Topical preparations for pain relief: efficacy and patient adherence

Liliana L Jorge, Caroline C Feres, Vitor Ep Teles, Liliana L Jorge, Caroline C Feres, Vitor Ep Teles

Abstract

There has been an increasing focus on development of new routes of drug administration to provide tailored treatments for patients, without decreasing efficacy of analgesia, in proportion to the progression of the knowledge of pain mechanisms. While acute pain acts as an alarm, chronic pain is a syndrome requiring meticulous selection of analgesic drugs of high bioavailability for long-term use. Such criteria are challenges that topical medications aim to overcome, allowing progressive delivery of active component, maintaining stable plasma levels, with a good safety profile. This review presents recent findings regarding topical formulations of the most widely used drugs for pain treatment, such as nonsteroidal anti-inflammatory agents, anesthetics, and capsaicin, and the role of physical agents as delivery enhancers (phonophoresis and iontophoresis). Although the number of topical agents is limited for use in peripheral conditions, increasing evidence supports the efficacy of these preparations in blocking nociceptive and neuropathic pain. Patient adherence to medical treatment is also a challenge, especially in chronic painful conditions. It is known that reduction of treatment complexity and pill burden are good strategies to increase patient compliance, as discussed here. However, the role of topical presentations, when compared to traditional routes, has not yet been fully explored and thus remains unclear.

Keywords: administration; medication adherence; pain; patient compliance; therapeutics; topical.

Figures

Figure 1
Figure 1
Topical patch.
Figure 2
Figure 2
Opioid transdermal patch.
Figure 3
Figure 3
Iontophoretical transdermal system (ITS). ITS delivers drug into the bloodstream, and includes: anode hydrogel (ionized drug reservoir), cathode (inert ingredients), battery, and protective plastic liner.

