Pain is the most common reason patients consult primary care providers.1 According to recent surveys, 1 in 6 Americans live with chronic or recurrent pain, Americans pay an estimated $120 billion a year in medical costs and lost productivity, and pain accounts for 50 million sick days per year in the United States.2-5 Despite its potential devastating effects on patients, chronic pain is frequently under-treated or treated incorrectly. Forty million or more Americans experience chronic pain (pain that persists longer than 3 months)6,7 and suffer conditions such as arthritis, back pain, migraines, and cancer pain.2 Unfortunately, fewer than 6,000 providers have formal pain management training.8,9

Assessment of Pain

To adequately treat pain, it is essential to do a thorough pain assessment taking into account pain history and any medical evidence to help determine the most effective therapeutic options. This will enable the development and implementation of a comprehensive, individualized treatment plan. A thorough pain history including the onset, pattern, duration, location, intensity, and characteristics of pain, as well as any factors that aggravate or palliate the pain, should be discussed along with the impact of pain on the patient's quality-of-life. The healthcare provider should examine the site of reported pain, including trigger and tender points, note swelling and inflammation, perform range of motion testing, score the pain using pain scales, and characterize the pain qualities by encouraging the patient to use adjectives to describe the pain. Patients greatly benefit when a functional assessment is completed to determine the impact of pain on the patient's ability to work, engage in personal relationships, recreation, other physical activities, and sleep patterns. A successful pain management strategy requires the restoration of functionality to a level that is acceptable to the patient and healthcare provider.

Medication Management

Medications often produce unwanted systemic adverse events (AEs) and can interact with systemic medications that the patient may be taking for concomitant morbidities (see Sidebar: "Case Study"). Many systemic analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, antidepressants, antiepileptic drugs, and opioid compounds, are commonly used as first-line therapy to manage chronic pain conditions. Due to the risk of developing unwanted AEs or negative drug interactions, healthcare providers and patients are seeking alternative therapeutic options.

One approach is the topical application of a cream, lotion, gel, aerosol, or patch to peripheral site(s) of origin of the pain. In the case study, the patient tried methyl salicylate/menthol. Topical delivery systems exert their effects by targeting a site immediately adjacent to or in close proximity of the site of application. These drugs may allow for a higher local concentration of drug at the site of the pain with minimal systemic absorption. Although some degree of systemic absorption may occur with some lipid-soluble topical drugs, in general, negligible quantities of the active ingredients of topical analgesics are absorbed; hence, few or no systemic drug AEs occur, and drug interactions with concomitantly prescribed drugs are greatly minimized. This is in contrast to transdermal delivery systems (such as the fentanyl patch [Duragesic]), which use the skin as an alternate systemic delivery system and require substantial absorption into the circulation for analgesic effects to occur. Furthermore, unlike systemic analgesics, topical analgesics are easy to apply and do not require lengthy titration to improve their tolerability. The main drawback of topicals is that local AEs such as skin irritations and sensitivities can occur at the site of application and must be monitored.

Topical analgesics differ from topical anesthetics, which result in local pain relief by causing a reversible loss of sensation.10 One popular anesthetic is the eutectic mixture of local anesthetics (EMLA) cream, an oil-in-water emulsion in which the oil phase is a combination of 2.5% lidocaine and 2.5% prilocaine. A eutectic mixture has a lower melting temperature than any of its individual components. Other topical anesthetics include 4% lidocaine employing a liposomal delivery system to allow better penetration of the skin (L.M.X.4)10 and a lidocaine-tetracaine combination (S-Caine) available as a cream or patch (Synera).11 These anesthetics are typically not recommended for the control of chronic pain and their application is typically reserved for transient pain relief due to minor dermatologic procedures or venipuncture.

