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15 Articles in Volume 18, Issue #5
Chronic Pelvic Pain: The Need for Earlier Diagnosis and Diverse Treatment
Cross-Linked Hyaluronic Acid for the Management of Neuropathic Pelvic Pain
Fentanyl: Separating Fact from Fiction
Gender Bias and the Ongoing Need to Acknowledge Women’s Pain
Letters to the Editor: 90 MME/day Ceiling; Ehlers-Danlos; Redefining Pain
Post-Menopausal MSK Pain and Quality of Life
PPM Welcomes Dr. Fudin and Dr. Gudin as New Co-Editors
Practitioner as Patient: Understanding Disparities in CRPS
States Take Action to Manage Opioid Addiction
Step-by-Step Injection Technique to Target Endometriosis-Related Neuropathic Pelvic Pain
The Many Gender Gaps in Pain Medicine
The Need for Better Responses to Vulvar Pain
Topical Analgesics for Chronic Pain Conditions
Topical Medications for Common Orofacial Pain Conditions
What’s the safest, effective way to taper a patient off of opioid therapy?

Topical Analgesics for Chronic Pain Conditions

A look at alternative and combination therapies for treating musculoskeletal pain, osteoarthritis, post-herpetic neuralgia, and peripheral neuropathy.

Topical drug delivery offers a potential advantage of achieving therapeutic concentrations locally with minimal systemic absorption, thereby reducing systemic adverse effects. Topical analgesics may be useful in treating acute and chronic pain caused by a wide range of conditions, from musculoskeletal (MSK) pain to neuropathic pain syndromes. These agents are available in a variety of formulations including creams, ointments, gels, lotions, and patches. Application site, vascularity of tissue, surface area, and duration of application are important factors affecting the absorption and distribution of the active ingredient into tissues. For a local medication to be absorbed, it must penetrate the stratum corneum by either an intracellular, paracellular, or transappendageal route. Mucosal surfaces are often easier to penetrate than keratinized surfaces due to absence of the stratum corneum. The addition of skin permeation enhancers (eg, solvents, surfactants, urea) and physical measures (eg, skin exfoliation, patch delivery, iontophoresis) may further improve drug delivery.1,2

Topical drug delivery differs from transdermal drug delivery in that topical formulations are intended to have effects at the site of application whereas transdermal formulations are absorbed into the bloodstream and produce systemic effects.1 A patch may be considered topical if it produces local effects or transdermal if it produces systemic effects. For example, a fentanyl patch is considered a transdermal formulation. This article reviews the efficacy of select topical analgesics that are commonly used in clinical practice. Table I provides a brief overview of these agents.

Counterirritants and Rubefacients

Counterirritants represent an interesting class of topical analgesics that act to increase nerve stimulation, rather than decrease it.2 There has been some confusion among the pain management community regarding which agents are classified as counterirritants; however, salicylates, camphor, menthol, and capsaicin are usually classified within this category. Counterirritants come in a variety of over-the-counter formulations, including creams, lotions, gels, ointments, sprays, and patches.

The theory behind counterirritants’ mechanism of action is that irritation of sensory nerve endings helps alter or offset the original pain in the muscle or joints innervated by the same nerves.3 Some counterirritants, such as salicylates, are structurally related to aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) but they do not penetrate underlying tissues. These counterirritants are further classified as rubefacients and their primary action is to irritate the skin producing local vasodilation.

There is limited evidence supporting the role of counterirritants for management of acute injuries or chronic pain. A systematic review evaluated data from three double-blind, placebo-controlled trials of 182 patients with acute pain and from six trials of 429 patients with chronic pain.3 All studies included salicylate application. Among those with acute pain, the number of patients needed to treat (NNT) was 2.1 to achieve at least 50% pain relief compared to placebo at 7 days. For chronic pain, the NNT for topical salicylate was 5.3 (95% CI 3.6 to 10.2) to achieve at least 50% pain relief compared with placebo at 14 days. On the other hand, the NNT for topical NSAIDs was 3.1 (95% CI 2.7 to 3.8) with the same comparator group (placebo) in similar conditions with similar durations.

A Cochrane review evaluated seven randomized controlled studies involving just under 700 participants with acute pain, and nine studies involving just under 600 participants with chronic pain.4 The NNT for acute pain was 3.2 (95% CI: 2.4 to 4.9) compared to placebo. However, when lower quality studies were excluded from the analysis, there were no significant differences between topical counterirritants and placebo. Among those with chronic conditions, the NNT was 6.2 (95% CI: 4 to 13) compared to placebo.

