TOPICAL ANALGESICSCasey Melby

Objectives• Define topical analgesic • List the benefits and limitations of topical pain

formulations.• Provide information about the drugs that are commonly

used in topical analgesic formulations.• Provide evidence based recommendations to limit the

exploitation of compounded pain medications that are made up and unproven because they create a medically obscure treatment options

Definition of Topical Analgesic• “Topical” means applied directly to a part of the body

• An “analgesic” is a medication designed to decrease pain

• This means that “topical analgesic” is a medication that is applied directly to the part of the body where pain is happening.

Benefits of topical pain medications• Less systemic absorption and minimization of side

effects• Application directly to the site of pain provides a localized action of

the drug which limits unnecessary systemic effects because their bioavailability is generally smaller than oral administration.

• While each drug has a specific pharmacokinetic profile that needs to be evaluated separately, there are many studies that confirm low serum levels (negligible-15%) when compared to oral dosing while achieving therapeutic drug levels in target tissues3

• Administration route specific side effects such as gastrointestinal disturbances, first-pass hepatic metabolism, and variable serum concentrations are avoided without compromising the desired effects

Benefits of topical pain medications• Customizable dosages, formulations, and drug

combinations• Each type of pain has a specific pathophysiology and should be

treated accordingly• Compounded transdermal formulations allow for a customizable

approach to pain management by tailoring the treatment to meet patient specific needs which leads to better clinical outcomes.6

• The addition of drugs from different drug classes is more tolerable with topical formulations which allows the ability to use multiple drugs without the adverse reactions associated with the oral formulations.2

• The ability to use various drugs with different mechanisms of action allows a “shotgun” approach to optimize drugs that provide a synergistic effects.

Benefits of topical pain medications• Minimization of abuse and addiction risk

• Transdermal compounds are a beneficial tool to help manage pain and reduce the need for addictive oral narcotics.2

• Many case studies show a significant reduction in pain score which make people satisfied with their treatment without having to resort to addictive pain medications. 2,6

Benefits of topical pain medications• Can be complemented with oral medications

• While topical pain medications offer an effective means to pain management, it doesn’t have to be used as monotherapy

• After first line oral drugs fail to reduce pain sufficiently, they are a good option to complement the oral dosing regimen and its effects to a local area

Limitations of topical pain medications

• Patient tailored therapies require substantial skill of both the physician and pharmacist. 6

• There is limited comprehensive, peer reviewed, evidence based assessments of compounded formulations so their efficacy and safety are of limited knowledge. 6

• Many of the clinical trials that have been conducted are limited because of a small treatment groups and/or lack of a placebo treatment group which leads to an overestimate of efficacy and underestimate of safety concerns.

• Administration of a measured dose is difficult because the amount of gel applied varies significantly and it can be rubbed off the site of application before penetration occurs.7

Limitations of topical pain medications• Topical agents must have appropriate molecular size and

physiochemical properties for dermal and tissue penetration.7

• Disease states and skin conditions bay alter dermal absorption.7

• Pain measurement is a qualitative measurement that is reported by the patient so its effectiveness is determined by patient perspectives:• Patient ability to rationale the application of analgesics directly on

the site of soreness provides an enhanced placebo element of topical analgesia3

• Drug seeking patients may claim ineffectiveness with hopes of being prescribed a narcotic

Nonsteroidal anti-inflammatory drugs• Mechanism of action:

• Reduce the inflammatory cascade by inhibiting cyclooxygenases and reducing prostaglandin synthesis which lead to reduction in pain, fever, platelet aggregation, and inflammatory response. 4

• Topical Pharmacokinetics:• Overall when NSAIDs are applied topically there is a high concentration

of the drug observed in the dermis and muscles while only reaching 5-15% of the plasma concentrations when compared to oral dosing. 3

• Strong level of evidence for their safety and efficacy• A systematic review of topical NSAIDs for acute musculoskeletal

conditions studied 3455 subjects and concluded that the preparations can provide significant amount of pain relief without the adverse events associated oral NSAIDs (primarily GI disturbances and CV risk). 3

• Strongest correlation of positive outcomes were observed with the use of diclofenac, ibuprofen, and ketoprofen.

