Oli Abate Fulas & Terence J. Coderre Department of Anesthesia and Alan Edwards Centre for Research on Pain, McGill University, Montréal, Québec, Canada Topical analgesics are local treatments applied to the skin or mucous membranes that alleviate pain by acting on the underlying soft tissue and peripheral nerve endings [1]. After penetrating the surface of application, these agents act on varying targets in the local tissue and sensory nerve terminals to reduce the induction and transmission of pain signal to the central nervous system (CNS). Topically applied analgesics are used to treat acute pain conditions due to wounds, ulcers, muscle aches, sprains and strains [2]. They are also recommended for the treatment of chronic pain due to osteoarthritis, neuropathic pain and complex regional pain syndrome [3–5]. Topical analgesic formulations are available in the form of solutions, ointments, creams, gels, foams, sprays, patches or plaster. The constitution of topical preparations determines their ability to penetrate the relatively impermeable epidermal skin, more specifically the stratum corneum, which is the lipophilic outermost layer of the epidermis. Topical formulations with active ingredients of greater lipophilicity and lower molecular weight can more efficiently permeate the skin to reach their local targets. New approaches to enhancing skin penetration are being developed with permeability enhancers like liposomes, lecithin organogels, flexible vesicles and nanocarriers [1]. Microemulsions and nanoemulsions have also been developed to enhance skin flux through the solubilization of lipophilic and low molecular weight active ingredients [1]. Another fundamental determinant of topical delivery is the physical status of the skin as determined by age, sex hormones, skin type and integrity [6]. Additionally, the concentration of active ingredients in topical formulations, frequency of administration and duration of exposure to the agents all factor into the delivery and effectiveness of topical treatments [6]. Analgesics applied on the skin can be purposed for either topical or transdermal drug delivery. While topical analgesics cross the skin barrier to act on the local tissue with little systemic uptake, transdermal analgesics act on remote targets, usually the CNS, after being absorbed directly into the systemic circulation, bypassing gastrointestinal absorption and hepatic first‐pass metabolism. The serum therapeutic level achieved with the transdermal route is comparable to other systemic routes as is the frequency of side effects and drug‐drug interactions associated with it. Topical analgesics, in contrast, feature optimal delivery of therapeutic local drug levels for pain‐relieving peripheral effects and minimal risk of adverse effects (See Table 19.1). Topical analgesics in current clinical and experimental use fall into categories that: (1) block sensory inputs; (2) activate peripheral inhibitory mechanisms; (3) target peripheral source of underling pathology; (4) are multifunctional topical combinations; and (5) those primarily intended for mucosal pain conditions. (See Table 19.2 for the mostly commonly used topical agents). Topical local anesthetic formulations mostly contain lidocaine with the seldom additions of prilocaine or tetracaine. These local anesthetics are neuronal membrane stabilizers that inhibit the frequency of opening of voltage‐gated sodium channels to impair the propagation of sensory input. They can specifically block ectopic discharge from regenerating nerve fibers in which sodium channels are upregulated. They additionally act on keratinocytes, endothelial and immune cells to inhibit the release of inflammatory mediators. Table 19.1 The benefits and shortcomings of topically delivered analgesics Table 19.2 Common topical analgesics with their mechanism of action and indications. NNT, number needed to treat; CI, confidence interval; PHN, post‐herpetic neuralgia; PDN, painful diabetic neuropathy, TRPV1, transient receptor potential vanilloid‐1; HIV, human immunodeficiency virus; NSAIDs, non‐steroidal antinflammatory drugs; COX, cyclooxygenase; NE, norepinephrine. Lidocaine is available as 5% gel, cream and patch and 8% spray. The 5% lidocaine patch is registered for first line use in post‐herpetic neuralgia (PHN). The patch, worn for 12 hours in every 24 hours, also provides protection against dynamic allodynia due to mechanical stimulation. At this dose, topical lidocaine also alleviates post‐surgical neuropathy, carpal tunnel syndrome and diabetic‐ and cancer‐related neuropathies. In a randomized‐control trial (RCT) on patients with focal peripheral neuropathy of varying etiologies, the 5% lidocaine patch has produced 50% relief from ongoing pain with a number needed to treat (NNT) of 4.4 (95% CI 2.5–17.5) after 7 days of administration. This efficacy was found to be comparable to other systemic agents like gabapentin and tricyclic antidepressants (TCAs) [7]. The analgesic effects of topical lidocaine depend on peripheral actions as only 3% of the drug penetrates