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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)

      References

        • Roy S.
        • Wang J.
        • Kelschenbach J.
        • Koodie L.
        • Martin J.
        Modulation of immune function by morphine: implications for susceptibility to infection.
        J Neuroimmune Pharamcol. 2006; 1: 77-89
        • Finley M.J.
        • Happel C.M.
        • Kaminsky D.E.
        • Rogers T.J.
        Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression.
        Cell Immunol. 2008; 252: 146-154
        • Porreca F.
        • Ossipov M.H.
        Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: mechanisms, implications, and management options.
        Pain Med. 2009; 10: 654-662
        • Dahan A.
        • Aarts L.
        • Smith T.W.
        Incidence, reversal, and prevention of opioid-induced respiratory depression.
        Anesthesiology. 2010; 112: 226-238
        • Camilleri M.
        Opioid-induced constipation: challenges and therapeutic opportunities.
        Am J Gastroenterol. 2011; 106: 835-842
        • Manubay J.M.
        • Muchow C.
        • Sullivan M.A.
        Prescription drug abuse: epidemiology, regulatory issues, chronic pain management with narcotic analgesics.
        Prim Care Clin Office Pract. 2011; 38: 71-90
        • Tey H.L.
        • Yosipovitch G.
        Targeted treatment of pruritus: a look into the future.
        Br J Dermatol. 2011; 165: 5-17
        • Farkouh M.E.
        • Greenberg B.P.
        An evidence-based review of the cardiovascular risks of nonsteroidal anti-inflammatory drugs.
        Am J Cardiol. 2009; 103: 1227-1237
        • Harirforoosh S.
        • Jamali F.
        Renal adverse effects of nonsteroidal anti-inflammatory drugs.
        Expert Opin Drug Saf. 2009; 8: 669-681
        • John R.
        • Herzenberg A.M.
        Renal toxicity of therapeutic drugs.
        J Clin Pathol. 2009; 62: 505-515
        • Lazzaroni M.
        • Porro G.B.
        Management of NSAID-induced gastrointestinal toxicity: focus on proton pump inhibitors.
        Drugs. 2009; 69: 51-69
        • Scarpignato C.
        • Hunt R.H.
        Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention.
        Gastroenterol Clin North Am. 2010; 39: 433-464
        • Trelle S.
        • Reichenbach S.
        • Wandel S.
        • et al.
        Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.
        BMJ. 2011; 342: c7086
        • Hedner T.
        • Everts B.
        The early clinical history of salicylates in rheumatology and pain.
        Clin Rheumatol. 1998; 17: 17-25
        • Peura D.A.
        • Goldkind L.
        Balancing the gastrointestinal benefits and risks of nonselective NSAIDs.
        Arthritis Res Ther. 2005; 7: S7-S13
        • Glasgow J.F.
        Reye's syndrome: the case for a causal link with aspirin.
        Drug Saf. 2006; 29: 1111-1112
        • Heyneman C.A.
        • Lawless-Liday C.
        • Wall G.C.
        Oral versus topical NSAIDs in rheumatic diseases: a comparison.
        Drugs. 2000; 60: 555-574
        • Haroutiunian S.
        • Drennan D.A.
        • Lipman A.G.
        Topical NSAID therapy for musculoskeletal pain.
        Pain Med. 2010; 11: 535-549
        • Ribeiro M.D.
        • Joel S.P.
        • Zeppetella G.
        The bioavailability of morphine applied topically to cutaneous ulcers.
        J Pain Symptom Manage. 2004; 27: 434-439
        • 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.
        J Pain Symptom Manage. 2008; 35: 314-320
        • Jorge L.L.
        • Feres C.C.
        • Teles V.E.
        Topical preparations for pain relief: efficacy and patient adherence.
        J Pain Res. 2010; 4: 11-24
        • Mason L.
        • Moore R.A.
        • Edwards J.E.
        • Derry S.
        • McQuay H.J.
        Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis.
        BMC Musculoskelet Disord. 2004; 5: 28
        • Mason L.
        • Moore R.A.
        • Edwards J.E.
        • Derry S.
        • McQuay H.J.
        Topical NSAIDs for acute pain: a meta-analysis.
