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THE TOPICAL PAIN RELIEFREVOLUTION: PRINCIPLES AND PRACTICE

OF COMPOUNDING PHARMACY

www.numedcare.comPublished by the HOLT INSTITUTE OF MEDICINE, Little Falls, NJ 07424

www.hiom.org

STEPHEN HOLT, MD, PhD, DSc, LLD,DISTINGUISHED PROFESSOR OF MEDICINE (Emeritus)

UZOMA NWOSU, MDSCIENTIFIC OFFICER, NUMEDCARE, LLC, BOCA RATON, FL

CLIFFORD B. CARROLLSCIENTIFIC OFFICER, NUMEDCARE, LLC, BOCA RATON, FL

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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 MDClifford B. Carroll

Library in CatalogueISBN: 978-0-9830793-4-7

Copyright © Stephen Holt MD, Holt Institute of Medicine

KEY WORDS

1. Pain control 2. Topical pain control3. Topical analgesia 4. Compounding pharmacy

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TABLE OF CONTENTS

FOREWORD ................................................................................................................. 5

ACKNOWLEDGEMENTS ............................................................................................. 7

NuMedCare: Compounding Excellence ................................................................. 8

INTRODUCTION

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 ................................. 34

NEUROMODULATORS .............................................................................................. 36

OPIOIDS ...................................................................................................................... 36

ANESTHETICS ............................................................................................................ 39

AMITRIPTYLINE ......................................................................................................... 40

CAPSAICIN ................................................................................................................. 41

NMDA RECEPTOR ANTAGONISTS .......................................................................... 43

AMANTADINE ............................................................................................................ 45

KETAMINE .................................................................................................................. 46

CLONIDINE ................................................................................................................ 51

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SYNERGY IN PAIN CONTROL .................................................................................. 51

CLINICAL APPLICATIONS ........................................................................................ 52

CLINICAL CONCEPTS OF PAIN CONTROL ............................................................. 53

Compounded Products: An Overview ................................................................. 54

TOWARDS THE APPLICATION OF TOPICAL AGENTS .......................................... 57

Dermatomal Directions .......................................................................................... 57

Payment for Compounded Pain Medications .................................................... 59

References ................................................................................................................. 60

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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 with the recent calls to limit prescriptions

of drugs that have the capability of inducing dependence or addiction.

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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

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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.

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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 info@numedcare.com.

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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

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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 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.

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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.

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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 habitua-

tion. 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 estimated

that compounding pharmacists make about 1-3% of the prescription topical

drug market which is generating high revenue.

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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 Hydroproges-

terone 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 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.

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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 the use of dietary supplements.

While dietary supplements for bone and joint health are not drugs or consid-

ered 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.”

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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.

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.

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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.

MEDICATION CONCENTRATION % MEDICATAL USEKetamine

MagnesiumChloride

Ketoprofen

Amitriptyline

Gabapentin

Clonidine

2May combine with Baclofen or capsaicin

6

0.1- 0.2

Local analgesia

Local analgesia

Local analgesia

Lidocaine 1-2 Local analgesia

10 Fibromyalgia

5-20May combine with Clonidine, 2 and Gabapentin 6

10-20May combine with ketamine 10%Cyclobenzaprine,and Buvipavcaine 0.5

Anti-inflammatoryeffects, low backpain, arthritis

Neuropathic pain,herpetic and myofascial trigger points, neuralgia, by local analgesia.

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References (continued):

• 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 prepara-

tions comes information relevant to further advantages of this mode of treat-

ment. Topical pain control appears quite safe except for the occurrence of

occasional local reactions (e.g. pain and irritation caused by 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.

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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 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.

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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

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

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ADHERENCE TO MEDICATION REGIMENS (COMPLIANCE)

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.

- 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.

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- 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

relationship, continuous education, and reinforcement regarding the

benefit of treatment.

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- 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

CONCEPTS OF ADJUVANT ANALGESICS

In an excellent reviewed article, Lussier et al discussed the characteristics and

use of adjuvant analgesics in cancer 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”.

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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: antide-

pressants, 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, bisphos-

phonates, 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 analge-

sic by consideration of the underlying diagnosis and satisfaction 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.

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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).

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.

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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.

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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.

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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.

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.

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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 biodegrad-

able, 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, 199-121, 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).

29

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 OFMEDICATION

EXAMPLES

Non-Steroidal AntiInflammatoryDrugs (NSAID)

Legend to Table 2. Examples of classes of drugs that are used in topical analgesic preparations produced in a compounding pharmacy.

