A Spicy New Treatment for Postoperative Pain

Fundamental advancements in our field do not occur every day, so it is particularly exciting when early reports of innovative new treatments are published. In this issue of Anesthesiology, Shafer et al. describe the results of a phase 2 clinical trial in which vocacapsaicin, a soluble prodrug of capsaicin, was administered to patients undergoing bunionectomy with the hope of providing long-lasting analgesia.  Capsaicin, it should be recalled, works as a potent agonist of the TRPV1 receptor, initially causing pain and hyperalgesia but over time providing desensitization of primary afferent sensory neurons. Past studies demonstrated that local infiltration of tissues around an incision with capsaicin reduces hyperalgesia and pain-related behaviors in laboratory animals.  In the current study, participants reported 33% less pain when calculated using area under the numerical rating scale curve through 96 postoperative hours (AUC_0-96h) and consumed 50% less oxycodone during the same time interval. In addition, the effects of locally administered vocacapsaicin were dose-dependent, and the safety profile was favorable with no serious adverse events recorded among patients receiving the study drug at any dose tested. Thus, while prescription and over-the-counter patch and ointment-based preparations of capsaicin have been available for years, this new prodrug formulation may provide a novel approach to postoperative analgesia resulting from a single local injection that lasts for days.

The potential value of this type of treatment is enormous as it may help us to address two clear shortcomings of our current postoperative analgesic strategies. The first, as has been carefully reviewed many times, is that the use of oral opioids as a mainstay for postprocedural pain management contributed to the rise of the nation’s opioid epidemic.  The ability to provide effective analgesia during the first few postoperative days when pain is most intense could reduce patients’ opioid exposure and allow for reductions in the number of opioid tablets dispensed to outpatients. Such reductions in opioids flowing into the community would represent an advancement in opioid stewardship. The second major challenge to our field long predating the opioid crisis is our suboptimal overall record in controlling postoperative pain. Despite how well the problem is known and the use of multimodal therapies, many patients experience moderate to severe postoperative pain during the first 2 postoperative weeks.  A safe, one-shot local analgesic not requiring special expertise or equipment to administer with duration of action extending beyond that provided by our traditional local anesthetics would be warmly welcomed.

So, is it now clear that we will have a wonderful new tool, or is there still work to be done? In short, there are still important challenges to be addressed. The first issue relates to what the clinical effectiveness of vocacapsaicin (as opposed to experimental efficacy) will prove to be. The study by Shafer et al. was designed as a Food and Drug Administration (Silver Spring, Maryland) phase 2 trial intended to measure analgesic efficacy in a relatively homogeneous patient population as well as to collect safety data beyond the basic outcomes measured in phase 1.  Bunionectomy is a widely accepted model of acute postoperative pain related to orthopedic surgeries that has been used numerous times for the phase 2 evaluation of pain medications including locally administered drugs. In the case of this postoperative pain trial, like many others, coexisting medical and psychologic diseases in the study population were minimized through the entry criteria. In addition, the vocacapsaicin injections were compared to vehicle (not local anesthetic) injections. Single intraoperative doses of acetaminophen and ketorolac were used, but there was no postoperative access to additional nonopioid analgesics until after the initial 96-h study period. Ongoing postoperative access to acetaminophen and/or a nonsteroidal anti-inflammatory drug is common and recommended in the recently published guidelines for pain control after bunionectomy.  It is perhaps relevant in this regard that the pain scores only appeared to be clinically significantly different between vocacapsaicin and placebo for the first 96 h after surgery. In addition, aside from a standard Mayo field block performed by the surgeon, there were no formal one-shot or continuous regional techniques such as sciatic nerve block as are used for bunionectomy in many centers. The authors reported that two subjects from the placebo group dropped from the study due to inadequate analgesia, suggesting that background analgesia was indeed minimal. Because a critical goal of a phase 2 study is to identify basic treatment efficacy, these were not necessarily inappropriate features of the trial. However, these are not the circumstances under which the drug is likely to be used in clinical practice. Along the same lines, the study’s findings regarding opioid sparing effects need to be taken with a grain of salt as patients only had access to opioids as a breakthrough analgesic option for the first 96 postoperative hours. Common advice would be to try acetaminophen or a nonsteroidal anti-inflammatory drug during this interval. If vocacapsaicin advances in its development, the results of comparative effectiveness studies against our more typical analgesic strategies including regional techniques and inexpensive nonopioid analgesics will be important.

The second major issue somewhat downplayed in the report was the substantial flare in pain immediately after surgery very likely resulting from the conversion of vocacapsaicin to capsaicin within the surgical wound. The injection of capsaicin into experimental subjects is quite painful and is a common model of experimental neuropathic pain.  Even topical application of capsaicin can cause significant burning pain; the use of the 8% capsaicin patch for postherpetic neuralgia, for example, requires topical anesthetic premedication and occasionally intravenous analgesia. We would therefore predict at least transient pain after study drug administration, and in fact the data seem to show significantly elevated pain scores in those receiving vocacapsaicin for the first few hours after surgery. Clearly this initial pain flare represents a clinical challenge even if pain later declines to levels below those measured after placebo administration. The authors do mention new but as yet unpublished results showing that this early pain flare can be reduced with the inclusion of local anesthetic along with vocacapsaicin as a component of the administration protocol. It is regrettable that those data were not available in this report, but the approach described seems entirely reasonable and has some precedent. Other investigators evaluating the analgesic effects of intraarticular capsaicin injection for osteoarthritis pain first administered 2% lidocaine to reduce capsaicin-induced discomfort.  We do not know whether the developers of vocacapsaicin will attempt to reformulate their candidate drug with local anesthetic or whether clinicians will need to administer a separate local anesthetic when using the new drug.

In the end, there is reason for excitement over this newly described candidate drug as there is over the recent report of a systemically administered sodium ion channel NaV1.8 antagonist (VX-548) that operates via a very different mechanism of action to reduce postoperative pain.  The identification of the targets for these candidate medications, the design of the molecules, and our understanding of their mechanisms of action are the products of years of basic science and translational research. In fact, the 2021 Nobel Prize in Physiology or Medicine was shared by David Julius for a long program of studies that began with a basic curiosity about the relationship between capsaicin and the sensations of pain and temperature.  During the past few decades, we have tried many individual drugs and combinations of systemic medications, often with creative regional anesthetic strategies to control postoperative pain. While such multimodal approaches may optimize the use of already available tools, perhaps we are now near the point of a breakthrough. Ultimately, the effectiveness in comparison to established alternatives, side-effect profile, and cost may dictate whether these new drugs will be available to address the relatively recent opioid crisis and the long challenging problem of postoperative pain.