        BMC Fam Pract. 2004; 5: 10
        • Borg-Stein J.
        • Zaremski J.L.
        • Hanford M.A.
        New concepts in the assessment and treatment of regional musculoskeletal pain and sports injury.
        PM R. 2009; 1: 744-754
        • Kroenke K.
        • Krebs E.E.
        • Bair M.J.
        Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews.
        Gen Hosp Psychiatry. 2009; 31: 206-219
        • Barthel H.R.
        • Axford-Gatley R.A.
        Topical nonsteroidal anti-inflammatory drugs for osteoarthritis.
        Postgrad Med. 2010; 122: 98-106
        • Argoff C.E.
        Review of current guidelines on the care of postherpetic neuralgia.
        Postgrad Med. 2011; 123: 134-142
        • 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.
        J Am Acad Dermatol. 2011; 64: e99-e104
        • 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.
        Pain Med. 2011; 12: 99-109
        • 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.
        Clin Drug Investig. 2011; 31: 15-26
        • Tiso R.L.
        • Tong-Ngork S.
        • Fredlund K.L.
        Oral versus topical ibuprofen for chronic knee pain: a prospective randomized pilot study.
        Pain Physician. 2010; 13: 457-467
        • 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.
        Curr Med Res Opin. 2010; 26: 2221-2228
        • 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.
        J Eur Acad Dermatol Venereol. 2011; 25: 138-144
        • 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.
        Support Care Cancer. 2011; 19: 833-841
        • Cianchetti C.
        Capsaicin jelly against migraine pain.
        Int J Clin Pract. 2010; 64: 457-459
        • 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.
        Curr Med Res Opin. 2010; 26: 1607-1619
        • 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.
        Expert Opin Pharmacother. 2010; 11: 493-498
        • 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.
        Pain Med. 2010; 11: 600-608
        • 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.
        J Pain Symptom Manage. 2010; 39: 116-125
        • 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.
        Curr Med Res Opin. 2009; 25: 1663-1676
        • 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.
        Clin Drug Investig. 2009; 29: 393-408
        • 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.
        Clin Drug Investig. 2009; 29: 231-241
        • 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.
        Anesth Analg. 2009; 108: 987-991
        • 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.
        Br J Sports Med. 2009; 43: 299-302
        • 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.
        Anesthesiology. 2008; 108: 714-721
        • D'Anchise R.
        • Bulitta M.
        • Giannetti B.
        Comfrey extract ointment in comparison to diclofenac gel in the treatment of acute unilateral ankle sprains (distortions).
        Arzneimittelforschung. 2007; 57: 712-716
        • 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.
        Clin J Pain. 2008; 24: 51-55
        • Paoloni J.A.
        • Murrell G.A.
        Three-year followup study of topical glyceryl trinitrate treatment of chronic noninsertional Achilles tendinopathy.
        Foot Ankle Int. 2007; 28: 1064-1068
        • 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.
        J Am Acad Dermatol. 2007; 57: 806-813
        • 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.
        Emerg Med J. 2007; 24: 408-412
        • 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).
        Int Wound J. 2007; 4: 16-23
        • 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.
        Int Wound J. 2007; 4: 24-34
        • Lee Y.S.
        • Kho H.S.
        • Kim Y.K.
        • Chung S.C.
        Influence of topical capsaicin on facial sensitivity in response to experimental pain.
        J Oral Rehabil. 2007; 34: 9-14
        • 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.
        Br J Sports Med. 2007; 41: 134-139
        • 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.
        J Pain. 2006; 7: 823-832
        • Pöyhiä R.
        • Vainio A.
        Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia.
        Clin J Pain. 2006; 22: 32-36
        • 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.
        Phytomedicine. 2005; 12: 707-714
        • 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].
        BMC Musculoskelet Disord. 2005; 6: 44
        • 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.
        Anesthesiology. 2005; 103: 140-146
        • Vernassiere C.
        • Cornet C.
        • Trechot P.
        • et al.
        Study to determine the efficacy of topical morphine on painful chronic skin ulcers.
        J Wound Care. 2005; 14: 289-293
        • 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.
        Acta Otorhinolaryngol Ital. 2004; 24: 279-283
        • Myrer J.W.
