27(5):745–754.
Houck CS, Sethna NF. Transdermal analgesia with local
anesthetics in children: review, update and future
directions. Expert Rev Neurother. 2005;5(5):625–634.
78
Hrobjartsson A, Gotzsche PC. Placebo interventions for all
clinical conditions. Cochrane Database Syst Rev.
2010;1:CD003974.
Huskisson EC, Scott PJ, Boyle S, Patrick M. Flurbiprofen at night. Curr Med Res Opin 1977; 5: 85–7.
Jackson L, Leclerc J, Erskine Y, Linden W. Getting the most
out of cardiac rehabilitation: a review of referral and
adherence predictors. Heart. 2005;91(1):10–14.
Jenoure P, Segesser B, Lühti U, Gremion G. A trial with diclofenac HEP plaster as topical treatment in minor sport injuries. Drugs Exp Clin Res. 1993;19(3):125-31.
Katz NP, Davis MW, Dworkin RH: Topical lidocaine patch
produces a significant improvement in mean pain scores
and pain relief in treated PHN patients: results of a
multicenter open-label trial. J Pain 2001, 2:9-18.
Keitel W, Frerick H, Kuhn U, Schmidt U, Kuhlmann
M, Bredehorst A.Capsicum pain plaster in chronic non-
specific low back pain. Arzneimittelforschung. 2001
Nov;51(11):896-903.
Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of post-herpetic neuralgia. Cochrane Database Syst Rev. 2007;2:CD004846.
79
Knadler MP, Brater DC, Hall SD. Stereoselective disposition of flurbiprofen in uraemic patients. Br J Clin Pharmacol 1992;33: 377–83.
Kneer W, Rother I, Rother M, Seidel E. IDEA-033-III-01 Study
Group. A multiple-dose, open-label, safety, compliance, and
usage evaluation study of epicutaneously applied Diractin
(ketoprofen in Transfersome) in joint/musculoskeletal pain
or soft tissue inflammation. Curr Drug Saf. 2009;4(1):5–10.
Kozanoglu E, Basaran S, Guzel R, Guler-Uysal F. Short term
efficacy of ibuprofen phonophoresis versus continuous
ultrasound therapy in knee osteoarthritis. Swiss Med Wkly.
2003; 133(23-24):333-338.
Kreitler S, Niv D. Cognitive impairment in chronic pain. Pain
Clinical Updates 2007; XV(4):1-4.
Kress HG. Clinical update on the pharmacology, efficacy and
safety of transdermal buprenorphine. Eur J Pain.
2009;13(3):219–230.
Kronenberg RH. Ketamine as an analgesic: parenteral, oral,
rectal, subcutaneous, transdermal and intranasal
administration. J Pain Palliat Care Pharmacother.
2002;16(3):27–35.
Kubacka RT, Juhl RP. Attitudes of patients with
hypertension or arthritis toward the frequency of
80
medication administration. Am J Hosp Pharm.
1985;42(11):2499–2501.
Lander JA, Weltman BJ, So SS. EMLA and amethocaine for
reduction of children’s pain associated with needle
insertion. Cochrane Database Syst Rev. 2006;3:CD004236.
Lehman JS, Sciallis GF. Effective use of topical amitriptyline
hydrochloride 2.5% and ketamine hydrochloride 0.5% for
analgesia in refractory proctodynia. J Drugs Dermatol.
2008;7(9):887–889.
Litman SJ, Vitkun SA, Poppers PJ. Use of EMLA cream in the treatment of post-herpetic neuralgia. J Clin Anesth. 1996 Feb;8(1):54-7.
Loghman-Adham M. Medication noncompliance in patients
with chronic disease: issues in dialysis and renal
transplantation. Am J Manag Care. 2003;9(2):155–171.
Lynch ME, Clark AJ, Sawynok J: A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain 19:323- 328, 2003.
Machen J, Whitefield M. Efficacy of a proprietary ibuprofen gel in soft tissue injuries: a randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2002 Mar;56(2):102-6.
81
Martens M. Efficacy and tolerability of a topical NSAID patch (local action transcutaneous flurbiprofen) and oral diclofenac in the treatment of soft- tissue rheumatism. Clin Rheumatol. 1997 Jan;16(1):25-31.
Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ.
Systematic review of topical capsaicin for the treatment of
chronic pain. BMJ. 2004;328(7446):991–995.
Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs
for acute pain in adults. Cochrane Database Syst Rev.
2010;6:CD007402.
Mayes S, Ferrone M. Fentanyl HCl patient-controlled
iontophoretic transdermal system for the management of
acute postoperative pain. Ann Pharmacother.
2006;40(12):2178–2186.
