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The Future of Topical Analgesics Paul M. Arnstein To cite this article: Paul M. Arnstein (2013) The Future of Topical Analgesics, Postgraduate Medicine, 125:sup1, 34-41, DOI: 10.1080/00325481.2013.1110567211 To link to this article:

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The Future of Topical Analgesics

Paul M. Arnstein, PhD, RN, FAAN 1

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1 Clinical Nurse Specialist, Massachusetts General Hospital, Boston, MA

Abstract: Topically applied analgesic therapies have been used throughout history to treat a variety of patient conditions that present with pain. Before modern pharmaceuticals became readily available, mud-based emollients, salves, cold therapies, and other natural remedies were often used. Now we have effective therapies and are developing advanced topical analgesics as we learn more about the physiology and pathophysiology of pain. The use of topical analgesics may be associated with fewer patient systemic side effects than are seen with oral, parenteral, or transdermally administered agents, making the topical route of administration attractive to prescribers and patients. With further refinement of existing drugs and the development of novel agents, topical analgesics may offer relief for treating patient pain conditions that are currently challenging to treat, such as pain resulting from burns, wound debridement, and pressure ulcers. Recognizing the value of a multimodal approach, topical analgesics may offer a therapeutic option that can become part of a comprehensive treatment plan for the patient. With continued advancements in targeted drug-delivery systems, topical analgesics may be able to provide a method to prevent or reverse the phenomena of peripheral and central sensitization, or the neuroplastic changes believed to be responsible for the transition from acute to chronic pain states in patients. For those patients at risk for developing chronic pain states, such as complex regional pain syndrome, the combination of cutaneous stimulation (achieved through rubbing during application) and analgesic effects produced by the drug itself may prevent the disabling pain that often emerges during the subacute phase of disease. In summary, better utilization of currently available topical analgesics and continued research promise to ensure that topical analgesics are, and will continue to be, important tools in the treatment of patients with resistant pain. Keywords: pain; analgesics; nonsteroidal anti-inflammatory drugs; NSAIDs; topical NSAIDs


Correspondence: Paul M. Arnstein, RN, PhD, FAAN, Massachusetts General Hospital, GRB-1034, 55 Fruit St., Boston, MA 02114. Tel: 617–724–8517 Fax: 617–724–3754 E-mail: [email protected]


Throughout history, topical therapies have been used as analgesics. Before modern pharmaceuticals became readily available, mud-based emollients, salves, cold therapies, and other natural remedies were often used to treat patients. In addition, massaging and rubbing areas of discomfort have long been recognized as natural ways to alleviate patient pain.1,2 As discussed in the other articles that comprise this supplement, a number of topical therapies are currently available that provide an alternative delivery method for the management of localized patient pain and go beyond the benefits of older topical treatment modalities. Indeed, topical analgesics, such as the local anesthetics (eg, lidocaine), counterirritants (eg, methyl salicylate and capsaicin), and nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac, ketoprofen, and ibuprofen, have been studied and used to treat patients with a variety of painful conditions.3–8 Topical analgesics are viable alternatives to systemic agents, and enhanced skin

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Future of Topical Analgesics

penetration methods are being developed to further refine the safety and efficacy of topical formulations for treatment of an even wider range of pain indications. This article evaluates available topical analgesic formulations and reviews trends that may impact the development of emerging therapies to treat patient pain. In addition, new indications for topical analgesic treatment options are discussed. The article also provides insight into mechanical innovations in topical analgesic formulations, such as nanotechnology, that allows for enhanced delivery of drug to specified target areas. The role that topical analgesics could play as part of a multimodal patient treatment plan is then discussed.

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Topical Analgesics: Meeting Unmet Needs in Pain Management

Despite the substantial progress made in understanding and managing patients with various types of painful conditions, inadequate analgesia continues to be a problem for many patients. For example, it has been estimated that nearly half of all patients with chronic pain report that their pain is inadequately controlled.9 Almost 40% of postoperative patients experience severe or extreme pain after discharge from the hospital, even though they were prescribed analgesic medications.10 This level of pain intensity could detrimentally impact a patient’s quality of life and may put them at risk for developing chronic pain.11 In a survey of Massachusetts residents, 20% of those with chronic pain reported that they had stopped trying to find pain relief through pharmacologic means; instead, many of these patients had chosen prayer as a source of strength and comfort.12 A portion of these patients could likely find effective pain relief if currently available treatments were better understood and made more accessible.13 Even though there has been an expansion in the number of available therapeutic options for managing patients with acute and chronic pain, the World Health Organization’s Principles of Analgesia, which were introduced in 1986, remain generally unchanged today.14 Oral aspirin, traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase [COX]-2 inhibitors, and acetaminophen continue to be the most prescribed treatment agents, yet many patients find these options to be ineffective for alleviating their pain.15 Additionally, in certain patient populations, oral analgesics are contraindicated because of the potential for developing dangerous adverse events. For example, . 85 000 adults, aged . 50 years were admitted to the emergency department in 2008 because of serious adverse events resulting from the use of oral non-opioid analgesics,

