Postgraduate Medicine
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Topical Therapies in the Management of Chronic Pain Steven P. Stanos & Katherine E. Galluzzi To cite this article: Steven P. Stanos & Katherine E. Galluzzi (2013) Topical Therapies in the Management of Chronic Pain, Postgraduate Medicine, 125:sup1, 25-33, DOI: 10.1080/00325481.2013.1110567111 To link to this article: http://dx.doi.org/10.1080/00325481.2013.1110567111
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Topical Therapies in the Management of Chronic Pain
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Steven P. Stanos, DO 1 Katherine E. Galluzzi, DO 2 1 Assistant Professor in Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Ill; 2Professor/ Chair, Department of Geriatrics, Philadelphia College of Osteopathic Medicine, Philadelphia, PA
Abstract: Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting . 25% of adults in the United States. Oral agents are the cornerstone of chronic pain treatment, but their use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, infections, and systemic side effects. Several types of topical agents have been shown to be useful in the treatment of patients with chronic pain. Both capsaicin and topical diclofenac have been shown to be effective in the treatment of patients with chronic soft-tissue pain. In patients with hand and knee osteoarthritis (OA), the American College of Rheumatology generally recommends oral treatments (acetaminophen, oral nonsteroidal anti-inflammatory drugs [NSAIDs], tramadol, and intra-articular corticosteroids) and topical NSAIDs equally, favoring topical agents only for patients who have pre-existing gastrointestinal risk or are aged $ 75 years. Topical NSAIDs have been shown to provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients with knee OA. Different formulations of topical diclofenac (including the diclofenac hydroxyethyl pyrrolidine patch, diclofenac sodium gel, and diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide USP) have been shown to be superior to placebo and comparable to oral diclofenac in the treatment of patients with pain due to knee OA, with a lower incidence of gastrointestinal complaints than with the oral formulation. In patients with neuropathic pain, topical forms of both capsaicin and lidocaine have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain. Lidocaine has also demonstrated efficacy in relieving patient pain due to complex regional pain syndrome and may be useful in the treatment of patients with neuropathic pain who have cancer, although clinical trial results have not been consistent. Data suggest that topical therapies may offer a safe, well-tolerated, and effective alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain. Keywords: pain; analgesics; nonsteroidal anti-inflammatory drugs; NSAIDs; topical NSAIDs
Introduction
Correspondence: Steven Stanos, DO, 980 N. Michigan Ave., Suite 800, Chicago, IL 60611. Tel: 312-238-7809 Fax: 312-238-7801 E-mail: [email protected]
Chronic pain is increasingly prevalent, affecting . 25% of Americans (an estimated 76.5 million people)—more than all of the people affected by diabetes, heart disease, and cancer combined.1 Patient pain may be localized (such as that due to trauma, repetitive strain injury, or arthritis), or generalized (such as that due to fibromyalgia).2 In the last few decades, great strides have been made in understanding pain-signaling pathophysiology, allowing for an appreciation of the diversity of the body’s mechanisms that can modulate the pain signal peripherally and centrally.3 Such research
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has led to the broad categorization of chronic pain states as nociceptive conditions (such as osteoarthritis [OA]), neuropathic conditions (eg, postherpetic neuralgia [PHN]), or a mix of both etiologies (such as fibromyalgia and lower back pain).4 Recognition of the etiology of the pain state by the physician is helpful in predicting which form of treatment will benefit the patient most,4 because although nociceptive and neuropathic pain signals are transmitted via the same nerve pathways, the different states process and resolve painful stimuli through different physiologic mechanisms.5 This may be the reason why patients with neuropathic pain often do not respond as well to conventional analgesic therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs).4 Although oral agents are the cornerstone of treatment for patients with chronic pain, their use may be limited in certain patients. Many patients are unable to tolerate oral pain agents due to advanced age (. 65 years), medical comorbidities, end-organ damage, adverse effects, or drug interactions.6,7 Moreover, tolerance and physical dependence can occur with chronic use of opioids.8,9 Topical therapies have a number of advantages compared with systemically administered medications, including achievement of pain relief in some patients at a lower total systemic daily dose, site-specific drug delivery, and avoidance of first-pass metabolism, major drug–drug interactions, and systemic side effects.10 Because topical agents exert their pharmacologic effects locally, the most common adverse events in patients with use of these drugs are cutaneous (ie, application site reactions, which are usually mild and reversible).3 For patients with localized pain, topical medications may be particularly appropriate.11 Therefore, knowledge about pain treatment options beyond the use of oral agents is important. We review the utility of topical therapies for patients with various chronic pain states, based on the data resulting from clinical trials.
Patient Chronic Pain States Appropriate for use of T opical Analgesics Musculoskeletal Pain
Chronic musculoskeletal pain comprises a spectrum of patient conditions including OA, rheumatoid arthritis, fibromyalgia, and spinal conditions (eg, disc degeneration or herniation) that can lead to low back pain. Population surveys have consistently shown that musculoskeletal pain, particularly back and joint pain, is the most frequently occurring type of chronic pain in patients.4 Although oral NSAIDs are highly effective and extensively used for treating patients with many types of musculoskeletal pain, 26
concerns about drug gastrointestinal (GI), renal, hepatic, and cardiovascular toxicities12–15 have focused attention on modes of therapy that could bypass these adverse effects. Several topical agents, particularly topical NSAIDs, have been shown to be effective in the treatment of patients with chronic musculoskeletal conditions, including low back pain and OA.16 Topically applied NSAIDs are well-suited for the treatment of patients with many OA conditions and other forms of musculoskeletal pain because the formulations may be able to penetrate patient muscle, synovium, and joint tissues proximal to and below the site of application.17 A systematic review and meta-analysis of topical NSAIDs for treating patients with chronic musculoskeletal pain showed that compared with topical salicylate and capsaicin, topical NSAIDs have been tested in more studies and in 4 times as many patients, and have demonstrated the lowest (best) number needed to treat (NNT; ie, the average number of patients who need to be treated for 1 patient to achieve pain relief).18
Soft-Tissue Pain Both capsaicin and topical diclofenac have been studied for the treatment of patients with soft-tissue pain. In one study, 130 patients experiencing chronic soft-tissue musculoskeletal pain were treated with a capsaicin 0.05% cream or placebo for 3 weeks.19 At the end of the study, the median pain sum score had decreased by 49% in the capsaicin-treated group compared with a 23% reduction in the placebo group (P , 0.001), showing that capsaicin cream is useful in treating patients with chronic soft-tissue pain.19 Zacher et al conducted an evidence-based review to examine the pharmacokinetic and pharmacodynamic profiles, as well as the safety and efficacy of diclofenac patches and gels in the treatment of patients with pain caused by soft-tissue rheumatic disorders and OA.20 Nineteen double-blind, randomized, controlled clinical studies were included, involving . 3000 patients. Most of these trials (16) were in patients who had chronic pain conditions.20 Across studies, topical diclofenac (gel, patch, and solution) was shown to be more effective than placebo and comparable to some other topical NSAIDs (indomethacin gel and plaster [or patch], ketoprofen gel, and piroxicam gel) and to some oral NSAIDs treatments (diclofenac, ibuprofen, and naproxen) in relieving patient pain.20 The review supported the effectiveness, safety, and tolerability of topical diclofenac, used for # 12 weeks, in treating patients with a variety of painful and inflammatory chronic pain conditions, including soft-tissue injuries.20