References

    1. Kreitler S, Niv D. Cognitive impairment in chronic pain. Pain Clinical Updates. 2007;XV(4):1–4.
    1. Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinical conditions. Cochrane Database Syst Rev. 2010;1:CD003974.
    1. Argoff CE. Targeted peripheral analgesics therapy for neuropathic pain. Curr Pain Headache Rep. 2004;8(3):199–204.
    1. de Paula E, Cereda CM, Tofoli GR, Franz-Montan M, Fraceto LF, de Araújo DR. Drug delivery systems for local anesthetics. Recent Pat Drug Deliv Formul. 2010;4(1):23–34.
    1. Byl NN. The use of ultrasound as an enhancer for transcutaneous drug delivery: phonophoresis. Phys Ther. 1995;75(6):539–553.
    1. Tiwari SB, Pai RM, Udupa N. Influence of ultrasound on the percutaneous absorption of ketorolac tromethamine in vitro across rat skin. Drug Deliv. 2004;11(1):47–51.
    1. Kozanoglu E, Basaran S, Guzel R, Guler-Uysal F. Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis. Swiss Med Wkly. 2003;133(23–24):333–338.
    1. Sammeta SM, Murthy SN. “ChilDrive”: a technique of combining regional cutaneous hypothermia with iontophoresis for the delivery of drugs to synovial fluid. Pharm Res. 2009;26(11):2535–2540.
    1. Motta AF, Borges Junior NG, da Fonseca JC, Tonussi CR. The antinociceptive effect of iontophoretic direct application of diclofenac to arthritic knee-joints of rats. Life Sci. 2003;73(15):1995–2004.
    1. Başkurt F, Ozcan A, Algun C. Comparison of effects of phonophoresis and iontophoresis of naproxen in the treatment of lateral epicondylitis. Clin Rehabil. 2003;17(1):96–100.
    1. Hassan AH, Ableitner A, Stein C, Herz A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience. 1993;55(1):185–195.
    1. Cerchietti LC, Navigante AH, Körte MW, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain. 2003;105(1–2):265–273.
    1. Varrassi G, Marinangeli F, Ciccozzi A, Iovinelli G, Facchetti G, Ciccone A. Intra-articular buprenorphine after knee arthroscopy. A randomised, prospective, double-blind study. Acta Anaesthesiol Scand. 1999;43(1):51–55.
    1. Wrench IJ, Taylor P, Hobbs GJ. Lack of efficacy of intra-articular opioids for analgesia after day-case arthroscopy. Anaesthesia. 1996;51(10):920–922.
    1. Faymonville ME, Libbrecht D. Transdermal buprenorphine: a current overview of pharmacological and clinical data. Rev Med Liege. 2008;63(11):671–676.
    1. Hans G, Robert D. Transdermal buprenorphine – a critical appraisal of its role in pain management. J Pain Res. 2009;2:117–134.
    1. Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. Eur J Pain. 2009;13(3):219–230.
    1. Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of transdermal opiates treating moderate-severe cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the literature. J Palliat Med. 2008;11(3):492–501.
    1. Gibbs M. The role of transdermal fentanyl patches in the effective management of cancer pain. Int J Palliat Nurs. 2009;15(7):354–359.
    1. Nüesch E, Rutjes AW, Husni E, Qelch V, Jüni P. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;4:CD003115.
    1. Hair PI, Keating GM, McKeage K. Transdermal matrix fentanyl membrane patch (matrifen): in severe cancer-related chronic pain. Drugs. 2008;68(14):2001–2009.
    1. Herndon CM. Iontophoretic drug delivery system: focus on fentanyl. Pharmacotherapy. 2007;27(5):745–754.
    1. Mayes S, Ferrone M. Fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain. Ann Pharmacother. 2006;40(12):2178–2186.
    1. Zernikow B, Michel E, Anderson B. Transdermal fentanyl in childhood and adolescence: a comprehensive literature review. J Pain. 2007;8(3):187–207.
    1. Mitchell A, Smith HS. Applying partially occluded fentanyl transdermal patches to manage pain in pediatric patients. J Opioid Manag. 2010;6(4):290–294.
    1. Houck CS, Sethna NF. Transdermal analgesia with local anesthetics in children: review, update and future directions. Expert Rev Neurother. 2005;5(5):625–634.
    1. Lander JA, Weltman BJ, So SS. EMLA and amethocaine for reduction of children’s pain associated with needle insertion. Cochrane Database Syst Rev. 2006;3:CD004236.
    1. Briggs M, Nelson EA. Topical agents or dressings for pain in venous leg ulcers. Cochrane Database Syst Rev. 2010;4:CD001177.
    1. Sawyer J, Febbraro S, Masud S, Ashburn MA, Campbell JC. Heated lidocaine/tetracaine patch (Synera, Rapydan) compared with lidocaine/prilocaine cream (EMLA) for topical anaesthesia before vascular access. Br J Anaesth. 2009;102(2):210–215.