Mazières B. Topical ketoprofen patch. Drugs RD.
2005;6(6):337–344.
McCleane G. Topical application of doxepin hydrochloride,
capsaicin and a combination of both produces analgesia in
chronic human neuropathic pain. Br J Clin Pharmacol. 2000
Jun;49(6):574-9.
Mitchell A, Smith HS. Applying partially occluded fentanyl transdermal patches to manage pain in pediatric patients. J Opioid Manag. 2010;6(4):290–294.
82
Miyatake S, Ichiyama H, Kondo E, Yasuda K. Randomized clinical comparisons of diclofenac concentration in the soft tissues and the blood plasma between topical and oral applications. Br J Clin Pharmacol 2009; 67: 125–9.
Morgenlander JC, Hurwitz BJ, Massey EW. Capsaicin for the
treatment of pain in Guillain–Barré syndrome. Ann Neurol.
1990;28(2):199.
Motta AF, Borges Junior NG, da Fonseca JC, Tonussi CR. The
antinociceptive effect of iontophoretic direct application of
diclofenac to arthritic knee-joints of rats. Life Sci.
2003;73(15):1995-2004.
Nosé M, Barbui C, Gray R, Tansella M. Clinical interventions
for treatment non-adherence in psychosis: meta-analysis.
Br J Psychiatry. 2003;183:197–206.
Nüesch E, Rutjes AW, Husni E, Qelch V, Jüni P. Oral or
transdermal opioids for osteoarthritis of the knee or hip.
Cochrane Database Syst Rev. 2009;4:CD003115.
Petersen B, Rovati S. Diclofenac epolamine (Flector) patch: evidence for topical activity. Clin Drug Investig. 2009;29(1):1–9.
Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging. 1995 Oct;7(4):317-28.
83
Rainsford KD, Kean WF, Ehrlich GE. Review of the
pharmaceutical properties and clinical effects of the topical
NSAID formulation, diclofenac epolamine. Curr Med Res
Opin. 2008;24(10):2967–2992.
Rao P, Knaus EE. Evolution of nonsteroidal anti-
inflammatory drugs (NSAIDs): cyclooxygenase (COX)
inhibition and beyond. J Pharm Pharm Sci. 2008;11(2):81s–
110s.
Restrepo RD, Alvarez MT, Wittnebel LD, et al. Medication
adherence issues in patients treated for COPD. Int J Chron
Obstruct Pulmon Dis. 2008;3(3):371–384.
Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain. 1998;75(1):111–119.
Ritschel WA, Panchagnula R, Stemmer K, et al:
Development of an intracutaneous depot for drugs.
Binding, drug accumulation and retention studies, and
mechanism of depot. Skin Pharmacol 4:235-245, 1991.
Robbins W: Clinical applications of Capsaicinoids. Clin J Pain
2000, 16 (suppl 2):s86-S89.
Robbins WR, Staats PS, Levine J, Fields HL, Allen RW,
Campbell JN, Pappagallo M. Treatment of intractable pain
with topical large-dose capsaicin: preliminary report. Anesth
84
Analg. 1998 Mar;86(3):579-83.
Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized,
controlled trial of cannabis-based medicine in central pain
in multiple sclerosis. Neurology. 2005;65(6):812–819.
Ingersoll KS, Cohen J. The impact of medication regimen
factors on adherence to chronic treatment: a review of
literature. J Behav Med. 2008;31(3):213–224.
Rother M, Lavins BJ, Kneer W, Lehnhardt K, Seidel EJ,
Mazgareanu S. Efficacy and safety of epicutaneous
ketoprofen in Transfersome (IDEA033) versus oral celecoxib
and placebo in osteoarthritis of the knee: multicentre
randomised controlled trial. Ann Rheum Dis.
2007;66(9):1178–1183.
Rowbotham MC, Davies PS, Verkempick C, Galer BS.
Lidocaine patch: double-blind controlled study of a new
treatment of post-herpetic neuralgia. Pain. 1996;65(1):39–
44.
Sammeta SM, Murthy SN. ‘ChilDrive’. A technique of combining regional cutaneous hypothermia with iontophoresis for the delivery of drugs to synovial fluid. Pharm Res 2009; 26: 2535–40.
85
Sandelin J, Harilainen A, Crone H, Hamberg P, Forsskåhl
B, Tamelander G. Local NSAID gel (eltenac) in the
treatment of osteoarthritis of the knee. A double blind
study comparing eltenac with oral diclofenac and
placebo gel. Scand J Rheumatol. 1997;26(4):287-92.
Sawyer J, Febbraro S, Masud S, Ashburn MA, Campbell JC.
