The use of topical analgesics can offer a potentially valuable strategy in the management of a variety of conditions associated with acute or chronic pain, including acute soft tissue injuries, chronic musculoskeletal pain, and various neuropathic pain disorders. Initially, they were developed to provide symptomatic benefits without the systemic adverse effects (AEs) associated with their oral counterparts. They can produce clinically effective drug concentrations at a peripherally located site of injury or inflammation, without resulting in high systemic concentrations that may increase the likelihood of AEs. They probably get unfairly criticised because of irregular and inadequate application.
In this overview, we have restricted our scope to non-opioid drugs that are applied to intact skin, which is the situation where topical analgesics are most frequently used outside special circumstances. The reader is directed to Derry et al. 2017 for the Cochrane review.
How do topical analgesics work?
For a topical formulation to be effective, it must first pass through the skin at or near the injury site. Individual drugs have different degrees of penetration, and some formulations add substances that improve skin penetration and result in higher drug concentrations in tissues. The balance between lipid and aqueous solubility is used to optimise penetration. The use of prodrug esters has been suggested as a way of enhancing permeability. Experiments with artificial membranes or human epidermis suggest that creams are generally less effective than gels or sprays, but newer formulations such as microemulsions may have greater potential. More recently the use of a patch system to deliver the product can increase the opportunity to penetrate the skin over time.
Description of the interventions
A number of different topical analgesics have been tested in a wide range of different painful conditions. The scope of this overview covers several possible interventions.
Table 1 Indications for topical analgesics
• For strains and sprains, topical nonsteroidal anti-inflammatory drugs (NSAIDs) or topical rubefacients.
• For osteoarthritis, topical NSAIDs, topical rubefacients, and low concentration topical capsaicin.
• For neuropathic pain, topical local anaesthetic (lidocaine, for example) or high-concentration topical capsaicin.
• Topical herbal medicines have been used for a variety of painful conditions.
Topical NSAIDs
Non-steroidal anti-inflammatory medication (NSAIDs) reversibly inhibit the enzyme cyclooxygenase (prostaglandin endoperoxide synthase or COX), now recognised to consist of two isoforms, COX-1 and COX-2, mediating production of prostaglandins and thromboxane A2. Inhibition of the COX-2 format reduces inflammation and produces analgesic effects.
The rationale behind topical application is based on the ability of NSAIDs to inhibit COX enzymes locally and peripherally, with minimum systemic uptake. Their use is therefore limited to conditions where the pain is superficial and localised, such as in joints and skeletal muscle.
Once the drug has reached the site of action, it must be present at a sufficiently high concentration to inhibit COX enzymes and produce pain relief. It is probable that topical NSAIDs exert their action by local reduction of symptoms arising from periarticular and intracapsular structures. Tissue levels of NSAIDs applied topically certainly reach levels high enough to inhibit COX-2. Plasma concentrations found after topical administration, however, are only a fraction (usually much less than 5%) of the levels found in plasma following oral administration. Topical application can potentially limit systemic adverse events by minimising systemic concentrations of the drug. Current guidelines in the UK encourage use of topical NSAIDs ahead of oral agents where possible.
Topical capsaicin
Capsaicin is the active compound present in chili peppers, responsible for making them hot when eaten. It binds to nociceptors (sensory receptors responsible for sending signals that cause the perception of pain) in the skin, and specifically to the TRPV1 receptor, which controls movement of sodium and calcium ions across the cell membrane. Initially, binding opens the ion channel (influx of sodium and calcium ions), causing depolarisation and the production of action potentials, which are usually perceived as itching, pricking, or burning sensations.
Repeated applications or high concentrations give rise to a long-lasting effect, which has been termed desensitisation, probably owing to a number of different effects that together overwhelm the cell’s normal functions and can lead to reversible degeneration of nerve terminals.
Topical creams with lowconcentration capsaicin designed for repeated applications are used to treat pain from a wide range of chronic conditions including postherpetic neuralgia (PHN), peripheral diabetic neuropathy (PDN), osteoarthritis and rheumatoid arthritis, in addition to pruritus and psoriasis. The creams typically contain capsaicin 0.025% or 0.075%, but in some countries 0.25% creams are available.
A high-concentration (8%) patch has been developed to increase the amount and speed of delivery of capsaicin to the skin and improve tolerability. Rapid delivery is thought to improve tolerability because cutaneous nociceptors are desensitisation quickly, and the single application avoids both noncompliance and contamination of the home environment with particles of dried capsaicin cream (Anand 2011). The high concentration product is a single application with a minimum interval of 3 months, performed in a clinic, with cooling, local anaesthesia or short-acting opioids to reduce local pain on application. Patients are usually monitored for up to two hours after treatment.
Stringent conditions are required, and as well as using trained healthcare professionals, the treatment setting needs to be well ventilated and spacious due to the vapour of the capsaicin, and cough due to inhalation of capsaicin particles/dust is a hazard for both the healthcare professionals and the patients.
High-concentration capsaicin is licensed in the European Union (EU) to treat neuropathic pain, and in the USA to treat peripheral postherpetic neuralgia. It is available on prescription only; it was licensed in 2009 in Europe and the USA. The US Food and Drug Administration (FDA) refused a licence for neuropathic pain in HIV in 2012. The EU licence originally restricted use to non-diabetic patients, but this restriction was lifted in 2015.