    1. Soltesz S, Dittrich K, Teschendorf P, Fuss I, Molter G. Topical anesthesia before vascular access in children. Comparison of a warmth-producing lidocaine–tetracaine patch with a lidocaine–prilocaine patch. Anaesthesist. 2010;59(6):519–523.
    1. Wasner G, Kleinert A, Binder A, Schattschneider J, Baron R. Postherpetic neuralgia: topical lidocaine is effective in nociceptor-deprived skin. J Neurol. 2005;252(6):677–686.
    1. Rowbotham MC, Davies PS, Verkempick C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment of post-herpetic neuralgia. Pain. 1996;65(1):39–44.
    1. Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study. Pain. 1999;80(3):533–538.
    1. Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin J Pain. 2000;16(3):205–208.
    1. Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev. 2007;2:CD004846.
    1. Hedayati H, Parsons J, Crowther CA. Topically applied anaesthetics for treating perineal pain after childbirth. Cochrane Database Syst Rev. 2005;2:CD004223.
    1. Wiles MD, Dobson SA, Moppett IK. The effect of a new topical local anaesthetic delivery system on forearm skin blood flow reactivity. Anaesthesia. 2010;65(2):178–183.
    1. Gimbel J, Linn R, Hale M, Nicholson B. Lidocaine patch treatment in patients with low back pain: results of an open-label, nonrandomized pilot study. Am J Ther. 2005;12(4):311–319.
    1. Fleming JA, O’Connor BD. Use of lidocaine patches for neuropathic pain in a comprehensive cancer centre. Pain Res Manag. 2009;14(5):381–388.
    1. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64(9):937–947.
    1. Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci. 2008;11(2):81s–110s.
    1. Massey T, Derry S, Moore RA, McQuay HJ. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev. 2010;6:CD007402.
    1. Altman R, Barkin RL. Topical therapy for osteoarthritis: clinical and pharmacologic perspectives. Postgrad Med. 2009;121(2):139–147.
    1. Conaghan PG, Dickson J, Grant RL Guideline Development Group. Care and management of osteoarthritis in adults: summary of NICE guidance. BMJ. 2008;336(7642):502–503.
    1. Yang JH, Kim TY, Lee JH, Yoon SW, Yang KH, Shin SC. Anti- hyperalgesic and anti-inflammatory effects of ketorolac tromethamine gel using pulsed ultrasound in inflamed rats. Arch Pharm Res. 2008;31(4):511–517.
    1. Petersen B, Rovati S. Diclofenac epolamine (Flector) patch: evidence for topical activity. Clin Drug Investig. 2009;29(1):1–9.
    1. Barthel HR, Haselwood D, Longley S, 3rd, Gold MS, Altman RD. Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009;39(3):203–212.
    1. Altman RD, Dreiser RL, Fisher CL, Chase WF, Dreher DS, Zacher J. Diclofenac sodium gel in patients with primary hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36(9):1991–1999.
    1. Towheed TE. Pennsaid therapy for osteoarthritis of the knee: a systematic review and metaanalysis of randomized controlled trials. J Rheumatol. 2006;33(3):567–573.
    1. Rainsford KD, Kean WF, Ehrlich GE. Review of the pharmaceutical properties and clinical effects of the topical NSAID formulation, diclofenac epolamine. Curr Med Res Opin. 2008;24(10):2967–2992.
    1. Mazières B. Topical ketoprofen patch. Drugs RD. 2005;6(6):337–344.
    1. Rother M, Lavins BJ, Kneer W, Lehnhardt K, Seidel EJ, Mazgareanu S. Efficacy and safety of epicutaneous ketoprofen in Transfersome ( IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial. Ann Rheum Dis. 2007;66(9):1178–1183.
    1. Stucki G, Rother M European IDEA-033 Study Group. Randomized, double-blind, placebo-controlled study of three dosages of epicutaneously applied IDEA-033 (keteprofen in Transfersome) in patients with osteoarthritis of the knee. Ann Rheum Dis. 2007;66 (Suppl 2):S510.
    1. Kneer W, Rother I, Rother M, Seidel E IDEA-033-III-01 Study Group. A multiple-dose, open-label, safety, compliance, and usage evaluation study of epicutaneously applied Diractin (ketoprofen in Transfersome) in joint/musculoskeletal pain or soft tissue inflammation. Curr Drug Saf. 2009;4(1):5–10.
    1. Whitefield M, O’Kane CJ, 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(6):409–417.
    1. Trnavský K, Fischer M, Vögtle-Junkert U, Schreyger F. Efficacy and safety of 5% ibuprofen cream treatment in knee osteoarthritis. Results of a randomized, double-blind, placebo-controlled study. J Rheumatol. 2004;31(3):565–572.