such as NSAIDs and acetaminophen.16 Even over-the-counter (OTC) oral analgesics, such as aspirin and acetaminophen, are associated with systemic adverse events that can lead to patient discontinuation of therapy or life-threatening toxicity, including impaired kidney function, liver toxicity, and gastrointestinal (GI) ulceration.17 Orally administered opioids continue to be the mainstay for treating patients with moderate-to-severe chronic pain. However, prescribing regulations are continually evolving to manage access to these medications, in part due to statebased data on fatal overdoses and the 2012 Centers for Disease Control and Prevention report that describes the recent increases in opioid-related deaths as an “epidemic.”18,19 Furthermore, intolerable adverse events associated with the use of opioids, which typically involve the central and peripheral nervous systems,20,21 GI system,22,23 immune system,24,25 and endocrine system,26,27 often result in patient discontinuation.28 Moreover, although the development of tolerance and dependence are anticipated effects of patients on prolonged opioid therapy, these issues create substantial concerns for both patients and providers, who may misinterpret them as signs of addiction.29 Although topical analgesics cannot be expected to replace oral opioids for the treatment of patients with moderate-tosevere chronic peripheral pain, they may prove to be useful adjunctive therapies, particularly among patients at risk for experiencing opioid-induced adverse events or for those who may misuse or abuse opioid therapy.29,30 Oral NSAIDs also are used to treat patients with acute and chronic pain; however, oral NSAID therapy is associated with adverse events that involve the GI,31,32 cardiovascular,33,34 and renal35,36 systems. For patients at risk for these undesired effects, particularly those with compromised GI, cardiovascular, and/or renal function, topical NSAIDs may provide a safer approach for the treatment of localized pain. Additionally, a multimodal treatment approach that combines pharmacologic and nonpharmacologic techniques with complementary mechanisms of action may work synergistically to relieve patient pain and lower the required analgesic doses, which could decrease the risk of drug toxicity in vulnerable patients.

Emerging Therapeutic Areas of Topical Analgesics: Looking Ahead

As discussed in the other articles in the supplement, results of numerous clinical trials support the efficacy and safety of topical analgesics for treating patients with a number of pain-producing conditions, including osteoarthritis (OA),5 peripheral neuropathic pain,37,38 and musculoskeletal injury.39

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Paul M.  Arnstein

However, by making additional refinements to existing formulations, researchers may be able to extend the therapeutic use of topical analgesics to treat patients with other painful conditions as a means of meeting some of the unmet needs that patients may be experiencing. For example, topical capsaicin formulations, which are primarily available over the counter (OTC) at concentrations of , 1% and require multiple daily applications, have demonstrated only modest effects for treatment of patients with musculoskeletal and neuropathic pain.3,40,41 However, use of a patch containing an 8% capsaicin concentration has been effective in treating patients with postherpetic neuralgia, with application required only every 3 months.42 In addition, a high-concentration capsaicin 10% lotion is under development for treatment of the same indication.43,44 Further improvements may also come from determining ways to refine existing topical analgesics to help physicians address challenges encountered during routine clinical practice. For example, a topical cream containing a 1% concentration of the local ion-channel blocker lidocaine has been shown to produce a significant analgesic effect for patients undergoing vacuum-assisted wound closure removal. Importantly, a decrease of 1.7 mg in morphine-equivalent doses of breakthrough analgesics was observed in patients when concurrent topical lidocaine treatment was given compared with a saline control group.45 The development of sterile topical analgesics would provide additional benefits by permitting their use in patients with painful conditions that involve compromised skin integrity, such as those with burns, open wounds, and pressure ulcers.46–48 A currently available cream that contains a eutectic mixture of the local anesthetics lidocaine 2.5% and prilocaine 2.5% has been shown in multiple studies to provide patients with pain relief when used prior to leg ulcer debridement, without affecting bacterial flora.49,50 In addition, several topical morphine formulations also have been assessed for managing pain in patient conditions associated with compromised skin integrity. These formulations do not appear to significantly enter systemic circulation, as suggested by nearly undetectable morphine blood plasma concentrations, so that the mechanism of analgesia is thought to occur locally at peripheral opioid receptors.46,51 Refinement of sterile topical analgesics will improve their utility in patients with burns, open wounds, pressure ulcers, and even in patients with mucositis.46–48,50–53 Because the skin and/or mucus membrane is compromised in these conditions, issues related to direct contact, penetration through subcutaneous structures, and systemic absorption 36

