1. TOPICALANALGESICS
Casey Melby

2. 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

3. 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.

4. 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

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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.

11. 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

12. 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

13. 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

14. 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

15. 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)

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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.

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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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