Topical NSAIDs: Diclofenac • PCCA lists the treatment strength of common compounded

topical diclofenac to range from 2-10% however the stronger formulations don’t have evidence to support their safety and efficacy

• Most widely studied topical agent with three formulations that are FDA approved• Diclofenac sodium 1% gel for osteoarthritis• Diclofenac epolamine 1.3% topical patch for acute musculoskeletal

pain• Diclofenac 1.5% solution for osteoarthritis of the knee

• Smallest flow and permeability coefficient when compared to other NSAIDs3

• Maximum daily dose should not exceed 32g/day3

Topical NSAIDs: Diclofenac • Evidence for efficacy: superior to placebo, non-inferior to oral

administration, and/or resolution in symptoms• Musculoskeletal pain: 38, 49,50,51

• Osteoarthritis pain:• Topical diclofenac produced greater pain reduction and increase in physical function

when compared to a placebo group.59

• 3% diclofenac gel in 2.5 % sodium hyaluronate was more effective in relieving breakthrough pain in 119 patients with osteoarthritis who have been on long term NSAID therapy (>1month) but was not considered statistically significant (P=0.057). 56

• Soft tissue injury• Diclofenac patch was statically better than placebo after blunt injuries 39 and a 60%

reduction in pain after acute sport injuries 40,41

• Myofascial pain involving the upper trapezius• Topical diclofenac was able to show a significant reduction in pain, increase in

cervical range of motion, and improve measures of disability. (n=153) 53

• Chronic lateral epicondylitis (tennis elbow):• 2% gel produced a significant improvement in pain and wrist extension strength 63

Topical NSAIDs: Diclofenac • Evidence for Safety: More safe when compared to oral

dosing• One study showed that patients treated with topical diclofenac

experienced less gastrointestinal side effects (25.4% vs. 39%, P<0.0001) and cardiovascular side effects (1.5% vs. 3.5%, P<0.055) when compared to oral administration of diclofenac. The oral diclofenac group was also associated with significantly greater increases in liver enzymes and creatinine (P<0.001). The topical formulation was associated with more dry skin at the application site (24.1% vs 1.9%, P<0.0001). 37

• Another study showed that the most common side effect was skin dryness that occurred in 39% of people using topical diclofenac vs. 21% in the placebo group (P=0.04). 59

Topical NSAIDs: Ibuprofen• PCCA lists the treatment strength of common

compounded topical ibuprofen to range from 5-30%• Not as much evidence as diclofenac but similar MOA

would indicate similar indications as diclofenac. • Evidence for efficacy

• chronic leg ulcers: The use of ibuprofen foam dressings applied to the ulcers produced a significantly greater reduction in wound pain when compared to the placebo group (P<0.5). 58

• soft tissue: Ibuprofen gel was found to have efficacy comparable (non-inferior) to that of oral ibuprofen (n=199). 61

• Ankle sprain: 5% ibuprofen cream produced significant reduction in visual analog scale scores compared to the placebo during the first 48 hours of treatment. 67

Topical NSAIDs: Ketoprofen• PCCA lists the treatment strength of common

compounded topical ibuprofen to range from 5-20%• Not as much evidence as diclofenac but similar MOA

would indicate similar indications as diclofenac. • Evidence of efficacy

• Acute soft tissue injuries: treatment with 2.5% ketoprofen gel results in a significant reduction in baseline pain scores at rest on days 3-7 of treatment (P<0.001) 68

• All studies show that it is well tolerated (weak evidence)

Topical NSAIDs: Aspirin• PCCA does not list them on their “drugs used in transdermal

pain management” however there is evidence supporting its use

• One double blind, placebo controlled, 4-week crossover study compared the efficacy of topical application of an aspirin/diethyl ether combination, diclofenac, indomethacin, and placebo for the treatment of nerve herpetic nerve pain (zoster virus).• Aspirin in diethyl ether was the only treatment group to significantly

reduce pain associated with acute herpetic neuralgia and postherpetic nuralgia.64,69

• A second trial showed that analgesic effect was obtained only after the topical but not after oral administration of aspirin.62