of topical analgesics are clinically important hurdles for researchers to overcome. Sterile formulations of topical analgesics will need to be developed and tested in the setting of patients with compromised tissue integrity before they can be used in patients to alleviate these types of pain. With an increased understanding of the underlying pathophysiology of common pain conditions, novel topical analgesics can be developed. An astounding 40% of patients still have surgical-site pain # 3 years after surgery. This suggests the need for a fuller understanding of the relative contributions of the changes that take place at the tissue level, the processes of peripheral and central nerve sensitization, and neuroplasticity changes, which may explain why some patients experience postoperative pain that is more intense or lasts longer than expected.54 Whether postoperative pain involves mechanisms similar to those described in other articles in the supplement (eg, changes in sodium ion channels, activity of the transient receptor potential vanilloid [TRPV] subtypes, etc) is unclear, but many potential drug targets have been identified, particularly for patients with neuropathic pain that develops postoperatively.55 Topical analgesics may be able to target mechanisms involved in neuroplasticity and peripheral and central nerve sensitization—phenomena that are believed to be responsible for the transition from acute to chronic pain and the development of neuropathic pain states in patients.56 A host of new types of topical analgesics are in development offering patients future possibilities for preventing and treating chronic pain. Such agents include glutamate antagonists, cytokine inhibitors, TRPV agonists, catecholamine modulators, ion-channel blockers, cannabinoids, peptide α-conotoxins, and a variety of other biologicals.57–60 One topical therapy with a novel mechanism of action is a compound that contains quercetin, a plant-derived flavonoid, ascorbyl palmitate, and vitamin D3; it is being studied as a potential treatment for patients with diabetic peripheral neuropathy (DPN). The mechanism of action of this formulation does not involve the modulation of pain signals, as do treatments for patients with neuropathic pain. Instead, it is thought to act primarily through aldose reductase inhibition, which decreases the oxidative stress that stems from the hyperglycemia that is the hallmark of patients with diabetes. The results of a preliminary safety study have suggested that this topical formulation can reduce some of the patient symptoms associated with diabetic neuropathy, although on the majority of outcomes, no significant differences between active treatment and placebo were observed.61 As a

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Future of Topical Analgesics

result, a controlled, phase-2 clinical trial is being conducted to more specifically assess the treatment effects of this formulation.62 In a similar manner to other topical analgesic formulations, which were developed in part to improve upon existing oral formulations, novel topical analgesics are being advanced from other existing oral agents. Tricyclic antidepressants (TCAs) are known to be associated with a significant patient risk for toxicity that stems from elevated blood plasma concentrations that are observed with systemic administration.63,64 The risk requires continuous monitoring of patient blood plasma levels to ensure that TCA concentrations fit within the narrow therapeutic window between a lack of effect and systemic toxicity.64 Therefore, despite being recommended as first-line treatments for managing patients with neuropathic pain,63 the risk-benefit ratio of the TCAs may make them inappropriate for use in certain patients, particularly those receiving multiple concomitant medications, especially given the risk for potentially dangerous interactions between TCAs and many other drugs.63 To offset these potential risks, topical formulations that contain TCAs and another analgesic have been tested to determine their effectiveness for managing patients with neuropathic pain.65,66 For example, a formulation containing 2% amitriptyline and 1% ketamine has demonstrated efficacy for managing patients with a variety of neuropathic pain conditions and the treatment has not led to substantial systemic concentrations. 67,68 Additionally, a topical formulation consisting of 3.3% doxepin and 0.025% capsaicin has also been shown to be effective in the treatment of patients with neuropathic pain.69 In addition to introducing new topical formulations of existing oral agents or those with novel mechanisms of action, further improvements in topical analgesics may come from maximizing drug delivery by developing more efficient and better tolerated penetration enhancers. These improvements may either come from improving the ability of drugs to pass through the skin into the target tissue or by reducing application site reactions, which can limit the use of certain topical analgesics. Nanotechnologies may provide an opportunity for developing drug vehicles that provide enhanced delivery or reduced site reactions. For example, nanoemulsions, which are submicron oil-in-water emulsions, are currently being explored for use in pharmaceutical foams, creams, liquids, and sprays to provide more efficient drug delivery.70 A highly soluble topical 3% diclofenac nanoemulsion cream is currently being developed for the treatment of patients with OA.71