Current clinical usage of counterirritants and rubefacients is for the short-term treatment of mild to moderate MSK pain due to injury. Evidence of counterirritants effectively treating chronic pain conditions is limited; efficacy is not robust enough to support their widespread use.


Capsaicin, an active component of chili peppers, is a transient receptor potential vanilloid-1 receptor (TRPV1) agonist.2 Activation of TRPV1 channels on nociceptive nerve fibers often results in reduced initiation and transmission of pain signals to the spinal cord. Capsaicin induces a mass release of Substance P leading to its depletion. This process often leads to an initial excitation of sensory neurons followed by desensitization after repeated use.

Capsaicin is available over-the-counter in topical cream, liquid, gel, and lotion dosage forms for the treatment of MSK and joint pain associated with arthritis. An 8% patch formulation, Qutenza, is available by prescription as a patch and is FDA-approved for the treatment of neuropathic pain associated with post-herpetic neuralgia (PHN). Qutenza treatments may only be performed by healthcare providers and need to be repeated once every 3 months or longer.5 Initial response to the topical patch may be seen in individuals at approximately one week compared to over-the-counter formulations, which may take upwards of 6 weeks before relief is observed.5,6

Overall, capsaicin offers an affordable therapy for MSK, joint, and neuropathic pain. Its downside is the duration and frequency of use required to achieve relief. Often, an initial use of capsaicin enhances analgesia, rather than pain relief. Since consistent use is needed, patient compliance should be a determining factor when recommending capsaicin as a treatment.

Topical NSAIDs: Diclofenac

Diclofenac is an NSAID that exhibits antipyretic, analgesic, and anti-inflammatory properties.7,8 The primary mechanism of diclofenac is reversible inhibition of cyclooxygenase (COX)-1 and 2 enzymes, resulting in decreased formation of prostaglandin precursors. Prostanoids are involved in the modulation of transduction and transmission of nociceptive pain signals. COX-2 is found expressed in injured tissue and is a main source of prostanoid production in inflammation.

Topical NSAIDs enhance penetration at the source of inflammation, allowing the medication to concentrate specifically on peripheral COX enzymes while avoiding side effects often observed with systemic use.8 Diclofenac is the only NSAID commercially available in topical formulations in the United States; see Table II for specific formulations and recommended dosing regimens.9-11 Topical diclofenac is available outside the US without a prescription. Of note, diclofenac 3% gel (Solaraze) is approved for actinic keratosis and does not carry an indication for pain.12

The US Food and Drug Administration requires inclusion of warnings for topical NSAIDs on adverse cardiovascular and gastrointestinal effects.13 There has been controversy regarding these warnings due to limited systemic absorption of topical NSAIDs. For instance, diclofenac 50-mg tablet taken by mouth 3 times daily generates a maximum plasma concentration (Cmax) of 2270 ng/mL.9 Conversely, diclofenac 1% gel given at 48 g/day (max FDA approved dosing is 32 g/day) resulted in a Cmax of 53.8 ± 32 ng/mL, which is nearly 40 times less than that of oral diclofenac. Notwithstanding, diclofenac is highly albumin bound (> 99%) where the amount of free drug available to cause systemic toxicity is negligent.

For patients with osteoarthritis pain or acute MSK sprains, topical diclofenac may be a viable option to consider before or instead of oral NSAIDs, especially among the elderly.8 Further studies are needed to evaluate its efficacy in managing other pain syndromes such as low back pain.


Lidocaine is a local anesthetic that has indicated for use since the 1960s for arrhythmia, regional blocks, vocal improvement, and neuropathic pain. Lidocaine elicits analgesic effects through partial inhibition of voltage-gated sodium channels, which attenuates nociceptive stimuli from damaged or dysfunctional unmyelinated C fibers and small myelinated Aδ fibers.14 Simply put, lidocaine interrupts peripheral conduction of the pain signal. Topical lidocaine has demonstrated efficacy in localized neuropathic pain and allodynia.14-16 Available formulations include patches, creams, gels, sprays, and solution.