• Even after administering 1g of aspirin topically, systemic levels were negligible or even undetectable. 64,69

NSAIDs recap• There is evidence to support the safe and efficacious use

of topical NSAIDs for musculoskeletal pain, osteoarthritis, soft tissue injuries, and pain from chronic leg ulcers.• Level of evidence: Diclofenac > ibuprofen> ketoprofen > all others

• I did not discover any substantial evidence to support their use in peripheral neuropathy

• Aspirin in diethyl ether can reduce herpetic pain• Overall, topical NSAIDs can provide localized pain relief

without as big of a risk for gastrointestinal, renal, and cardiovascular toxicity due to its low plasma concentrations.

• Possible to cause drug-induced photosensitivity.7

Topical Anesthetics• Mechanism of action:

• Blocks voltage-gated sodium channels on afferent fibers which decreases the fibers action potential, decreasing the amount of abnormal nerve firings. Topical formulations slow nociceptor sensitization and central hyperexcitability. 4

• Topical Lidocaine is the most widely studied with the most evidence for its efficacy and safety.

• Its absence of an oral formulation allows this medication to be a good adjunct to a patients oral regimen.

• Good candidates for neuropathic pain, no substantial evidence for its recommendation for other types of pain

• Would not recommend agents other than lidocaine because of lack of evidence for safety and efficacy

Lidocaine• PCCA lists the treatment strength of common compounded

topical lidocaine range from 2-10%• Evidence for efficacy (most for 5% patches)

• Postherpetic neuropathy• Diabetic neuropathy

• The efficacy of the 5% lidocaine medicated patch or plaster has consistently been reported to be superior to placebo and comparable or superior to oral pregabalin in patients with either neuropathy 52,54,55,56,83

• Posttraumatic neuropathy• A placebo controlled study showed that 8% lidocaine pump spray was

found to significantly reduce pain and tactile allodynia for a median of 5 hours after application.57

• Focal neuropathic pain syndromes (postsurgical neuralgia)66 All studies show that there are low incidences of AE when compared to placebos

Capsaicin• Mechanism of action: reversibly depletes sensory nerve

endings of substance P and by reducing the density of epidermal nerve fibers (mcclene)

• Evidence for efficacy• Diabetic neuropathy8,9,10,11

• Postherpetic neuralgia12,13,14

• Surgical neuropathic pain15

• Chronic distal painful polyneuropathy16 • Osteoarthritis18,19,20,21,23,24

• Neck pain25

Capsaicin• Safety and Adverse Reactions:• In practice, repeated application of capsaicin is required before

clinical effect may be apparent. The major side effect associated with use is a burning, tingling sensation and allodynia at the application site. Although usually this settles with repeated use, it can be of a severity that significantly reduces compliance. 4

• Several strategies can be used to reduce the burning discomfort of application. These include preadministration of ketamine26 or lidocaine 5% cream27 or the coadministration of glyceryl trinitrate (GTN) 17,22,23 which also can enhance the analgesic effect of the capsaicin.23

Nitrates• Mechanism of action: exogenous nitrates stimulate release of

nitric oxide which helps in inflammatory mediated pain.• Glyceryl trinitrate has been the most extensively studied.• From a clinical perspective, topical glyceryl trinitrate can reduce

the pain from any inflammatory condition that is superficial and localized.

• Evidence for efficacy: • chronic supraspinatus tendonitis4 27,28

• Osteoarthritis.22.,30 • infusion-related thrombophlebitis.31

• Nitrates should have an important role in the management of localized pain in elderly patients, particularly as they may reduce reliance on other potentially more toxic analgesic classes.

