In contrast to the use of a systemic analgesic, use of a topical analgesic may result in relief of pain without the requirement for notable systemic absorption. A topical analgesic is not a transdermal analgesic. For example, the mechanism of action of transdermal nitroglycerin or fentanyl and clonidine patches is systemic, which requires systemic absorption through the skin, as well as a systemic concentration of the specific drug. A topical analgesic requires neither systemic absorption nor a significant systemic concentration to be clinically effective. A topical analgesic is an analgesic that is applied locally and directly to the painful areas, with the primary site of action being local to the site of application. As noted previously, it is not a “transdermal analgesic,” which unlike a topical analgesic, requires a systemic analgesic concentration for its analgesic action. This is not a trivial distinction; analgesics have been inappropriately considered “topical” agents even when formal pharmacologic studies to demonstrate a lack of systemic activity or systemic drug concentration (or both) had not been completed, and at other times, true topical agents have been incorrectly described as transdermal agents. As discussed in this chapter, topical analgesics have been studied and are used for acute pain, as well as for a variety of types of chronic neuropathic and non-neuropathic pain. Different topical analgesics are associated with different mechanisms of action, a point to be considered when choosing a topical analgesic for a patient with chronic pain. Of great interest is the recent observation (described in greater detail later in this chapter) that although a topical analgesic’s primary mechanism of action may occur locally and within the peripheral nervous system (PNS), the effect of a topical analgesic can be detected in the central nervous system (CNS) by functional neuroimaging.
Background
Undoubtedly, pain cannot be ultimately experienced in the absence of relevant brain activity; however, we have also appreciated for many years the importance of PNS activity, including provision of input to the CNS, in initiating and maintaining acute and some chronic painful conditions. There are specific painful conditions, such as central post-stroke pain and spinal cord injury pain, in which the pain mechanisms lie within the CNS and do not respond to topical analgesics. Many common chronic pain syndromes, including post-herpetic neuralgia (PHN), chronic low back pain (CLBP), and osteoarthritis (OA), probably result from mechanisms involving both the PNS and CNS.
If pain cannot be experienced without brain activation, how can a topical analgesic whose primary mechanism of action is largely within the PNS be helpful? A topical analgesic may interrupt, depending on the specific analgesic, certain mechanisms of pain transmission and by doing so may actually lead to a reduction in central pain mechanisms and thus pain as well. In other words, acknowledging that the experience of pain cannot occur without the brain, less pain may be experienced if use of a topical analgesic leads to reduced activation of PNS mechanisms, which if activated would facilitate transmission of pain signals to the CNS for central processing. This chapter reviews the use of topical analgesics for the treatment of various painful conditions and provides an update of previously published similar reviews.
The potential clinical benefit of any analgesic—or for that matter any medical treatment—is diminished by its adverse effect profile, toxicities, and drug-drug interactions. When considering the use of a topical analgesic, the risk for and severity of significant adverse effects and drug-drug interactions are often less than those for the same analgesic administered systemically. Consider, for example, the treatment of OA with a nonsteroidal anti-inflammatory drug (NSAID). If one can successfully treat someone with a topical NSAID versus a systemic NSAID, this may be helpful in reducing the risk for systemic side effects typically associated with NSAIDs. Rash and unpleasant skin sensations may occur with the use of a topical analgesic, but neither is typically experienced. Among the topical analgesics currently approved by the Food and Drug Administration (FDA) (see Box 42.1 ), the 5% lidocaine patch (Lidoderm) has been studied widely. Several studies of the 5% lidocaine patch have been designed to evaluate its safety and tolerability. For example, the outcome of one study assessing the tolerability and safety of 24-hr/day use of four 5% lidocaine patches demonstrated that there were no significant systemic side effects and that plasma lidocaine levels remained below those known to be associated with cardiac abnormalities. In this study, the safety and tolerability were similar if the subject used the patch for 12 or for 24 hr/day. In a multicenter open-label study, patients with a history of CLBP from a variety of causes were treated safely with four 5% lidocaine patches every 24 hours for extended periods. In each of these reports, no significant dermal reactions were experienced.