Diclofenac, Ibuprofen, Ketoprofen,Piroxicam, Baclofen, Ketorolac(Tromethamine), Naproxen Flurbiprofen

Opioids

Anesthetics

Capsaicin

Nitroglycerin

Ketamine

Clonidine

Lidocaine, Prilocaine, Tetracaine

Zostrix®Qutenza® Capzasin P®Zostrix HP®

Organic nitrate, Nitro Dur®,Nitrodisc®, Transderm - Nitro®Glyceryl Trinitrate

Kealar®, Ketanest®, Ketaset® (withhydrogel or ganogel, Pluronic®, PLO)

Catapres TTS®

Buprenorphine, Fentanyl

30

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 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 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 observa-

tions mainly of single agents (NSAIDs) in humans. For example, in an in vitro

inflammatory/pain model, Ketorolac Tromethamine gel, delivered by phono-

phoresis, 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 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

31

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).

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 piroxi-

cam 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,

32

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 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.

33

34

TOPICAL PREPARATIONS OF NSAID FOR TENNIS ELBOW

CLateral 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 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.

35

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 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.

36

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 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.

37

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 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

38

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 adminis-

tration 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 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.

39

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 prepara-

tions, with the 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).

40

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 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.

41

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 muscu-

loskeletal 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).

Overall, improvement in neuropathic pain can be expected with 0.75%

strength of Capsaicin cream or single patch application of 8% Capsaicin.

42

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 uncom-

mon 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 consid-

erable 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 varia-

tion in outcome with different measures of beneficial outcome. Only two

studies reported at least 50% pain relief. The outcome of this research

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.

43

These authors reviewed six studies which examined 2073 participants in

comparisons of 8% topical Capsaicin versus a control of 0.04% topical Capsa-

icin. As anticipated, mild to moderate local adverse effects were common, but

serious side effects were not significantly greater in the high capsaicin concen-

tration 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 periph-

eral 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.

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.

44

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 recep-

tor 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 dizzi-

ness, fatigue, headache, nightmares and sensory changes. These circumstances

have led to a preference for the use of amantadine.

Table 4. NMDA Antagonists for Pain Management

DRUG Analgesic Dosing Side EffectsKetamine

Methadone

Amantadine

Methadone

IM: 2-4 mg/kg

IV: 0.2-0.75mg/kg

Continuous iv infusion: 2-7Mcg/kg/min

CNS effects: Hallucinations,confusion, dreamlike state, irrational behavior. Other effects: Respiratory depression, increased CSF pressure, hypertension, Tachycardia, tremor, nystagmus, myocardial depression.

Reproduced from: http://www.uspharmacist.com/content/d/feature/i/1500/c/28282

Opioid naive: Initial dose: 2.5-10 mg q8-12th (interval may range from 4-12 h as analgesic duration is short during initialtherapy, although it increases with prolonged therapy).Opioid-tolerant: Oral morphine to oral methadone conversion is variable.

CNS depression, respiratorydepression, QTc prolongation, constipation, nausea and vomiting, dizziness, disorientation.

IV:200 mg infused over

3h PO: 100-200 mg/day

PO:45-400 mg/dayy

Orthostatic hypotension, drymouth, drowsiness, agitation,confusion, hallucinations, dyskinesia.

Light-headedness, drowsiness,confusion, nervousness, visualdisturbances, serotonin syndrome.

45

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 prelimi-

nary 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 neuro-

pathic 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 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.

46

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 experi-

enced 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. Gluta-

mate receptors are present on afferent nerve terminals in the peripheral

nervous system and on membranes of unmyelinated peripheral axons.

Table 4 summarizes four topical (alone or in combination) Ketamine studies:

Author Design PatientPopulationand numbers

Design/Methodology

Outcomes Withdrawal/Side Effects

Barton(2011)

DB RCTPLC

N-208:Chemotherapyassociatedperipheralneuropathyfor 1 month

Topical Gelof 10 mgbaclofen, 40 mg amitriptyline and 20 ug ketamine vs placebo 10ml applied daily x 4 weeks

Statisticallysignificant improvement in motor neuropathy symptoms on CIPN-20questionnaire; trend towards improvement in sensory neuropathy symptoms

Nosignificant difference in adverse events between placebo and treatment

47

Table 4 summarizes four topical (alone or in combination) Ketamine studies:

(continued)