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Osteoarthritis and Other Joint Pain International guidelines for the treatment of patients with OA currently recommend certain topical analgesics. The American College of Rheumatology (ACR) recommends the use of topical NSAIDs or topical capsaicin as options for the initial management of pain in patients with OA of the hand, and topical NSAIDs for patients with OA of the knee.21 Furthermore, the ACR strongly recommends the use of topical NSAIDs for patients with knee OA who do not have a satisfactory clinical response to full-dose acetaminophen, and for persons aged $ 75 years for whom treatment with NSAIDs is indicated.21 The ACR conditionally recommends topical rather than oral NSAID treatment for patients aged $ 75 years who have OA of the hand.21 Topical capsaicin is not recommended for the treatment of patients with knee OA.21 The ACR cautions that oral NSAIDs should not be used in patients with chronic kidney disease (CKD) Stage IV or V (estimated glomerular filtration rate [GFR] , 30 cc/min) and advises practitioners to consider the benefits and risks on an individual patient basis before deciding to use oral NSAIDs to treat patients with CKD Stage III (estimated GFR between 30 and 59 cc/min).21 In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has advised that topical NSAID therapy should be considered before oral NSAID therapy (including selective cyclooxygenase [COX]-2 inhibitors) or opioids for the treatment of adults with OA.22 Rubefacients (salicylates and nicotinic esters) are used to relieve patient pain due to various types of musculoskeletal conditions.18,23 The agents are thought to relieve patient pain in muscles, joints, and tendons through counterirritation mediated by increased blood flow to the site of application.18,23 A review of topical rubefacients containing salicylates showed that for patients with chronic pain conditions, such as OA, rubefacients appear to provide clinically relevant pain relief in only 1 of every 6 patients, over and above those who also responded to placebo.23 The authors of the review suggest that this degree of efficacy compares poorly with that of topical NSAID treatment, which has been shown to provide useful levels of pain relief in 1 of every 3 patients, over and above those patients who also responded to placebo.23 Many studies have been conducted to investigate the efficacy and safety of topical NSAID therapy in patients with OA. In a study of 50 patients with knee OA, a larger percentage of patients responded to treatment with ibuprofen 5% cream than to placebo (84% vs 40%; P , 0.0001). Response was defined as a decrease in pain score (on a 100-mm visual
analog scale [VAS]) of $ 18 mm or a $ 23% reduction from baseline. Also, patients treated with ibuprofen 5% cream achieved greater improvement on the Lequesne index (an OA pain functional measure) than those in the placebo group (27.5% vs 10.7%).24 The Lequesne index for patients with knee OA assesses pain, maximum distance walked, and activities of daily living on a 24-point scale, in which a score of , 5 indicates minor disability, and $ 14 denotes extremely severe disability.24 Topical ibuprofen cream (dose defined as 1.5 g/day for 1 knee) also showed analgesic efficacy equivalent to that of oral ibuprofen (1.2 g/day) during 12 months in a trial of 282 elderly patients with chronic knee pain, as determined by Western Ontario and McMaster Universities (WOMAC) global scores.25 Mean WOMAC global score changes from baseline at the 12-month follow-up were –0.5 in the oral NSAID group and 1.1 in the topical NSAID group, a nonsignificant difference.25 The WOMAC scores reflect patient pain, stiffness, and physical function measured by a multidimensional, self-administered health status instrument in patients with OA of the hip or knee.26 Lower scores on the WOMAC represent better health status.26 Ketoprofen gel, 100 mg, was compared with oral celecoxib 100 mg, and placebo in 397 patients with pain flare due to knee OA.27 After 6 weeks of therapy, the ketoprofen formulation was shown to be significantly superior to placebo and similar to celecoxib in patient pain reduction, as assessed by changes from baseline in WOMAC pain scores (P , 0.05 vs placebo for both ketoprofen gel and oral celecoxib).27 Topical diclofenac has been shown to produce analgesic and anti-inflammatory effects similar to those produced by oral dosage forms, with less potential for systemically mediated complications in patients with pain.16,20 The evidencebased review conducted by Zacher et al (discussed earlier in this article with respect to studies in patients with soft-tissue pain) showed that in studies in patients with knee OA, topical diclofenac was superior to placebo in relieving patient pain as measured by the Lequesne index, VAS, and WOMAC scores.20 Furthermore, treatment of patients with diclofenac sodium topical solution showed efficacy comparable to that of oral diclofenac, as measured by WOMAC scores.28 Diclofenac diethylamine 1.16% topical gel has been used extensively in Europe for . 25 years in the treatment of patients with OA of the knee and other painful, inflammatory conditions of the tendon, ligament, muscle, and joint.29 In a 3-week study involving 238 patients, diclofenac gel applied 4 times daily was shown to effectively relieve patient pain from OA of the knee.29 For the primary efficacy outcome―patient
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diary assessment of daily pain on movement, averaged over days 1 to 14―treatment with diclofenac gel was significantly superior to placebo, with a difference of 4 mm on a 100-mm VAS (P = 0.02).29 The diclofenac hydroxyethylpyrrolidine (DHEP) patch (or plaster) has been studied extensively in the treatment of patients with pain due to OA. A study of 155 adult patients with OA of the knee showed that the diclofenac patch produced significantly greater pain relief than the placebo patch, as evaluated by both the Huskisson VAS (global spontaneous pain) and the Lequesne index, beginning with day 4 of therapy (P , 0.001 for both outcome measures).30 In addition, patients wearing the DHEP patch recorded significantly fewer night awakenings than patients wearing the placebo patch (P , 0.005).30 In a 2-week trial in 103 outpatients with pain due to knee OA, patients treated with the DHEP patch showed significantly greater improvement than those receiving placebo in Lequesne index scores (P , 0.01), spontaneous pain relief (P , 0.01), and physician (P , 0.01) and patient (P , 0.05) global assessments of efficacy of treatment.31 Diclofenac sodium topical solution (1.5% w/w with dimethyl sulfoxide USP [DMSO]) is indicated in the United States for the treatment of patients with OA of the knee.32 In a 12-week study of the treatment of 326 patients with knee OA, diclofenac sodium 1.5% topical solution was well tolerated and significantly more effective than a vehicle control solution in reducing patient pain (P , 0.005) and improving physical function (P , 0.005), stiffness (P , 0.01), and patient global status (P , 0.005).33 Similarly, another 12-week study in 775 patients with OA of the knee showed that treatment with diclofenac sodium 1.5% topical solution was well tolerated and effective, according to the following measured outcomes: treatment of pain evaluated on the WOMAC scale (P = 0.015 vs placebo; P = 0.009 vs vehicle), physical function evaluated on the WOMAC scale (P = 0.034 vs placebo; P = 0.026 vs vehicle), overall health (P , 0.0001 vs placebo; P = 0.016 vs vehicle), patient global assessments of the study knee (P = 0.016 vs placebo; P = 0.018 vs vehicle), and stiffness evaluated on the WOMAC scale (P = 0.035 vs vehicle).34 For all of these efficacy variables, patient treatment with diclofenac sodium 1.5% topical solution was comparable to treatment with oral diclofenac, with no significant differences observed between the treatment groups.34 In another treatment comparison of diclofenac sodium 1.5% topical solution and oral diclofenac in 622 patients with OA of the knee, no clinically significant difference was found between the therapies in patient pain relief, physical 28
function, stiffness, or patient global assessments.28 Patients in the topical treatment group showed improvements in measures of these variables of 36% to 44% over baseline values, and patients treated with oral diclofenac showed improvements of 42% to 49%;28 however, the incidence of GI adverse events was significantly higher in patients treated with oral diclofenac than with topical diclofenac (48% vs 35%; P = 0.0006).28 Furthermore, significantly greater mean changes from baseline were observed in patients treated with oral diclofenac compared with topical diclofenac sodium 1.5% solution in patient liver enzymes (P # 0.0004), hemoglobin (P # 0.0001), and creatinine (P = 0.003) levels, as well as creatinine clearance (P = 0.006).28 A review of studies in patients with OA of the knee showed that treatment with diclofenac sodium 1.5% topical solution provided analgesic efficacy equivalent to that of oral diclofenac.35 A treatment algorithm for patients with symptomatic OA is presented in Figure 1. A combination of pharmacologic therapy (including topical NSAIDs) and nonpharmacologic therapy (eg, exercise) is often warranted in the treatment of patients with OA, but basic education on the disease state should always precede treatment.36,37
Neuropathic Pain
In guidelines for the treatment of patients with neuropathic pain, the lidocaine 5% patch (or “topical plaster”) is recommended as first-line treatment, particularly in patients with postherpetic neuralgia (PHN) and allodynia (pain induced by a normally nonprovocative stimulus, such as light touch/pressure or mild temperatures) by the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group and the European Federation of Neurological Societies (EFNS); and as second-line treatment (after tricyclic antidepressants and calcium channel α2δ ligands) by the Canadian Pain Society.38 A study of 77 patients with 3 different chronic pain conditions, including painful diabetic neuropathy, PHN, or chronic low back pain, showed that 2 weeks of treatment with the lidocaine topical patch significantly reduced all pain measures assessed by the Neuropathic Pain Scale (NPS) composite score (P , 0.01).39 In addition, use of the patch was well tolerated by patients, with no serious systemic adverse events or drug reactions.39 A review of randomized, placebo-controlled, doubleblind studies of therapies for patients with neuropathic pain showed that topically applied low-concentration capsaicin relieved pain in patients with PHN, nerve injury pain, mixed neuropathic pain conditions, and diabetic neuropathy, with
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Figure 1. Treatment algorithm for symptomatic osteoarthritis.