Heated lidocaine/tetracaine patch (Synera, Rapydan)
compared with lidocaine/prilocaine cream (EMLA) for
topical anaesthesia before vascular access. Br J Anaesth.
2009;102(2):210–215.
Schwartz SI, Allin D, Kipness MS: Dose ranging and tolerance study of 0.05% clonidine gel in patients with painful diabetic neuropathy. Program and abstracts of the 19th Annual Scientific Meeting of the American Pain Society; November 2-5, 2000; Atlanta, Georgia. Abstract 671.
Smith IJ, Hinson JL, Johnson VA et al. Flurbiprofen in postpartum women: plasma and breast milk disposition. J Clin Pharmacol 1989; 29: 174–84.
Soltesz S, Dittrich K, Teschendorf P, Fuss I, Molter G. Topical
anesthesia before vascular access in children. Comparison
of a warmth-producing lidocaine–tetracaine patch with a
lidocaine–prilocaine patch. Anaesthesist. 2010;59(6):519–
523.
86
Stucki G, Rother M. European IDEA-033 Study Group.
Randomized, double-blind, placebo-controlled study of
three dosages of epicutaneously applied IDEA-033
(keteprofen in Transfersome) in patients with osteoarthritis
of the knee. Ann Rheum Dis. 2007;66 (Suppl 2):S510.
Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of
transdermal opiates treating moderate-severe cancer pain
in comparison to long-acting morphine: a meta-analysis and
systematic review of the literature. J Palliat Med.
2008;11(3):492–501.
Tegeder I, Muth-Selbach U, Lötsch J, Rüsing G, Oelkers R,Brune K, Meller S, Kelm GR, Sörgel F, Geisslinger G. Application of microdialysis for the determination of muscle and sub-cutaneous tissue concentrations after oral and topical ibuprofen administration. Clin Pharmacol Ther 1999; 65: 357–68.
Tiwari SB, Pai RM, Udupa N. Influence of ultrasound on the
percutaneous absorption of ketorolac tromethamine in
vitro across rat skin. Drug Deliv. 2004; 11(1):47-51.
Towheed TE. Pennsaid therapy for osteoarthritis of the
knee: a systematic review and meta-analysis of randomized
controlled trials. J Rheumatol. 2006;33(3):567–573.
Trnavský K, Fischer M, Vögtle-Junkert U, Schreyger F.
Efficacy and safety of 5% ibuprofen cream treatment in
knee osteoarthritis. Results of a randomized, double-blind,
87
placebo-controlled study. J Rheumatol. 2004;31(3):565–
572.
Ushida T, Tani T, Kanbara T, Zinchuk VS, Kawasaki M,
Yamamoto H. Analgesic effects of ketamine ointment in
patients with complex regional pain syndrome type 1. Reg
Anesth Pain Med. 2002;27(5):524–528.
Varrassi G, Marinangeli F, Ciccozzi A, lovinelli G, Facchetti G,
Ciccone A. Intra-articular buprenorphine after knee
arthroscopy. A randomized, prospective, double-blind
study. Acta Anaesthesiol Scand. 1999;43(1):51-55.
Wasner G, Kleinert A, Binder A, Schattschneider J, Baron R.
Postherpetic neuralgia: topical lidocaine is effective in
nociceptor-deprived skin. J Neurol. 2005;252(6):677–686.
Watson CP Topical capsaicin as an adjuvant analgesic. J Pain
Symptom Manage. 1994 Oct;9(7):425-33.
Whitefield M, O’Kane CJ, Anderson S. Comparative efficacy
of a proprietary topical ibuprofen gel and oral ibuprofen in
acute soft tissue injuries: a randomized, double-blind study.
J Clin Pharm Ther. 2002;27(6):409–417.
Wiles MD, Dobson SA, Moppett IK. The effect of a new topical local anaesthetic delivery system on forearm skin blood flow reactivity. Anaesthesia. 2010;65(2):178–183.
88
Williman H, Walde P, Luisi PL, et al: Lecithin organogel as matrix for transdermal transport of drugs. J Pharm Sci 81:871-874, 1992.
Wrench IJ, Taylor P, Hobbs GJ. Lack of efficacy of intra-
articular opioids for analgesia after day-case arthroscopy.
Anaesthesia. 1996;51(10):920–922.
Yang JH, Kim TY, Lee JH, Yoon SW, Yang KH, Shin SC. Anti-
hyperalgesic and anti-inflammatory effects of ketorolac
tromethamine gel using pulsed ultrasound in inflamed rats.
Arch Pharm Res. 2008;31(4):511–517.
Zernikow B, Michel E, Anderson B. Transdermal fentanyl in
childhood and adolescence: a comprehensive literature
review. J Pain. 2007;8(3):187–207.