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In this review, we explain our current understanding of the molecular basis for pain relief by capsaicin and other transient receptor potential vanilloid subfamily, member 1 (TRPV1) agonists. We summarize disease-related changes in TRPV1 expression and its implications for therapy and potential adverse effects. Last, we provide an overview of the current clinical uses of topical and injectable TRPV1 agonist preparations in both oncologic and nononcologic populations.Search of MEDLINE and other databases.The capsaicin receptor TRPV1 is a polymodal nociceptor exhibiting a dynamic threshold of activation that could be lowered under inflammatory conditions. Consistent with this model, TRPV1 knock-out mice are devoid of post-inflammatory thermal hyperalgesia. TRPV1 desensitization of primary sensory neurons is a powerful approach to relieve symptoms of nociceptive behavior in animal models of chronic pain. However, over-the-counter capsaicin creams have shown moderate to poor analgesic efficacy. This is in part related to low dose, poor skin absorption, and compliance factors. Recently developed site-specific capsaicin therapy with high-dose patches and injectable preparations seem to be safe and reportedly provide long-lasting analgesia with rapid onset.We argue that TRPV1 agonists and antagonists are not mutually exclusive but rather complimentary pharmacologic approaches for pain relief and we predict a “revival” for capsaicin and other TRPV1 agonists in the clinical management of pain associated with inflammation, metabolic imbalances (eg, diabetes), infections (HIV), and cancer, despite the current focus of the pharmaceutical industry on TRPV1 antagonists.