Significant advances in the understanding of peripheral pain signaling mechanisms and the pathophysiology of peripheral pain have occurred in the past decades and are comprehensively reviewed by Sawynok.12 Under normal physiologic conditions, nociceptive signals are produced by intense stimulation of primary afferent sensory A-delta and C nerve fiber terminals. Nociceptive signals are transmitted to the dorsal spinal cord where they are modulated by local and supraspinal structures which project to the cortex via the brainstem and the thalamus (see Figure: "Transmission of Pain Signals"). Under pathophysiologic conditions, such as in the case of chronic inflammation or nerve injury, there can be alterations in the response to pain at three levels: (1) peripheral sensitization may occur where the peripheral nerves have altered expression of neurotransmitters, enzymes, receptors, or ion channels; (2) there can be changes in the tissue surrounding the peripheral nerve so that there are changes in blood flow, vascular permeability, activation and migration of immune cells, and the release of certain growth factors; and (3) central sensitization may also occur where there are alterations in the spinal processing of pain signals. Recent studies of animal models of osteoarthritis (OA) have suggested that the up-regulation of sodium channel expression in primary afferent neurons induced by joint inflammation may be an important mechanism involved in chronic OA pain.13 Medications applied topically to control pathophysiologic peripheral pain responses will act locally on peripheral nerves or on damaged or dysfunctional soft tissues to elicit an analgesic response.

Patient Selection

Qualities of the painful condition and characteristics inherent to the patient due to genetics or the presence of comorbid diseases must be assessed to determine if a patient would benefit from a topical analgesic (see Table: "Key Diagnostic Points for the Use of Topical Analgesics"). Topical analgesics are particularly well suited if a patient's pain complaint is restricted to a localized region of the body. In some cases, the pain complaint, though regionalized, may be in a location where it is difficult to apply a topical analgesic, such as around a joint. To aid in its application, a wrap can be used to hold a patch, cream, gel, or ointment around the pain-afflicted area. Topical analgesics are not suitable for painful conditions where there is broken skin or lesions, as these products are not antiseptic. Such application may result in severe skin irritation and burning, and might also allow for systemic absorption of the active ingredient, thereby potentially eliciting treatment-related systemic AEs.

Patients who have one or more chronic conditions, such as hypertension or diabetes, and must be managed with systemic drugs are also good candidates for the management of pain with a topical analgesic, as this greatly minimizes the potential for drug interactions. In addition, patients with cardiovascular and gastrointestinal risk factors may be at higher risk for AEs that can occur with some systemic pain medications such as NSAIDs and COX-2 inhibitors; hence, topical analgesics may be a good option. Patients with renal or hepatic insufficiencies may have difficulty in the metabolism and clearance of systemic analgesics and may benefit from topical analgesic therapy as well. Topical analgesics may also be a good option for elderly patients who might have a higher susceptibility to AEs or drug interactions due to preexisting comorbidities such as a heart condition. However, as with all medications, patients should consult their healthcare provider before starting any new medications.

Key Treatment Options

Topical heat can be administered by a variety of products (heating pads and heat wraps) available in the drugstore. An investigator-blind clinical trial was conducted to test the efficacy of continuous low-level heat wraps compared with over-the-counter dosages of ibuprofen (1,200 mg/day) and acetaminophen (4,000 mg/day), oral placebo, or unheated wraps. Patients with moderate-to-severe low back pain were randomized for 2 days of treatment with heat wraps or one of the other active controls or placebo groups followed by 2 days of subsequent observations and evaluation.14 Heat wrap therapy was statistically superior for pain relief, improved flexibility, reduction in muscle stiffness, and reduction in disability scores compared with both acetaminophen and ibuprofen over the course of the treatment and its benefits extended beyond the treatment period. In a similar study, patients with moderate-to-severe knee OA treated with heat wraps experienced improved pain relief with heat wraps compared to acetaminophen-treated patients, and improved range of motion, as well as reduced disability, compared to ibuprofen-treated patients.15

Heat should never be applied over the site of a patch such as the fentanyl patch or a topical medication such as methyl salicylate/menthol. Heat can accelerate the absorption of medication and can cause severe burns if placed over the site where a mentholated product has been applied. Although ice is commonly thought to be a short-term analgesic in many painful conditions, scientific evidence from clinical trials is fragmentary, making it difficult to evaluate the efficacy of this treatment modality.