Author Design PatientPopulationand numbers

Design/Methodology

Outcomes Withdrawal/Side Effects

Lynch(2003)

DB RCTPLC:sub-sequent open label prospective in “ketamine responders” subgroup

DB RCTPLC

N=20:Chronic neuropathic pain

N=92:Diabetic neuropathy, Post- Herpetic neuralgia or Post traumatic neuralgia

Topicalketamine cream (0.5%) vs.topical amitriptyline cream (0.1%) vs.combination cream vs. placebo 5ml daily x 2 days: subsequent 7 day open label trial ofcombination creamTopicalketamine cream (0.1% vs. Topical amitriptyline cream (0.2%) vs.combination cream vs. Placebo (emulsant only); all creams 4 mlTID x 3Weeks

No differenceon McGill Pain Questionnaire or VAS between treatment arms in 2 day trial; open label arm showed significant decrease in pain by day3-7

Nostatistically significant difference in pain reduction on NRS- PI scale between 1-1.5 decrease in spontaneous pain

2 patientsExperienced “minor” side effects

1 episodeof local skin irritation; 1 swollenfeet; 2 episodes of drowsiness

Lynch(2005)

DB RCTPLC

N=33:Central Neuropathic Pain

Iontopatchadministered 50 mg ketamine vs. 75 mg ketamine vs. placebo (NS) over 24hr x 5 days

No significantdifference between any groups in change of VAS scores after 7 days; significant improvement in PDI, EQ-5Dand SF-6 scores in the 75 mg ketamine group

3 patientsin ketamine arms reported sedation, 1 each of nausea/vomiting, confusion, dizziness, vivid dreams

Vranken(2005)

48

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).

Ketamine (Ketalar®, Ketanest®, Ketaset®) comes in intravenous and intramuscu-

lar preparations, but studies have been undertaken with intranasal, transder-

mal and rectal administration to evaluate its analgesic effects. Ketamine is a

phencyclidine analogue and it is not routinely used as an anesthetic. Transder-

mal 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).

49

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 amitripty-

line 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 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

50

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 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+ channels. In addition,

ketamine blocks tissue edema response of inflammation. Ketamine applied

topically is ideal for delivering pain relief without significant side effects.

51

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 pres-

ence 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 multilay-

ered film of the drug that is designed for slow and continuous release, over a

seven day period (Jorge et al ibid, 2011).

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.

52

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 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”.

53

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 of delivering

systemic concentrations of analgesics (eg. fentanyl patch), whereas targeted

peripheral analgesics are used only for the accumulation of local concentra-

tions 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

- Plantar fasciitis

- Post herpetic neuralgia

- Prior to minor surgery

- Post-surgical pain

- Trigeminal neuralgia

- Tendonitis (Tennis elbow)

- Tendinosis

54

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.

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.

55

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.

Medication Mode of actionAmantadine 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

56

Table 8. Numedcare formulations.

SPORTS INJURIES OVERUSE SYNDROMESPlantar FasciitisTendonitis Bursitis Epicondylitis Osteoarthritis

Standard

Advanced

Advanced with Neuropathic

Flurbiprofen 20%, Tramadol 5%, Clonidine 0.2%,Cyclobenzaprine 4%, Bupivacaine 1%

Flurbiprofen 20%, Tramadol 5%, Clonidine 0.2%,Cyclobenzaprine 4%, Bupivacaine 1%

Flurbiprofen 10%, Gabapentin 6%, Nifedipine 7%,Pentoxifylline 5%, Lidocaine 3%, Clonidine 0.2%

Chemo-inducedNeuropathy RSD/CRPSGeneral Neuropathy Post-Herpetic Neuralgia Diabetic Neuropathy

Back Pain Myofascial Pain Fibromyalgia Post Laminectomy Pain

Chemo Neuropathic

Standard Neuropathic

Diabetic Neuropathic

Standard with anti-muscle spasm

(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%

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%

(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%

Advanced Formulation

Flurbiprofen 20%, Tramadol 5%, Clonidine 0.2%,Cyclobenzaprine 4%, Bupivacaine 1%

Flurbiprofen 20%, Baclofen 4%, Cyclobenzaprine 2%,Gabapentin 6%, Lidocaine 5%

(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%

57

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 applica-

tion 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 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.

58

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 physi-

cian should take care to explain optimal site of administration of topical pain control

agents, preferably by using a dermatome chart.

Fig 1 Examples of dermatomes

59

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.

60

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