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Topical Analgesics in the Management of Acute and Chronic Pain

      Abstract

      Oral analgesics are commonly prescribed for the treatment of acute and chronic pain, but these agents often produce adverse systemic effects, which sometimes are severe. Topical analgesics offer the potential to provide the same analgesic relief provided by oral analgesics but with minimal adverse systemic effects. This article describes the results of a systematic review of the efficacy of topical analgesics in the management of acute and chronic pain conditions. A literature search of MEDLINE/PubMed was conducted using the keywords topical analgesic AND chronic pain OR acute pain OR neuropathic pain and focused only on individual clinical trials published in English-language journals. The search identified 92 articles, of which 65 were eligible for inclusion in the review. The most commonly studied topical analgesics were nonsteroidal anti-inflammatory drugs (n=27), followed by lidocaine (n=9), capsaicin (n=6), amitriptyline (n=5), glyceryl trinitrate (n=3), opioids (n=2), menthol (n=2), pimecrolimus (n=2), and phenytoin (n=2). The most common indications were acute soft tissue injuries (n=18), followed by neuropathic pain (n=17), experimental pain (n=6), osteoarthritis and other chronic joint-related conditions (n=5), skin or leg ulcers (n=5), and chronic knee pain (n=2). Strong evidence was identified for the use of topical diclofenac and topical ibuprofen in the treatment of acute soft tissue injuries or chronic joint-related conditions, such as osteoarthritis. Evidence also supports the use of topical lidocaine in the treatment of postherpetic neuralgia and diabetic neuropathy. Currently, limited evidence is available to support the use of other topical analgesics in acute and chronic pain.

      Abbreviations and Acronyms:

      AE (adverse event), AHN (acute herpetic neuralgia), NSAID (nonsteroidal anti-inflammatory drug), PHN (postherpetic neuralgia)
      Oral medications, including opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly prescribed for the treatment of acute pain. In addition to these agents, various types of oral neuromodulators, such as certain antidepressants and anticonvulsants, are often prescribed for chronic pain. Although potentially effective in providing meaningful pain relief, oral administration of these systemic agents frequently results in adverse events (AEs), which may preclude their ongoing use and result in discontinuation. For example, oral opioids are associated with a wide variety of AEs that affect the central and peripheral nervous systems, including potentially fatal respiratory depression, addiction, pruritus, nausea, and constipation.
      • Roy S.
      • Wang J.
      • Kelschenbach J.
      • Koodie L.
      • Martin J.
      Modulation of immune function by morphine: implications for susceptibility to infection.
      • Finley M.J.
      • Happel C.M.
      • Kaminsky D.E.
      • Rogers T.J.
      Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression.
      • Porreca F.
      • Ossipov M.H.
      Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: mechanisms, implications, and management options.
      • Dahan A.
      • Aarts L.
      • Smith T.W.
      Incidence, reversal, and prevention of opioid-induced respiratory depression.
      • Camilleri M.
      Opioid-induced constipation: challenges and therapeutic opportunities.
      • Manubay J.M.
      • Muchow C.
      • Sullivan M.A.
      Prescription drug abuse: epidemiology, regulatory issues, chronic pain management with narcotic analgesics.
      • Tey H.L.
      • Yosipovitch G.
      Targeted treatment of pruritus: a look into the future.
      Use of oral NSAIDs also can result in serious AEs, including gastrointestinal bleeding, cardiovascular complications (such as hypertension and increased risk for myocardial infarction), and renal dysfunction or failure.
      • Farkouh M.E.
      • Greenberg B.P.
      An evidence-based review of the cardiovascular risks of nonsteroidal anti-inflammatory drugs.
      • Harirforoosh S.
      • Jamali F.
      Renal adverse effects of nonsteroidal anti-inflammatory drugs.
      • John R.
      • Herzenberg A.M.
      Renal toxicity of therapeutic drugs.
      • Lazzaroni M.
      • Porro G.B.
      Management of NSAID-induced gastrointestinal toxicity: focus on proton pump inhibitors.
      • Scarpignato C.
      • Hunt R.H.
      Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention.
      • Trelle S.
      • Reichenbach S.
      • Wandel S.
      • et al.
      Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.
      Salicylates, such as acetylsalicylic acid (aspirin), produce analgesic effects through a mechanism similar to that of other NSAIDs and, therefore, are associated with similar AE profiles.
      • Hedner T.
      • Everts B.
      The early clinical history of salicylates in rheumatology and pain.
      • Peura D.A.
      • Goldkind L.
      Balancing the gastrointestinal benefits and risks of nonselective NSAIDs.
      In addition, aspirin has been closely linked to the development of Reye syndrome, a rare but often fatal pediatric syndrome.
      • Glasgow J.F.
      Reye's syndrome: the case for a causal link with aspirin.
      Topical analgesics were developed, in part, to provide the symptomatic benefits seen with oral agents but without the systemic AEs associated with oral analgesics. Topical administration of analgesics 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.
      • Heyneman C.A.
      • Lawless-Liday C.
      • Wall G.C.
      Oral versus topical NSAIDs in rheumatic diseases: a comparison.
      • Haroutiunian S.
      • Drennan D.A.
      • Lipman A.G.
      Topical NSAID therapy for musculoskeletal pain.
      • Ribeiro M.D.
      • Joel S.P.
      • Zeppetella G.
      The bioavailability of morphine applied topically to cutaneous ulcers.
      • Paice J.A.
      • Von Roenn J.H.
      • Hudgins J.C.
      • Luong L.
      • Krejcie T.C.
      • Avram M.J.
      Morphine bioavailability from a topical gel formulation in volunteers.
      Not all topical analgesics produce therapeutic effects strictly at peripheral sites of action. For example, topical application of opioids, such as morphine or fentanyl, produces analgesia by both central and peripheral mechanisms of action,
      • Jorge L.L.
      • Feres C.C.
      • Teles V.E.
      Topical preparations for pain relief: efficacy and patient adherence.
      although systemic concentrations are low after topical administration.
      • Paice J.A.
      • Von Roenn J.H.
      • Hudgins J.C.
      • Luong L.
      • Krejcie T.C.
      • Avram M.J.
      Morphine bioavailability from a topical gel formulation in volunteers.
      • Jorge L.L.
      • Feres C.C.
      • Teles V.E.
      Topical preparations for pain relief: efficacy and patient adherence.
      Various factors influence the penetration and absorption of topical analgesics, including the biochemical properties of any adjuvants included in the topical formulation and interindividual variability in skin absorption.
      • Jorge L.L.
      • Feres C.C.
      • Teles V.E.
      Topical preparations for pain relief: efficacy and patient adherence.
      Topical analgesic therapy is nonetheless 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.
      • Haroutiunian S.
      • Drennan D.A.
      • Lipman A.G.
      Topical NSAID therapy for musculoskeletal pain.
      • Mason L.
      • Moore R.A.
      • Edwards J.E.
      • Derry S.
      • McQuay H.J.
      Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis.
      • Mason L.
      • Moore R.A.
      • Edwards J.E.
      • Derry S.
      • McQuay H.J.
      Topical NSAIDs for acute pain: a meta-analysis.
      • Borg-Stein J.
      • Zaremski J.L.
      • Hanford M.A.
      New concepts in the assessment and treatment of regional musculoskeletal pain and sports injury.
      • Kroenke K.
      • Krebs E.E.
      • Bair M.J.
      Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews.
      • Barthel H.R.
      • Axford-Gatley R.A.
      Topical nonsteroidal anti-inflammatory drugs for osteoarthritis.
      • Argoff C.E.
      Review of current guidelines on the care of postherpetic neuralgia.
      • Goldstein A.T.
      • Creasey A.
      • Pfau R.
      • Phillips D.
      • Burrows L.J.
      A double-blind, randomized controlled trial of clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus.
      Three systematic reviews or meta-analyses have investigated the efficacy of topical NSAIDs in the treatment of musculoskeletal pain
      • Haroutiunian S.
      • Drennan D.A.
      • Lipman A.G.
      Topical NSAID therapy for musculoskeletal pain.
      • Mason L.
      • Moore R.A.
      • Edwards J.E.
      • Derry S.
      • McQuay H.J.
      Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis.
      • Mason L.
      • Moore R.A.
      • Edwards J.E.
      • Derry S.
      • McQuay H.J.
      Topical NSAIDs for acute pain: a meta-analysis.
      ; however, no systematic review or meta-analysis has been conducted to examine the efficacy of other topical analgesics for other indications. Thus, a systematic review was conducted to evaluate the efficacy of topical analgesic therapy in the management of acute and chronic pain conditions.

      Methods

      A MEDLINE/PubMed search, covering the period from inception through August 2011, was conducted using the keywords topical analgesic AND chronic pain OR acute pain OR neuropathic pain. The keyword postoperative pain was not included in the search, which largely restricted the search to acute pain conditions other than postoperative pain. In addition, the search was restricted to English-language articles describing individual clinical trials (not reviews of published clinical trials) in humans (patients or healthy volunteers). Evidence for efficacy and tolerability of a specific topical analgesic was reviewed only if 2 or more published clinical trials were available for that drug, irrespective of indication; in other words, if a particular disease state was the focus of only one published clinical trial but the topical analgesic that was studied in that clinical trial was studied in at least one other clinical trial, then that clinical trial was included in the review.