the systemic circulation. Its long‐term use in localized neuropathic pain provides sustained pain relief causing only reversible erythema and no systemic side effects [8]. Other topical local anesthetics are available as combinations of lidocaine with tetracaine (cream, 7% each), lidocaine with tetracaine (self‐heating patch, 70 mg each) and lidocaine with prilocaine (EMLA cream, 2.5% each). These preparations are commonly used to treat patients with acute pain. Topical EMLA cream alleviates pain due to facial and perineal lacerations [9, 10]. The cream is also effective in reducing wound‐related pain associated with chronic leg ulcers [11]. The capsaicinoids act by binding to the transient receptor potential vanilloid 1 (TRPV1), a non‐selective cation permeable transduction channel expressed on nociceptors. While this binding causes an initial activation with the release of neuropeptides, repeated application of capsaicin or single exposure to high concentrations of capsaicin causes over‐stimulation followed by desensitization of TRPV1, depletion of neuropeptides and a reversible degeneration of sensory terminals. The outcome is a defunctionalization of nociceptors that results in analgesia. Capsaicin and its synthetic cis isomer, zucapsaicin, have been clinically used as topical preparations for the alleviation of pain. Low‐concentration (0.025–0.075 %) capsaicin creams, gels and patches are available over the counter for the treatment of localized neuropathic pain but have shown little effect beyond that found with placebo treatments [12]. Recent recommendations have conditionally approved low dose topical capsaicin for the treatment of knee osteoarthritis [13]. According to a current meta‐analysis, the 0.025% cream used four times a day produces clinically meaningful alleviation of pain in these patients (effect size: 0.41, 95% CI 0.17–0.64) [14]. The high‐concentration (8%) capsaicin patch has analgesic effects in PHN, neuropathic back pain, human immunodeficiency virus (HIV)‐neuropathy, painful diabetic neuropathy (PDN), cancer‐related and post‐traumatic neuropathy. In a recent systematic review, a single treatment with 8% capsaicin patch produced significant pain relief in postherpetic neuralgia at 2 to 12 weeks with NNT to obtain 30% pain reduction of 10 (95% CI 6.3–28) [15]. Similarly, the patch produced analgesia in painful HIV‐neuropathy that lasted 2 to 12 weeks with NNT of 11 (95% CI 6.2–47) for a 30% reduction in pain intensity. The studies included used a low dose (0.04%) capsaicin patch as their control‐treatment to prevent unblinding as topical application of capsaicin causes transient erythema and burning sensations. Patients with mixed localized neuropathic pain have been shown to get greater relief from allodynia with 8% capsaicin patch as compared to oral pregabalin [16]. While low concentration formulations of capsaicin need repeated administration to produce an effect, a single application of the 8% capsaicin patch for 30–60 mins produces analgesic effects lasting for up to 3 months [15]. Local reactions like burning pain, erythema, swelling and pruritus that occur after the topical treatment are more frequent and severe with these high concentration patches. This is the reason behind the recommendations for obtaining the 8% capsaicin patch treatment in the presence of a health care professional. The adverse effects are managed with pre‐treatment using local anesthetics or cooling after patch application. Even at low concentrations capsaicin has been found to cause a reversible degeneration of sensory and autonomic intraepidermal nerve fibers (IENFs) [17]. Zucapsaicin is a synthetic cis
Chapter 19
Topical analgesics
Introduction
Topical therapeutics that block sensory input
Local anesthetics
Benefits
Shortcomings
Steady and therapeutic tissue concentrations achieved with minimal systemic distribution
Optimal molecular size and physicochemical properties required for efficient dermal penetration
Bioavailability unaffected by gastrointestinal absorption and hepatic first‐pass effect
Bioavailability affected by variations in skin permeability and local drug metabolism
Greater patient compliance, not precluded by factors that impair oral administration
Limited use in disease states that alter dermal absorptive properties
Topical Agent
Mechanism of Action
Clinical/Experimental Use
NNT
(95% CI)
Local Anesthetics
5% Lidocaine patch
Suppress activity of voltage‐gated Na+ channels on sensory afferents
PHN, PDN
4.4 (2.5 ‐ 17.5) 7
Capsaicinoids
8% Capsaicin patch
Overstimulate & desensitize TRPV1 channels on sensory afferents
PHN, PDN, HIV‐neuropathy
10 (6.3 ‐ 28) 15
NSAIDs
e.g. Diclofenac gel
Suppress inflammation through COX inhibition
Soft tissue injury
(strains, sprains)
1.8 (1.5 ‐ 2.1) 26
osteoarthritis, rheumatism, back pain
9.8 (7.1 ‐ 16) 27
Nitrates
Release NO for vasodilation
PDN
4 (2 ‐ 7) 36
Clonidine
(0.1% gel)
Block of NE‐mediated vasoconstriction & reduce nociceptor hyperexcitability
PDN
8.88 (4.3 ‐ 50) 31
Capsaicinoids
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