Lidocaine
Lidocaine/prilocaine
Diclofenac
Doxepin
Capsaicin
Dermal sensitivity is a potential side effect of all topical analgesics; however, other adverse effects may be experienced as a result of the use of a specific topical analgesic that may be more related to the specific medication in the specific topical analgesic. An example is capsaicin. After the topical application of capsaicin, severe burning at the site of application commonly occurs. This particular side effect may in fact not infrequently lead to reduced clinical effectiveness of this specific topical analgesic. Capsaicin, when applied topically in its currently available forms, does not result in significant systemic accumulation or in any life- threatening outcomes, and the incidence of burning may decrease with repeated use; however, frequent occurrence of this side effect may negatively affect treatment adherence and consequently the patient’s ability to benefit from its use. The 8% capsaicin patch (Qutenza), approved by the FDA for the treatment of PHN, was generally well tolerated in clinical trials even though burning did occur. In contrast to over-the-counter preparations of capsaicin that may need to be applied multiple times daily, the 8% capsaicin patch is applied for a single hour and may result in effective outcomes for 12 weeks or longer.
It is generally acknowledged that a patient being treated for chronic pain may also have other medical comorbid conditions that would be treated with pharmacologic therapies as well. Recognizing that drug-drug interactions are minimized with topical analgesics may be clinically relevant when managing a patient who has been prescribed systemic medications concurrently for comorbid medical conditions. Recently published guidelines regarding the pharmacologic management of persistent pain in older adults emphasize this point in their recommendations. A clinical example would be a 79-year-old woman being treated for hyperlipidemia, hypertension, coronary artery disease, and type 2 diabetes mellitus and OA. She requires analgesics for the chronic pain associated with her OA and is already taking four oral systemic medications on a daily basis for the other chronic medical conditions A trial of the use of a topical medication for her may offer several advantages over a systemic medication because of reduced drug-drug interactions, assuming that she achieves adequate pain relief. Since the topical analgesics available typically do not involve dose titration and many systemic agents do, this may provide an additional potential benefit for a patient.
The prescriber must recognize the difference between topical analgesics that are prescribed as commercially available, FDA-approved agents and those that are touted as “topical” agents by various compounding pharmacies but in fact have not been proved to be such following appropriate testing. Commercially available FDA-approved topical analgesics must have demonstrated to the FDA consistent manufacturing standards and quality control, in contrast to those manufactured and sold by a specialized compounding pharmacy. The reader should keep in mind that the so-called topical analgesics that may be made by a compounding pharmacy may consist of a combination of substances, such as a local anesthetic, NSAID, and antidepressant combined together in a chemical base, that are not commercially available, FDA-approved topical products. There is no current general requirement for compounding pharmacies to demonstrate manufacturing consistency, and this is an important point for a prescriber to recognize. Even though for many compounding pharmacies there is no documentation of quality control or preparation consistency such as would be required for an FDA-approved product, these products are commonly prescribed. In a survey of members of the American Society of Regional Anesthesia and Pain Medicine, 27% of the respondents reported prescribing such an agent, and 47% of the respondents noted a positive impression suggesting that they thought that patients responded well to the preparation. Of interest is continued commercial development of new topical analgesic preparations. Recently, three topical NSAIDs and the 8% capsaicin preparation have been approved by the FDA. Topical preparations containing opioids, local anesthetics, antidepressants, glutamate receptor antagonists, α-adrenergic receptor agonists, adenosine, cannabinoids, cholinergic receptor agonists, gabapentinoids, prostanoids, bradykinin, adenosine triphosphate, biogenic amines, and nerve growth factor are each at various stages of clinical development.