      Results

      Study Identification

      The literature search identified a total of 92 articles, of which 65 were eligible for inclusion (Figure).
      • Irving G.A.
      • Backonja M.M.
      • Dunteman E.
      • et al.
      NGX-4010 C117 Study Group
      A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.
      • Costantino C.
      • Kwarecki J.
      • Samokhin A.V.
      • Mautone G.
      • Rovati S.
      Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.
      • Tiso R.L.
      • Tong-Ngork S.
      • Fredlund K.L.
      Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.
      • Coudreuse J.M.
      • de Vathaire F.
      Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.
      • Claeys A.
      • Gaudy-Marqueste C.
      • Pauly V.
      • et al.
      Management of pain associated with debridement of leg ulcers: a randomized, multicentre, pilot study comparing nitrous oxide–oxygen mixture inhalation and lidocaine-prilocaïne cream.
      • Barton D.L.
      • Wos E.J.
      • Qin R.
      • et al.
      A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.
      • Cianchetti C.
      Capsaicin jelly against migraine pain.
      • Rehm S.
      • Binder A.
      • Baron R.
      Post-herpetic neuralgia: 5% lidocaine medicated plaster, pregabalin, or a combination of both? A randomized, open, clinical effectiveness study.
      • Mueller E.A.
      • Kirch W.
      • Reiter S.
      Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial.
      • Backonja M.M.
      • Malan T.P.
      • Vanhove G.F.
      • Tobias J.K.
      C102/106 Study Group
      NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension.
      • Hsieh L.F.
      • Hong C.Z.
      • Chern S.H.
      • Chen C.C.
      Efficacy and side effects of diclofenac patch in treatment of patients with myofascial pain syndrome of the upper trapezius.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      5% Lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study.
      • Binder A.
      • Bruxelle J.
      • Rogers P.
      • Hans G.
      • Bösl I.
      • Baron R.
      Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: interim analysis from an open-label, two-stage adaptive, randomized, controlled trial.
      • Kanai A.
      • Segawa Y.
      • Okamoto T.
      • Koto M.
      • Okamoto H.
      The analgesic effect of a metered-dose 8% lidocaine pump spray in posttraumatic peripheral neuropathy: a pilot study.
      • Paoloni J.A.
      • Murrell G.A.
      • Burch R.M.
      • Ang R.Y.
      Randomised, double-blind, placebo-controlled clinical trial of a new topical glyceryl trinitrate patch for chronic lateral epicondylosis.
      • Dualé C.
      • Daveau J.
      • Cardot J.-M.
      • Boyer-Grand A.
      • Schoeffler P.
      • Dubray C.
      Cutaneous amitriptyline in human volunteers: differential effects on the components of sensory information.
      • D'Anchise R.
      • Bulitta M.
      • Giannetti B.
      Comfrey extract ointment in comparison to diclofenac gel in the treatment of acute unilateral ankle sprains (distortions).
      • Ho K.Y.
      • Huh B.K.
      • White W.D.
      • Yeh C.C.
      • Miller E.J.
      Topical amitriptyline versus lidocaine in the treatment of neuropathic pain.
      • Paoloni J.A.
      • Murrell G.A.
      Three-year followup study of topical glyceryl trinitrate treatment of chronic noninsertional Achilles tendinopathy.
      • Gorouhi F.
      • Solhpour A.
      • Beitollahi J.M.
      • et al.
      Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus.
      • Welling A.
      A randomised controlled trial to test the analgesic efficacy of topical morphine on minor superficial and partial thickness burns in accident and emergency departments.
      • Sibbald R.G.
      • Coutts P.
      • Fierheller M.
      • Woo K.
      A pilot (real-life) randomised clinical evaluation of a pain-relieving foam dressing: (ibuprofen-foam versus local best practice).
      • Gottrup F.
      • Jørgensen B.
      • Karlsmark T.
      • et al.
      Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers.
      • Lee Y.S.
      • Kho H.S.
      • Kim Y.K.
      • Chung S.C.
      Influence of topical capsaicin on facial sensitivity in response to experimental pain.
      • Esparza F.
      • Cobián C.
      • Jiménez J.F.
      • García-Cota J.J.
      • Sánchez C.
      • Maestro A.
      Working group for the acute pain study of SETRADE
      Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries.
      • Jensen M.P.
      • Gammaitoni A.R.
      • Olaleye D.O.
      • Oleka N.
      • Nalamachu S.R.
      • Galer B.S.
      The pain quality assessment scale: assessment of pain quality in carpal tunnel syndrome.
      • Pöyhiä R.
      • Vainio A.
      Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia.
      • Predel H.G.
      • Giannetti B.
      • Koll R.
      • Bulitta M.
      • Staiger C.
      Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study.
      • Baer P.A.
      • Thomas L.M.
      • Shainhouse Z.
      Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886].
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      • Sullivan M.J.
      Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.
      • Vernassiere C.
      • Cornet C.
      • Trechot P.
      • et al.
      Study to determine the efficacy of topical morphine on painful chronic skin ulcers.
      • Di Rienzo Businco L.
      • Di Rienzo Businco A.
      • D'Emilia M.
      • Lauriello M.
      • Coen Tirelli G.
      Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms.
      • Myrer J.W.
      • Feland J.B.
      • Fellingham G.W.
      The effects of a topical analgesic and placebo in treatment of chronic knee pain.
      • Predel H.G.
      • Koll R.
      • Pabst H.
      • et al.
      Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
      • Kucera M.
      • Horácek O.
      • Kálal J.
      • Korbelar P.
      • Polesná Z.
      Synergetic analgesic effect of the combination of arnica and hydroxyethyl salicylate in ethanolic solution following cutaneous application by transcutaneous electrostimulation.
      • Meier T.
      • Wasner G.
      • Faust M.
      • et al.
      Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study.
      • Carneiro P.M.
      • Rwanyuma L.R.
      • Mkony C.A.
      A comparison of topical Phenytoin with Silverex in the treatment of superficial dermal burn wounds.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.
      • Gerner P.
      • Kao G.
      • Srinivasa V.
      • Narang S.
      • Wang G.K.
      Topical amitriptyline in healthy volunteers.
      • Hwang D.Y.
      • Yoon S.G.
      • Kim H.S.
      • Lee J.K.
      • Kim K.Y.
      Effect of 0.2 percent glyceryl trinitrate ointment on wound healing after a hemorrhoidectomy: results of a randomized, prospective, double-blind, placebo-controlled trial.
      • Carneiro P.M.
      • Nyawawa E.T.
      Topical phenytoin versus EUSOL in the treatment of non-malignant chronic leg ulcers.
      • Whitefield M.
      • O'Kane C.J.
      • Anderson S.
      Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomized, double-blind study.
      • Balakrishnan S.
      • Bhushan K.
      • Bhargava V.K.
      • Pandhi P.
      A randomized parallel trial of topical aspirin-moisturizer solution vs. oral aspirin for acute herpetic neuralgia.
      • McCleane G.
      Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study.
      • Galer B.S.
      • Rowbotham M.
      • Perander J.
      • Devers A.
      • Friedman E.
      Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.
      • Paice J.A.
      • Ferrans C.E.
      • Lashley F.R.
      • Shott S.
      • Vizgirda V.
      • Pitrak D.
      Topical capsaicin in the management of HIV-associated peripheral neuropathy.
      • Sjölund K.F.
      • Segerdahl M.
      • Sollevi A.
      Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain.
      • Hadley H.W.
      • Fischer L.A.
      • Whitaker J.
      A topically applied quaternary ammonium compound exhibits analgesic effects for orthopedic pain.
      • Bareggi S.R.
      • Pirola R.
      • De Benedittis G.
      Skin and plasma levels of acetylsalicylic acid: a comparison between topical aspirin/diethyl ether mixture and oral aspirin in acute herpes zoster and postherpetic neuralgia.
      • Svensson P.
      • Houe L.
      • Arendt-Nielsen L.
      Effect of systemic versus topical nonsteroidal anti-inflammatory drugs on postexercise jaw-muscle soreness: a placebo-controlled study.
      • Burnham R.
      • Gregg R.
      • Healy P.
      • Steadward R.
      The effectiveness of topical diclofenac for lateral epicondylitis.
      • Patel R.K.
      • Leswell P.F.
      Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group.
      • De Benedittis G.
      • Lorenzetti A.
      Topical aspirin/diethyl ether mixture versus indomethacin and diclofenac/diethyl ether mixtures for acute herpetic neuralgia and postherpetic neuralgia: a double-blind crossover placebo-controlled study.
      • Rowbotham M.C.
      • Davies P.S.
      • Verkempinck C.
      • Galer B.S.
      Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia.
      • Roth S.H.
      A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis.
      • Campbell J.
      • Dunn T.
      Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains.
      • Airaksinen O.
      • Venãlãinen J.
      • Pietilãinen T.
      Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries.
      • De Benedittis G.
      • Besana F.
      • Lorenzetti A.
      A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin/diethyl ether mixture. An open-label study plus a double-blind controlled clinical trial.
      • Russell A.L.
      Piroxicam 0.5% topical gel compared to placebo in the treatment of acute soft tissue injuries: a double-blind study comparing efficacy and safety.
      • Akermark C.
      • Forsskåhl B.
      Topical indomethacin in overuse injuries in athletes: a randomized double-blind study comparing Elmetacin with oral indomethacin and placebo.
      • Baixauli F.
      • Inglés F.
      • Alcántara P.
      • Navarrete R.
      • Puchol E.
      • Vidal F.
      Percutaneous treatment of acute soft tissue lesions with naproxen gel and ketoprofen gel.
      • Bouchier-Hayes T.A.
      • Rotman H.
      • Darekar B.S.
      Comparison of the efficacy and tolerability of diclofenac gel (Voltarol Emulgel) and felbinac gel (Traxam) in the treatment of soft tissue injuries.
      • Ginsberg F.
      • Famaey J.P.
      A double-blind study of topical massage with Rado-Salil ointment in mechanical low-back pain.
      A total of 27 articles were excluded: 7 articles
      • Eisenach J.C.
      • Curry R.
      • Tong C.
      • Houle T.T.
      • Yaksh T.L.
      Effects of intrathecal ketorolac on human experimental pain.
      • Frymoyer A.R.
      • Rowbotham M.C.
      • Petersen K.L.
      Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers.
      • Baad-Hansen L.
      • Juhl G.I.
      • Jensen T.S.
      • Brandsborg B.
      • Svensson P.
      Differential effect of intravenous S-ketamine and fentanyl on atypical odontalgia and capsaicin-evoked pain.
      • Mathiesen O.
      • Imbimbo B.P.
      • Hilsted K.L.
      • Fabbri L.
      • Dahl J.B.
      CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model.
      • Siproudhis L.
      • Sébille V.
      • Pigot F.
      • Hémery P.
      • Juguet F.
      • Bellissant E.
      Lack of efficacy of botulinum toxin in chronic anal fissure.
      • Eisenach J.C.
      • Curry R.
      • Hood D.D.
      Dose response of intrathecal adenosine in experimental pain and allodynia.
      • Cospite M.
      Double-blind, placebo-controlled evaluation of clinical activity and safety of Daflon 500 mg in the treatment of acute hemorrhoids.
      described studies in which the analgesic was not administered topically; 6 articles
      • Garra G.
      • Singer A.J.
      • Leno R.
      • et al.
      Heat or cold packs for neck and back strain: a randomized controlled trial of efficacy.
      • Underwood M.
      • Ashby D.
      • Carnes D.
      • et al.
      Topical or oral ibuprofen for chronic knee pain in older people: the TOIB study.
      • Underwood M.
      • Ashby D.
      • Cross P.
      • et al.
      TOIB Study Team
      Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study.
      • Cross P.L.
      • Ashby D.
      • Harding G.
      • et al.
      TOIB Study Team
      TOIB Study: are topical or oral ibuprofen equally effective for the treatment of chronic knee pain presenting in primary care; a randomised controlled trial with patient preference study [ISRCTN79353052].
      • Nadler S.F.
      • Steiner D.J.
      • Erasala G.N.
      • et al.
      Continuous low-level heat wrap therapy provides more efficacy than ibuprofen and acetaminophen for acute low back pain.
      • Schlesinger N.
      • Detry M.A.
      • Holland B.K.
      • et al.
      Local ice therapy during bouts of acute gouty arthritis.
      described clinical trials of nonpharmacologic treatments (ie, ice, heat, or practitioner advice); 5 articles
      • Wetzel D.
      • Menke W.
      • Dieter R.
      • Smasal V.
      • Giannetti B.
      • Bulitta M.
      Escin/diethylammonium salicylate/heparin combination gels for the topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
      • Perrotti P.
      • Antropoli C.
      • Molino D.
      • De Stefano G.
      • Antropoli M.
      Conservative treatment of acute thrombosed external hemorrhoids with topical nifedipine.
      • Stam C.
      • Bonnet M.S.
      • van Haselen R.A.
      The efficacy and safety of a homeopathic gel in the treatment of acute low back pain: a multi-centre, randomised, double-blind comparative clinical trial.
      • Sandelin J.
      • Harilainen A.
      • Crone H.
      • et al.
      Local NSAID gel (eltenac) in the treatment of osteoarthritis of the knee: a double blind study comparing eltenac with oral diclofenac and placebo gel.
      • Dreiser R.L.
      • Ditisheim A.
      • Charlot J.
      • Lopez A.
      A double blind, placebo controlled study of niflumic acid gel in the treatment of acute tendinitis.
      focused on analgesics that were studied in only 1 clinical trial; 3 articles
      • Ball I.M.
      • Seabrook J.
      • Desai N.
      • Allen L.
      • Anderson S.
      Dilute proparacaine for the management of acute corneal injuries in the emergency department.
      • Kosrirukvongs P.
      Topical piroxicam and conjunctivitis.
      • Arshinoff S.A.
      • Mills M.D.
      • Haber S.
      Pharmacotherapy of photorefractive keratectomy.
      dealt with ophthalmic indications rather than acute or chronic pain; 3 articles
      • Pergolizzi J.V.
      • Pappagallo M.
      • Raffa R.B.
      • et al.
      Preliminary observations of a novel topical oil with analgesic properties for treatment of acute and chronic pain syndromes.
      • Beydoun A.
      Postherpetic neuralgia: role of gabapentin and other treatment modalities.
      • Buckley M.M.
      • Brogden R.N.
      Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.
      were reviews; 1 article
      • Finnerup N.B.
      • Pedersen L.H.
      • Terkelsen A.J.
      • Johannesen I.J.
      • Jensen T.S.
      Reaction to topical capsaicin in spinal cord injury patients with and without central pain.
      described an experimental study in which capsaicin was used as a stimulus rather than as a therapy; 1 article
      • Ritchie M.
      • Liedgens H.
      • Nuijten M.
      Cost effectiveness of a lidocaine 5% medicated plaster compared with pregabalin for the treatment of postherpetic neuralgia in the UK: a Markov model analysis.
      described a mathematical modeling study; and 1 article
      • Moore K.T.
      • Adams H.D.
      • Natarajan J.
      • et al.
      Bioequivalence and safety of a novel fentanyl transdermal matrix system compared with a transdermal reservoir system.
      dealt with a pharmacokinetic study with no pain assessment.
      Figure thumbnail gr1
      FigureFlowchart depicting the methods used to select articles for the systematic review.

