Topical Analgesics

Background

A topical analgesic may interrupt specific mechanisms of pain transmission and, by doing so, lead to a reduction in central pain mechanisms and, consequently, perception of pain. As such, skin application of a topical analgesic may reduce activation of the PNS, thus minimizing pain signal transmission and central processing by the CNS. This chapter reviews the use of topical analgesics to treat various painful conditions and provides an update of previously published similar reviews.

As topical analgesics are locally applied, without significant systemic absorption, the risk for and severity of significant adverse effects and drug-drug interactions are often less than those for the same analgesic administered systemically. As such, using topical nonsteroidal anti-inflammatory drugs (NSAIDs) versus oral formulations in knee osteoarthritis (OA) may prove effective in limiting the side effects. 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 Table 57.1 ) is the 5% lidocaine patch (Lidoderm). Several studies have confirmed the safety and tolerability of topical lidocaine. When using 12 h/day, 5% lidocaine patches demonstrated no significant systemic side effects with plasma lidocaine levels significantly below those known to be associated with cardiac abnormalities. No significant dermal reaction was observed in patients treated long-term with 24 h lidocaine patches.

While dermal sensitivity is a potential side effect of all topical analgesics, specific topical analgesics such as capsaicin can be associated with other local adverse effects. After its application, topical capsaicin is commonly associated with severe localized burning. Skin application of capsaicin, at currently available low-dose formulations, does not result in significant systemic accumulation or any life-threatening outcomes; the incidence of burning may decrease with repeated use. However, the occurrence of this side effect may negatively affect treatment adherence and, consequently, the patient’s ability to benefit from its use. In contrast to the over-the-counter capsaicin formulations that need to be applied multiple times, the 8% capsaicin patch (Qutenza) can be applied once for 1 h for analgesic effects lasting up to 12 weeks. Qutenza was generally well tolerated in clinical trials even though burning occurred, and the FDA approved it for the treatment of postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy in July 2020.

In patients suffering from chronic pain in addition to other afflictions and comorbid conditions, such as hyperlipidemia, hypertension, coronary artery disease, and diabetes, a trial of topical analgesics may be beneficial in limiting drug-drug interactions, especially if patients have been administered significant amounts of systemic medications for their underlying conditions. ^, 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.

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. Topical analgesics made by a compounding pharmacy may consist of a combination of substances, such as a local anesthetic, NSAIDs, and anti-depressants combined in a chemical base that is not commercially available and FDA approved topical products. There is no current general requirement for compounding pharmacies to demonstrate manufacturing consistency. However, those compounds are commonly prescribed as almost 1/3 of pain physicians members of the American Society of Regional Anesthesia and Pain Medicine have reported that they prescribe topical analgesics. Topical preparations containing opioids, local anesthetics, anti-depressants, 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.

The mechanism of action of a specific topical analgesic depends on the chemical entity or entities in the specific agent. In the case of the topical agent capsaicin, the mechanism appears to be through agonist activity at the transient receptor potential vanilloid 1 (TRPV1) on Aδ and C-fibers. ^, Substance P and calcitonin gene-related peptide are released as a result of this activity. Subsequent depletion of substance P in the C-fibers induces reduced peripheral and central excitability, resulting in less pain through reduced afferent input in response to capsaicin application. ^{, ,} 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 is probably associated with the inhibition of prostaglandin synthesis and the resulting anti-inflammatory effect. However, the extent of the anti-inflammatory effect is not consistently proportional to the pain relief experienced; therefore other mechanisms of action might be considered.

It may be worthwhile to consider the potential benefits of mixed agents with potentially more and synergistic mechanisms of action. For example, the antinociceptive effects of topical morphine may be enhanced by a topical cannabinoid, as demonstrated in studies in rats.

Local anesthetic agents are known to suppress the activity of peripheral sodium channels within sensory afferents and subsequent pain transmission. It has been noted that decreased expression of mRNA for specific sodium channel subtypes may occur following local anesthetic use. ^, Several local anesthetic 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 the use of EMLA cream or the FDA approved Synera patch may create both analgesia and anesthesia. This difference among the preparations is useful for application in specific clinical settings, such as venipuncture, lumbar puncture, intramuscular injections, and circumcision, for which creating both anesthesia and analgesia would be helpful.

A novel area of topical analgesic development involves the use of tricyclic anti-depressants as topical analgesics. Certain tricyclic anti-depressants 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 seems to be especially effective in chemotherapy-induced peripheral neuropathy. ^, One commercially available topical anti-depressant, 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.

Use of Topical Analgesics for Specific Clinical Conditions (see

Box 57.1 )