As one would expect for an oral systemic analgesic, the mechanism of action of a specific topical analgesic depends on the chemical entity or entities in the specific agent, and this may be considered when choosing a particular agent for a patient. The mechanism of action of the topical agent capsaicin, for example, appears to be through agonist activity at the transient receptor potential vanilloid 1 (TRPV1) on Aδ and C fibers. As a result of this activity at the TRPV1 receptor, release of substance P and calcitonin gene-related peptide takes place, and it is hypothesized that reduced peripheral as well as central excitability with resulting less pain through reduced afferent input occurs because of the depletion of substance P in C fibers associated with the application of topical capsaicin. The results of both human nerve biopsy and animal studies demonstrate nerve fiber degeneration in the skin underneath the site of capsaicin application. Such nerve fiber degeneration associated with the application of capsaicin has been suggested to be one of the mechanisms through which its use results in pain relief. The mechanism of action of a topical NSAID, in contrast to capsaicin, is probably associated with inhibition of prostaglandin synthesis and the resulting anti-inflammatory effect. Keeping in mind that the extent of anti-inflammatory effect is not consistently proportional to the pain relief experienced, perhaps other mechanisms of action might be considered. It may be worthwhile to consider the potential benefit of an agent with more than one mechanism of action. For example, the antinociceptive effects of topical morphine may be enhanced by a topical cannabinoid as demonstrated in a study in rats in which the radiant tail flick test was used. Local anesthetic agents are known to suppress the activity of peripheral sodium channels within sensory afferents and subsequent pain transmission; however, other mechanisms of action are under investigation. It has been noted that decreased expression of mRNA for specific sodium channel subtypes may occur following local anesthetic use. Several local anesthetic-containing topical analgesics are currently available commercially, including the 5% lidocaine patch, EMLA cream (eutectic mixture of local anesthetics, 2.5% lidocaine/2.5% prilocaine), and the Synera patch (lidocaine, 70 mg/tetracaine, 70 mg). Of these three agents, only the 5% lidocaine patch is associated with an analgesic effect without creating anesthetic skin, whereas use of EMLA cream or the FDA-approved Synera patch may create both analgesia and anesthesia. This difference among the preparations is useful to apply in specific clinical settings, such as venipuncture, lumbar puncture, intramuscular injections, and circumcision, for which creating both anesthesia and analgesia would be helpful. Choosing which topical analgesic to use clearly depends on the clinical setting in which the medication is being used. At least for the 5% lidocaine patch, it has been noted that application of the patch itself, by protecting allodynic skin from being stimulated, may reduce the allodynia experienced by those afflicted by neuropathic pain states such as PHN.
One novel area of topical analgesic development involves the use of tricyclic antidepressants as topical analgesics. Certain tricyclic antidepressants such as amitriptyline and doxepin have been demonstrated to block sodium channels, and the potential clinical benefit of this mechanism when such an agent is topically applied is being actively investigated at this time. One commercially available topical antidepressant, doxepin hydrochloride (Zonalon) cream, is currently approved by the FDA for the short-term treatment of adult patients with pruritus associated with atopic dermatitis or lichen simplex chronicus. Of interest have been reports of use of this agent in an “off-label” manner as a topical analgesic. Other topical agents, including topical opioids, glutamate receptor antagonists, and cannabinoids, have potential as topical analgesics as well. Certain studies of some of these agents are discussed in the following sections.
Use of Topical Analgesics for Specific Clinical Conditions (See Box 42.2 )
Neuropathic Pain
The use of specific topical analgesics for the management of neuropathic pain has been established by a number of clinical trials, and more than one published review of the management of neuropathic pain has emphasized their efficacy.
Neuropathic pain (various syndromes)
Musculoskeletal pain (acute and chronic)
Soft tissue pain (acute and chronic)
Other pain (dressing changes, cancer treatment related)
Local Anesthetics
The first medication to receive FDA approval for the treatment of PHN was in fact the 5% lidocaine patch. The clinical trials that led to the FDA approval of this preparation for the management of PHN demonstrated that when compared with patients treated with placebo patches, patients who were treated with 5% lidocaine patches experienced statistically significantly more pain reduction in a safe and well-tolerated manner. A phase IV open-label study involving PHN patients was completed to evaluate whether treatment of PHN with the 5% lidocaine patch affected various quality-of-life measures. A study of 332 patients with PHN used the Brief Pain Inventory (BPI), a validated pain assessment tool. During the study period, enrolled patients were able to use up to three 5% lidocaine patches 12 hours each day, and the BPI was completed daily for 4 weeks. Sixty-one percent (204/332) of the subjects enrolled noted decreased pain intensity by the end of the first week of the study. A reduction in pain intensity was noted by the second week of patch use in more than 40% of the 128 subjects who had not experienced pain relief by the end of the first week of the study. Overall, 70% of enrolled patients experienced improvement by the study’s conclusion. In another open-label study, treatment with the 5% lidocaine patch was compared with treatment with pregabalin (Lyrica) for PHN. The study results demonstrated that the 5% lidocaine patch was at least as effective as pregabalin for pain relief in PHN patients. Among the study’s most interesting results was that for patients who had not responded to either the 5% lidocaine patch or pregabalin alone, using these agents in combination resulted in greater benefit, and the combination was well tolerated by these patients. This observation is particularly important to note when managing patients with PHN.