      Study Characteristics

      Detailed information can be found in the Supplemental Table (available online at http://www.mayoclinicproceedings.org). The most commonly studied agents were NSAIDs (n=26),
      • Costantino C.
      • Kwarecki J.
      • Samokhin A.V.
      • Mautone G.
      • Rovati S.
      Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.
      • Tiso R.L.
      • Tong-Ngork S.
      • Fredlund K.L.
      Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.
      • Coudreuse J.M.
      • de Vathaire F.
      Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.
      • Mueller E.A.
      • Kirch W.
      • Reiter S.
      Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial.
      • Hsieh L.F.
      • Hong C.Z.
      • Chern S.H.
      • Chen C.C.
      Efficacy and side effects of diclofenac patch in treatment of patients with myofascial pain syndrome of the upper trapezius.
      • Sibbald R.G.
      • Coutts P.
      • Fierheller M.
      • Woo K.
      A pilot (real-life) randomised clinical evaluation of a pain-relieving foam dressing: (ibuprofen-foam versus local best practice).
      • Gottrup F.
      • Jørgensen B.
      • Karlsmark T.
      • et al.
      Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers.
      • Esparza F.
      • Cobián C.
      • Jiménez J.F.
      • García-Cota J.J.
      • Sánchez C.
      • Maestro A.
      Working group for the acute pain study of SETRADE
      Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries.
      • Baer P.A.
      • Thomas L.M.
      • Shainhouse Z.
      Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886].
      • Di Rienzo Businco L.
      • Di Rienzo Businco A.
      • D'Emilia M.
      • Lauriello M.
      • Coen Tirelli G.
      Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms.
      • Kucera M.
      • Horácek O.
      • Kálal J.
      • Korbelar P.
      • Polesná Z.
      Synergetic analgesic effect of the combination of arnica and hydroxyethyl salicylate in ethanolic solution following cutaneous application by transcutaneous electrostimulation.
      • Whitefield M.
      • O'Kane C.J.
      • Anderson S.
      Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomized, double-blind study.
      • Balakrishnan S.
      • Bhushan K.
      • Bhargava V.K.
      • Pandhi P.
      A randomized parallel trial of topical aspirin-moisturizer solution vs. oral aspirin for acute herpetic neuralgia.
      • Galer B.S.
      • Rowbotham M.
      • Perander J.
      • Devers A.
      • Friedman E.
      Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.
      • Bareggi S.R.
      • Pirola R.
      • De Benedittis G.
      Skin and plasma levels of acetylsalicylic acid: a comparison between topical aspirin/diethyl ether mixture and oral aspirin in acute herpes zoster and postherpetic neuralgia.
      • Burnham R.
      • Gregg R.
      • Healy P.
      • Steadward R.
      The effectiveness of topical diclofenac for lateral epicondylitis.
      • Patel R.K.
      • Leswell P.F.
      Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group.
      • De Benedittis G.
      • Lorenzetti A.
      Topical aspirin/diethyl ether mixture versus indomethacin and diclofenac/diethyl ether mixtures for acute herpetic neuralgia and postherpetic neuralgia: a double-blind crossover placebo-controlled study.
      • Roth S.H.
      A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis.
      • Campbell J.
      • Dunn T.
      Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains.
      • Airaksinen O.
      • Venãlãinen J.
      • Pietilãinen T.
      Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries.
      • De Benedittis G.
      • Besana F.
      • Lorenzetti A.
      A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin/diethyl ether mixture. An open-label study plus a double-blind controlled clinical trial.
      • Russell A.L.
      Piroxicam 0.5% topical gel compared to placebo in the treatment of acute soft tissue injuries: a double-blind study comparing efficacy and safety.
      • Akermark C.
      • Forsskåhl B.
      Topical indomethacin in overuse injuries in athletes: a randomized double-blind study comparing Elmetacin with oral indomethacin and placebo.
      • Baixauli F.
      • Inglés F.
      • Alcántara P.
      • Navarrete R.
      • Puchol E.
      • Vidal F.
      Percutaneous treatment of acute soft tissue lesions with naproxen gel and ketoprofen gel.
      • Bouchier-Hayes T.A.
      • Rotman H.
      • Darekar B.S.
      Comparison of the efficacy and tolerability of diclofenac gel (Voltarol Emulgel) and felbinac gel (Traxam) in the treatment of soft tissue injuries.
      followed by lidocaine (n=9),
      • Claeys A.
      • Gaudy-Marqueste C.
      • Pauly V.
      • et al.
      Management of pain associated with debridement of leg ulcers: a randomized, multicentre, pilot study comparing nitrous oxide–oxygen mixture inhalation and lidocaine-prilocaïne cream.
      • Rehm S.
      • Binder A.
      • Baron R.
      Post-herpetic neuralgia: 5% lidocaine medicated plaster, pregabalin, or a combination of both? A randomized, open, clinical effectiveness study.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      5% Lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study.
      • Binder A.
      • Bruxelle J.
      • Rogers P.
      • Hans G.
      • Bösl I.
      • Baron R.
      Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: interim analysis from an open-label, two-stage adaptive, randomized, controlled trial.
      • Kanai A.
      • Segawa Y.
      • Okamoto T.
      • Koto M.
      • Okamoto H.
      The analgesic effect of a metered-dose 8% lidocaine pump spray in posttraumatic peripheral neuropathy: a pilot study.
      • Jensen M.P.
      • Gammaitoni A.R.
      • Olaleye D.O.
      • Oleka N.
      • Nalamachu S.R.
      • Galer B.S.
      The pain quality assessment scale: assessment of pain quality in carpal tunnel syndrome.
      • Meier T.
      • Wasner G.
      • Faust M.
      • et al.
      Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study.
      • Rowbotham M.C.
      • Davies P.S.
      • Verkempinck C.
      • Galer B.S.
      Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia.
      capsaicin (n=6),
      • Irving G.A.
      • Backonja M.M.
      • Dunteman E.
      • et al.
      NGX-4010 C117 Study Group
      A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.
      • Cianchetti C.
      Capsaicin jelly against migraine pain.
      • Backonja M.M.
      • Malan T.P.
      • Vanhove G.F.
      • Tobias J.K.
      C102/106 Study Group
      NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension.
      • Lee Y.S.
      • Kho H.S.
      • Kim Y.K.
      • Chung S.C.
      Influence of topical capsaicin on facial sensitivity in response to experimental pain.
      • McCleane G.
      Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study.
      • Paice J.A.
      • Ferrans C.E.
      • Lashley F.R.
      • Shott S.
      • Vizgirda V.
      • Pitrak D.
      Topical capsaicin in the management of HIV-associated peripheral neuropathy.
      and amitriptyline (n=5).
      • Dualé C.
      • Daveau J.
      • Cardot J.-M.
      • Boyer-Grand A.
      • Schoeffler P.
      • Dubray C.
      Cutaneous amitriptyline in human volunteers: differential effects on the components of sensory information.
      • Ho K.Y.
      • Huh B.K.
      • White W.D.
      • Yeh C.C.
      • Miller E.J.
      Topical amitriptyline versus lidocaine in the treatment of neuropathic pain.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      • Sullivan M.J.
      Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.
      • Gerner P.
      • Kao G.
      • Srinivasa V.
      • Narang S.
      • Wang G.K.
      Topical amitriptyline in healthy volunteers.
      Other agents studied included glyceryl trinitrate (n=3),
      • Paoloni J.A.
      • Murrell G.A.
      • Burch R.M.
      • Ang R.Y.
      Randomised, double-blind, placebo-controlled clinical trial of a new topical glyceryl trinitrate patch for chronic lateral epicondylosis.
      • Paoloni J.A.
      • Murrell G.A.
      Three-year followup study of topical glyceryl trinitrate treatment of chronic noninsertional Achilles tendinopathy.
      • Hwang D.Y.
      • Yoon S.G.
      • Kim H.S.
      • Lee J.K.
      • Kim K.Y.
      Effect of 0.2 percent glyceryl trinitrate ointment on wound healing after a hemorrhoidectomy: results of a randomized, prospective, double-blind, placebo-controlled trial.
      opioids (n=2),
      • Welling A.
      A randomised controlled trial to test the analgesic efficacy of topical morphine on minor superficial and partial thickness burns in accident and emergency departments.
      • Vernassiere C.
      • Cornet C.
      • Trechot P.
      • et al.
      Study to determine the efficacy of topical morphine on painful chronic skin ulcers.
      menthol (n=2),
      • Myrer J.W.
      • Feland J.B.
      • Fellingham G.W.
      The effects of a topical analgesic and placebo in treatment of chronic knee pain.
      • Ginsberg F.
      • Famaey J.P.
      A double-blind study of topical massage with Rado-Salil ointment in mechanical low-back pain.
      pimecrolimus (n=2),
