BOLO alert: Vocacapsaicin: has the holy grail of pain management been found?

Elliot J. Krane MD

“Fundamental advancements in our field do not occur every day, so it is particularly exciting when early reports of innovative new treatments are published.“¹ Today’s PAAD by Shafer et al.²  and its accompanying editorial¹ describe the results of a phase 2 trial in which VOCACAPSAICIN, a soluble pro-drug of capsaicin, was administered in a drug company sponsored trial, to adult patients undergoing bunionectomy. Why bunionectomy? It is one of the classic models used in studying acute pain (the other is 3d molar extraction). The goal: could VOCACAPSAICIN provide long-lasting (96 hours) analgesia? Cutting to the chase: YES, it could! 

Most of you are familiar with capsaicin, the heat in chilies.  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.  Prescription and over-the-counter patch and ointment-based preparations of capsaicin have been available for years; this new prodrug formulation, injected at the time of surgery, may provide a novel approach to postoperative analgesia resulting in pain relief that lasts for days.

Thus, this is incredibly exciting news and the quest for an alternative to opioids, the holy grail of pain research (and treatment) may be on the horizon.  I’ve asked Dr. Elliot Krane, the recent Robert M. Smith award winner and and a new addition to the PAAD’s editorial council to review and summarize the findings of this study for us.  It’s a bit longer than our routine 5-6 minute reads but I think it’ll be well worth your time and effort to read both the PAAD and the original article and editorial in their entirety.  Myron Yaster MD

Original article

Shafer SL, Teichman SL, Gottlieb IJ, Singla N, Minkowitz HS, Leiman D, Vaughn B, Donovan JF. Safety and Efficacy of Vocacapsaicin for Management of Postsurgical Pain: A Randomized Clinical Trial. Anesthesiology. 2024 Aug 1;141(2):250-261. doi: 10.1097/ALN.0000000000005027. PMID: 38662910.

Editorial

Clark JD. A Spicy New Treatment for Postoperative Pain. Anesthesiology. 2024 Aug 1;141(2):201-203. doi: 10.1097/ALN.0000000000004999. PMID: 38980161; PMCID: PMC11239119.

Opioids have been the mainstay drug for the treatment of pain for at least 4,000 years in spite of their liabilities, risks and social consequences – these have been recognized for only the last two centuries.  (More accurately, the archeological record suggests the ancient Sumerians, Assyrians, Egyptians and Babylonians probably used opium for pleasure not pain.  But certainly, by the year 1,000 B.C.E. the classical Greeks described opium for the treatment of pain, and in the following centuries opioids were indeed used to treat pain, to prevent pain before surgery, to treat diarrhea, and to induce sleep.

Then given the well-known risks of opioids, why is it that opioids have been used for centuries, even millennia, in spite of the risk of death and dependence?   Simply and obviously because opioids work and work well for pain, and no better and safer analgesic has been found.

Of course, since 2010, the “opioid epidemic” has captured and even dominated our attention and has soundly moved opioids into the “BAD DRUG” column. Wrongfully or rightfully, this has led to a global effort to find a substitute drug that will effectively treat pain without the risks associated with opioids, today seen most importantly as opioid use disorder.  In this paper, Shafer and his colleagues at Stanford and in industry report the first experience with a derivative of capsaicin for the treatment of acute surgical pain. So, has the holy grail of pain treatment been at last found?  Is opioid-free surgery now a reality?

Dr. Steve Shafer is the first author of a study of vocacapsaicin (VC), a water-soluble pro-drug of capsaicin for surgical site injection for the treatment or prevention of postoperative pain.  Dr. Shafer is the former editor-in-chief of Anesthesia and Analgesia, and is doubtlessly one of the smartest scientists, pharmacologists, biostatisticians and clinicians we have had in our profession, so a paper first authored by him is a paper worth reading. 

But bearing that in mind, it is equally important to recognize the study was supported by Concentric Analgesics, the pharmaceutical company that manufacturers and assumedly has patent exclusivity for VC, and that Steve and other authors are disclosed as consultants to and equity holders in the company. Caveat emptor.

The study of VC for surgical pain used a standard clinical acute pain model, bunionectomy surgery.  Adult subjects underwent elective surgery and then were observed in a research center as inpatients for the next 96 hours, 4 days if you do the math.  The protocol had the following features: (1) the procedures were performed with light to moderate sedation and forefoot field blocks with 0.5% bupivacaine, (2) before wound closure the surgeon administered 14ml of the study drug in one of 3 concentrations, or the drug vehicle (saline/mannitol/buffer) as placebo, in a standardized fashion into the osteotomy surfaces, soft tissues, and incisional wound, (3) during the next 96 hours no additional analgesics were administered other than 5mg of oxycodone on demand as “rescue” analgesia, and (4) after discharge at 96 hours subjects were prescribed ibuprofen/acetaminophen as needed for mild-moderate pain, and “opioid analgesics” (unspecified drug and dose) for moderate to severe “breakthrough” pain, as defined by each subject. 