Although use of topical analgesics has been shown to be relatively safer than oral or parenteral analgesics for certain patients with intact skin, topical analgesics are not devoid of adverse effects.72 As described previously, skin irritation and dryness are the most common adverse effects associated with the use of topical analgesics. Currently utilized penetration enhancers, such as those that include an ethanol-water mixture or dimethyl sulfoxide (DMSO), are associated with the occurrence of significant skin dryness that likely stems from the lipids dissolving on the surface of the skin.73,74 Studies have shown that the incidence of dry skin is as high as 39% in patients with OA treated with topical NSAID formulations, such as diclofenac sodium 1.5% topical solution, diclofenac sodium 1% gel, and ibuprofen 5% gel.75 Although the use of emollients may help to reduce skin dryness and maintain treatment compliance in patients who cannot tolerate skin irritation and dryness, the development of better tolerated topical treatments will provide the most effective means of improving these formulations. Topical analgesic formulations that utilize nanoemulsion carriers are not only expected to provide more efficient drug delivery, they are also anticipated to be non-toxic, non-irritating, and antimicrobial.70 More empiric data are required to determine whether these emerging technologies will indeed improve patient tolerability. In addition to available chemical penetration enhancers, electrical (iontophoresis), ultrasound (phonophoresis), and thermal penetration enhancers have been used to increase permeability of substances into and through the stratum corneum.72,76,77 For example, a lidocaine (70 mg) and tetracaine (70 mg) patch uses an oxygen-activated heating component that enhances drug delivery.76 In a controlled trial designed to compare the analgesic effect of the lidocaine-tetracaine patch compared with an EMLA (lidocaine 2.5% and prilocaine 2.5%) cream, the patch technology was shown to produce greater analgesia in patients than the cream during the first 30 minutes after application.77

Safety of T   opical Analgesics: New Directions

The lower incidence of systemic adverse events associated with the use of topical analgesics, compared with those seen with the use of oral analgesics, suggests that these formulations might be useful for treating patients at high risk for toxicity related to systemic absorption. Prolonged use of oral NSAID therapy is not recommended for most geriatric patients due to age-related compromises in cardiovascular, GI, renal, and hepatic function.78,79 Older

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Paul M.  Arnstein

patients also often have multiple comorbidities requiring the simultaneous use of other medications that further complicate pain management.77,78 Therefore, the practice guidelines put forth by the American Geriatrics Society recommend extreme caution when using oral NSAIDs in elderly patients, and they support the use of topical NSAIDs for chronic, non-neuropathic pain, and the use of topical capsaicin or menthol for treating elderly patients with regional pain syndrome.79 Newer guidelines released by the American College of Rheumatology (ACR) specifically recommend the use of topical NSAIDs, rather than oral NSAIDs, for the treatment of patients with hand or knee OA, who are aged $ 75 years, and have not responded to first-line acetaminophen treatment.80 Given these recommendations, as well as the fact that many geriatric patients have undertreated pain, topical analgesics should be considered more frequently as an option for firstline or adjunctive therapy instead of potentially inappropriate long-term oral NSAID therapy.81 Neonatal and pediatric patients are also at high risk of oral analgesic–induced systemic adverse events due to their physiologic immaturity and the vulnerability of their developing major organ systems. Pediatric patients also display a wide range of developmental differences in their experience and expression of pain, and thus present a challenge in pain management.82,83 Additionally, neonates are frequently exposed to noxious stimuli during medical procedures. Given their neurologic immaturity, they are also highly susceptible to the short- and long-term consequences of painful stimuli during critical periods of cardiovascular and neurologic development.83 Although the medical community is aware of the issues associated with pain management in young patients, pain can be untreated or undertreated in this population, primarily because of legitimate safety concerns about potential adverse events, even when the child’s pain is obvious, according to pain management guidelines for neonatal patients from pre-term to 1 month old to infants, children, and adolescents.82,83 Use of EMLA is approved for treating children with pain associated with common medical procedures, such as venipuncture, intravenous catheter insertion, and other painful procedures49,84; however, after these procedures are completed and the local anesthetic is no longer active, procedural pain may continue for the patient if there is no administration of additional analgesics.85 Given the ease of administration of topical analgesics, the use of these drugs should be explored as an option for treating pediatric patients with pain. 38

Similarly, pregnant women are generally advised to avoid certain pain medications because of concerns related to fetal exposure and potential alterations in pharmacokinetics resulting from physiologic changes that occur during pregnancy and fetal development.63,86 Topical analgesics are minimally absorbed into systemic circulation,87 so that these formulations might provide a safe and effective alternative or adjunct to oral analgesics to treat pregnant or lactating women with pain. The use of topical analgesics could be explored in pregnant women with acute or chronic pain, although clinical trials in this population would have to be very selective in the application site, dose, and timing (ie, trimester) of topical application. Someday, very young, very old, critically ill, or pregnant patients will be able to fully benefit from the use of topical analgesics to relieve pain that would ordinarily be undertreated because of the risks associated with current treatment options in these populations. One of the challenges in improving drug-delivery systems for various patient populations is addressing the differences in patient absorption patterns at different ages and stages of life.