      • Goldstein A.T.
      • Creasey A.
      • Pfau R.
      • Phillips D.
      • Burrows L.J.
      A double-blind, randomized controlled trial of clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus.
      • Gorouhi F.
      • Solhpour A.
      • Beitollahi J.M.
      • et al.
      Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus.
      and phenytoin (n=2).
      • Carneiro P.M.
      • Rwanyuma L.R.
      • Mkony C.A.
      A comparison of topical Phenytoin with Silverex in the treatment of superficial dermal burn wounds.
      • Carneiro P.M.
      • Nyawawa E.T.
      Topical phenytoin versus EUSOL in the treatment of non-malignant chronic leg ulcers.
      The most common indications were soft tissue injuries and related conditions (n=17),
      • Costantino C.
      • Kwarecki J.
      • Samokhin A.V.
      • Mautone G.
      • Rovati S.
      Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.
      • Coudreuse J.M.
      • de Vathaire F.
      Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.
      • Mueller E.A.
      • Kirch W.
      • Reiter S.
      Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial.
      • Paoloni J.A.
      • Murrell G.A.
      Three-year followup study of topical glyceryl trinitrate treatment of chronic noninsertional Achilles tendinopathy.
      • Welling A.
      A randomised controlled trial to test the analgesic efficacy of topical morphine on minor superficial and partial thickness burns in accident and emergency departments.
      • Esparza F.
      • Cobián C.
      • Jiménez J.F.
      • García-Cota J.J.
      • Sánchez C.
      • Maestro A.
      Working group for the acute pain study of SETRADE
      Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries.
      • Predel H.G.
      • Giannetti B.
      • Koll R.
      • Bulitta M.
      • Staiger C.
      Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study.
      • Predel H.G.
      • Koll R.
      • Pabst H.
      • et al.
      Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
      • Carneiro P.M.
      • Rwanyuma L.R.
      • Mkony C.A.
      A comparison of topical Phenytoin with Silverex in the treatment of superficial dermal burn wounds.
      • Whitefield M.
      • O'Kane C.J.
      • Anderson S.
      Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomized, double-blind study.
      • Galer B.S.
      • Rowbotham M.
      • Perander J.
      • Devers A.
      • Friedman E.
      Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.
      • Patel R.K.
      • Leswell P.F.
      Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group.
      • Campbell J.
      • Dunn T.
      Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains.
      • Airaksinen O.
      • Venãlãinen J.
      • Pietilãinen T.
      Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries.
      • Akermark C.
      • Forsskåhl B.
      Topical indomethacin in overuse injuries in athletes: a randomized double-blind study comparing Elmetacin with oral indomethacin and placebo.
      • Baixauli F.
      • Inglés F.
      • Alcántara P.
      • Navarrete R.
      • Puchol E.
      • Vidal F.
      Percutaneous treatment of acute soft tissue lesions with naproxen gel and ketoprofen gel.
      • Bouchier-Hayes T.A.
      • Rotman H.
      • Darekar B.S.
      Comparison of the efficacy and tolerability of diclofenac gel (Voltarol Emulgel) and felbinac gel (Traxam) in the treatment of soft tissue injuries.
      followed by neuropathic pain (n=17),
      • Irving G.A.
      • Backonja M.M.
      • Dunteman E.
      • et al.
      NGX-4010 C117 Study Group
      A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.
      • Barton D.L.
      • Wos E.J.
      • Qin R.
      • et al.
      A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.
      • Rehm S.
      • Binder A.
      • Baron R.
      Post-herpetic neuralgia: 5% lidocaine medicated plaster, pregabalin, or a combination of both? A randomized, open, clinical effectiveness study.
      • Backonja M.M.
      • Malan T.P.
      • Vanhove G.F.
      • Tobias J.K.
      C102/106 Study Group
      NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      5% Lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study.
      • Binder A.
      • Bruxelle J.
      • Rogers P.
      • Hans G.
      • Bösl I.
      • Baron R.
      Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: interim analysis from an open-label, two-stage adaptive, randomized, controlled trial.
      • Kanai A.
      • Segawa Y.
      • Okamoto T.
      • Koto M.
      • Okamoto H.
      The analgesic effect of a metered-dose 8% lidocaine pump spray in posttraumatic peripheral neuropathy: a pilot study.
      • Ho K.Y.
      • Huh B.K.
      • White W.D.
      • Yeh C.C.
      • Miller E.J.
      Topical amitriptyline versus lidocaine in the treatment of neuropathic pain.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      • Sullivan M.J.
      Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.
      • Meier T.
      • Wasner G.
      • Faust M.
      • et al.
      Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.
      • Balakrishnan S.
      • Bhushan K.
      • Bhargava V.K.
      • Pandhi P.
      A randomized parallel trial of topical aspirin-moisturizer solution vs. oral aspirin for acute herpetic neuralgia.
      • McCleane G.
      Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study.
      • Bareggi S.R.
      • Pirola R.
      • De Benedittis G.
      Skin and plasma levels of acetylsalicylic acid: a comparison between topical aspirin/diethyl ether mixture and oral aspirin in acute herpes zoster and postherpetic neuralgia.
      • De Benedittis G.
      • Lorenzetti A.
      Topical aspirin/diethyl ether mixture versus indomethacin and diclofenac/diethyl ether mixtures for acute herpetic neuralgia and postherpetic neuralgia: a double-blind crossover placebo-controlled study.
      • De Benedittis G.
      • Besana F.
      • Lorenzetti A.
      A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin/diethyl ether mixture. An open-label study plus a double-blind controlled clinical trial.
      experimental pain (n=6),
      • Dualé C.
      • Daveau J.
      • Cardot J.-M.
      • Boyer-Grand A.
      • Schoeffler P.
      • Dubray C.
      Cutaneous amitriptyline in human volunteers: differential effects on the components of sensory information.
      • Lee Y.S.
      • Kho H.S.
      • Kim Y.K.
      • Chung S.C.
      Influence of topical capsaicin on facial sensitivity in response to experimental pain.
      • Pöyhiä R.
      • Vainio A.
      Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia.
      • Kucera M.
      • Horácek O.
      • Kálal J.
      • Korbelar P.
      • Polesná Z.
      Synergetic analgesic effect of the combination of arnica and hydroxyethyl salicylate in ethanolic solution following cutaneous application by transcutaneous electrostimulation.
      • Gerner P.
      • Kao G.
      • Srinivasa V.
      • Narang S.
      • Wang G.K.
      Topical amitriptyline in healthy volunteers.
      • Sjölund K.F.
      • Segerdahl M.
      • Sollevi A.
      Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain.
      osteoarthritis and other joint-related conditions (n=5),
      • Paoloni J.A.
      • Murrell G.A.
      • Burch R.M.
      • Ang R.Y.
      Randomised, double-blind, placebo-controlled clinical trial of a new topical glyceryl trinitrate patch for chronic lateral epicondylosis.
      • Baer P.A.
      • Thomas L.M.
      • Shainhouse Z.
      Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886].
      • Hadley H.W.
      • Fischer L.A.
      • Whitaker J.
      A topically applied quaternary ammonium compound exhibits analgesic effects for orthopedic pain.
      • Burnham R.
      • Gregg R.
      • Healy P.
      • Steadward R.
      The effectiveness of topical diclofenac for lateral epicondylitis.
      • Roth S.H.
      A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis.
      skin or leg ulcers (n=5),
      • Claeys A.
      • Gaudy-Marqueste C.
      • Pauly V.
      • et al.
      Management of pain associated with debridement of leg ulcers: a randomized, multicentre, pilot study comparing nitrous oxide–oxygen mixture inhalation and lidocaine-prilocaïne cream.
      • Sibbald R.G.
      • Coutts P.
      • Fierheller M.
      • Woo K.
      A pilot (real-life) randomised clinical evaluation of a pain-relieving foam dressing: (ibuprofen-foam versus local best practice).
      • Gottrup F.
      • Jørgensen B.
      • Karlsmark T.
      • et al.
      Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers.
      • Vernassiere C.
      • Cornet C.
      • Trechot P.
      • et al.
      Study to determine the efficacy of topical morphine on painful chronic skin ulcers.
      • Carneiro P.M.
      • Nyawawa E.T.
      Topical phenytoin versus EUSOL in the treatment of non-malignant chronic leg ulcers.
      and chronic knee pain (n=2).
      • Tiso R.L.
      • Tong-Ngork S.
      • Fredlund K.L.
      Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.
      • Myrer J.W.
      • Feland J.B.
      • Fellingham G.W.
      The effects of a topical analgesic and placebo in treatment of chronic knee pain.