        • Feland J.B.
        • Fellingham G.W.
        The effects of a topical analgesic and placebo in treatment of chronic knee pain.
        J Aging Phys Act. 2004; 12: 199-213
        • 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.
        Br J Sports Med. 2004; 38: 318-323
        • 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.
        Arzneimittelforschung. 2003; 53: 850-856
        • 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.
        Pain. 2003; 106: 151-158
        • Carneiro P.M.
        • Rwanyuma L.R.
        • Mkony C.A.
        A comparison of topical Phenytoin with Silverex in the treatment of superficial dermal burn wounds.
        Cent Afr J Med. 2002; 48: 105-108
        • 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.
        Clin J Pain. 2003; 19: 323-328
        • Gerner P.
        • Kao G.
        • Srinivasa V.
        • Narang S.
        • Wang G.K.
        Topical amitriptyline in healthy volunteers.
        Reg Anesth Pain Med. 2003; 28: 289-293
        • 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.
        Dis Colon Rectum. 2003; 46: 950-954
        • Carneiro P.M.
        • Nyawawa E.T.
        Topical phenytoin versus EUSOL in the treatment of non-malignant chronic leg ulcers.
        East Afr Med J. 2003; 80: 124-129
        • 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.
        J Clin Pharm Ther. 2002; 27: 409-417
        • 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.
        Int J Dermatol. 2001; 40: 535-538
        • 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.
        Br J Clin Pharmacol. 2000; 49: 574-579
        • 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.
        J Pain Symptom Manage. 2000; 19: 287-294
        • 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.
        J Pain Symptom Manage. 2000; 19: 45-52
        • Sjölund K.F.
        • Segerdahl M.
        • Sollevi A.
        Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain.
        Anesth Analg. 1999; 88: 605-610
        • Hadley H.W.
        • Fischer L.A.
        • Whitaker J.
        A topically applied quaternary ammonium compound exhibits analgesic effects for orthopedic pain.
        Altern Med Rev. 1998; 3: 361-366
        • 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.
        Eur J Clin Pharmacol. 1998; 54: 231-235
        • 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.
        J Orofac Pain. 1997; 11: 353-362
        • Burnham R.
        • Gregg R.
        • Healy P.
        • Steadward R.
        The effectiveness of topical diclofenac for lateral epicondylitis.
        Clin J Sport Med. 1998; 8: 78-81
        • 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.
        Clin Ther. 1996; 18: 497-507
        • 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.
        Pain. 1996; 65: 45-51
        • 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.
        Pain. 1996; 65: 39-44
        • 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.
        Int J Tissue React. 1995; 17: 129-132
        • Campbell J.
        • Dunn T.
        Evaluation of topical ibuprofen cream in the treatment of acute ankle sprains.
        J Accid Emerg Med. 1994; 11: 178-182
        • Airaksinen O.
        • Venãlãinen J.
        • Pietilãinen T.
        Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries.
        Int J Clin Pharmacol Ther Toxicol. 1993; 31: 561-563
        • 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.
        Pain. 1992; 48: 383-390
        • 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.
        Clin Invest Med. 1991; 14: 35-43
        • Akermark C.
        • Forsskåhl B.
        Topical indomethacin in overuse injuries in athletes: a randomized double-blind study comparing Elmetacin with oral indomethacin and placebo.
        Int J Sports Med. 1990; 11: 393-396
        • 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.
        J Int Med Res. 1990; 18: 372-378
        • 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.
        Br J Clin Pract. 1990; 44: 319-320
        • Ginsberg F.
        • Famaey J.P.
        A double-blind study of topical massage with Rado-Salil ointment in mechanical low-back pain.
        J Int Med Res. 1987; 15: 148-153
        • Eisenach J.C.
        • Curry R.
        • Tong C.
        • Houle T.T.
        • Yaksh T.L.
        Effects of intrathecal ketorolac on human experimental pain.
        Anesthesiology. 2010; 112: 1216-1224
        • 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.
        J Pain. 2007; 8: 19-25
        • 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.
        Pain. 2007; 129: 46-54
        • 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.
        J Pain. 2006; 7: 565-574
        • Siproudhis L.
        • Sébille V.
