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Topical Agents for the Management of Musculoskeletal Pain Steven P 342 Journal of Pain and Symptom Management Vol. 33 No. 3 March 2007 Special Article Topical Agents for the Management of Musculoskeletal Pain Steven P. Stanos, DO Chronic Pain Care Center, Rehabilitation Institute of Chicago, and Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Abstract The recent recognition of the magnitude of cardiovascular risk of both nonselective nonsteroidal anti-inflammatory drugs and COX-2 selective inhibitors, in addition to the persistent concerns about the use of opioids, has brought increased attention to nonsystemic, topical analgesics. These agents have a favorable safety profile and there is increasing evidence indicating their efficacy for a variety of pain disorders. The use of topical analgesics in the treatment of the most prevalent musculoskeletal pain syndromes is described, with a focus on mechanisms for drug delivery and clinical trials data. J Pain Symptom Manage 2007;33:342e355. Ó 2007 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Counterirritants, local anesthetics, musculoskeletal pain, topical analgesics Introduction may provide a safe and effective therapeutic approach for some musculoskeletal pains. Musculoskeletal pain encompasses a wide spectrum of disorders from simple ligamen- tous injuries (e.g., ankle sprains) to intra- articular disorders (e.g., osteoarthritis and rheumatoid arthritis), muscle pain syndromes Epidemiology (e.g., myofascial pain and fibromyalgia), and Low back pain (LBP) and osteoarthritis are various spine-related neck and low back condi- the most common musculoskeletal disorders. tions (e.g., disc degeneration, disc herniation, LBP creates a significant burden on society facet arthropathies, and spondylosis). These due to its high prevalence (17.6% within the 1 disorders are highly prevalent and exact U.S. work force) and consequent economic 2 a huge toll in terms of individual quality of impact (estimated to exceed $50 billion). life and cost to society. Topical analgesics LBP is the most reported musculoskeletal pain3 and as many as 84% of adults will experi- ence LBP in their lifetime.4 When chronic, the complex pathophysiology, often involving both musculoskeletal and neuropathic compo- Address reprint requests to: Steven P. Stanos, DO, Reha- nents, may cause the management of LBP to bilitation Institute of Chicago, Chronic Pain Care be notoriously challenging. Center, 1030 North Clark Street, Suite 320, Chicago, IL 60610, USA. E-mail: [email protected] Osteoarthritis affects more than 20 million Americans between the ages of 25 years and Accepted for publication: November 28, 2006. 75 years5 and is predicted to become the Ó 2007 U.S. Cancer Pain Relief Committee 0885-3924/07/$esee front matter Published by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2006.11.005 Vol. 33 No. 3 March 2007 Topical Agents for Musculoskeletal Pain 343 fourth leading cause of disability by the year Topical Drug Delivery 2020, worldwide.3 Over the course of the dis- Controversy regarding postmarketing ad- ease progression, joints undergo degeneration verse event (AE) data and a re-examination of articular cartilage, osteophyte formation, of coxib and traditional NSAID safety studies and subchondral bone sclerosis.5 Nerve fibers ignited intense debate within both popular localize densely within bone, and chronic and medical media starting from the end of pain is thought to arise from sensitized noci- 12 2004 and still ongoing currently. Certainly, ceptors that become exposed due to the ero- the debates brought the issue of pharmaco- sion of articular cartilage.6 therapy safety to the forefront, and conse- Numerous other musculoskeletal pains are quently may have positively affected the prevalent. Ankle sprain alone has an incidence prescribing habits of clinicians. Hence, health of 52.7 per 10,000, according to a study con- care providers and the pharmaceutical indus- ducted in the United Kingdom.7 Bone pain try are currently reassessing the potential anal- may result from metastatic cancer, orthopedic gesic and additional safety advantages of one surgery, and traumatic injuriesdpotentially af- of the oldest routes of delivery, topical applica- fecting many people. Although the majority of 13 tion. Potentially, topical agents can achieve these injuries are benign and self-limiting, a similar efficacy to oral formulations without many patients may experience intermittent or the associated systemic side effects. Some evi- more persistent pain and/or loss of function, dence has shown that topically delivered both of which adversely affect a patient’s gen- agents can accumulate to therapeutic concen- eral quality of life.8 trations within the local tissues to