    1. Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006.
    1. Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328(7446):991–995.
    1. Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009;(4):CD007393.
    1. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol. 1997;15(8):2974–2980.
    1. Morgenlander JC, Hurwitz BJ, Massey EW. Capsaicin for the treatment of pain in Guillain–Barré syndrome. Ann Neurol. 1990;28(2):199.
    1. Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med. 2005;2(7):e164.
    1. Aronson JK, editor. Meyler’s Side Effects of Drugs – The International Encyclopedia of Adverse Drug Reactions and Interactions. 15th ed. Amsterdam, The Netherlands: Elsevier Science; 2005.
    1. Cumpston M, Johnston RV, Wengier L, Buchbinder R. Topical glyceryl trinitrate for rotator cuff disease. Cochrane Database Syst Rev. 2009;3:CD006355.
    1. Davis KD, Treede RD, Raja SN, Meyer RA, Campbell JN. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain. 1991;47(3):309–317.
    1. Epstein JB, Grushka M, Le N. Topical clonidine for orofacial pain: a pilot study. J Orofac Pain. 1997;11(4):346–352.
    1. Ushida T, Tani T, Kanbara T, Zinchuk VS, Kawasaki M, Yamamoto H. Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1. Reg Anesth Pain Med. 2002;27(5):524–528.
    1. Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother. 2002;16(3):27–35.
    1. Lehman JS, Sciallis GF. Effective use of topical amitriptyline hydrochloride 2.5% and ketamine hydrochloride 0.5% for analgesia in refractory proctodynia. J Drugs Dermatol. 2008;7(9):887–889.
    1. Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer RA, Campbell JN. Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain. 2000;88(2):161–168.
    1. Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain. 1998;75(1):111–119.
    1. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65(6):812–819.
    1. Ingersoll KS, Cohen J. The impact of medication regimen factors on adherence to chronic treatment: a review of literature. J Behav Med. 2008;31(3):213–224.
    1. Henry A, Batey RG. Enhancing compliance not a prerequisite for effective eradication of Helicobacter pylori: the HelP study. Am J Gastroenterol. 1999;94(3):811–815.
    1. Gani F, Pozzi E, Crivellaro MA, et al. The role of patient training in the management of seasonal rhinitis and asthma: clinical implications. Allergy. 2001;56(1):65–68.
    1. Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2008;2:CD000011.
    1. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23(8):1296–1310.
    1. Harbeck N, Haidinger R. The patient experience. Breast Cancer Res Treat. 2007;105 (Suppl 1):91–103.
    1. Jackson L, Leclerc J, Erskine Y, Linden W. Getting the most out of cardiac rehabilitation: a review of referral and adherence predictors. Heart. 2005;91(1):10–14.
    1. Barnett AH. Treating to goal: challenges of current management. Eur J Endocrinol. 2004;151 (Suppl 2):T3–T7.
    1. Nosé M, Barbui C, Gray R, Tansella M. Clinical interventions for treatment non-adherence in psychosis: meta-analysis. Br J Psychiatry. 2003;183:197–206.
    1. Loghman-Adham M. Medication noncompliance in patients with chronic disease: issues in dialysis and renal transplantation. Am J Manag Care. 2003;9(2):155–171.
    1. Costello K, Kennedy P, Scanzillo J. Recognizing nonadherence in patients with multiple sclerosis and maintaining treatment adherence in the long term. Medscape J Med. 2008;10(9):225.
    1. Restrepo RD, Alvarez MT, Wittnebel LD, et al. Medication adherence issues in patients treated for COPD. Int J Chron Obstruct Pulmon Dis. 2008;3(3):371–384.
    1. After the diagnosis: adherence and persistence with hypertension therapy. Am J Manag Care. 2005;11(13 Suppl):S395–S399.
    1. Brown BG, Bardsley J, Poulin D, et al. Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol. 1997;80(2):111–115.
    1. Girvin B, McDermott BJ, Johnston GD. A comparison of enalapril 20 mg once daily vs 10 mg twice daily in terms of blood pressure lowering and patient compliance. J Hypertens. 1999;17(11):1627–1631.
    1. Kubacka RT, Juhl RP. Attitudes of patients with hypertension or arthritis toward the frequency of medication administration. Am J Hosp Pharm. 1985;42(11):2499–2501.
    1. Edwards JE. Thesis. Oxford UK: University of Oxford; 2000. Determination of analgesic efficacy and harm in acute postoperative pain using systematic review methods.

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