Tricyclic antidepressants• Mechanism of action: Many effects on the nerve that reduces the

magnitude of signal transmission.4 • Doxepin and amitriptyline were the most commonly studied drugs with

some conflicting evidence• Maximum recommended amitriptyline dose of 240 mg • Evidence of efficacy:• Several randomized trials in human subjects who had neuropathic pain

show statistically significant reductions in pain scores when topical 5% doxepin was applied32,33,34

• Maximum effect was observed after 2 weeks’ treatment and side effects were infrequent and mild. In particular, those side effects associated with oral use of TCAs were observed infrequently

• Lynch et al showed no difference between amitriptyline 2% cream and placebo. Other studies that combine other drugs show possible effectiveness. 47

a-Adrenoreceptor antagonists• Mechanism of action: case analgesia by reducing the

abnormal signaling that arises from sensitized hyperactive cutaneous nociceptors. 7

• The only studied agent is clonidine with a dose of 3.9 mg applied daily. 42

• Evidence of efficacy and safety:• One study showed that clonidine 0.1% gel TID significantly

reduced the level of pain in participants with diabetic neuropathy in whom there are functional nociceptors in the affected skin. No significant adverse drug reactions when compared to placebo with plasma levels below level of detection.42

• Potential benefit for sympathetically independent pain35 and orofacial neuralgia-like pain.36

Ketamine• Mechanism of action: its analgesic effect is derived from

antagonism of not only glutamate receptors but also ketamine may block voltage-sensitive calcium channels, alter cholinergic and monoaminergic actions, and interfere with opioid receptors4

• Max dosing recommendation of 120mg/day7

• Evidence of efficacy:• Ketamine 5% was not effective in relieving pain caused by diabetic

neuropathy when compared to the placeebo.48

• Ketamine 10% in PLO did not lead to a pain reduction but there was a reduction in allodynia for patients with Chronic Regional Pain syndrome (CRPS).44 • Neither ketamine or norketamine were detectable in the blood

Combination compounds• Ketamine 1% and Amitriptyline 2%

• One study (n=92) showed that there was not a statistically significant difference between that and the placebo compound to treat neuropathic pain. 47

• One study (n=21, open label) showed that the compound was associated with long-term reduction (6-12mo) in perceived pain, moderate to complete satisfaction. 44

• Average of a 34% reduction in pain at 6 months• At the end of the study (12mo) 89% of participants rated their satisfaction as 3/5 or

greater and 10% were pain free• It is possible that these concentrations are too low to produce significant analgesia

• Baclofen 0.76%, amitriptyline 3%, and ketamine 1.5%• There was a trend of improvement in the active arm in both sensory (P=0.053) and

motor subscales (P=0.021). The greatest improvements were related to symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen• Well tolerated without evidence of systemic toxicity • Overall evidence shows to somewhat improve symptoms of Chemotherapy induced

peripheral neuropathy.43

Combination compounds• Amitriptyline 2%, ketamine 1%, and lidocaine 5%

• Used to treat neuropathic pain caused by radiation skin reaction over 2 weeks after radiotherapy

• 4ml applied to most painful areas TID• The combo gel significantly (P<0.05)

• Reduced pain intensity sharpness burning sensitivity, itchiness, unpleasantness, deepness, and surfaceness levels on a short term basis (30 min post treatment)

• Significantly reduced burning levels on a long term basis

• This combination gel was considered a save intervention to use with minimal toxicity and good compliance. It significantly reduced several measures of radiotherapy associated neuropathic pain46

Recommended treatments• Musculoskeletal pain

• Strong evidence to support topical NSAIDs• Osteoarthritis:

• Strong evidence to support topical NSAIDs• Moderate evidence to support topical capsasin and glyceryl trinitrate

• Diabetic neuropathy• Relatively strong evidence supporting topical Lidocaine and capsasin• Moderate evidence supporting topical doxepin and clonidine• weak/conflicting/no evidence for ketamine, amitriptyline, NSAIDs

• Chemotherapy induced peripheral neuropathy • Moderate evidence to support Amitriptyline 2%, ketamine 1%, and lidocaine 5%• Mild evidence to support Baclofen 0.76%, amitriptyline 3%, and ketamine 1.5%

combination • Herpetic Neuropathy

• Moderate evidence to support aspirin in diethyl ether, lidocaine, and capsasin

Conclusion• It is apparent that the field of topical analgesics need to be

studied more in order to prove the efficacy and safety of each compound in order to validate their place in modern medicine

• Many prescribers are reluctant to prescribe these compounds because their not held to the high standard that the FDA requires to prove their safety and efficacy.

• Compounded pain medications certainty can have a beneficial impact on pain management and should be conisdered

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