Fig. 5.1
Potential for TRPV1 modulation to reduce pain related to opioid-induced hyperalgesia. Either capsaicin-based defunctionalization or outright TRPV1 antagonism may be useful in alleviating this subset of chronic pain
Further investigation into TRPV1 antagonists may continue to yield fruitful results; however, work must be done to investigate further the potential of that drug class to induce hyperthermia in humans in the hope of mitigating that potentially deleterious effect and thus removing a major roadblock to the therapeutic potential of TRPV1 antagonists as a whole.
5.7 Summary and Conclusions
Capsaicin has long held a place in our understanding of nociception and antinociception, even significantly predating our knowledge of its molecular mechanism and the molecular biology of its target, the TRPV1 receptor (Prekumar and Abooj 2013). The growing body of research into transient receptor-potential vanilloid receptors has yielded an understanding of a class of receptor that is involved in multiple types of nociception across multiple organ systems, with additional roles in physiologic processes such as the inflammatory response and thermoregulation in the mammalian organism (Nilius 2007). It is of no surprise, given the diversity of TRPV1 location and functions, that it has emerged as a potential therapeutic target in multiple painful conditions in which the desire for either more effective therapies or therapies that might reduce overall opioid, or even pill, burden has fostered the search for available, effective, and safe therapeutic options (Derry et al. 2009).
TRPV1 antagonists have been investigated; the premise behind investigation being that they may provide effective antinociception by interfering with an otherwise nociceptive ion channel. The major roadblock in this route of therapy remains the class’ potential for inducing hyperthermia in humans. Thus TRPV1 antagonism, while a logical next step in theory, has to date yet to pan out in terms of being a safe therapeutic option (Wong and Gavva 2009, Chizh et al. 2007).
TRPV1 agonism, such as that produced by capsaicin and resiferatoxin, produces a predictable initial painful stimulus followed by a refractory state at the receptor. Over time, this leads to degeneration of the receptor itself and an overall reduction in capacity for nociceptive input (Derry and Moore 2012). While the TRPV1 receptor has been traditionally thought of as mediating inflammatory pain through its interaction with the inflammatory milieu produced by any number of stimuli, the ability to reduce the functional capacity for peripheral sensory nerve activity has led to research into TRPV1 agonism as a potential treatment for musculoskeletal and, more frequently, multiple forms of chronic neuropathic pain, from diabetic neuropathy to postherpetic neuralgia among several others.
Research into TRPV1 agonism has taken the form of application of topical capsaicin in one of two forms: low dose (0.075 %) and high dose (8 %). Commercial preparations of both these doses are available currently. The available data point to three main conclusions: (1) that low-dose topical capsaicin does not seem to be particularly effective at treating chronic musculoskeletal pain especially compared with topical NSAID treatment, (2) low-dose capsaicin does not appear to be effective at treating multiple forms of chronic neuropathic pain in adults, although this conclusion is limited by a relative lack of evidence, and finally that (3) high-dose capsaicin does appear to be safe and effective in the treatment of HIV neuropathy and postherpetic neuralgia in adults (Derry and Moore 2012). Topical capsaicin is not without its drawbacks, however. While not appearing to put patients at a significant risk of systemic effects, local pain and erythema have the potential to limit the use of topical capsaicin in the arena of pain treatment (Wong and Gavva 2009); certainly the creation of pain appears counterintuitive in patients with whom pain is already a significant problem and a significant limitation to an acceptable quality of life. However, especially in the case of high-dose capsaicin, long-term pain reduction may be worth the short-term painful effects of drug administration. Furthermore, pretreatment with local anesthetics and pre and posttreatment with oral opioids appears to reduce overall discomfort and dissatisfaction to the point where adherence is optimized and long-term effects may be realized (Wong and Gavva 2009). This is no small achievement, especially given the propensity of these patient populations to not only experience suboptimal pain control and a significant pill burden.
Certainly, more work needs to be done. Overall evidence for or against topical capsaicin is limited. Furthermore, the effectiveness of 8 % capsaicin has only been shown in two specific types of neuropathy. The potential for high-dose application to provide relief in not only other types of chronic neuropathy (distal painful polyneuropathy, trigeminal neuralgia, cancer-related pain, and others) but also in other painful conditions including migraine and musculoskeletal pain should prompt further research into high-dose applications of capsaicin, both alone and in conjunction with other more established therapies. While more work obviously needs to be done, the available evidence points to the conclusion that, in sufficient doses, TRPV1 agonism with capsaicin can be used as an effective analgesic, at least in certain types of adult chronic neuropathic pain.
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