which they have been applied while maintaining low se- rum levels. Potentially, lowering the systemic levels of medications reduces the associated risk of organ or tissue toxicity; a more com- The Biology of Pain: Pathologic plete list of the benefits and limitations of der- 14e32 vs. Physiologic Pain mal and transdermal delivery systems are listed in Table 1. In a healthy individual, pain may be defined Topical agents comprise a growing part of as a complex sensory experience associated the over-the-counter analgesic market, as well with actual or potential tissue damage.9 Injury as a smaller evolving niche market of com- in the periphery induces keratinocytes and pounding pharmacies in the United States blood vessels in the dermis to release excit- and Europe. Topical medications for pain ac- atory factors, such as prostaglandins, substance counted for 6.1% of the U.S. analgesic market P (SP), and calcitonin gene-related peptide, in 2000.33 Yet, an email survey in 2002 con- which bind to receptors on nociceptive fibers ducted by the American Society of Regional and cause depolarization. These unspecial- Anesthesia and Pain Medicine indicated that ized, peripheral nerve fibersdC and Ad poly- only 27% of clinicians prescribe compounded modal nociceptorsdcan be stimulated by topical analgesics, despite the perception that noxious thermal, chemical, and mechanical in- 43 Æ 3% of treated patients respond favorably puts. They transmit signals from the periphery to topical agents, with an average of 47 Æ 3% via the dorsal horn to higher cerebral struc- pain relief and few side effects.34 tures.10 Generally, the intensity, localization, and timing of the initiating stimuli are re- flected in the level of the neuronal signal.11 Topical vs. Transdermal In contrast, with inflamed tissue, an external The terms ‘‘topical’’ and ‘‘transdermal’’ are stimulus is not required to generate signal sometimes used interchangeably, although im- transduction and transmission to the dorsal portant differences need to be considered. horn. This hypersensitivity, seen in diseases Both delivery methods must transverse the like osteoarthritis, can be inhibited by a num- stratum corneumdthe major barrier to de- ber of different pharmacologic agents, such livering treatment.6 Transdermal methods as nonsteroidal anti-inflammatory drugs deliver medication through percutaneous ab- (NSAIDs), opioids, and cannabinoids.11 sorption, with the goal of achieving 344 Stanos Vol. 33 No. 3 March 2007 Table 1 shelters the live epidermis (Fig. 1).6,14 Once Benefits and Limitations of Analgesia past this relatively impermeable barrier, anal- by Cutaneous Delivery gesics may access the unmyelinated C-fibers Benefits Limitations and encounter the predominant keratinocytes First pass Diffusion across and melanocytes of the epidermal layer. Below metabolism and other the stratum corneum the epidermis, the dermal layer also contains variables associated with only occurs for the gastrointestinal tract molecules <500 Da.25 nociceptive fibers, along with fibroblasts, con- (such as pH and gastric Topical agents nective tissue, blood vessels, hair follicles, emptying time) are must have both e and glands. Collectively, the nerves present in avoided.15 17 aqueous and lipid Reduced side effects, and solubility.26 the epidermis and dermis are referred to as 6 the minimization of drug Both intra- and the cutaneous nociceptors. concentration peaks and interindividual Animal models have suggested that the vari- troughs in the blood.17,18 variability in the Ease of dose termination permeability ability in transcutaneous absorption rates be- in the event of untoward of skin, as well as tween topical agents is likely derived from side effects. differences between their ability to negotiate the superficial Delivery can be sustained healthy and diseased 35 and controlled over a skin, causes variable skin. Ideally, a topical agent will have a low 14 prolonged period.19,20 efficacy.27,28 molecular weight (<500 Da) and have both Direct access to the Skin enzymes can cause hydrophobic features in order to transverse target site.13,14 metabolism before Convenient and painless cutaneous absorption, the stratum corneum and hydrophilic charac- administration.15,16 reducing the potency teristics to penetrate the predominantly aque- Improved patient of the drug.29 ous epidermis.35,36 Furthermore, ex vivo acceptance and adherence Localized skin e to therapy.21 23 irritation, such studies of human skin tissue indicate that non- Ease of use may reduce as erythema, can be physiological pHs of the vehicle can reduce e overall health treatment common.30 32 the skin penetration of an agent, while occlu- costs.24 Provides a viable sion of the skin surface can have a beneficial
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