Reprinted with permission of Informa UK Ltd. from Altman R. New guidelines for topical NSAIDs in the osteoarthritis treatment program. Curr Med Res Opin. 2010:26(12):2871–287637; permission conveyed through Copyright Clearance Center, Inc. Abbreviations: COX-2, cyclo-oxygenase-2; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2; PO, oral; PPI, proton pump inhibitor; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
a combined NNT of 6.7 (4.6–12) and number needed to harm (NNH; the average number of patients needed to be exposed to capsaicin in order to cause an adverse event in 1 patient) of 11.5 (8.1–19.8).40 It should be noted that although topical analgesic treatments are useful for some types of neuropathic pain, oral and intravenous anticonvulsants play a major therapeutic role in the management of patients with neuropathic pain. In particular, the new neuromodulators (eg, gabapentin and pregabalin) have ushered in a new era in the treatment of patients with neuropathic pain.41
Postherpetic Neuralgia The most frequent and debilitating sequelae of herpes zoster (ie, shingles) is PHN, the pain that can develop along cutaneous nerves of the patient after the lesions from the acute infectious rash stage have healed. Postherpetic neuralgia generally persists for approximately 30 days, but it may last longer.42,43 In some patients, particularly the elderly, PHN can last many months or years and result in not only considerable pain but also loss of independence and financial burdens.42 The chronic patient pain associated with PHN has been managed with an array of oral medications, including antidepressants, antiepileptic drugs, and opioids.44 However,
because PHN is especially common and severe in the elderly, and this patient population is particularly susceptible to the adverse effects of systemic drugs, topical analgesics are a valuable treatment option.44 Topical forms of both capsaicin and lidocaine have been shown to be therapeutically useful in this indication.45,46 (For a discussion of topical treatment of the initial, acute stage of herpes zoster infection, please see the article in this supplement, “Options in Topical Therapies in the Management of Acute Pain” by Bill McCarberg, MD, and Yvonne D’Arcy, CRNP.) The 8% capsaicin patch, a localized dermal delivery system that contains a synthetic equivalent of the compound found naturally in chili peppers, is indicated for the management of patients with neuropathic pain associated with PHN.47 In a study of 402 patients with PHN, a single 60-minute application of the 8% capsaicin patch produced significantly greater pain reduction, as measured by the Numeric Pain Rating Scale (NPRS), than the control patch (containing 0.04% capsaicin) at every time point evaluated (P , 0.05, weeks 1, 5, and 11; P , 0.01, weeks 3, 4, 6–8, 10, and 12; P , 0.001, weeks 2 and 9).48 In a similar study in 418 patients, a single 60-minute application of the 8% capsaicin patch resulted in significantly greater reductions
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in NPRS scores than a similar application of the 0.04% capsaicin patch during weeks 2 to 8 of follow-up (32.0% vs 24.4%, respectively; P = 0.011).49 An extension of a 4-week trial in patients with PHN (N = 24) showed that the efficacy of the 8% capsaicin patch was maintained for # 48 weeks after the 4-week double-blind trial, based on NPRS results.50 During the extension phase, patients received up to 4 treatment applications, 6 to 12 weeks apart.50 Patient pain scores during weeks 2 through 12 were reduced by 33.8% in the capsaicin 8% group but increased by 4.9% in the control group.50 The lidocaine 5% patch is indicated in the United States for the treatment of patients with pain associated with PHN.51 The current IASP guidelines for the treatment of patients with neuropathic pain recommend the lidocaine 5% preparation as first-line therapy in patients with well-localized PHN and allodynia, and in patients with allodynia due to different types of peripheral neuropathic pain.38 The lidocaine topical patch was compared with a placebo patch in a 28-day crossover study of 32 patients with PHN.52 The median time to exiting the treatment period (the need to discontinue treatment because of a prespecified extent of deterioration in pain relief score compared with prestudy baseline [ie, a reduction of $ 2 categories on a 6-item pain-relief scale for any 2 consecutive days]) was . 14 days for the lidocaine 5% patch, compared with 3.8 days for placebo (P , 0.001).52 Additionally, 78% of subjects preferred the lidocaine 5% patch (P , 0.001).52 Overall, a review of short-term and long-term studies found the lidocaine patch 5% to be well tolerated and consistently effective in the treatment of patients with PHN.53 However, a Cochrane Database systematic review concluded that there is insufficient evidence to recommend topical lidocaine as a first-line agent in the treatment of patients with PHN with allodynia because of the lack of data comparing topical lidocaine treatment with other medications currently used for the treatment of PHN.54
Complex Regional Pain Syndrome Complex regional pain syndrome (CRPS) is a chronic pain condition believed to be caused by central or peripheral nervous system dysfunction.55 Type 2 CRPS is associated with an underlying nerve injury (formerly described as causalgia). Type I CRPS is not associated with an underlying nerve injury and is primarily due to localized crush injury or tissue trauma.55 There is little evidence of efficacy of any oral or topical medications in relieving patient pain from CRPS. However, some case series and case report data suggest that topical lidocaine may be effective in relieving patient 30
pain due to type 2 CRPS. In 1 report, a patient with type 2 CRPS was successfully treated with a lumbar epidural opioid infusion and the lidocaine 5% patch, supporting the theory that application of local anesthetics to sites along the patient’s peripheral nervous system (and into the epidural space) early in the course of type 2 CRPS may “shut down” the process by which the disorder establishes itself.56 Further evidence came from a study of 20 patients with neuropathic pain (postoperative neuropathic pain, type 2 CRPS, or PHN) that was refractory to treatment with antidepressants, anticonvulsants, or opioids.57 Patients were treated with the lidocaine 5% patch for # 5 years.57 Treatment with the lidocaine patch was well tolerated and provided sustained pain relief during long-term treatment; similar levels of analgesic efficacy were reported for 10 of the 20 initial responders at follow-up at 3 years, and for 8 patients at follow-up at 5 years.57
Painful Peripheral Neuropathy Associated With Diabetes Also known as diabetic peripheral neuropathic pain (DPNP), peripheral neuropathy in patients with diabetes continues to remain an issue for individuals with poorly controlled diabetes. Based on evidence from clinical trials and the committee’s clinical experience, the Diabetic Peripheral Neuropathic Pain Consensus Treatment Guidelines Advisory Board recommends use of capsaicin and the lidocaine 5% patch as appropriate second-line agents for the treatment of patients with DPNP.58 Capsaicin has been used with some success in the treatment of patients with diabetic neuropathic pain; it should be used only for patients with localized discomfort rather than patients with generalized pain.59
Pain In The Cancer And Palliative Care Setting
The complexity of neuropathic pain in patients with cancer presents treating physicians with many therapeutic challenges. 60 The National Comprehensive Cancer Network 2008 Adult Cancer Pain Guidelines generally recommend opioids for the treatment of cancer pain.61 To complement management, they recommend considering an adjuvant therapy with the lidocaine 5% patch for peripheral neuropathic pain following trials of anticonvulsants and/or antidepressants.61 This topical form of treatment has been shown to have variable effectiveness in different studies. A retrospective audit of 97 patients with cancer and neuropathic pain (including postsurgical pain and PHN) who had their pain successfully managed with the lidocaine
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5% patch showed that both patients and physicians liked the lidocaine patch, owing to a low incidence of adverse events and because the patch provided clear benefit in approximately 25% of patients.60 Patients with allodynia,62 which was a significant feature of neuropathic pain in at least 60% of patients, appeared to respond well to the lidocaine patch.60 However, in a double-blind placebo-controlled crossover study consisting of 2 4-week treatment phases, the lidocaine 5% patch did not significantly reduce pain intensity in 28 patients with cancer and persistent postsurgical incisional pain.63 Relief of chronic pain is one of the main goals of palliative care.64 According to the International Association for Hospice and Palliative Care, the treatment of chronic pain in palliative care should be an integrated part of the interdisciplinary plan of total care, including the management of psychosocial issues.65 The form of treatment should employ the appropriate modality or modalities, and be appropriate to the stage of the patient’s disease.65 The health care provider should strive to provide consistent treatment, avoiding repeated changes of analgesics.65 Additionally, treatment in this setting requires continuity of care and repeated reassessment.65 Box 1 outlines the potential role of topical analgesics in pain management for patients in the palliative care setting.
Conclusion
Although an ever-expanding understanding of the pathophysiology of pain has led to the development of an array of treatment options, chronic pain often remains difficult to treat because of a lack of patient response or intolerance to available therapies. When effective, topical therapies offer a potentially better-tolerated alternative to systemically administered medications, which carry risks of organ toxicity, tolerance, and drug–drug interaction. In patients with chronic musculoskeletal pain, including OA, topical NSAIDs have been shown to be the most effective form of topical therapy, providing greater pain relief than alternatives, such as lidocaine, capsaicin, and rubefacients. In various types of neuropathic pain, including PHN, CRPS, and DPNP, topical formulations of lidocaine and capsaicin have proven to be effective treatment. In particular, topical lidocaine is recommended for first-line treatment of neuropathic pain in patients with PHN and allodynia by the IASP Neuropathic Pain Special Interest Group and the EFNS. Therefore, for patients who cannot or choose not to take systemic therapies for chronic pain, well-chosen topical therapies offer a safe,
BOX 1 Use of T opical Analgesics in Palliative Care • Topical analgesics may be advantageous in the palliative care setting because of their non-oral route of delivery and the fact that they exert their therapeutic effects without significant systemic absorption, avoiding the interactions and toxicities characteristic of systemically delivered agents (both oral and intranasal), such as opioid-induced constipation.66,67 • Special issues that increase the risk of adverse reactions from oral drugs in patients receiving palliative care, many of whom are elderly (. 65 years), include the following: Elderly patients are likely to have age-related changes in pharmacokinetic parameters, such as reduced renal excretion and hepatic metabolism, which increase sensitivity to certain oral analgesics, particularly opioids.7 Elderly patients may be taking multiple medications, increasing the risk of drug–drug interactions.7 Patients in the hospice or palliative care setting may be unable to swallow or tolerate oral medications due to their disease state or side effects of treatments used to manage their disease (eg, chemotherapy-induced emesis).67–69
well-tolerated, and effective alternative. The use of topical medications along with oral agents may also offer patients synergistic analgesic effects as part of a polypharmacy approach to managing chronic musculoskeletal and neuropathic pain.
Acknowledgments
Technical editorial and medical writing support for the preparation of this manuscript was provided by Julia Schroeder and Synchrony Medical Communications, LLC, West Chester, PA. Funding for this support was provided by Mallinckrodt Inc., the Pharmaceuticals business of Covidien, Hazelwood, MO.
Conflict of Interest Statement
Steven P. Stanos, MD, discloses the following relationships: Covidien (consultant); Eli Lilly and Company (speakers bureau, consultant); Endo Pharmaceuticals (speakers bureau, consultant); Forest Pharmaceuticals, Inc. (speakers bureau); GlaxoSmithKline (consultant); King Pharmaceuticals, Inc. (speakers bureau, consultant); Ortho-McNeil-Janssen Pharmaceuticals, Inc. (speakers bureau, consultant); Pfizer Inc (speakers bureau, consultant, research grants); and Purdue Pharma L.P. (consultant). Katherine E. Galluzzi, DO, discloses the following relationships: PriMed (speakers bureau); California Academy of Family Physicians (speakers bureau); and University of North Texas Health Science Center (speakers bureau).