      NSAIDs

      The most widely studied topical NSAIDs included diclofenac (n=14),
      • Costantino C.
      • Kwarecki J.
      • Samokhin A.V.
      • Mautone G.
      • Rovati S.
      Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.
      • Coudreuse J.M.
      • de Vathaire F.
      Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.
      • Mueller E.A.
      • Kirch W.
      • Reiter S.
      Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial.
      • Hsieh L.F.
      • Hong C.Z.
      • Chern S.H.
      • Chen C.C.
      Efficacy and side effects of diclofenac patch in treatment of patients with myofascial pain syndrome of the upper trapezius.
      • Esparza F.
      • Cobián C.
      • Jiménez J.F.
      • García-Cota J.J.
      • Sánchez C.
      • Maestro A.
      Working group for the acute pain study of SETRADE
      Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries.
      • Baer P.A.
      • Thomas L.M.
      • Shainhouse Z.
      Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886].
      • Di Rienzo Businco L.
      • Di Rienzo Businco A.
      • D'Emilia M.
      • Lauriello M.
      • Coen Tirelli G.
      Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms.
      • Predel H.G.
      • Koll R.
      • Pabst H.
      • et al.
      Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
      • Galer B.S.
      • Rowbotham M.
      • Perander J.
      • Devers A.
      • Friedman E.
      Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.
      • Burnham R.
      • Gregg R.
      • Healy P.
      • Steadward R.
      The effectiveness of topical diclofenac for lateral epicondylitis.
      • Patel R.K.
      • Leswell P.F.
      Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group.
      • De Benedittis G.
      • Lorenzetti A.
      Topical aspirin/diethyl ether mixture versus indomethacin and diclofenac/diethyl ether mixtures for acute herpetic neuralgia and postherpetic neuralgia: a double-blind crossover placebo-controlled study.
      • Roth S.H.
      A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis.
      • Bouchier-Hayes T.A.
      • Rotman H.
      • Darekar B.S.
      Comparison of the efficacy and tolerability of diclofenac gel (Voltarol Emulgel) and felbinac gel (Traxam) in the treatment of soft tissue injuries.
      ibuprofen (n=5),
      • Tiso R.L.
      • Tong-Ngork S.
      • Fredlund K.L.
      Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.
      • Gottrup F.
      • Jørgensen B.
      • Karlsmark T.
      • et al.
      Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers.
      • Whitefield M.
      • O'Kane C.J.
      • Anderson S.
      Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomized, double-blind study.
      • Svensson P.
      • Houe L.
      • Arendt-Nielsen L.
      Effect of systemic versus topical nonsteroidal anti-inflammatory drugs on postexercise jaw-muscle soreness: a placebo-controlled study.
      • Campbell J.
      • Dunn T.
      Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains.
      ketoprofen (n=4),
      • Esparza F.
      • Cobián C.
      • Jiménez J.F.
      • García-Cota J.J.
      • Sánchez C.
      • Maestro A.
      Working group for the acute pain study of SETRADE
      Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries.
      • Airaksinen O.
      • Venãlãinen J.
      • Pietilãinen T.
      Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries.
      • Akermark C.
      • Forsskåhl B.
      Topical indomethacin in overuse injuries in athletes: a randomized double-blind study comparing Elmetacin with oral indomethacin and placebo.
      • Baixauli F.
      • Inglés F.
      • Alcántara P.
      • Navarrete R.
      • Puchol E.
      • Vidal F.
      Percutaneous treatment of acute soft tissue lesions with naproxen gel and ketoprofen gel.
      piroxicam (n=2),
      • Patel R.K.
      • Leswell P.F.
      Comparison of ketoprofen, piroxicam, and diclofenac gels in the treatment of acute soft-tissue injury in general practice. General Practice Study Group.
      • Russell A.L.
      Piroxicam 0.5% topical gel compared to placebo in the treatment of acute soft tissue injuries: a double-blind study comparing efficacy and safety.
      and indomethacin (n=2).
      • De Benedittis G.
      • Lorenzetti A.
      Topical aspirin/diethyl ether mixture versus indomethacin and diclofenac/diethyl ether mixtures for acute herpetic neuralgia and postherpetic neuralgia: a double-blind crossover placebo-controlled study.
      • Akermark C.
      • Forsskåhl B.
      Topical indomethacin in overuse injuries in athletes: a randomized double-blind study comparing Elmetacin with oral indomethacin and placebo.

      Diclofenac

      Acute Soft Tissue Injury

      In a study involving 222 patients with minor sports injuries, a diclofenac epolamine patch (1% diclofenac free acid) was found to be significantly more effective than placebo in relieving pain throughout the 2-week treatment period (P≤.05).
      • Galer B.S.
      • Rowbotham M.
      • Perander J.
      • Devers A.
      • Friedman E.
      Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.
      Similar results were obtained in 2 studies that evaluated the efficacy of a patch formulation containing 140 mg of diclofenac sodium in patients with traumatic blunt soft tissue injuries.
      • Mueller E.A.
      • Kirch W.
      • Reiter S.
      Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial.
      • Predel H.G.
      • Koll R.
      • Pabst H.
      • et al.
      Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
      A diclofenac epolamine plaster also has been reported to be effective in relieving pain in patients with acute ankle sprains.
      • Costantino C.
      • Kwarecki J.
      • Samokhin A.V.
      • Mautone G.
      • Rovati S.
      Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.
      • Coudreuse J.M.
      • de Vathaire F.
      Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.
      Studies consistently report that topical diclofenac, compared with placebo, significantly reduced pain within 2 to 3 days of treatment (P<.05).
      • Costantino C.
      • Kwarecki J.
      • Samokhin A.V.
      • Mautone G.
      • Rovati S.
      Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.
      • Mueller E.A.
      • Kirch W.
      • Reiter S.
      Extent and time course of pain intensity upon treatment with a topical diclofenac sodium patch versus placebo in acute traumatic injury based on a validated end point: post hoc analysis of a randomized placebo-controlled trial.
      • Predel H.G.
      • Koll R.
      • Pabst H.
      • et al.
      Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
      • Galer B.S.
      • Rowbotham M.
      • Perander J.
      • Devers A.
      • Friedman E.
      Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.
      In a study of 233 patients, a reduction in pain on active mobilization was reported during the first 6 hours immediately after the first plaster application.
      • Coudreuse J.M.
      • de Vathaire F.
      Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.
      The tolerability profile of topical diclofenac was similar to that of placebo in the reviewed studies.
      • Costantino C.
      • Kwarecki J.
      • Samokhin A.V.
      • Mautone G.
      • Rovati S.
      Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.
      • Coudreuse J.M.
      • de Vathaire F.
      Effect of a plaster containing DHEP and heparin in acute ankle sprains with oedema: a randomized, double-blind, placebo-controlled, clinical study.
      • Predel H.G.
      • Koll R.
      • Pabst H.
      • et al.
      Diclofenac patch for topical treatment of acute impact injuries: a randomised, double blind, placebo controlled, multicentre study.
      • Galer B.S.
      • Rowbotham M.
      • Perander J.
      • Devers A.
      • Friedman E.
      Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.
      In each, the most common AEs were mild application site reactions, such as erythema or pruritus; no severe or systemic gastrointestinal AEs were observed during treatment with topical diclofenac.
      A randomized, observer-blind trial involving 384 patients with acute soft tissue injuries reported that diclofenac gel was more effective than felbinac gel (another NSAID) on a variety of pain-related measures, including pain at rest, pain with movement or local pressure, swelling, mobility, bruising, and use of rescue analgesics.
      • Bouchier-Hayes T.A.
      • Rotman H.
      • Darekar B.S.
      Comparison of the efficacy and tolerability of diclofenac gel (Voltarol Emulgel) and felbinac gel (Traxam) in the treatment of soft tissue injuries.
      Treatment differences were significant in favor of diclofenac for pain at rest (P=.03) and bruising on day 3 (P=.03) and for pain on pressure on day 7 (P=.009).