In addition to PHN, use of the 5% lidocaine patch for the management of other neuropathic pain states has been evaluated in various studies. A study conducted in Europe, a randomized, double-blind, placebo-controlled trial evaluated the analgesic efficacy of the 5% lidocaine patch for the treatment of “focal” neuropathic pain syndromes. The painful conditions included in the study were mononeuropathies, intercostal neuralgia, and ilioinguinal neuralgia. The results of this study demonstrated that adding the 5% lidocaine patch to other pharmacotherapeutic regimens could reduce ongoing pain and allodynia as quickly as within the first 8 hours following application in some patients, as well as in other patients over a period of 7 days. A smaller open-label study of 16 patients with various chronic neuropathic pain conditions (post-thoracotomy pain, complex regional pain syndrome, postamputation pain, painful diabetic neuropathy, meralgia paresthetica, postmastectomy pain, neuroma-related pain) demonstrated that the 5% lidocaine patch provided pain relief without significant side effects in 81% of these patients. It is worthy to note that according to the study’s authors, patients enrolled in this study, before use of the 5% lidocaine patch, had experienced suboptimal outcomes with numerous other agents commonly prescribed for the treatment of neuropathic pain. Several other noncontrolled studies of patients with painful diabetic neuropathy who were treated with the 5% lidocaine patch have been completed. These studies allowed patients to use as many as four 5% lidocaine patches for as long as 18 hr/day. Viewing these studies as a group, the majority of enrolled subjects reported pain reduction and good tolerability of this medication. An additional study, a 3-week single-center, open-label study of the 5% lidocaine patch in patients with painful idiopathic sensory polyneuropathy, noted significant improvements in both pain and quality-of-life measures.
In addition to measuring any changes in pain intensity or function (or both) in patients treated with the 5% lidocaine patch, changes in pain quality in patients with PHN have been studied as well. Changes in the quality of pain in patients with PHN treated with the 5% lidocaine patch versus placebo were evaluated in a multicenter, randomized, vehicle-controlled study of 150 PHN patients. Reduced intensity of certain neuropathic pain qualities according to the Neuropathic Pain Scale was more likely to occur in patients treated with the 5% lidocaine patch than in those given the placebo patch (up to three patches for 12 hours each day). Also of interest was that certain types of neuropathic pain (deep, sharp, and burning) that were reduced had previously been assumed to not be related to PNS but to CNS mechanisms. In their discussion of the study’s results, the authors proposed that given the localized primary PNS mechanism of action of the 5% lidocaine patch, peripheral mechanisms of neuropathic pain might also be important in the development of these neuropathic pain qualities. The results of a functional brain magnetic resonance imaging study of patients with PHN treated with the 5% lidocaine patch for various lengths of time demonstrated that the brain activity occurring with the spontaneous pain of PHN appeared to be modulated in a manner related to the length of application of this medication, thus suggesting again that a peripherally acting agent may have an impact on CNS pain mechanisms.
Another local anesthetic preparation that is currently commercially available is EMLA cream. Its FDA-approved indication is as a topical anesthetic for use on normal intact skin for analgesia, but it is not FDA-approved for any specific neuropathic pain disorder. Several studies of EMLA cream for the treatment of PHN have been completed, with mixed results. The results of a randomized, controlled study of PHN patients treated with EMLA cream or placebo cream did not demonstrate a significant difference in treatment outcome between the two groups. The results of two uncontrolled studies were more favorable and suggested that use of EMLA cream could relieve the pain associated with PHN.
Capsaicin
Even though there has been interest in using capsaicin for a number of neuropathic pain disorders such as diabetic neuropathy, painful human immunodeficiency virus (HIV)-related neuropathy, PHN, and postmastectomy pain, many of the older studies had yielded disappointing results, perhaps partly as a result of the weakness of past available strengths of capsaicin (0.025% and 0.075%), as well as poor toleration of the treatment, poor treatment adherence, and the resulting insufficient pain relief. However, in contrast, the results of a higher-strength capsaicin preparation demonstrated better analgesia. In one reported study of patients with painful HIV neuropathy treated with 7.5% topical capsaicin cream, the patients experienced notable pain relief, but to be able to tolerate this medication, concurrent treatment with epidural anesthesia was required. At the 2004 Annual Scientific Meeting of the American Academy of Neurology, two open-label studies, one involving patients with PHN and one involving patients with painful HIV-associated distal symmetrical polyneuropathy, reported notable pain relief in the majority of patients following the single application of a high-concentration (8%) capsaicin patch. The duration of pain relief lasted as long as 48 weeks (PHN). A review of the published randomized trials on the use of topical capsaicin for the treatment of either neuropathic or musculoskeletal pain syndromes concluded that “although topically applied capsaicin has moderate to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain, it may be useful as an adjunct or sole therapy for a small number of patients who are unresponsive to, or intolerant of, other treatments.” Recently, the 8% capsaicin patch (Qutenza) received FDA approval for the treatment of PHN. In studies leading to its FDA approval, it was shown to be more effective in reducing pain intensity than was an active, lower-concentration capsaicin product that served as placebo, and it was generally well tolerated. It has also been studied for other neuropathic pain states such as painful HIV neuropathy, with a favorable outcome as well.