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References
1. American Pain Foundation. Pain facts and figures. http://www. painfoundation.org/media/resources/ pain-facts-figures.html. Accessed March 8, 2012. 2. Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat Rev Rheumatol. 2010;6(10):599–606. 3. Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev. 2003;55(1):1–20. 4. Croft P, Blyth FM, van der Windt D, eds. Chronic Pain Epidemiology. From Aetiology to Public Health. Oxford, England: Oxford University Press; 2010. 5. Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc. 2007;107(10 suppl 6):ES39–ES48. 6. Barkin RL, Beckerman M, Blum SL, Clark FM, Koh E, Wu DS. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging. 2010;27(10):775–789. 7. Cavalieri TA. Managing pain in geriatric patients. J Am Osteopath Assoc. 2007;107(6; suppl 4):ES10–ES16. 8. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician. 2005;71(5):913–918. 9. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9(4):444–459. 10. Moody ML. Topical medications in the treatment of pain. Pain Med News. 2010;Dec:15–31. 11. McCarberg B, D’Arcy Y. Target pain with topical peripheral analgesics. Nurse Pract. 2007;32(7):44–49. 12. Vardeny O, Solomon SD. Cyclooxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, and cardiovascular risk. Cardiol Clin. 2008;26(4):589–601. 13. Borer JS, Simon LS. Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: achieving a balance. Arthritis Res Ther. 2005;7(suppl 4):S14–S22. 14. Harirforoosh S, Jamali F. Renal adverse effects of nonsteroidal antiinflammatory drugs. Expert Opin Drug Saf. 2009;8(6):669–681. 15. Björnsson E. Review article: drug-induced liver injury in clinical practice. Aliment Pharmacol Ther. 2010;32(1):3–13. 16. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med. 2010;11(4):535–549. 17. Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs. 2000;60(3): 555–574. 18. Mason L, Moore RA, Edwards JE, McQuay HJ, Derry S, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ. 2004; 328(7446):995. 19. Chrubasik S, Weiser T, Beime B. Effectiveness and safety of topical capsaicin cream in the treatment of chronic soft tissue pain. Phytother Res. 2010;24(12):1877–1885. 20. Zacher J, Altman R, Bellamy N, et al. Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr Med Res Opin. 2008;24(4):925–950. 21. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip and knee. Arthritis Care Res. 2012;64(4):465–474. 22. National Institute for Health and Clinical Excellence. Osteoarthritis: The Care and Management of Osteoarthritis in Adults. NICE clinical guideline 59. London, United Kingdom: National Institute for Health and Clinical Excellence; 2008. 23. Matthews P, Derry S, Moore RA, McQuay HJ. Topical rubefacients for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;(3):CD007403.
32
24. 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. 25. 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(7636):138–142. 26. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988; 15(12):1833–1840. 27. Rother M, Lavins BJ, Kneer W, Lehnhardt K, Seidel EJ, Mazgareanu S. Efficacy and safety of epicutaneous ketoprofen in Transfersome (lDEA033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial. Ann Rheum Dis. 2007; 66(9):1178–1183. 28. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (Pennsaid®) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31(10):2002–2012. 29. Niethard FU, Gold MS, Solomon GS, et al. Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee. J Rheumatol. 2005;32(12):2384–2392. 30. Dreiser RL, Tisne-Camus M. DHEP plasters as a topical treatment of knee osteoarthritis—a double-blind placebo-controlled study. Drugs Exp Clin Res. 1993;19(3):117–123. 31. Brühlmann P, Michel BA. Topical diclofenac patch in patients with knee osteoarthritis: a randomized, double-blind, controlled clinical trial. Clin Exp Rheumatol. 2003;21(2):193–198. 32. Pennsaid [package insert]. Hazelwood, MO: Mallinckrodt Brand Pharmaceuticals, Inc; 2010. 33. Roth SH, Shainhouse Z. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee. A randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164(18):2017–2023. 34. Simon LS, Grierson LM, Naseer Z, Bookman AA, Shainhouse JZ. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143(3):238–245. 35. Ozgüney I. An alternative topical treatment of osteoarthritis of the knee with cutaneous diclofenac solution. Expert Opin Pharmacother. 2008;9(10):1805–1816. 36. Argoff CE, Gloth FM. Topical nonsteroidal anti-inflammatory drugs for management of osteoarthritis in long-term care patients. Ther Clin Risk Manag. 2011;7:393–399. 37. Altman R. New guidelines for topical NSAIDs in the osteoarthritis treatment program. Curr Med Res Opin. 2010:26(12):2871–2876. 38. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009,122(10 suppl):S22–S32. 39. Argoff CE, Galer BS, Jensen MP, Oleka N, Gammaitoni AR. Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the Neuropathic Pain Scale. Curr Med Res Opin. 2004;20(suppl 2):S21–S28. 40. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118(3):289–305. 41. Berger JM, Zaghi S. Nonopioid analgesics in pain management. In: Vadivelu N, Urman RD, Hines RL, eds. Essentials of Pain Management. New York, NY: Springer; 2011:117–150. 42. Johnson RW. Zoster-associated pain: what is known, who is at risk and how can it be managed? Herpes. 2007;14(suppl 2):30–34. 43. Yawn BP, Saddier P, Wollan PC, St. Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341–1349.
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Topical Therapies in Chronic Pain 44. Pappagallo M, Haldey EJ. Pharmacological management of postherpetic neuralgia. CNS Drugs. 2003;17(11):771–780. 45. Edelsberg JS, Lord C, Oster G. Systemic review and meta-analysis of efficacy, safety, and tolerability data from randomized controlled trials of drugs used to treat postherpetic neuralgia. Ann Pharmacother. 2011;45(12):1483–1490. 46. Argoff CE. Review of current guidelines on the care of postherpetic neuralgia. Postgrad Med. 2011;123(5):134–142. 47. Qutenza [package insert]. San Mateo, CA: NeurogesX, Inc; 2009. 48. Backonja M, Wallace MS, Blonsky ER, et al; NGX-4010 C116 Study Group. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol. 2008;7(12):1106–1112. 49. Irving GA, Backonja MM, 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(1):99–109. 50. Backonja MM, Malan TP, Vanhove GF, Tobias JK; 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(4):600–608. 51. Lidoderm [package insert]. Chadds Ford, PA: Endo Pharmaceuticals; 2010. 52. 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. 53. Garnock-Jones KP, Keating GM. Lidocaine 5% medicated plaster: a review of its use in postherpetic neuralgia. Drugs. 2009;69 (15):2149–2165. 54. Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev. 2007;(2):CD004846. 55. United States National Institutes of Health, National Institute of Neurological Disorders and Stroke. Complex regional pain syndrome fact sheet, NINDS. NIH Publication No. 04–4173. Published November 2003. Updated April 12, 2011. http://www.ninds.nih.gov/disorders/ reflex_sympathetic_dystrophy/detail_reflex_sympathetic_dystrophy. htm. Accessed March 13, 2012. 56. Vorobeychik Y, Giampetro DM. Topical lidocaine and epidural bupivacaine/hydromorphone in the treatment of complex regional pain syndrome type 2. Pain Physician. 2007;10(3):513–514.
57. Wilhelm IR, Tzabazis A, Likar R, Sittl R, Griessinger N. Long-term treatment of neuropathic pain with a 5% lidocaine medicated plaster. Eur J Anaesthesiol. 2010;27(2):169–173. 58. Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(4 suppl):S12–S25. 59. Boulton AJM. Management of diabetic peripheral neuropathy. Clin Diabetes. 2005;23(1):9–15. 60. 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. 61. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Adult Cancer Pain. Version 2.2011. http://www.nccn.org/. Accessed March 13, 2012. 62. Fu X, Froicu D, Sinatra R. Anatomic and physiologic principles of pain. In: Vadivelu N, Urman RD, Hines RL, eds. Essentials of Pain Management. New York, NY: Springer; 2011:31–44. 63. Cheville AL, Sloan JA, Northfelt DW, et al. Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB). Support Care Cancer. 2009;17(4):451–460. 64. Davies E, Higginson IJ, eds. World Health Organization. Better palliative care for older people. 2004. http://www.euro.who.int/__data/assets/ pdf_file/0009/98235/E82933.pdf. Accessed March 13, 2012. 65. Doyle D, Woodruff R; The International Association for Hospice and Palliative Care. The IAHPC Manual of Palliative Care, 2nd ed. Houston, TX; IAHPC Press; 2008. http://www.hospicecare.com/manual/tocmain.html. Accessed March 13, 2012. 66. Argoff C. Topical local anesthetics. In: McCleane G, Smith H, Smith H, eds. Clinical Management of the Elderly Patient in Pain. Binghamton, NY: The Haworth Press, Inc; 2006;75–89. 67. Hicks F, Rees E. A ‘pain-free’ death. Br Med Bull. 2008;88(1):23–41. 68. Vadivelu N, Hines RL. Management of chronic pain in the elderly: focus on transdermal buprenorphine. Clin Interv Aging. 2008;3(3): 421–430. 69. Jakobsen JN, Herrstedt J. Prevention of chemotherapy-induced nausea and vomiting in elderly cancer patients. Crit Rev Oncol/Hematol. 2009;71(3):214–221.