      Arthritic Disorders

      The efficacy of diclofenac sodium topical solution was investigated in a randomized, double-blind, vehicle-controlled trial involving 216 patients with osteoarthritis of the knee.
      • Baer P.A.
      • Thomas L.M.
      • Shainhouse Z.
      Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886].
      At 6 weeks, topical diclofenac produced significantly greater reductions than vehicle in Western Ontario and McMaster Universities pain scores (−5.2 vs −3.3; P=.003) and physical function (−13.4 vs −6.9; P=.001). Stiffness also was significantly reduced in patients receiving topical diclofenac, compared with the vehicle group (–1.8 vs –0.9; P=.002). The most common AE in both groups was skin dryness, which occurred in significantly more patients receiving topical diclofenac than those receiving vehicle (39% vs 21%; P=.004); however, only 4.7% of patients treated with diclofenac discontinued treatment because of skin reactions, suggesting that such reactions generally were well tolerated.
      A randomized, double-blind, crossover study investigated the efficacy of 2% diclofenac sodium in a pluronic lecithin liposomal organogel formulation in 14 patients with chronic lateral epicondylitis.
      • Burnham R.
      • Gregg R.
      • Healy P.
      • Steadward R.
      The effectiveness of topical diclofenac for lateral epicondylitis.
      Compared with placebo, diclofenac gel produced significant improvements in pain (P=.007) and wrist extension strength (P=.03). Only one patient developed a local rash during diclofenac gel treatment.
      A gel containing 3% diclofenac in 2.5% sodium hyaluronate was more effective than placebo in relieving breakthrough pain in 119 patients with osteoarthritis who were receiving long-term NSAID therapy (≥1 month).
      • Roth S.H.
      A controlled clinical investigation of 3% diclofenac/2.5% sodium hyaluronate topical gel in the treatment of uncontrolled pain in chronic oral NSAID users with osteoarthritis.
      However, the effect was not statistically significant (P=.057).

      Other Indications

      A randomized, double-blind, placebo-controlled trial investigated the efficacy of the diclofenac sodium patch in 153 patients with myofascial pain involving the upper trapezius.
      • Hsieh L.F.
      • Hong C.Z.
      • Chern S.H.
      • Chen C.C.
      Efficacy and side effects of diclofenac patch in treatment of patients with myofascial pain syndrome of the upper trapezius.
      Treatment differences favoring diclofenac were seen at each time point during the 7-day treatment period; compared with placebo, diclofenac patch treatment produced significant improvement in pain, cervical range of motion, and measures of disability (P<.05), but it had no effect on the pressure pain threshold of the myofascial trigger point. Skin irritation was significantly less common with the diclofenac patch (P<.05).
      A further study compared the efficacy of diclofenac sodium topical solution (16 mg/mL, 10 drops, 4 times daily) with that of oral diclofenac (50 mg, twice daily) in 36 patients with symptoms of temporomandibular joint dysfunction.
      • Di Rienzo Businco L.
      • Di Rienzo Businco A.
      • D'Emilia M.
      • Lauriello M.
      • Coen Tirelli G.
      Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms.
      No significant group difference in pain relief was found after 2 weeks of treatment. However, 88.9% of patients receiving oral diclofenac reported epigastric symptoms, whereas no such symptoms were reported by patients receiving topical therapy. Few patients (16.7%) treated with diclofenac sodium topical solution reported mild and transient local irritation.

      Ibuprofen

      Chronic Knee Pain

      Comparable efficacy of topical and oral ibuprofen was reported in a randomized, unblinded trial involving 20 patients with chronic knee pain.
      • Tiso R.L.
      • Tong-Ngork S.
      • Fredlund K.L.
      Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.

      Chronic Leg Ulcers

      In a pilot study conducted at a Canadian wound clinic and involving 24 patients with chronic leg ulcers, the use of an ibuprofen foam dressing produced a significantly greater reduction in wound pain (P<.05) when compared with local best practice in wound management (eg, moist healing dressings and antimicrobial or anti-inflammatory dressings).
      • Sibbald R.G.
      • Coutts P.
      • Fierheller M.
      • Woo K.
      A pilot (real-life) randomised clinical evaluation of a pain-relieving foam dressing: (ibuprofen-foam versus local best practice).
      The efficacy of the ibuprofen dressing was further confirmed in a randomized, double-blind trial of 122 patients.
      • Gottrup F.
      • Jørgensen B.
      • Karlsmark T.
      • et al.
      Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers.
      In that study, pain during the first 5 days of treatment was significantly decreased in the ibuprofen group when compared with the control group (40% vs 30% decrease from baseline in pain intensity scores and 74% vs 58% of patients reporting pain relief; P<.05).

      Soft Tissue Injuries

      In a randomized, double-blind, double-dummy, parallel-group trial involving 100 patients with acute soft tissue injuries, ibuprofen gel was found to have efficacy comparable to that of oral ibuprofen.
      • Whitefield M.
      • O'Kane C.J.
      • Anderson S.
      Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomized, double-blind study.
      The median time for the injury to be rated by patients as “completely better” (the primary end point) was 13.5 days with oral treatment and more than 14 days with topical therapy, with no significant group difference. Similarly, no significant differences were found between the treatment groups in swelling or in time to relief from pain at rest or with movement.
      In a randomized, double-blind, placebo-controlled trial of 100 patients with acute ankle sprains, 5% ibuprofen cream produced a significant reduction in visual analog scale scores compared with placebo during the first 48 hours of treatment (P<.05).
      • Campbell J.
      • Dunn T.
      Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains.
      However, no significant differences were found between the treatment groups in time to improvement of function or in use of rescue medication.

      Other Studies

      In a study of 10 healthy volunteers, 5% ibuprofen gel produced a significantly greater increase than oral treatment in pressure pain thresholds after exercise-induced jaw muscle soreness (P<.05).
      • Svensson P.
      • Houe L.
      • Arendt-Nielsen L.
      Effect of systemic versus topical nonsteroidal anti-inflammatory drugs on postexercise jaw-muscle soreness: a placebo-controlled study.

      Ketoprofen

      In a randomized, double-blind trial, 56 patients with acute soft tissue injuries were treated twice daily with 2.5% ketoprofen gel (total daily dose of 250 mg) or placebo for 7 days.86 Treatment with ketoprofen gel resulted in a significant reduction in baseline pain scores at rest on days 3 and 7 of treatment (P<.001), whereas no significant change was found in baseline pain scores among placebo-treated patients. Ketoprofen gel also was associated with a greater improvement in function than placebo, but the between-group difference was not statistically significant. The incidence of local skin irritation was similar in the treatment and placebo groups (15% vs 17%).
      In an open-label, randomized, multicenter trial of 1575 patients with acute soft tissue injuries, 2.5% ketoprofen gel compared favorably in efficacy to 1% diclofenac gel and was superior to 0.5% piroxicam gel in terms of improvements in mobility, pain on pressure or movement, and global pain assessments.
      • Schlesinger N.
      • Detry M.A.
      • Holland B.K.
      • et al.
      Local ice therapy during bouts of acute gouty arthritis.
      In a study of 30 patients with moderate or severe pain, 10% ketoprofen gel and 10% naproxen gel were found to be comparable in efficacy and tolerability, except for a greater reduction in pain with deep palpation in the naproxen group on day 3 of the 2-week study.
      • Baixauli F.
      • Inglés F.
      • Alcántara P.
      • Navarrete R.
      • Puchol E.
      • Vidal F.
      Percutaneous treatment of acute soft tissue lesions with naproxen gel and ketoprofen gel.
      The efficacy and tolerability of a ketoprofen transdermal delivery system patch and diclofenac gel were compared in a randomized, open-label trial of 223 patients with acute sports-related soft tissue injuries.
      • Esparza F.
      • Cobián C.
      • Jiménez J.F.
      • García-Cota J.J.
      • Sánchez C.
      • Maestro A.
      Working group for the acute pain study of SETRADE
      Topical ketoprofen TDS patch versus diclofenac gel: efficacy and tolerability in benign sport related soft-tissue injuries.
      After 7 to 14 days of treatment, the ketoprofen patch was comparable (not inferior) to diclofenac gel in reduction of pain during daily activities (the primary end point). Both treatments were well tolerated.