Topical ointments with menthol (Joint-Ritis) have been marketed as pain analgesics because they cause cool or hot sensations that mask pain, but these products are not usually effective for most chronic pain conditions. In a double-blind, randomized, placebo-controlled clinical trial, 46 patients with moderate-to-severe knee pain were treated with Joint-Ritis for up to 35 days, but no differences between the placebo and treatment groups were noted.16 Patients will often try these types of products and experience limited pain relief before seeking a primary care provider.

Patients often self-administer over-the-counter topical products containing combinations of methyl salicylate and menthol (Bengay and Mentholatum Deep Heat) to relieve mild pain. In a systematic review of the efficacy of topical rubefacients containing salicylates for treatment of pain, 9 placebo-controlled trials were included in a meta-analysis of 611 patients.17 The trials indicated that topical rubefacients may be efficacious in the treatment of acute pain, but may have moderate-to-poor efficacy for musculoskeletal and arthritic pain.17 Adverse events were rarely reported in these studies, but the manufacturers report that redness or irritation may occur, and the products should only be applied to intact skin.

Capsaicin is a natural constituent in pungent red chili peppers and, depending on the concentration used, it can activate, desensitize, or exert a neurotoxic effect on small diameter sensory afferent nerves in the local area of application. Its mechanism of action is through a receptor-mediated process which involves calcium-dependent channels and results in the release of substance P and calcitonin gene-related peptide.12 With repeated capsaicin application, this release is attenuated as the nerves become desensitized.12 Pain relief has a gradual onset and only occurs with repeated application. The stinging at the time of capsaicin application limits its effectiveness but despite the increased pain with (or following) application, no damage to the skin occurs. To make the cream more tolerable, applying a thin coating of petroleum jelly before applying the capsaicin cream can decrease discomfort.

Capsaicin is available over the counter as a cream in two strengths: 0.025% (Zostrix) or 0.075% (Zostrix-HP) or as a patch (Salonpas, Capzasin) at the 0.025% strength. Nine double-blind, placebo-controlled trials have tested the efficacy of capsaicin at 0.075% and 0.025% in moderate-to-severe neuropathic pain and musculoskeletal conditions, respectively. It was found to have poor-to-moderate efficacy when used as a monotherapy.17 One-third of patients suffered mild local AEs and 10% of patients withdrew from the study due to these local events.17 In addition, a high-dose (640 mcg/cm2) dermal patch of synthetic trans-capsaicin that is applied for 1 hour is currently under development (NGX-4010; NeurogesX). In a Phase II trial, this patch demonstrated a one-third reduction in pain for 4 weeks after a single application (P = 0.004).18 The manufacturer has initiated Phase III trials to evaluate the efficacy of this 1-hour patch in postherpetic neuralgia. Topical capsaicin treatments are generally not considered a satisfactory sole therapy for chronic pain conditions and are often considered an adjuvant to other approaches.12 Gloves should be worn while applying capsaicin creams. These creams should not be applied to broken skin, eyes, or genitalia, as excessive burning will result. Extended use may cause a mostly reversible loss of sensory fibers within the skin resulting in desensitization to mechanical and thermal stimulation. The loss of sensation can further exacerbate the pain symptoms experienced by diabetic polyneuropathy patients and hence would not be a good choice for these patients.

Prescription Topical Analgesics

Topical lidocaine patch 5% (Lidoderm), an adhesive patch, relieves pain associated with postherpetic neuralgia. In many chronic pain states, areas of peripheral nerve injury have been associated with an abnormally elevated expression of sodium channels, which may contribute to the hyperexcitability of nerves.12 Topical lidocaine patch 5% may block abnormal activity of these sodium channels, providing analgesia to a local area with minimal systemic absorption of lidocaine. Functional magnetic resonance imaging studies show topical lidocaine blunts cortical pain activation. In double-blind, placebo-controlled studies using a balanced-random assignment, 78% of postherpetic neuralgia patients preferred the pain relief of the lidocaine patch 5% compared with vehicle patch (P = 0.001) and no significant differences in side effects, such as local skin reactions, were reported for placebo and active treatments.19 The effectiveness of lidocaine patch 5% is also being investigated in painful diabetic neuropathy,20,21 low back pain,20-22 and OA,20,21,23 but controlled trial data are not yet available in these pain states.20,21 Lidocaine patch 5% should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic. There is an insignificant absorption of lidocaine with the normal use of the lidocaine patch 5%. Also, due to the large amounts of lidocaine in each patch, patches should be stored and discarded out of reach of children and pets to avoid accidental ingestion.