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Topical Therapies in the Management of Chronic Pain Steven P. Stanos & Katherine E. Galluzzi To cite this article: Steven P. Stanos & Katherine E. Galluzzi (2013) Topical Therapies in the Management of Chronic Pain, Postgraduate Medicine, 125:sup1, 25-33, DOI: 10.1080/00325481.2013.1110567111 To link to this article: http://dx.doi.org/10.1080/00325481.2013.1110567111
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Topical Therapies in the Management of Chronic Pain
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Steven P. Stanos, DO 1 Katherine E. Galluzzi, DO 2 1 Assistant Professor in Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Ill; 2Professor/ Chair, Department of Geriatrics, Philadelphia College of Osteopathic Medicine, Philadelphia, PA
Abstract: Chronic pain, whether localized or generalized, is a widespread, often debilitating condition affecting . 25% of adults in the United States. Oral agents are the cornerstone of chronic pain treatment, but their use may be limited in certain patients, particularly the elderly. Topical therapies offer advantages over systemically administered medications, including the requirement of a lower total systemic daily dose for patients to achieve pain relief, site-specific drug delivery, and avoidance of first-pass metabolism, major drug interactions, infections, and systemic side effects. Several types of topical agents have been shown to be useful in the treatment of patients with chronic pain. Both capsaicin and topical diclofenac have been shown to be effective in the treatment of patients with chronic soft-tissue pain. In patients with hand and knee osteoarthritis (OA), the American College of Rheumatology generally recommends oral treatments (acetaminophen, oral nonsteroidal anti-inflammatory drugs [NSAIDs], tramadol, and intra-articular corticosteroids) and topical NSAIDs equally, favoring topical agents only for patients who have pre-existing gastrointestinal risk or are aged $ 75 years. Topical NSAIDs have been shown to provide relief superior to that of placebo and comparable to that of oral ibuprofen. Similarly, ketoprofen gel has been shown to be superior to placebo and similar to oral celecoxib in reducing pain in patients with knee OA. Different formulations of topical diclofenac (including the diclofenac hydroxyethyl pyrrolidine patch, diclofenac sodium gel, and diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide USP) have been shown to be superior to placebo and comparable to oral diclofenac in the treatment of patients with pain due to knee OA, with a lower incidence of gastrointestinal complaints than with the oral formulation. In patients with neuropathic pain, topical forms of both capsaicin and lidocaine have been shown to be useful in the treatment of postherpetic neuralgia and diabetic peripheral neuropathic pain. Lidocaine has also demonstrated efficacy in relieving patient pain due to complex regional pain syndrome and may be useful in the treatment of patients with neuropathic pain who have cancer, although clinical trial results have not been consistent. Data suggest that topical therapies may offer a safe, well-tolerated, and effective alternative to systemic therapies in the treatment of patients with chronic, localized musculoskeletal and neuropathic pain. Keywords: pain; analgesics; nonsteroidal anti-inflammatory drugs; NSAIDs; topical NSAIDs
Introduction
Correspondence: Steven Stanos, DO, 980 N. Michigan Ave., Suite 800, Chicago, IL 60611. Tel: 312-238-7809 Fax: 312-238-7801 E-mail: [email protected]
Chronic pain is increasingly prevalent, affecting . 25% of Americans (an estimated 76.5 million people)—more than all of the people affected by diabetes, heart disease, and cancer combined.1 Patient pain may be localized (such as that due to trauma, repetitive strain injury, or arthritis), or generalized (such as that due to fibromyalgia).2 In the last few decades, great strides have been made in understanding pain-signaling pathophysiology, allowing for an appreciation of the diversity of the body’s mechanisms that can modulate the pain signal peripherally and centrally.3 Such research
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Steven P. Stanos and Katherine E. Galluzzi
has led to the broad categorization of chronic pain states as nociceptive conditions (such as osteoarthritis [OA]), neuropathic conditions (eg, postherpetic neuralgia [PHN]), or a mix of both etiologies (such as fibromyalgia and lower back pain).4 Recognition of the etiology of the pain state by the physician is helpful in predicting which form of treatment will benefit the patient most,4 because although nociceptive and neuropathic pain signals are transmitted via the same nerve pathways, the different states process and resolve painful stimuli through different physiologic mechanisms.5 This may be the reason why patients with neuropathic pain often do not respond as well to conventional analgesic therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs).4 Although oral agents are the cornerstone of treatment for patients with chronic pain, their use may be limited in certain patients. Many patients are unable to tolerate oral pain agents due to advanced age (. 65 years), medical comorbidities, end-organ damage, adverse effects, or drug interactions.6,7 Moreover, tolerance and physical dependence can occur with chronic use of opioids.8,9 Topical therapies have a number of advantages compared with systemically administered medications, including achievement of pain relief in some patients at a lower total systemic daily dose, site-specific drug delivery, and avoidance of first-pass metabolism, major drug–drug interactions, and systemic side effects.10 Because topical agents exert their pharmacologic effects locally, the most common adverse events in patients with use of these drugs are cutaneous (ie, application site reactions, which are usually mild and reversible).3 For patients with localized pain, topical medications may be particularly appropriate.11 Therefore, knowledge about pain treatment options beyond the use of oral agents is important. We review the utility of topical therapies for patients with various chronic pain states, based on the data resulting from clinical trials.
Patient Chronic Pain States Appropriate for use of T opical Analgesics Musculoskeletal Pain
Chronic musculoskeletal pain comprises a spectrum of patient conditions including OA, rheumatoid arthritis, fibromyalgia, and spinal conditions (eg, disc degeneration or herniation) that can lead to low back pain. Population surveys have consistently shown that musculoskeletal pain, particularly back and joint pain, is the most frequently occurring type of chronic pain in patients.4 Although oral NSAIDs are highly effective and extensively used for treating patients with many types of musculoskeletal pain, 26
concerns about drug gastrointestinal (GI), renal, hepatic, and cardiovascular toxicities12–15 have focused attention on modes of therapy that could bypass these adverse effects. Several topical agents, particularly topical NSAIDs, have been shown to be effective in the treatment of patients with chronic musculoskeletal conditions, including low back pain and OA.16 Topically applied NSAIDs are well-suited for the treatment of patients with many OA conditions and other forms of musculoskeletal pain because the formulations may be able to penetrate patient muscle, synovium, and joint tissues proximal to and below the site of application.17 A systematic review and meta-analysis of topical NSAIDs for treating patients with chronic musculoskeletal pain showed that compared with topical salicylate and capsaicin, topical NSAIDs have been tested in more studies and in 4 times as many patients, and have demonstrated the lowest (best) number needed to treat (NNT; ie, the average number of patients who need to be treated for 1 patient to achieve pain relief).18
Soft-Tissue Pain Both capsaicin and topical diclofenac have been studied for the treatment of patients with soft-tissue pain. In one study, 130 patients experiencing chronic soft-tissue musculoskeletal pain were treated with a capsaicin 0.05% cream or placebo for 3 weeks.19 At the end of the study, the median pain sum score had decreased by 49% in the capsaicin-treated group compared with a 23% reduction in the placebo group (P , 0.001), showing that capsaicin cream is useful in treating patients with chronic soft-tissue pain.19 Zacher et al conducted an evidence-based review to examine the pharmacokinetic and pharmacodynamic profiles, as well as the safety and efficacy of diclofenac patches and gels in the treatment of patients with pain caused by soft-tissue rheumatic disorders and OA.20 Nineteen double-blind, randomized, controlled clinical studies were included, involving . 3000 patients. Most of these trials (16) were in patients who had chronic pain conditions.20 Across studies, topical diclofenac (gel, patch, and solution) was shown to be more effective than placebo and comparable to some other topical NSAIDs (indomethacin gel and plaster [or patch], ketoprofen gel, and piroxicam gel) and to some oral NSAIDs treatments (diclofenac, ibuprofen, and naproxen) in relieving patient pain.20 The review supported the effectiveness, safety, and tolerability of topical diclofenac, used for # 12 weeks, in treating patients with a variety of painful and inflammatory chronic pain conditions, including soft-tissue injuries.20
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Topical Therapies in Chronic Pain