      Salicylates

      In an open-label trial involving 45 patients with acute herpetic neuralgia (AHN) or postherpetic neuralgia (PHN), topical administration of a mixture of aspirin and diethyl ether produced effective pain relief, with most patients reporting “good to excellent” results.
      • De Benedittis G.
      • Besana F.
      • Lorenzetti A.
      A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin/diethyl ether mixture. An open-label study plus a double-blind controlled clinical trial.
      A pilot double-blind, placebo-controlled, crossover trial involving 11 patients found that the topical aspirin and diethyl ether mixture was significantly more effective in relieving pain than placebo (P<.05), whereas topical mixtures of indomethacin or diclofenac in diethyl ether were not.
      • De Benedittis G.
      • Besana F.
      • Lorenzetti A.
      A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin/diethyl ether mixture. An open-label study plus a double-blind controlled clinical trial.
      These initial findings were supported by a subsequent double-blind, placebo-controlled, crossover trial of 37 patients with AHN or PHN, in which the mean pain reduction was greater with the topical aspirin and diethyl ether mixture than with placebo (AHN, 66.7% vs 31.3%; PHN, 65.7% vs 34.1%), whereas topical mixtures of indomethacin or diclofenac had little effect.
      • De Benedittis G.
      • Lorenzetti A.
      Topical aspirin/diethyl ether mixture versus indomethacin and diclofenac/diethyl ether mixtures for acute herpetic neuralgia and postherpetic neuralgia: a double-blind crossover placebo-controlled study.
      In a study of 19 patients with AHN or PHN, topical application of the aspirin and diethyl ether mixture (750 mg of aspirin) was associated with superior pain relief when compared with oral aspirin (500 mg; 82.6% vs 15.4% decrease in pain scores).
      • Bareggi S.R.
      • Pirola R.
      • De Benedittis G.
      Skin and plasma levels of acetylsalicylic acid: a comparison between topical aspirin/diethyl ether mixture and oral aspirin in acute herpes zoster and postherpetic neuralgia.
      An additional study involving 30 patients with AHN reported significantly greater pain relief (P<.001) after administration of topical aspirin (75 mg/mL, 3 times daily) than after oral aspirin (375-750 mg, 3 times daily).
      • Balakrishnan S.
      • Bhushan K.
      • Bhargava V.K.
      • Pandhi P.
      A randomized parallel trial of topical aspirin-moisturizer solution vs. oral aspirin for acute herpetic neuralgia.

      Lidocaine

      PHN and 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 PHN pain or painful diabetic neuropathy.
      • Rehm S.
      • Binder A.
      • Baron R.
      Post-herpetic neuralgia: 5% lidocaine medicated plaster, pregabalin, or a combination of both? A randomized, open, clinical effectiveness study.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      5% Lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study.
      • Binder A.
      • Bruxelle J.
      • Rogers P.
      • Hans G.
      • Bösl I.
      • Baron R.
      Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: interim analysis from an open-label, two-stage adaptive, randomized, controlled trial.
      • Rowbotham M.C.
      • Davies P.S.
      • Verkempinck C.
      • Galer B.S.
      Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia.
      A randomized, double-blind, placebo-controlled trial involving 71 patients with PHN found that 2 weeks of lidocaine plaster therapy was associated with improvements in pain, allodynia, quality of life, and sleep measures when compared with placebo.
      • Binder A.
      • Bruxelle J.
      • Rogers P.
      • Hans G.
      • Bösl I.
      • Baron R.
      Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial.
      However, a limitation of this study was the use of an enriched enrollment protocol in which patients who did not respond to lidocaine during an open-label, run-in period were excluded from the double-blind phase. Two further studies from the same group compared the efficacy of 5% lidocaine plasters and oral pregabalin in mixed groups of patients with PHN or painful diabetic neuropathy.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      5% Lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: interim analysis from an open-label, two-stage adaptive, randomized, controlled trial.
      In both studies, the primary end point was the response rate at 4 weeks, which was defined as a change of 2 or more points from baseline or an absolute value of 4 or fewer points on an 11-point numerical rating scale of recalled mean pain intensity during the previous 3 days. Lidocaine plaster produced response rates of approximately 65% to 66% compared with 61% to 62% with oral pregabalin. In both studies, the response rates were higher with lidocaine plaster than with oral pregabalin among patients with PHN, whereas the 2 treatments produced comparable response rates among patients with diabetic neuropathy. Compared with oral pregabalin, lidocaine plaster also was associated with greater improvements in quality-of-life measures and a lower incidence of AEs.

      Posttraumatic Neuropathy

      In a pilot placebo-controlled study of 31 patients with posttraumatic peripheral neuropathy, 8% lidocaine pump spray was found to significantly reduce pain and tactile allodynia (P<.01) for a median of 5 hours (range, 2-60 hours) after application.
      • Kanai A.
      • Segawa Y.
      • Okamoto T.
      • Koto M.
      • Okamoto H.
      The analgesic effect of a metered-dose 8% lidocaine pump spray in posttraumatic peripheral neuropathy: a pilot study.
      Treatment-associated AEs were limited to mild local irritation or flare and resolved within hours.

      Other Indications

      The efficacy of the 5% lidocaine patch was investigated in a randomized, placebo-controlled, crossover trial involving 40 patients with various focal neuropathic pain syndromes (principally PHN and postsurgical neuralgia).
      • Meier T.
      • Wasner G.
      • Faust M.
      • et al.
      Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study.
      Patches (up to 4560 cm2 maximum) were applied for 12 hours daily for 1 week as an adjunct to concomitant oral pain medication (nonopioids such as NSAIDs, opioids, tricyclic antidepressants, or anticonvulsants). Compared with placebo, the lidocaine patch produced significant reductions in ongoing pain (P=.017) and allodynia (P=.023) during the first 8 hours after application, and efficacy was maintained for 7 days.
      In a randomized, open-label trial of 41 patients, an emulsion containing 2.5% lidocaine and 2.5% prilocaine cream was found to be significantly more effective than inhalation of a nitrous oxide–oxygen mixture in relieving pain associated with debridement of leg ulcers (P<.001).
      • Claeys A.
      • Gaudy-Marqueste C.
      • Pauly V.
      • et al.
      Management of pain associated with debridement of leg ulcers: a randomized, multicentre, pilot study comparing nitrous oxide–oxygen mixture inhalation and lidocaine-prilocaïne cream.

      Capsaicin

      Neuropathic Pain

      In a randomized, double-blind, placebo-controlled trial of 200 patients with neuropathic pain (origin not reported), 0.025% capsaicin cream was significantly more effective in relieving pain than placebo (P<.001).
      • McCleane G.
      Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study.
      In the same study, a combination cream consisting of 0.025% capsaicin and 3.3% doxepin produced a similar reduction in pain when compared with 0.025% capsaicin or doxepin cream alone, but analgesia was achieved more quickly with the combination. Burning discomfort after application of the cream was reported by 81% of patients receiving 0.025% capsaicin alone and 61% of those receiving the capsaicin-doxepin combination. In contrast to the efficacy reported in this study, a randomized, double-blind trial of 26 patients with human immunodeficiency virus–associated peripheral neuropathy found that 0.075% capsaicin cream had no significant effect on neuropathic pain.
      • Paice J.A.
      • Ferrans C.E.
      • Lashley F.R.
      • Shott S.
      • Vizgirda V.
      • Pitrak D.
      Topical capsaicin in the management of HIV-associated peripheral neuropathy.
      Two randomized controlled trials of patients with PHN reported that a single 60-minute application of a high-concentration (8%) capsaicin patch produced significant pain relief (P<.05) when compared with a low-concentration (0.04%) patch, and this effect was sustained for up to 12 weeks.
      • Irving G.A.
      • Backonja M.M.
      • Dunteman E.
      • et al.
      NGX-4010 C117 Study Group
      A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.
      • Backonja M.M.
      • Malan T.P.
      • Vanhove G.F.
      • Tobias J.K.
      C102/106 Study Group
      NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension.

      Migraine

      A single small study of 23 patients reported that 0.1% capsaicin gel is effective in relieving mild or moderate pain in patients with acute migraine.
      • Cianchetti C.
      Capsaicin jelly against migraine pain.

      Experimental Pain

      In a study of 20 healthy volunteers, 0.075% capsaicin cream reduced facial sensitivity in response to mechanical, heat, or cold pain without affecting the response to nonpainful tactile stimuli.
      • Lee Y.S.
      • Kho H.S.
      • Kim Y.K.
      • Chung S.C.
      Influence of topical capsaicin on facial sensitivity in response to experimental pain.
      In that study, capsaicin (40 μL, 6-mm strip) was applied 4 times daily for 2 weeks, and the burning sensations commonly induced by topical capsaicin decreased with repeated application.

      Amitriptyline

      Although the only approved use of amitriptyline is for the treatment of depression (amitriptyline hydrochloride, Qualitest Pharmaceuticals), amitriptyline is widely used off-label for a variety of conditions; in fact, the rate at which amitriptyline is used off-label is among the highest of all medications.
      • Radley D.C.
      • Finkelstein S.N.
      • Stafford R.S.
      Off-label prescribing among office-based physicians.
      The off-label use primarily involves oral amitriptyline for the treatment of neuropathic pain,
      • Saarto T.
      • Wiffen P.J.
      Antidepressants for neuropathic pain.
      although it also is prescribed for the treatment of headache and certain types of musculoskeletal pain.
      • Cairns B.E.
      Pathophysiology of TMD pain: basic mechanisms and their implications for pharmacotherapy.
      • Smitherman T.A.
      • Walters A.B.
      • Maizels M.
      • Penzien D.B.
      The use of antidepressants for headache prophylaxis.

      Neuropathic Pain

      A number of placebo-controlled trials have examined the use of topical amitriptyline for the treatment of neuropathic pain.
      • Ho K.Y.
      • Huh B.K.
      • White W.D.
      • Yeh C.C.
      • Miller E.J.
      Topical amitriptyline versus lidocaine in the treatment of neuropathic pain.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      • Sullivan M.J.
      Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.
      These studies failed to show a significant benefit of topical amitriptyline at concentrations of 1% to 5% in patients with neuropathic pain of various causes.
      • Ho K.Y.
      • Huh B.K.
      • White W.D.
      • Yeh C.C.
      • Miller E.J.
      Topical amitriptyline versus lidocaine in the treatment of neuropathic pain.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      • Sullivan M.J.
      Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.
      However, the duration of the double-blind treatment in these studies was short, ranging from 2 days to 3 weeks. In a study of 20 patients with neuropathic pain, neither amitriptyline nor ketamine cream had a significant effect on pain when compared with placebo during 2 days of double-blind treatment; however, a significant decrease in pain was seen during subsequent open-label treatment with a combination cream consisting of 1% amitriptyline and 0.5% ketamine (P<.05).
      • Lynch M.E.
      • Clark A.J.
      • Sawynok J.
      A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain.