The results of a novel study comparing the pain-reducing effect of a topical preparation containing 3.3% doxepin alone or a topical preparation containing 3.3% doxepin combined with 0.075% capsaicin versus placebo in patients with a variety of chronic neuropathic pain problems indicated that each treatment provided similar pain-reducing effects and that each was superior to placebo.
Other Agents
Interest in the use of topical tricyclic antidepressants for the treatment of neuropathic pain has resulted in multiple clinical trials, including the trial on topical doxepin described earlier. For several such trials, the topical preparation examined was a combination of 2% amitriptyline and 1% ketamine. One of these studies, a double-blind, randomized, placebo-controlled study involving 92 patients with diabetic neuropathy, PHN, or postsurgical or post-traumatic neuropathic pain, resulted in no difference in analgesic benefit among any of the four treatment groups (placebo, 2% amitriptyline alone, 1% ketamine alone, or a combination of 2% amitriptyline and 1% ketamine). The results of an open-label study completed by similar investigators involving 28 patients with neuropathic pain for 6 to 12 months treated with the combination topical analgesic 2% amitriptyline and 1% ketamine demonstrated that the average reduction in pain was 34%. Another open-label study by similar investigators using the same type of preparation also demonstrated encouraging results. Noncontrolled trials evaluating the use of topical ketamine, one in PHN patients and one in patients with complex regional pain syndrome type 1, each concluded that topical ketamine may be an effective topical analgesic; however, serum ketamine levels were not measured in either study, and thus it is not clear how truly “topical” the ketamine preparations were. There is one report suggesting that topical application of geranium oil may provide temporary relief of PHN.
Soft Tissue Injuries and Osteoarthritis
Common musculoskeletal pain conditions include soft tissue injuries and OA. Since 2007, the FDA has approved three topical NSAIDs, including 1% diclofenac sodium gel (1% Voltaren gel), the 1.3% diclofenac epolamine topical patch (Flector patch), and 1.5% diclofenac topical solution (Pennsaid). Each of these FDA-approved topical NSAIDs has different indications. Diclofenac sodium 1% gel (1% Voltaren gel) is FDA-approved for treating pain associated with OA in joints that can be managed with topical treatment, such as the knees and hands. The diclofenac epolamine topical patch (Flector patch) is FDA-approved for the topical treatment of acute pain from minor strains, sprains, and contusions. The diclofenac sodium topical solution (Pennsaid) is FDA-approved for treatment of the signs and symptoms of OA of the knee.