Lidocaine 5% patch (Lidoderm) is FDA-approved for pain relief associated with PHN.17 Each patch contains 700 mg of lidocaine and the patches may be cut before peeling off the release liner. The maximum-labeled dose is three patches applied to the painful area for 12 hours per day with a 12-hour break. However, extended application of four patches for up to 72 consecutive hours has been well tolerated.18 When used according to directions, systemic absorption was 3 +/- 2% (64 +/- 32 mg) of the dose applied while at least 95% (665 mg) of lidocaine will remain in the used patch. Mean Cmax was approximately 0.13 mcg/mL, around 1/10th of the concentration needed to treat cardiac arrhythmias.17

Lidocaine 5% patch has also demonstrated efficacy in trigeminal neuralgia, myofascial pain syndrome of the upper trapezius, and localized neuropathic pain after traumatic brain injury. Two studies compared lidocaine 5% patch (3 to 4 patches for 12 hours within a 24-hour period) to pregabalin (300 to 600 mg/day) in patients with PHN or diabetic peripheral neuropathy (DPN).16 In both studies, treatment response was defined as a reduction of 2 or more points from baseline pain score or an absolute pain score of 4 or less on the 11-item rating scale. Overall, 65.3% of patients treated with the 5% lidocaine patch had a treatment response compared to 62.0% receiving pregabalin. Lidocaine 5% patch was shown to be no different from placebo for persistent inguinal post-herniorrhaphy pain and in chronic back pain.19,20


Clonidine is an alpha-2-adenergic agonist that is FDA-approved for hypertension in oral and transdermal formulations. Intrathecal clonidine has been used for intractable pain syndromes, spasticity, complex regional pain syndrome (CRPS), neuropathic pain, and as an adjunct to bupivacaine to prolong the duration and quality of spinal anesthesia.21-23

Clonidine has demonstrated anti-nociceptive activity in neuropathic pain syndromes and has been increasingly used in pain management. Its hypothesized efficacy is due to clonidine’s activity on alpha-2-adrenoreceptors that are expressed on peripheral and central nerve terminals of nociceptive fibers.22 Peripherally damaged nerves generate ectopic impulses, which are attenuated by adrenergic agonism.

Topical clonidine is available through compounding pharmacies (topical clonidine gel is currently in the pipeline). In a Phase II clinical trial involving 179 participants, subjects in the 0.1% topical clonidine gel group had a 2.3-point reduction in pain scores compared to a 1.7-point reduction in the placebo group.24 Plasma concentrations with 0.1% topical clonidine gel were undetectable (<10 ng/ml). A Cochrane review of two studies involving 344 participants with DPN treated with 0.1% topical clonidine gel showed a NNT of 8.3 to achieve 30% pain reduction.25 Overall, clonidine when applied topically may provide partial pain relief to a subset of patients with DPN. It is important to note that efficacy in treating neuropathic pain was only seen with intrathecal and topical administration and not with oral and intravenous administration.26


It has been long suggested that the analgesic effect of systemic opioids is due to their activation of opioid receptors in the central nervous system, which inhibits ascending pain transmission. However, more recent research has suggested that opioids may also provide analgesia through the peripheral nervous system.27 Opioid receptors are expressed in the peripheral nervous system in sensory afferent neurons. Tissue injury and inflammation leads to upregulation of opioid receptors on peripheral nerve terminals and increased production of opioid peptides, resulting in anti-nociceptive and anti-inflammatory effects.

Several case reports have demonstrated the efficacy of topical opioids in treating painful skin ulcers in the palliative care setting.28,29 These included morphine 0.1 to 0.3%, oxycodone 0.1 to 0.3%, and hydromorphone 0.025 to 0.08%.30 These preparations are typically compounded using crushed tablets or capsules dissolved in a gel, cream, lotion, or ointment base.

Topical opioids may offer a promising new alternative to the treatment of painful skin conditions; however, more research is warranted as is the development of standardized formulations. A limiting factor to their accessibility is cost; many third-party payers do not cover compounded medications, thus requiring patients to pay out-of-pocket for topical opioids.


Topical analgesics offer valuable tools in the pain management armamentarium and may provide safer alternatives or complementary therapies for treating pain in select individuals (eg, those presenting with musculoskeletal pain, osteoarthritis, PHN, peripheral neuropathy, and elderly patients who may be sensitive to medication-related adverse effects). Topical drug delivery may further provide targeted analgesia with limited systemic exposure, lower risk of drug-drug interactions compared to systemic formulations, and reduced pill burden.

Topical analgesics may be used alone or in combination with oral therapies, when appropriate and warranted, to provide synergistic effects. Potential drawbacks may include the need for multiple daily applications, variable absorption depending on the patient’s skin integrity, and lack of commercially available formulations (eg, topical clonidine, opioids). Further studies are warranted to research the role of topical analgesics in other chronic pain syndromes such as low back pain.

Last updated on: August 2, 2018
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