      Experimental Pain

      Studies in healthy volunteers demonstrated that topical amitriptyline at concentrations of 50 and 100 mmol/L produced a significant analgesic effect (P<.05) when compared with placebo
      • Gerner P.
      • Kao G.
      • Srinivasa V.
      • Narang S.
      • Wang G.K.
      Topical amitriptyline in healthy volunteers.
      and was associated with transient increases in tactile and mechanical nociceptive thresholds.
      • Dualé C.
      • Daveau J.
      • Cardot J.-M.
      • Boyer-Grand A.
      • Schoeffler P.
      • Dubray C.
      Cutaneous amitriptyline in human volunteers: differential effects on the components of sensory information.

      Glyceryl Trinitrate

      A randomized, double-blind trial involving 154 patients with chronic lateral epicondylitis found a statistically significant analgesic effect (P=.04) at 8 weeks of treatment with topical glyceryl trinitrate (0.72 mg/d) when compared with placebo, but no significant differences were found between the 1.44-mg/d and 3.6-mg/d doses or between these 2 doses and placebo.
      • Paoloni J.A.
      • Murrell G.A.
      • Burch R.M.
      • Ang R.Y.
      Randomised, double-blind, placebo-controlled clinical trial of a new topical glyceryl trinitrate patch for chronic lateral epicondylosis.
      By contrast, in a follow-up study of 52 patients with chronic noninsertional Achilles tendinopathy, patients who had previously received topical glyceryl trinitrate for 6 months at a dose of 1.25 to 5 mg/d reported significantly less tendon tenderness (P=.03) and more improved function scores (P=.04) 3 years after the end of treatment when compared with patients who had received placebo.
      • Paoloni J.A.
      • Murrell G.A.
      Three-year followup study of topical glyceryl trinitrate treatment of chronic noninsertional Achilles tendinopathy.
      In addition, 88% of patients receiving topical glyceryl trinitrate were asymptomatic after 3 years compared with 67% of patients treated with rehabilitation alone (P=.03). Finally, a study of 110 patients reported that topical glyceryl trinitrate (0.2%) treatment produced significantly faster wound healing after hemorrhoidectomy than placebo (P=.002).
      • Hwang D.Y.
      • Yoon S.G.
      • Kim H.S.
      • Lee J.K.
      • Kim K.Y.
      Effect of 0.2 percent glyceryl trinitrate ointment on wound healing after a hemorrhoidectomy: results of a randomized, prospective, double-blind, placebo-controlled trial.

      Opioids

      A randomized, double-blind, placebo-controlled trial compared the analgesic efficacy of IntraSite gels (Smith and Nephew) containing morphine sulfate (10 mg/mL) or sterile water with that of conventional Jelonet dressings (Smith and Nephew) in 49 patients with superficial burns.
      • Welling A.
      A randomised controlled trial to test the analgesic efficacy of topical morphine on minor superficial and partial thickness burns in accident and emergency departments.
      Patients receiving topical morphine had the greatest decrease in pain scores (>20 mm on a 100-mm scale) at 2 and 6 hours after application. However, patients receiving topical morphine used more supplementary analgesia than the other 2 groups and reported the least reduction in pain scores at 12 hours (the last assessment). Similarly, a study involving 24 patients with painful chronic skin ulcers found that topical morphine (10 mg in a gel formulation) had no analgesic efficacy when compared with placebo.
      • Vernassiere C.
      • Cornet C.
      • Trechot P.
      • et al.
      Study to determine the efficacy of topical morphine on painful chronic skin ulcers.

      Miscellaneous Agents

      A number of miscellaneous agents have been reported to be effective in treating acute and chronic pain, including pimecrolimus 1% cream for the management of vulvar lichen sclerosus
      • Goldstein A.T.
      • Creasey A.
      • Pfau R.
      • Phillips D.
      • Burrows L.J.
      A double-blind, randomized controlled trial of clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus.
      and oral lichen planus,
      • Gorouhi F.
      • Solhpour A.
      • Beitollahi J.M.
      • et al.
      Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus.
      topical menthol for chronic knee pain
      • Myrer J.W.
      • Feland J.B.
      • Fellingham G.W.
      The effects of a topical analgesic and placebo in treatment of chronic knee pain.
      and mechanical low back pain,
      • Ginsberg F.
      • Famaey J.P.
      A double-blind study of topical massage with Rado-Salil ointment in mechanical low-back pain.
      and topical phenytoin for superficial burns
      • Carneiro P.M.
      • Rwanyuma L.R.
      • Mkony C.A.
      A comparison of topical Phenytoin with Silverex in the treatment of superficial dermal burn wounds.
      and chronic leg ulcers.
      • Carneiro P.M.
      • Nyawawa E.T.
      Topical phenytoin versus EUSOL in the treatment of non-malignant chronic leg ulcers.

      Discussion

      Topical formulations of a variety of analgesics have been studied for the treatment of diverse indications (Supplemental Table). However, many of the published studies were small, and studies involving patients with chronic pain were often of short duration. NSAIDs are among the most commonly prescribed drugs throughout the world,

      Centers for Disease Control and Prevention. FASTSTATS: Therapeutic Drug Use. http://www.cdc.gov/nchs/fastats/drugs.htm. Published February 18, 2011. Accessed May 1, 2012.

      and hence, it is not surprising that topical formulations of these agents have been studied more widely than topical formulations of other agents. The available evidence suggests that topical NSAIDs can be recommended for short-term pain relief in patients with acute soft tissue injuries or chronic joint-related conditions such as osteoarthritis.
      • Heyneman C.A.
      • Lawless-Liday C.
      • Wall G.C.
      Oral versus topical NSAIDs in rheumatic diseases: a comparison.
      • Mason L.
      • Moore R.A.
      • Edwards J.E.
      • Derry S.
      • McQuay H.J.
      Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis.
      • Mason L.
      • Moore R.A.
      • Edwards J.E.
      • Derry S.
      • McQuay H.J.
      Topical NSAIDs for acute pain: a meta-analysis.
      Topical ibuprofen and topical diclofenac have been widely studied. Topical ibuprofen appears to be comparable in efficacy to oral ibuprofen in the treatment of chronic knee pain
      • Tiso R.L.
      • Tong-Ngork S.
      • Fredlund K.L.
      Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.
      or acute soft tissue injuries.
      • Whitefield M.
      • O'Kane C.J.
      • Anderson S.
      Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomized, double-blind study.
      Topical diclofenac also has equivalent efficacy with oral diclofenac in the treatment of temporomandibular joint disorder.
      • Di Rienzo Businco L.
      • Di Rienzo Businco A.
      • D'Emilia M.
      • Lauriello M.
      • Coen Tirelli G.
      Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms.
      Topical lidocaine therapy can be recommended for use in patients with neuropathic pain, particularly PHN and diabetic neuropathy, and controlled trials have consistently found that such treatment can provide effective analgesia.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      5% Lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study.
      • Binder A.
      • Bruxelle J.
      • Rogers P.
      • Hans G.
      • Bösl I.
      • Baron R.
      Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: results of a double-blind, placebo-controlled, multinational efficacy and safety trial.
      • Baron R.
      • Mayoral V.
      • Leijon G.
      • Binder A.
      • Steigerwald I.
      • Serpell M.
      Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: interim analysis from an open-label, two-stage adaptive, randomized, controlled trial.
      • Rowbotham M.C.
      • Davies P.S.
      • Verkempinck C.
      • Galer B.S.
      Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia.
      Despite the widespread use of oral amitriptyline to relieve neuropathic pain, as well as the documented efficacy of oral amitriptyline in clinical trials,
      • Saarto T.
      • Wiffen P.J.
      Antidepressants for neuropathic pain.
      few data exist to support the use of topical amitriptyline. Of interest, a recently published case report presented evidence of a dose-response relationship for neuropathic pain, with topical amitriptyline providing considerable analgesia at concentrations of 5% and 10%; in one of the 2 cases presented, however, the higher concentration was associated with systemic AEs, particularly drowsiness.
      • Kopsky D.J.
      • Keppel Hesselink J.M.
      High doses of topical amitriptyline in neuropathic pain: two cases and literature review.
      Studies with topical capsaicin formulations have yielded varying results, depending on the dose used and the patient population studied. Furthermore, the burning sensation that follows the topical application of capsaicin may discourage the use of such treatment. Although no recommendations can be made at present for the use of topical capsaicin, topical capsaicin is approved for use in the treatment of pain associated with PHN (Qutenza [capsaicin] 8% patch, NeurogesX Inc).
      The limited number of studies on topical morphine suggests that such therapy does not offer a significant advantage over oral morphine. Few data are available on the analgesic properties of other topical medications, such as indomethacin, niflumic acid, eltenac, naproxen, pimecrolimus, phenytoin, or menthol, and no recommendations can be made about the topical use of these agents in the treatment of acute or chronic pain.
      Topical analgesics offer better tolerability than oral therapy. For example, studies comparing topical and oral NSAIDs have consistently reported more favorable tolerability profiles for topical agents.
      • Tiso R.L.
      • Tong-Ngork S.
      • Fredlund K.L.
      Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.
      • Di Rienzo Businco L.
      • Di Rienzo Businco A.
      • D'Emilia M.
      • Lauriello M.
      • Coen Tirelli G.
      Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms.
      In general, topical analgesics are devoid of systemic AEs, notably the gastrointestinal and cardiovascular events that often limit the usefulness of oral preparations of opioids, NSAIDs, and salicylates. Although application site reactions are common with some topical preparations, these generally have been mild, transient, and well tolerated.

      Conclusion

      Topical analgesic therapy using NSAIDs or lidocaine has an important place in the management of acute and chronic pain conditions and warrants further study.

      Acknowledgments

      Technical editorial and medical writing support for the preparation of this article was provided by Karamarie Fecho, PhD, and Synchrony Medical, LLC, West Chester, Pennsylvania.

      Supplemental Online Material

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