Topical lidocaine
Topical lidocaine dampens peripheral nociceptor sensitisation and central nervous system hyperexcitability if used in recommended doses. It may benefit people with PHN or traumatic nerve injury, where its lack of systemic side effects makes it an attractive option. As cream and gel, lidocaine is cumbersome to administer. The patch is more convenient, being worn for 12 hours in every 24 hours. In addition to the local anaesthetic effect, the patch provides protection against mechanical stimulation (dynamic allodynia), which is a frequent problem in PHN.
Lidocaine is an amide-type local anaesthetic agent that acts by stabilising neuronal membranes. It impairs membrane permeability to sodium, which in turn blocks impulse propagation, and thus dampens both peripheral nociceptor sensitisation, and eventually central nervous system hyperexcitability. It also suppresses neuronal discharge in A delta and C fibres. Regenerating nerve fibres have an accumulation of sodium channels. When lidocaine binds to such sodium channels it initiates an ‘inactive state’ from which normal activation is unable to occur. Lidocaine reduces the frequency rather than the duration of sodium channel opening. In a small dose it inhibits ectopic discharges, although it does not disrupt normal neuronal function. Lidocaine also suppresses spontaneous impulse generation from dorsal root ganglia, where the herpes virus remains dormant after initial infection by Varicella zoster (chickenpox).
Other effects on keratinocytes and immune cells, or activation of irritant receptors (TRPV1 and TRPA1), may also contribute to the analgesic effect of topical lidocaine (Long-term use may cause a loss of epidermal nerve fibres.
Expected outcomes
In acute musculoskeletal pain (strains and sprains) with assessment at about seven days, therapies were diclofenac Emulgel (78% Emulgel, 20% placebo; 2 studies, 314 participants, NNT 1.8 (95% confidence interval 1.5 to 2.1)), ketoprofen gel (72% ketoprofen, 33% placebo, 5 studies, 348 participants, NNT 2.5 (2.0 to 3.4)), piroxicam gel (70% piroxicam, 47% placebo, 3 studies, 522 participants, NNT 4.4 (3.2 to 6.9)), diclofenac Flector plaster (63% Flector, 41% placebo, 4 studies, 1030 participants, NNT 4.7 (3.7 to 6.5)), and diclofenac other plaster (88% diclofenac plaster, 57% placebo, 3 studies, 474 participants, NNT 3.2 (2.6 to 4.2)).
In chronic musculoskeletal pain (mainly hand and knee osteoarthritis) therapies were topical diclofenac preparations for less than six weeks (43% diclofenac, 23% placebo, 5 studies, 732 participants, NNT 5.0 (3.7 to 7.4)), ketoprofen over 6 to 12 weeks (63% ketoprofen, 48% placebo, 4 studies, 2573 participants, NNT 6.9 (5.4 to 9.3)), and topical diclofenac preparations over 6 to 12 weeks (60% diclofenac, 50% placebo, 4 studies, 2343 participants, NNT 9.8 (7.1 to 16)). In postherpetic neuralgia, topical high-concentration capsaicin had moderate equality evidence of limited efficacy (33% capsaicin, 24% placebo, 2 studies, 571 participants, NNT 11 (6.1 to 62)).
Summary
• There is good evidence that some formulations of topical analgesics can provide reasonable outcome without AE’s associated with oral products. Regular application is important to optimise the benefits.
• Patient selection is an important factor. The ability of the individual to “apply” the agent is important and “patch” delivery systems can offer more reliable options.
• Diclofenac and ketoprofen are useful in acute pain conditions such as sprains or strains, with low (good) NNT values. There is a strong message that the exact formulation used is critically important in acute conditions, and that might also apply to other pain conditions.
• In chronic musculoskeletal conditions with assessments over 6 to 12 weeks, topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis. Though NNTs were higher, this still indicates that a small proportion of people had good pain relief.
• Application of high-dose capsaicin in selective cohorts can have a significant impact although it might be 6-12 weeks before the full benefit can be seen. Topical lignocaine patches can be useful in some cases with benefits noticed usually after 5-10 days particularly in herpes zoster or persistent surgical incisional scar pain.
Author
Professor Dominic A. Hegarty. BSc., BMedSc., MB., MSc. (Pain Management), PhD. FCARSCI, FFPMCAI, FIPP
Consultant in Pain Management & Neuromodulation, Clinical Director Mater Private Hospital, Cork Associate Professor of Pain Medicine, UCC, Ireland
Honorary Consultant Guy’s & St. Thomas’ Hospital, London Clinical Lead Neuromodulation Research, Tyndall National Institute, UCC
President World Institute Of Pain (WIP)
Clinical Director Pain Relief Ireland www.painreliefireland.ie
Ref
Derry S, Wi en PJ, Kalso EA, Bell RF, Aldington D, Phillips T, Gaskell H, Moore RA. Topical analgesics for acute and chronic pain in adults – an overview of Cochrane Reviews. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No.: CD008609. DOI: 10.1002/14651858. CD008609.pub2.
Argoff C. Topical Analgesics in the Management of Acute and Chronic Pain Mayo Clin Proc. n February 2013;88(2):195-205 n http://dx.doi. org/10.1016/j.mayocp.2012.11.015
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