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Osteoarthritis and Other Joint Pain International guidelines for the treatment of patients with OA currently recommend certain topical analgesics. The American College of Rheumatology (ACR) recommends the use of topical NSAIDs or topical capsaicin as options for the initial management of pain in patients with OA of the hand, and topical NSAIDs for patients with OA of the knee.21 Furthermore, the ACR strongly recommends the use of topical NSAIDs for patients with knee OA who do not have a satisfactory clinical response to full-dose acetaminophen, and for persons aged $ 75 years for whom treatment with NSAIDs is indicated.21 The ACR conditionally recommends topical rather than oral NSAID treatment for patients aged $ 75 years who have OA of the hand.21 Topical capsaicin is not recommended for the treatment of patients with knee OA.21 The ACR cautions that oral NSAIDs should not be used in patients with chronic kidney disease (CKD) Stage IV or V (estimated glomerular filtration rate [GFR] , 30 cc/min) and advises practitioners to consider the benefits and risks on an individual patient basis before deciding to use oral NSAIDs to treat patients with CKD Stage III (estimated GFR between 30 and 59 cc/min).21 In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has advised that topical NSAID therapy should be considered before oral NSAID therapy (including selective cyclooxygenase [COX]-2 inhibitors) or opioids for the treatment of adults with OA.22 Rubefacients (salicylates and nicotinic esters) are used to relieve patient pain due to various types of musculoskeletal conditions.18,23 The agents are thought to relieve patient pain in muscles, joints, and tendons through counterirritation mediated by increased blood flow to the site of application.18,23 A review of topical rubefacients containing salicylates showed that for patients with chronic pain conditions, such as OA, rubefacients appear to provide clinically relevant pain relief in only 1 of every 6 patients, over and above those who also responded to placebo.23 The authors of the review suggest that this degree of efficacy compares poorly with that of topical NSAID treatment, which has been shown to provide useful levels of pain relief in 1 of every 3 patients, over and above those patients who also responded to placebo.23 Many studies have been conducted to investigate the efficacy and safety of topical NSAID therapy in patients with OA. In a study of 50 patients with knee OA, a larger percentage of patients responded to treatment with ibuprofen 5% cream than to placebo (84% vs 40%; P , 0.0001). Response was defined as a decrease in pain score (on a 100-mm visual
analog scale [VAS]) of $ 18 mm or a $ 23% reduction from baseline. Also, patients treated with ibuprofen 5% cream achieved greater improvement on the Lequesne index (an OA pain functional measure) than those in the placebo group (27.5% vs 10.7%).24 The Lequesne index for patients with knee OA assesses pain, maximum distance walked, and activities of daily living on a 24-point scale, in which a score of , 5 indicates minor disability, and $ 14 denotes extremely severe disability.24 Topical ibuprofen cream (dose defined as 1.5 g/day for 1 knee) also showed analgesic efficacy equivalent to that of oral ibuprofen (1.2 g/day) during 12 months in a trial of 282 elderly patients with chronic knee pain, as determined by Western Ontario and McMaster Universities (WOMAC) global scores.25 Mean WOMAC global score changes from baseline at the 12-month follow-up were –0.5 in the oral NSAID group and 1.1 in the topical NSAID group, a nonsignificant difference.25 The WOMAC scores reflect patient pain, stiffness, and physical function measured by a multidimensional, self-administered health status instrument in patients with OA of the hip or knee.26 Lower scores on the WOMAC represent better health status.26 Ketoprofen gel, 100 mg, was compared with oral celecoxib 100 mg, and placebo in 397 patients with pain flare due to knee OA.27 After 6 weeks of therapy, the ketoprofen formulation was shown to be significantly superior to placebo and similar to celecoxib in patient pain reduction, as assessed by changes from baseline in WOMAC pain scores (P , 0.05 vs placebo for both ketoprofen gel and oral celecoxib).27 Topical diclofenac has been shown to produce analgesic and anti-inflammatory effects similar to those produced by oral dosage forms, with less potential for systemically mediated complications in patients with pain.16,20 The evidencebased review conducted by Zacher et al (discussed earlier in this article with respect to studies in patients with soft-tissue pain) showed that in studies in patients with knee OA, topical diclofenac was superior to placebo in relieving patient pain as measured by the Lequesne index, VAS, and WOMAC scores.20 Furthermore, treatment of patients with diclofenac sodium topical solution showed efficacy comparable to that of oral diclofenac, as measured by WOMAC scores.28 Diclofenac diethylamine 1.16% topical gel has been used extensively in Europe for . 25 years in the treatment of patients with OA of the knee and other painful, inflammatory conditions of the tendon, ligament, muscle, and joint.29 In a 3-week study involving 238 patients, diclofenac gel applied 4 times daily was shown to effectively relieve patient pain from OA of the knee.29 For the primary efficacy outcome―patient
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Steven P. Stanos and Katherine E. Galluzzi
diary assessment of daily pain on movement, averaged over days 1 to 14―treatment with diclofenac gel was significantly superior to placebo, with a difference of 4 mm on a 100-mm VAS (P = 0.02).29 The diclofenac hydroxyethylpyrrolidine (DHEP) patch (or plaster) has been studied extensively in the treatment of patients with pain due to OA. A study of 155 adult patients with OA of the knee showed that the diclofenac patch produced significantly greater pain relief than the placebo patch, as evaluated by both the Huskisson VAS (global spontaneous pain) and the Lequesne index, beginning with day 4 of therapy (P , 0.001 for both outcome measures).30 In addition, patients wearing the DHEP patch recorded significantly fewer night awakenings than patients wearing the placebo patch (P , 0.005).30 In a 2-week trial in 103 outpatients with pain due to knee OA, patients treated with the DHEP patch showed significantly greater improvement than those receiving placebo in Lequesne index scores (P , 0.01), spontaneous pain relief (P , 0.01), and physician (P , 0.01) and patient (P , 0.05) global assessments of efficacy of treatment.31 Diclofenac sodium topical solution (1.5% w/w with dimethyl sulfoxide USP [DMSO]) is indicated in the United States for the treatment of patients with OA of the knee.32 In a 12-week study of the treatment of 326 patients with knee OA, diclofenac sodium 1.5% topical solution was well tolerated and significantly more effective than a vehicle control solution in reducing patient pain (P , 0.005) and improving physical function (P , 0.005), stiffness (P , 0.01), and patient global status (P , 0.005).33 Similarly, another 12-week study in 775 patients with OA of the knee showed that treatment with diclofenac sodium 1.5% topical solution was well tolerated and effective, according to the following measured outcomes: treatment of pain evaluated on the WOMAC scale (P = 0.015 vs placebo; P = 0.009 vs vehicle), physical function evaluated on the WOMAC scale (P = 0.034 vs placebo; P = 0.026 vs vehicle), overall health (P , 0.0001 vs placebo; P = 0.016 vs vehicle), patient global assessments of the study knee (P = 0.016 vs placebo; P = 0.018 vs vehicle), and stiffness evaluated on the WOMAC scale (P = 0.035 vs vehicle).34 For all of these efficacy variables, patient treatment with diclofenac sodium 1.5% topical solution was comparable to treatment with oral diclofenac, with no significant differences observed between the treatment groups.34 In another treatment comparison of diclofenac sodium 1.5% topical solution and oral diclofenac in 622 patients with OA of the knee, no clinically significant difference was found between the therapies in patient pain relief, physical 28
function, stiffness, or patient global assessments.28 Patients in the topical treatment group showed improvements in measures of these variables of 36% to 44% over baseline values, and patients treated with oral diclofenac showed improvements of 42% to 49%;28 however, the incidence of GI adverse events was significantly higher in patients treated with oral diclofenac than with topical diclofenac (48% vs 35%; P = 0.0006).28 Furthermore, significantly greater mean changes from baseline were observed in patients treated with oral diclofenac compared with topical diclofenac sodium 1.5% solution in patient liver enzymes (P # 0.0004), hemoglobin (P # 0.0001), and creatinine (P = 0.003) levels, as well as creatinine clearance (P = 0.006).28 A review of studies in patients with OA of the knee showed that treatment with diclofenac sodium 1.5% topical solution provided analgesic efficacy equivalent to that of oral diclofenac.35 A treatment algorithm for patients with symptomatic OA is presented in Figure 1. A combination of pharmacologic therapy (including topical NSAIDs) and nonpharmacologic therapy (eg, exercise) is often warranted in the treatment of patients with OA, but basic education on the disease state should always precede treatment.36,37
Neuropathic Pain
In guidelines for the treatment of patients with neuropathic pain, the lidocaine 5% patch (or “topical plaster”) is recommended as first-line treatment, particularly in patients with postherpetic neuralgia (PHN) and allodynia (pain induced by a normally nonprovocative stimulus, such as light touch/pressure or mild temperatures) by the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group and the European Federation of Neurological Societies (EFNS); and as second-line treatment (after tricyclic antidepressants and calcium channel α2δ ligands) by the Canadian Pain Society.38 A study of 77 patients with 3 different chronic pain conditions, including painful diabetic neuropathy, PHN, or chronic low back pain, showed that 2 weeks of treatment with the lidocaine topical patch significantly reduced all pain measures assessed by the Neuropathic Pain Scale (NPS) composite score (P , 0.01).39 In addition, use of the patch was well tolerated by patients, with no serious systemic adverse events or drug reactions.39 A review of randomized, placebo-controlled, doubleblind studies of therapies for patients with neuropathic pain showed that topically applied low-concentration capsaicin relieved pain in patients with PHN, nerve injury pain, mixed neuropathic pain conditions, and diabetic neuropathy, with
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Figure 1. Treatment algorithm for symptomatic osteoarthritis.