Nonsteroidal Anti-Inflammatory Drugs
The use of other topical NSAIDs has been studied most notably outside the United States. For example, a topical ketoprofen patch (100 mg) was found to be superior to placebo in reducing pain intensity following 7 days of treatment in a 2-week randomized, placebo-controlled study of 163 patients with pain from an ankle sprain. In a separate study, a comparable topical ketoprofen preparation was evaluated in patients with tendinitis in a randomized, double-blind, placebo-controlled study. Subjects treated with the active medication fared better than the placebo-treated group did, and except for the skin irritation experienced by some, the treatment was otherwise well tolerated. Ketoprofen gel has been reported to be helpful when used as an adjunct to physical therapy, with benefit reported in a child with Sever’s disease, a not uncommon source of heel pain in growing children. A randomized, controlled study of use of a diclofenac patch in 120 individuals experiencing acute pain after a “blunt” injury demonstrated that it was not only well tolerated but also reduced pain intensity greater than did placebo treatment. Treatment of acute sports injury-related pain with a diclofenac patch has also been studied. Two studies, one not controlled and the other a multicenter randomized, controlled study, noted that a diclofenac patch was found to be well tolerated and effective in patients with acute sports injuries. Patients experienced an average of 60% pain relief in the open-label study. Additional NSAIDs have also been studied, and in a noncontrolled study of patients described as experiencing “soft tissue pain,” the reported results indicated that topical flurbiprofen was associated with greater pain reduction than oral diclofenac was and that fewer adverse effects occurred when the topical preparation was used. This study is one of very few that actually compared a topical NSAID with an oral agent—an important study design for comparing not only efficacy but also adverse events. In another controlled study, use of topical ibuprofen cream for the management of acute ankle sprains was found to be superior to placebo in reducing pain. In a controlled study of ketoprofen gel for the management of acute soft tissue pain, it was found to be more effective than placebo in providing pain relief. A topical formulation of 5% ibuprofen gel was examined in a placebo-controlled study in patients with painful soft tissue injuries. Patients received either 5% ibuprofen gel or placebo gel for a maximum of 7 days. Pain intensity levels, as well as limitations in physical activity, were assessed daily. A significant reduction ( P < 0.001) in pain intensity plus improvement in physical activities was experienced by the patients who received the 5% ibuprofen gel versus placebo. A second study with similar patient types completed by the same investigators demonstrated similar results. Also of interest is a recent Cochrane database review in which it was concluded that topical NSAIDs can provide good levels of pain relief without the systemic adverse effects of oral NSAIDs in the treatment of acute musculoskeletal pain.
The use of topical analgesics for the treatment of OA has also been studied, and in fact, multiple reviews of this subject have recently been published. A diclofenac patch preparation, studied in a randomized, double-blind, controlled study in patients with chronic pain secondary to knee OA, demonstrated that this patch may be safe and effective for this common condition. A randomized controlled study comparing the use of a topical diclofenac solution and oral diclofenac for the treatment of OA of the knee concluded that use of the topical diclofenac solution produced relief of symptoms that was equivalent to that of oral diclofenac and resulted in a significantly reduced incidence of diclofenac-related gastrointestinal complaints. A recently published long-term study with the same topical diclofenac solution confirmed its safety during the study period. A study of individuals with pain in the temporomandibular joint compared treatment with diclofenac solution applied topically several times daily and treatment with oral diclofenac. Even though there was no significant difference in analgesic benefit between the two groups, significantly fewer gastrointestinal side effects were experienced by the patients receiving the diclofenac topical solution. Other completed topical NSAID trials include a placebo-controlled trial that demonstrated efficacy of 1.16% topical diclofenac gel in patients with OA of the knee and a randomized controlled study demonstrating benefit from the application of a topical diclofenac solution versus placebo after 6 weeks of treatment in patients with painful OA of the knee. One meta-analysis examining the use of topical NSAIDs for the treatment of OA found evidence suggesting that topical NSAIDs are more effective than placebo during the initial 2 weeks of treatment only. The authors concluded that the evidence available indicates that topical NSAIDs are inferior to oral NSAIDs during the first week of treatment. A separate meta-analysis reviewed the evidence for the use of topical NSAIDs for chronic musculoskeletal pain and concluded that topical NSAIDs are effective and safe in treating chronic musculoskeletal conditions for 2 weeks. Another meta-analysis on the use of topical NSAIDs for OA suggested that of the four studies that compared a topical NSAID with placebo or vehicle in patients with OA of the knee, pain relief did occur for a longer period with the topical NSAID than with placebo but that the results were not uniform for the preparations reviewed.
Health care professionals and especially prescribers must be aware of the fact that topical salicylates are used by patients in over-the-counter preparations. A meta-analysis reviewed the limited data available from trials of musculoskeletal and arthritic pain and concluded that topically applied rubefacients containing salicylates have moderate to poor efficacy in relieving acute and chronic pain. The authors emphasized that estimates of the efficacy of these rubefacients are currently unreliable because of a lack of appropriately designed clinical trials. A randomized controlled study completed in Europe with the topical NSAID eltenac examined its effect in comparison to placebo in 237 patients with knee OA and concluded that use of topical eltenac for the treatment of OA of the knee versus placebo is safe and effective. In an additional clinical trial, topical eltenac gel was compared with oral diclofenac and placebo in patients with knee OA. Each active treatment resulted in analgesia superior to that achieved with placebo, but as reported in the meta-analysis mentioned earlier, the incidence of gastrointestinal side effects was notably lower in the group treated with topical eltenac gel than in those treated with the oral NSAID diclofenac. Additional studies have demonstrated that topical diclofenac may be effective in reducing the pain associated with various types of degenerative joint disease.
