Authors: Sisignano, Marco et al.
Anesthesiology, September 18, 2025. DOI: 10.1097/ALN.0000000000005579
This comprehensive review explores the pharmacology, mechanisms of action, and clinical applications of topical analgesics—agents that deliver localized pain relief with minimal systemic side effects. These formulations are particularly useful when oral administration is impractical due to gastrointestinal issues or when pain is localized, as in osteoarthritis or neuropathic pain.
Topical nonsteroidal anti-inflammatory drugs (NSAIDs), lidocaine, and capsaicin are the most established agents. NSAIDs such as diclofenac and ketoprofen effectively reduce inflammatory pain while avoiding gastrointestinal toxicity, with evidence supporting their use in both acute musculoskeletal and osteoarthritis-related pain. Meta-analyses show diclofenac emulgel as the most effective, with a number needed to treat (NNT) of 1.8 for 50% pain reduction in acute pain. Gels are generally more effective than creams or patches due to improved skin penetration.
Capsaicin, a TRPV1 receptor agonist derived from chili peppers, offers a unique mechanism—inducing reversible defunctionalization of pain fibers. High-dose (8%) capsaicin patches produce long-lasting analgesia for postherpetic neuralgia and diabetic peripheral neuropathy by selectively ablating TRPV1-positive nerve fibers while preserving normal sensory function. However, efficacy remains modest (NNT ≈10.6), and evidence quality is low to moderate.
Topical lidocaine blocks voltage-gated sodium channels, reducing nociceptor excitability. Its 5% patch formulation provides localized analgesia with less than 3% systemic absorption, making it a safe second-line treatment for neuropathic pain conditions such as postherpetic neuralgia or diabetic neuropathy. Despite limited effect sizes in meta-analyses, lidocaine remains clinically valuable due to its excellent tolerability and minimal systemic toxicity.
Emerging technologies aim to enhance topical drug delivery through nanocarriers, microneedles, and lipid nanoparticles, offering potential improvements in skin penetration and efficacy. However, high costs, possible toxicity, and variability in patient skin physiology pose ongoing challenges.
What You Should Know:
Topical analgesics offer effective, well-tolerated options for managing localized acute, inflammatory, and neuropathic pain—particularly when systemic therapy is contraindicated. Among them, diclofenac gels remain the gold standard for musculoskeletal pain, while 8% capsaicin and 5% lidocaine patches serve as second-line treatments for peripheral neuropathic pain. Continued innovation in delivery systems, formulation design, and clinical research is essential to optimize their role in multimodal analgesia.
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Thank you to Anesthesiology for publishing this in-depth analysis of the pharmacology and clinical value of topical analgesics in pain management.