Reprinted with permission of Informa UK Ltd. from Altman R. New guidelines for topical NSAIDs in the osteoarthritis treatment program. Curr Med Res Opin. 2010:26(12):2871–287637; permission conveyed through Copyright Clearance Center, Inc. Abbreviations: COX-2, cyclo-oxygenase-2; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2; PO, oral; PPI, proton pump inhibitor; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
a combined NNT of 6.7 (4.6–12) and number needed to harm (NNH; the average number of patients needed to be exposed to capsaicin in order to cause an adverse event in 1 patient) of 11.5 (8.1–19.8).40 It should be noted that although topical analgesic treatments are useful for some types of neuropathic pain, oral and intravenous anticonvulsants play a major therapeutic role in the management of patients with neuropathic pain. In particular, the new neuromodulators (eg, gabapentin and pregabalin) have ushered in a new era in the treatment of patients with neuropathic pain.41
Postherpetic Neuralgia The most frequent and debilitating sequelae of herpes zoster (ie, shingles) is PHN, the pain that can develop along cutaneous nerves of the patient after the lesions from the acute infectious rash stage have healed. Postherpetic neuralgia generally persists for approximately 30 days, but it may last longer.42,43 In some patients, particularly the elderly, PHN can last many months or years and result in not only considerable pain but also loss of independence and financial burdens.42 The chronic patient pain associated with PHN has been managed with an array of oral medications, including antidepressants, antiepileptic drugs, and opioids.44 However,
because PHN is especially common and severe in the elderly, and this patient population is particularly susceptible to the adverse effects of systemic drugs, topical analgesics are a valuable treatment option.44 Topical forms of both capsaicin and lidocaine have been shown to be therapeutically useful in this indication.45,46 (For a discussion of topical treatment of the initial, acute stage of herpes zoster infection, please see the article in this supplement, “Options in Topical Therapies in the Management of Acute Pain” by Bill McCarberg, MD, and Yvonne D’Arcy, CRNP.) The 8% capsaicin patch, a localized dermal delivery system that contains a synthetic equivalent of the compound found naturally in chili peppers, is indicated for the management of patients with neuropathic pain associated with PHN.47 In a study of 402 patients with PHN, a single 60-minute application of the 8% capsaicin patch produced significantly greater pain reduction, as measured by the Numeric Pain Rating Scale (NPRS), than the control patch (containing 0.04% capsaicin) at every time point evaluated (P , 0.05, weeks 1, 5, and 11; P , 0.01, weeks 3, 4, 6–8, 10, and 12; P , 0.001, weeks 2 and 9).48 In a similar study in 418 patients, a single 60-minute application of the 8% capsaicin patch resulted in significantly greater reductions
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Steven P. Stanos and Katherine E. Galluzzi
in NPRS scores than a similar application of the 0.04% capsaicin patch during weeks 2 to 8 of follow-up (32.0% vs 24.4%, respectively; P = 0.011).49 An extension of a 4-week trial in patients with PHN (N = 24) showed that the efficacy of the 8% capsaicin patch was maintained for # 48 weeks after the 4-week double-blind trial, based on NPRS results.50 During the extension phase, patients received up to 4 treatment applications, 6 to 12 weeks apart.50 Patient pain scores during weeks 2 through 12 were reduced by 33.8% in the capsaicin 8% group but increased by 4.9% in the control group.50 The lidocaine 5% patch is indicated in the United States for the treatment of patients with pain associated with PHN.51 The current IASP guidelines for the treatment of patients with neuropathic pain recommend the lidocaine 5% preparation as first-line therapy in patients with well-localized PHN and allodynia, and in patients with allodynia due to different types of peripheral neuropathic pain.38 The lidocaine topical patch was compared with a placebo patch in a 28-day crossover study of 32 patients with PHN.52 The median time to exiting the treatment period (the need to discontinue treatment because of a prespecified extent of deterioration in pain relief score compared with prestudy baseline [ie, a reduction of $ 2 categories on a 6-item pain-relief scale for any 2 consecutive days]) was . 14 days for the lidocaine 5% patch, compared with 3.8 days for placebo (P , 0.001).52 Additionally, 78% of subjects preferred the lidocaine 5% patch (P , 0.001).52 Overall, a review of short-term and long-term studies found the lidocaine patch 5% to be well tolerated and consistently effective in the treatment of patients with PHN.53 However, a Cochrane Database systematic review concluded that there is insufficient evidence to recommend topical lidocaine as a first-line agent in the treatment of patients with PHN with allodynia because of the lack of data comparing topical lidocaine treatment with other medications currently used for the treatment of PHN.54
Complex Regional Pain Syndrome Complex regional pain syndrome (CRPS) is a chronic pain condition believed to be caused by central or peripheral nervous system dysfunction.55 Type 2 CRPS is associated with an underlying nerve injury (formerly described as causalgia). Type I CRPS is not associated with an underlying nerve injury and is primarily due to localized crush injury or tissue trauma.55 There is little evidence of efficacy of any oral or topical medications in relieving patient pain from CRPS. However, some case series and case report data suggest that topical lidocaine may be effective in relieving patient 30
pain due to type 2 CRPS. In 1 report, a patient with type 2 CRPS was successfully treated with a lumbar epidural opioid infusion and the lidocaine 5% patch, supporting the theory that application of local anesthetics to sites along the patient’s peripheral nervous system (and into the epidural space) early in the course of type 2 CRPS may “shut down” the process by which the disorder establishes itself.56 Further evidence came from a study of 20 patients with neuropathic pain (postoperative neuropathic pain, type 2 CRPS, or PHN) that was refractory to treatment with antidepressants, anticonvulsants, or opioids.57 Patients were treated with the lidocaine 5% patch for # 5 years.57 Treatment with the lidocaine patch was well tolerated and provided sustained pain relief during long-term treatment; similar levels of analgesic efficacy were reported for 10 of the 20 initial responders at follow-up at 3 years, and for 8 patients at follow-up at 5 years.57
Painful Peripheral Neuropathy Associated With Diabetes Also known as diabetic peripheral neuropathic pain (DPNP), peripheral neuropathy in patients with diabetes continues to remain an issue for individuals with poorly controlled diabetes. Based on evidence from clinical trials and the committee’s clinical experience, the Diabetic Peripheral Neuropathic Pain Consensus Treatment Guidelines Advisory Board recommends use of capsaicin and the lidocaine 5% patch as appropriate second-line agents for the treatment of patients with DPNP.58 Capsaicin has been used with some success in the treatment of patients with diabetic neuropathic pain; it should be used only for patients with localized discomfort rather than patients with generalized pain.59
Pain In The Cancer And Palliative Care Setting
The complexity of neuropathic pain in patients with cancer presents treating physicians with many therapeutic challenges. 60 The National Comprehensive Cancer Network 2008 Adult Cancer Pain Guidelines generally recommend opioids for the treatment of cancer pain.61 To complement management, they recommend considering an adjuvant therapy with the lidocaine 5% patch for peripheral neuropathic pain following trials of anticonvulsants and/or antidepressants.61 This topical form of treatment has been shown to have variable effectiveness in different studies. A retrospective audit of 97 patients with cancer and neuropathic pain (including postsurgical pain and PHN) who had their pain successfully managed with the lidocaine
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Topical Therapies in Chronic Pain
5% patch showed that both patients and physicians liked the lidocaine patch, owing to a low incidence of adverse events and because the patch provided clear benefit in approximately 25% of patients.60 Patients with allodynia,62 which was a significant feature of neuropathic pain in at least 60% of patients, appeared to respond well to the lidocaine patch.60 However, in a double-blind placebo-controlled crossover study consisting of 2 4-week treatment phases, the lidocaine 5% patch did not significantly reduce pain intensity in 28 patients with cancer and persistent postsurgical incisional pain.63 Relief of chronic pain is one of the main goals of palliative care.64 According to the International Association for Hospice and Palliative Care, the treatment of chronic pain in palliative care should be an integrated part of the interdisciplinary plan of total care, including the management of psychosocial issues.65 The form of treatment should employ the appropriate modality or modalities, and be appropriate to the stage of the patient’s disease.65 The health care provider should strive to provide consistent treatment, avoiding repeated changes of analgesics.65 Additionally, treatment in this setting requires continuity of care and repeated reassessment.65 Box 1 outlines the potential role of topical analgesics in pain management for patients in the palliative care setting.
Conclusion
Although an ever-expanding understanding of the pathophysiology of pain has led to the development of an array of treatment options, chronic pain often remains difficult to treat because of a lack of patient response or intolerance to available therapies. When effective, topical therapies offer a potentially better-tolerated alternative to systemically administered medications, which carry risks of organ toxicity, tolerance, and drug–drug interaction. In patients with chronic musculoskeletal pain, including OA, topical NSAIDs have been shown to be the most effective form of topical therapy, providing greater pain relief than alternatives, such as lidocaine, capsaicin, and rubefacients. In various types of neuropathic pain, including PHN, CRPS, and DPNP, topical formulations of lidocaine and capsaicin have proven to be effective treatment. In particular, topical lidocaine is recommended for first-line treatment of neuropathic pain in patients with PHN and allodynia by the IASP Neuropathic Pain Special Interest Group and the EFNS. Therefore, for patients who cannot or choose not to take systemic therapies for chronic pain, well-chosen topical therapies offer a safe,
BOX 1 Use of T opical Analgesics in Palliative Care • Topical analgesics may be advantageous in the palliative care setting because of their non-oral route of delivery and the fact that they exert their therapeutic effects without significant systemic absorption, avoiding the interactions and toxicities characteristic of systemically delivered agents (both oral and intranasal), such as opioid-induced constipation.66,67 • Special issues that increase the risk of adverse reactions from oral drugs in patients receiving palliative care, many of whom are elderly (. 65 years), include the following: Elderly patients are likely to have age-related changes in pharmacokinetic parameters, such as reduced renal excretion and hepatic metabolism, which increase sensitivity to certain oral analgesics, particularly opioids.7 Elderly patients may be taking multiple medications, increasing the risk of drug–drug interactions.7 Patients in the hospice or palliative care setting may be unable to swallow or tolerate oral medications due to their disease state or side effects of treatments used to manage their disease (eg, chemotherapy-induced emesis).67–69
well-tolerated, and effective alternative. The use of topical medications along with oral agents may also offer patients synergistic analgesic effects as part of a polypharmacy approach to managing chronic musculoskeletal and neuropathic pain.
Acknowledgments
Technical editorial and medical writing support for the preparation of this manuscript was provided by Julia Schroeder and Synchrony Medical Communications, LLC, West Chester, PA. Funding for this support was provided by Mallinckrodt Inc., the Pharmaceuticals business of Covidien, Hazelwood, MO.
Conflict of Interest Statement
Steven P. Stanos, MD, discloses the following relationships: Covidien (consultant); Eli Lilly and Company (speakers bureau, consultant); Endo Pharmaceuticals (speakers bureau, consultant); Forest Pharmaceuticals, Inc. (speakers bureau); GlaxoSmithKline (consultant); King Pharmaceuticals, Inc. (speakers bureau, consultant); Ortho-McNeil-Janssen Pharmaceuticals, Inc. (speakers bureau, consultant); Pfizer Inc (speakers bureau, consultant, research grants); and Purdue Pharma L.P. (consultant). Katherine E. Galluzzi, DO, discloses the following relationships: PriMed (speakers bureau); California Academy of Family Physicians (speakers bureau); and University of North Texas Health Science Center (speakers bureau).