Other topical agents have been studied for these musculoskeletal pain conditions as well. Capsaicin 0.025% cream was determined to be no better than the vehicle (not active) cream in a randomized, double-blind study of 30 patients with pain in the temporomandibular joint. A randomized controlled study of a topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for OA of the knee showed a significant reduction in pain in the treatment group after 8 weeks when compared with the placebo group.
Although a published case series reported the potential benefit of “topical” morphine in the management of chronic OA-related pain, this report emphasized that morphine or its metabolites, or both, were identifiable in the urine of treated patients, thus calling into question how truly “topical” this preparation was given its systemic effects.
Low Back and Myofascial Pain
Regrettably, substantially fewer studies examining the use of topical analgesics for low back pain or myofascial pain, two very common conditions, have been published. A randomized, double-blind, placebo-controlled study comparing the use of topical capsaicin with placebo in 154 patients with CLBP resulted in 60.8% of capsaicin-treated patients versus 42.1% of placebo patients experiencing 30% pain relief after 3 weeks of treatment ( P < 0.02). Unfortunately, additional studies have been published in abstract form only—two are novel (one will be mentioned) because they each involve the use of a local anesthetic for conditions not typically thought of as being responsive to this form of treatment. In one, a multicenter, open-label study involving 120 patients with acute (<6 weeks), subacute (<3 months), short-term chronic (3 to 12 months), or long-term chronic (>12 months) low back pain with four 5% lidocaine patches applied to the most painful areas in the low back region demonstrated that during the 6-week study period the majority of patients experienced moderate or a greater degree of pain relief.
Other Uses of Topical Analgesics
It is important to note other painful conditions in which topical analgesics have been used even if the number of patients studied in each study was relatively small. Various types of topical analgesics, including opiates, may be helpful in reducing the pain associated with pressure ulcers or dressing changes. Controlled studies have demonstrated the benefit of EMLA cream in reducing the pain associated with circumcision and venipuncture and, in addition, in reducing the pain associated with breast cancer surgery. At least two studies have suggested that either topical ketamine or topical morphine can be used for mucositis-associated pain following chemotherapy or radiation therapy in patients with head and neck carcinoma. Topical opiates have been reported to reduce pain in two children with epidermolysis bullosa. In one report, the analgesic effect of menthol, an ingredient common in many over-the-counter analgesic preparations, is hypothesized to be the result of activation of κ-opioid receptors. Burn pain has been reported to be treated effectively with a topical loperamide preparation. Two randomized controlled studies—one involving postoperative pain (diclofenac patch) and the other involving wound pain treatment (capsicum plaster topically applied at acupuncture sites)—have been published as well. Central neuropathic itch was treated successfully with the 5% lidocaine patch in a single case report. The results of an enriched enrollment study in which an open-label initial study led to the randomization of responders in a placebo-controlled study of the use of either 4% amitriptyline/2% ketamine cream, 2% amitriptyline/1% ketamine cream, or placebo in patients with PHN demonstrated that after 3 weeks of treatment the average daily pain intensity was lower in patients receiving the higher-concentration combination cream than in those receiving the lower concentration combination or placebo ( P = 0.026 for the high-concentration cream vs. placebo). Plasma levels of either drug were detected in less than 10% of the patients receiving active treatment. An open-label study of the use of a 0.25% capsaicin topical agent in a lidocaine-containing vehicle in 25 patients with painful diabetic polyneuropathy and 7 patients with PHN demonstrated pain relief in the majority of patients who were studied. In a noncontrolled study of 23 patients with acute migraine headache, 0.1% capsaicin gel applied topically was helpful in reducing mild or moderate pain. In a randomized, double-blind study assessing 154 patients with chronic pain from lateral epicondylitis, topical glyceryl trinitrate (0.72 mg/day) was found to provide statistically significantly greater pain relief after 8 weeks when compared with placebo. In a study of 52 patients with chronic pain secondary to chronic Achilles tendinopathy, patients who had been treated with topical glyceryl trinitrate for 6 months were more likely 3 years after treatment ended to have less pain and more function than those who had been treated with placebo. Published reports of the use of topical phenytoin for the treatment of pain from superficial burns or chronic leg ulcers are noted as well.
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