Topical NSAIDs, although not yet available in the United States, have been successfully marketed in Europe for many years. They share the anti-inflammatory properties of oral NSAIDs, but have fewer gastrointestinal AEs due to minimal systemic absorption of the active agent(s), although topical NSAID use has been associated with local skin irritations. Topical diclofenac (Pennsaid) for the relief of pain in the knees of OA patients24 and a topical ketoprofen patch (Endo Pharmaceuticals) for the relief of soft tissue and joint strain and sprains are currently in clinical development in the United States.25 In Europe, there is a large body of evidence to support the efficacy and safety of topical NSAIDs in comparison with placebo and oral counterparts. In a review analyzing 14 double-blind, placebo-controlled trials, topical NSAIDs were effective, as determined by a 50% reduction in pain, and safer in treating chronic musculoskeletal conditions; however, topical NSAID efficacy has only been demonstrated over a 2-week period.26 Clinical trial evidence from long-term studies are necessary to fully elucidate the role of topical NSAIDs in the management of chronic pain. Some topical NSAIDs, such as ibuprofen gel (Antares Pharma), are designed to deliver the NSAID both systemically and locally, and therefore would not carry the same safety benefits as topicals designed to deliver the drug only locally.

An Effective Treatment Modality

Evidence from randomized, controlled trials suggests that topical analgesics may represent an effective treatment modality for those patients that require analgesia and are unable or unwilling to tolerate the systemic AEs that may be associated with oral analgesics. In addition, since topical analgesics are associated with a low risk of toxicities due to their minimal systemic absorption, they may be good candidates for rational polypharmacy when medications that employ different mechanisms of action are combined in an attempt to obtain an additive analgesic effect. Lower effective doses of oral medications may be needed, decreasing the risk of dose-dependent systemic AEs when combined with topical treatment. Nurse practitioners must consider any potential adverse drug interactions that may arise when developing pain management strategies that require more than one pharmacologic intervention. The use of topical analgesics in the management of chronic pain conditions as monotherapy or in combination with other treatment options may be particularly useful in developing pain management strategies that enable effective pain control through pharmacologic interventions with the added benefit of minimizing the potential of systemic AEs.

Transmission of Pain Signals

Case Study

One of your regular patients, Jean Marie, a 65-year-old woman, continues to complain of pain in both knees. She describes the pain as moderate to severe, and has mentioned that sleeping is difficult and her ability to climb stairs is limited because of her pain. Methyl salicylate/menthol (Bengay) applied to her knees provided little relief. Jean Marie has been taking an NSAID for pain but she really wants to find an alternative. She is not interested in trying opioids because, she says, "they make me feel all fuzzy-headed."

Medical History Jean Marie was diagnosed with osteoarthritis 5 years ago. She has diabetes that is well-controlled with oral medication. She is obese and has been referred twice to weight control programs with little success. She has an allergy to eggs with urticarial wheals as the response. What can you offer to Jean Marie to help control her knee pain?

Case Study Treatment Rationale

There are several options to consider when offering treatment to Jean Marie. She has osteoarthritis pain in both knees and is looking for an alternative to oral NSAIDs. The literature supports the use of the lidocaine patch 5% for osteoarthritis and a topical application of an NSAID such as ketoprofen could eliminate the systemic effects and offer localized pain relief.21 She could apply the patches at night to help with pain control during rest. Using capsaicin cream could also provide enough pain relief to increase Jean Marie's mobility. A common therapy for osteoarthritis is a hyalgan injection, a substance made from rooster combs; however, Jean Marie is allergic to eggs, so this option is not viable. Since the patient is looking for alternate options to oral pain medication, a referral to a comprehensive pain clinic where medication choices can be discussed, exercise can be tailored to the patient, and coping support can help find alternatives that Jean Marie would find acceptable.

Key Diagnostic Points for the Use of Topical Analgesics

Key Treatment Options for Peripheral Pain

References