Topical Analgesics in Combination Pharmacotherapy and Multimodal Therapy

Topical analgesics may help balance concerns about the benefits of combination pharmacotherapy and polypharmacy because topical administration has lower systemic availability, which may reduce patient risk of additive adverse effects and drug interactions.88 For some conditions, treatment with topical analgesics can be substituted for oral NSAIDs without sacrificing efficacy or introducing serious GI adverse events for the patient, as shown by findings from a multi-arm clinical study in which a topical NSAID was as effective and better tolerated as an oral formulation of the same NSAID.89 Although treatment of patients with the combination of diclofenac sodium 1.5% topical solution and oral diclofenac 100 mg did not confer additional benefit compared with oral diclofenac alone in this study, further research is needed to validate the results of the study and explore the use of topical analgesics in combination pharmacotherapy, particularly when the active medications are different.89 Given justifiable concerns over the use of high doses of opioids and long-term therapy with opioids,27–30 opioidsparing regimens should be used to treat patients with pain whenever possible. If topical analgesics treatment can offer an effective and safer alternative, their role as opioid-sparing

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Future of Topical Analgesics

agents will be even more highly valued. It also has been suggested that topical analgesics may be used adjunctively in patients with pain to potentially decrease opioid use.90,91 Two meta-analyses have supported the use of oral NSAIDs in patients receiving opioid therapy, which significantly reduced patient postoperative opioid consumption and the incidence of opioid-related postoperative nausea and vomiting.92,93 Whether the use of topical NSAIDs would produce similar opioid-sparing effects for patients remains to be determined. Multimodal therapy, using different types of pharmacologic and nonpharmacologic therapies, has been advocated for the treatment of patients with acute94,95 or chronic96,97 pain. A multimodal approach may also provide the patients with opioid-sparing effects. Nonpharmacologic therapies, such as acupuncture and transcutaneous electrical nerve stimulation, are known to produce opioid-sparing effects.90 These and other approaches, such as weight loss and therapeutic exercise, are recommended by numerous professional organizations, including the ACR, American College of Physicians, the American Pain Society, and the American Academy of Orthopaedic Surgeons.79,98,99 Combined, these approaches help patients think, feel, and function better.100


Numerous possibilities exist for the development of future topical analgesics, including their use for new indications, use in high-risk patient populations, inclusion in combination pharmacotherapy regimens, and as an option in multimodal therapy. Among the potential new indications for topical analgesics are treatment for patients with postoperative pain, burns, wound debridement, and pressure ulcers. Patients at high risk for adverse events related to the therapeutic use of oral opioids or NSAIDs, including the geriatric and pediatric populations, as well as pregnant women, might benefit from more widespread use of topical analgesics once research demonstrates the safety and efficacy of these treatment modalities in vulnerable populations. Advancements in emollients and penetration enhancers in topical drug-delivery systems might improve both the safety and efficacy of topical analgesic therapy. Additionally, the limited systemic absorption of topical analgesics makes such products candidates for combination pharmacotherapy or multimodal therapy, including opioid-sparing treatment regimens. Topical analgesics are important, necessary tools to address troubling patient pain that remains undertreated or untreated due to safety concerns.


Technical editorial and medical writing support for the preparation of this manuscript was provided by Karamarie Fecho, PhD, 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

Paul M. Arnstein, PhD, RN, FAAN, discloses the following relationships: Nurse Practitioner Healthcare Foundation; Cephalon, Inc; Mallinckrodt Inc, the Pharmaceuticals business of Covidien; Ortho-McNeil-Janssen Pharmaceuticals, Inc, and Pfizer Inc (consultant or advisory board). He also has served as an editor and writer for PriCara Newsletter. References

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© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 41 ResearchSHARE®: • Permissions: [email protected] • Reprints: [email protected]

The future of topical analgesics.

Topically applied analgesic therapies have been used throughout history to treat a variety of patient conditions that present with pain. Before modem ...
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