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References
1. American Pain Foundation. Pain facts and figures. http://www. painfoundation.org/media/resources/ pain-facts-figures.html. Accessed March 8, 2012. 2. Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat Rev Rheumatol. 2010;6(10):599–606. 3. Sawynok J. Topical and peripherally acting analgesics. Pharmacol Rev. 2003;55(1):1–20. 4. Croft P, Blyth FM, van der Windt D, eds. Chronic Pain Epidemiology. From Aetiology to Public Health. Oxford, England: Oxford University Press; 2010. 5. Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc. 2007;107(10 suppl 6):ES39–ES48. 6. Barkin RL, Beckerman M, Blum SL, Clark FM, Koh E, Wu DS. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging. 2010;27(10):775–789. 7. Cavalieri TA. Managing pain in geriatric patients. J Am Osteopath Assoc. 2007;107(6; suppl 4):ES10–ES16. 8. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician. 2005;71(5):913–918. 9. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med. 2008;9(4):444–459. 10. Moody ML. Topical medications in the treatment of pain. Pain Med News. 2010;Dec:15–31. 11. McCarberg B, D’Arcy Y. Target pain with topical peripheral analgesics. Nurse Pract. 2007;32(7):44–49. 12. Vardeny O, Solomon SD. Cyclooxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, and cardiovascular risk. Cardiol Clin. 2008;26(4):589–601. 13. Borer JS, Simon LS. Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: achieving a balance. Arthritis Res Ther. 2005;7(suppl 4):S14–S22. 14. Harirforoosh S, Jamali F. Renal adverse effects of nonsteroidal antiinflammatory drugs. Expert Opin Drug Saf. 2009;8(6):669–681. 15. Björnsson E. Review article: drug-induced liver injury in clinical practice. Aliment Pharmacol Ther. 2010;32(1):3–13. 16. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med. 2010;11(4):535–549. 17. Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs. 2000;60(3): 555–574. 18. Mason L, Moore RA, Edwards JE, McQuay HJ, Derry S, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ. 2004; 328(7446):995. 19. Chrubasik S, Weiser T, Beime B. Effectiveness and safety of topical capsaicin cream in the treatment of chronic soft tissue pain. Phytother Res. 2010;24(12):1877–1885. 20. Zacher J, Altman R, Bellamy N, et al. Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr Med Res Opin. 2008;24(4):925–950. 21. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip and knee. Arthritis Care Res. 2012;64(4):465–474. 22. National Institute for Health and Clinical Excellence. Osteoarthritis: The Care and Management of Osteoarthritis in Adults. NICE clinical guideline 59. London, United Kingdom: National Institute for Health and Clinical Excellence; 2008. 23. Matthews P, Derry S, Moore RA, McQuay HJ. Topical rubefacients for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;(3):CD007403.
32
24. 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. 25. 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(7636):138–142. 26. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988; 15(12):1833–1840. 27. Rother M, Lavins BJ, Kneer W, Lehnhardt K, Seidel EJ, Mazgareanu S. Efficacy and safety of epicutaneous ketoprofen in Transfersome (lDEA033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial. Ann Rheum Dis. 2007; 66(9):1178–1183. 28. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution (Pennsaid®) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol. 2004;31(10):2002–2012. 29. Niethard FU, Gold MS, Solomon GS, et al. Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee. J Rheumatol. 2005;32(12):2384–2392. 30. Dreiser RL, Tisne-Camus M. DHEP plasters as a topical treatment of knee osteoarthritis—a double-blind placebo-controlled study. Drugs Exp Clin Res. 1993;19(3):117–123. 31. Brühlmann P, Michel BA. Topical diclofenac patch in patients with knee osteoarthritis: a randomized, double-blind, controlled clinical trial. Clin Exp Rheumatol. 2003;21(2):193–198. 32. Pennsaid [package insert]. Hazelwood, MO: Mallinckrodt Brand Pharmaceuticals, Inc; 2010. 33. Roth SH, Shainhouse Z. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee. A randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164(18):2017–2023. 34. Simon LS, Grierson LM, Naseer Z, Bookman AA, Shainhouse JZ. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143(3):238–245. 35. Ozgüney I. An alternative topical treatment of osteoarthritis of the knee with cutaneous diclofenac solution. Expert Opin Pharmacother. 2008;9(10):1805–1816. 36. Argoff CE, Gloth FM. Topical nonsteroidal anti-inflammatory drugs for management of osteoarthritis in long-term care patients. Ther Clin Risk Manag. 2011;7:393–399. 37. Altman R. New guidelines for topical NSAIDs in the osteoarthritis treatment program. Curr Med Res Opin. 2010:26(12):2871–2876. 38. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009,122(10 suppl):S22–S32. 39. Argoff CE, Galer BS, Jensen MP, Oleka N, Gammaitoni AR. Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the Neuropathic Pain Scale. Curr Med Res Opin. 2004;20(suppl 2):S21–S28. 40. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118(3):289–305. 41. Berger JM, Zaghi S. Nonopioid analgesics in pain management. In: Vadivelu N, Urman RD, Hines RL, eds. Essentials of Pain Management. New York, NY: Springer; 2011:117–150. 42. Johnson RW. Zoster-associated pain: what is known, who is at risk and how can it be managed? Herpes. 2007;14(suppl 2):30–34. 43. Yawn BP, Saddier P, Wollan PC, St. Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341–1349.
© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]
Downloaded by [Emory University] at 10:06 24 February 2016
Topical Therapies in Chronic Pain 44. Pappagallo M, Haldey EJ. Pharmacological management of postherpetic neuralgia. CNS Drugs. 2003;17(11):771–780. 45. Edelsberg JS, Lord C, Oster G. Systemic review and meta-analysis of efficacy, safety, and tolerability data from randomized controlled trials of drugs used to treat postherpetic neuralgia. Ann Pharmacother. 2011;45(12):1483–1490. 46. Argoff CE. Review of current guidelines on the care of postherpetic neuralgia. Postgrad Med. 2011;123(5):134–142. 47. Qutenza [package insert]. San Mateo, CA: NeurogesX, Inc; 2009. 48. Backonja M, Wallace MS, Blonsky ER, et al; NGX-4010 C116 Study Group. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol. 2008;7(12):1106–1112. 49. Irving GA, Backonja MM, 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(1):99–109. 50. Backonja MM, Malan TP, Vanhove GF, Tobias JK; 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(4):600–608. 51. Lidoderm [package insert]. Chadds Ford, PA: Endo Pharmaceuticals; 2010. 52. 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. 53. Garnock-Jones KP, Keating GM. Lidocaine 5% medicated plaster: a review of its use in postherpetic neuralgia. Drugs. 2009;69 (15):2149–2165. 54. Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev. 2007;(2):CD004846. 55. United States National Institutes of Health, National Institute of Neurological Disorders and Stroke. Complex regional pain syndrome fact sheet, NINDS. NIH Publication No. 04–4173. Published November 2003. Updated April 12, 2011. http://www.ninds.nih.gov/disorders/ reflex_sympathetic_dystrophy/detail_reflex_sympathetic_dystrophy. htm. Accessed March 13, 2012. 56. Vorobeychik Y, Giampetro DM. Topical lidocaine and epidural bupivacaine/hydromorphone in the treatment of complex regional pain syndrome type 2. Pain Physician. 2007;10(3):513–514.
57. Wilhelm IR, Tzabazis A, Likar R, Sittl R, Griessinger N. Long-term treatment of neuropathic pain with a 5% lidocaine medicated plaster. Eur J Anaesthesiol. 2010;27(2):169–173. 58. Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(4 suppl):S12–S25. 59. Boulton AJM. Management of diabetic peripheral neuropathy. Clin Diabetes. 2005;23(1):9–15. 60. 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. 61. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Adult Cancer Pain. Version 2.2011. http://www.nccn.org/. Accessed March 13, 2012. 62. Fu X, Froicu D, Sinatra R. Anatomic and physiologic principles of pain. In: Vadivelu N, Urman RD, Hines RL, eds. Essentials of Pain Management. New York, NY: Springer; 2011:31–44. 63. Cheville AL, Sloan JA, Northfelt DW, et al. Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB). Support Care Cancer. 2009;17(4):451–460. 64. Davies E, Higginson IJ, eds. World Health Organization. Better palliative care for older people. 2004. http://www.euro.who.int/__data/assets/ pdf_file/0009/98235/E82933.pdf. Accessed March 13, 2012. 65. Doyle D, Woodruff R; The International Association for Hospice and Palliative Care. The IAHPC Manual of Palliative Care, 2nd ed. Houston, TX; IAHPC Press; 2008. http://www.hospicecare.com/manual/tocmain.html. Accessed March 13, 2012. 66. Argoff C. Topical local anesthetics. In: McCleane G, Smith H, Smith H, eds. Clinical Management of the Elderly Patient in Pain. Binghamton, NY: The Haworth Press, Inc; 2006;75–89. 67. Hicks F, Rees E. A ‘pain-free’ death. Br Med Bull. 2008;88(1):23–41. 68. Vadivelu N, Hines RL. Management of chronic pain in the elderly: focus on transdermal buprenorphine. Clin Interv Aging. 2008;3(3): 421–430. 69. Jakobsen JN, Herrstedt J. Prevention of chemotherapy-induced nausea and vomiting in elderly cancer patients. Crit Rev Oncol/Hematol. 2009;71(3):214–221.
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