        • Pigot F.
        • Hémery P.
        • Juguet F.
        • Bellissant E.
        Lack of efficacy of botulinum toxin in chronic anal fissure.
        Aliment Pharmacol Ther. 2003; 18: 515-524
        • Eisenach J.C.
        • Curry R.
        • Hood D.D.
        Dose response of intrathecal adenosine in experimental pain and allodynia.
        Anesthesiology. 2002; 97: 938-942
        • Cospite M.
        Double-blind, placebo-controlled evaluation of clinical activity and safety of Daflon 500 mg in the treatment of acute hemorrhoids.
        Angiology. 1994; 45: 566-573
        • Garra G.
        • Singer A.J.
        • Leno R.
        • et al.
        Heat or cold packs for neck and back strain: a randomized controlled trial of efficacy.
        Acad Emerg Med. 2010; 17: 484-489
        • Underwood M.
        • Ashby D.
        • Carnes D.
        • et al.
        Topical or oral ibuprofen for chronic knee pain in older people: the TOIB study.
        Health Technol Assess. 2008; 12 (iii-iv, ix-155)
        • 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.
        BMJ. 2008; 336: 138-142
        • 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].
        BMC Musculoskelet Disord. 2005; 6: 55
        • 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.
        Spine. 2002; 27: 1012-1017
        • Schlesinger N.
        • Detry M.A.
        • Holland B.K.
        • et al.
        Local ice therapy during bouts of acute gouty arthritis.
        J Rheumatol. 2002; 29: 331-334
        • 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.
        Br J Sports Med. 2002; 36: 183-188
        • Perrotti P.
        • Antropoli C.
        • Molino D.
        • De Stefano G.
        • Antropoli M.
        Conservative treatment of acute thrombosed external hemorrhoids with topical nifedipine.
        Dis Colon Rectum. 2001; 44: 405-409
        • 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.
        Br Homeopath J. 2001; 90: 21-28
        • 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.
        Scand J Rheumatol. 1997; 26: 287-292
        • 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.
        Eur J Rheumatol Inflamm. 1991; 11: 38-45
        • Ball I.M.
        • Seabrook J.
        • Desai N.
        • Allen L.
        • Anderson S.
        Dilute proparacaine for the management of acute corneal injuries in the emergency department.
        CJEM. 2010; 12: 389-396
        • Kosrirukvongs P.
        Topical piroxicam and conjunctivitis.
        J Med Assoc Thai. 1997; 80: 287-292
        • Arshinoff S.A.
        • Mills M.D.
        • Haber S.
        Pharmacotherapy of photorefractive keratectomy.
        J Cataract Refract Surg. 1996; 22: 1037-1044
        • 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.
        Pain Pract. 2010; 10: 201-213
        • Beydoun A.
        Postherpetic neuralgia: role of gabapentin and other treatment modalities.
        Epilepsia. 1999; 40: S51-S56
        • Buckley M.M.
        • Brogden R.N.
        Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.
        Drugs. 1990; 39: 86-109
        • 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.
        Exp Neurol. 2007; 205: 190-200
        • 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.
        Clin Drug Investig. 2010; 30: 71-87
        • 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.
        J Opioid Manag. 2011; 7: 99-107
        • Radley D.C.
        • Finkelstein S.N.
        • Stafford R.S.
        Off-label prescribing among office-based physicians.
        Arch Intern Med. 2006; 166: 1021-1026
        • Saarto T.
        • Wiffen P.J.
        Antidepressants for neuropathic pain.
        Cochrane Database Syst Rev. 2007; : CD005454
        • Cairns B.E.
        Pathophysiology of TMD pain: basic mechanisms and their implications for pharmacotherapy.
        J Oral Rehabil. 2010; 37: 391-410
        • Smitherman T.A.
        • Walters A.B.
        • Maizels M.
        • Penzien D.B.
        The use of antidepressants for headache prophylaxis.
        CNS Neurosci Ther. 2011; 17: 462-469
      1. 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.

        • Kopsky D.J.
        • Keppel Hesselink J.M.
        High doses of topical amitriptyline in neuropathic pain: two cases and literature review.
        Pain Pract. 2012; 12: 148-153