The statistical analysis was robust and what is standard for industry sponsored acute analgesic trials: the primary outcome variable was the 96-hour area under the curve (AUC₉₆) for pain scores for the highest VC concentration and placebo groups, using a 0-10 numeric rating scale (NRS) obtained every 4 hours while awake, both at rest and while walking, as well as at every time of a demand for rescue oxycodone.  Secondary endpoints included the AUC₉₆ analysis for the 2 lower VC concentrations, and the percentage of subjects in each group who did not demand rescue oxycodone during the 96-hour study period.  

The salient findings were:

Vocacapsaicin…

1.    increased pain for the first few posts hours, as expected of capsaicin which causes intense burning pain until the vanilloid receptors involute,

2.    reduced pain over the 96hr observation period, by “134 NRS x h,” a 33% reduction,

3.    showed benefit in secondary outcome measures: 26% of VC subjects required no opioids over 96hr compared with 5% of placebo subjects,

4.    showed a dose response over the 3 doses studied,

5.    reduced pain at rest over 14 days by “376 NR x h,” or 37% c/w placebo,

6.    and at 48hrs the mean VC pain scores were 2.8±2.7 vs 4.6±2.9 in the placebo group.
At first glance these are impressive findings, and indeed one cannot argue with the conclusions that postoperative pain is reduced by a single dose of VC and for a remarkable length of time, as much as 6 days.  But while the “NRS x h” is an accepted measure used for pharmaceutical studies, it is not one that clinicians are familiar with, and that amplifies real differences by the multiplication of data over time, while meaningful differences in pain scores may tell a different story:

The 4-hourly pain scores graphically depicted in Figure 3 (below) show statistical differences at 48 and 96 hours (4.6 vs 2.9 and 3.0 vs 1.5) and at 168 hours (1.2 vs 0.3), but in clinical terms these differences may be statistically significant but are clinically quite small: most clinical pain studies define a reduction of a numerical score of at least 2 points on an NRS to be meaningful,^3,4  or even >50% reduction.⁵  This was said most eloquently by Smith, et al. “… (a) reduction in pain intensity of 10% to 20% is considered to be a “minimally important” pain intensity reduction …, a ≥30% reduction corresponds to what patients would consider a “moderately important” improvement in pain intensity, whereas reductions of approximately 50% or more can be considered “substantial” improvements in pain intensity for individuals with acute and chronic pain.”⁶

The authors further calculate the effect size of VC, which is 0.61 (moderate to strong), larger than both ibuprofen (0.49) and acetaminophen (0.53), but smaller than the effect size of the combination of ibuprofen plus acetaminophen (1.1), a drug combination that, of course, is commonly used.

The editorial by Clark¹ is very much worth a read because it is quite instructional in interpreting the results of industry sponsored pharmaceutical studies that adhere to the strict research paradigm expected for an FDA new drug application (NDA) submission, as the Shafer paper does, tempering the findings with the many factors that separate NDA supporting research papers from papers of a drug used in the “real world”: homogenous vs heterogeneous populations of subjects, uniform vs a multitude of types of surgery, and comparison of new therapies not against placebo but against one or more drugs used in current drug therapy, in this case which would be nerve blocks ± opioids ± NSAIDs ± acetaminophen. 

Therefore, should vocacapsaicin be approved? What will vocacapsaicin add to our armamentarium?  There is indeed promise that in combination with other analgesics it will relegate opioids to the dustbin of history.  I certainly hope this is the case, but today it is too early to sing hosannas.

Send your thoughts and comments to Myron who will post in a Friday reader response.

References

1.           Clark JD. A Spicy New Treatment for Postoperative Pain. Anesthesiology 2024;141(2):201-203. (In eng). DOI: 10.1097/aln.0000000000004999.

2.           Shafer SL, Teichman SL, Gottlieb IJ, et al. Safety and Efficacy of Vocacapsaicin for Management of Postsurgical Pain: A Randomized Clinical Trial. Anesthesiology 2024;141(2):250-261. (In eng). DOI: 10.1097/aln.0000000000005027.

3.           Farrar JT, Young JP, Jr., LaMoreaux L, Werth JL, Poole MR. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94(2):149-158. (In eng). DOI: 10.1016/s0304-3959(01)00349-9.

4.           Todd KH, Funk KG, Funk JP, Bonacci R. Clinical significance of reported changes in pain severity. Annals of emergency medicine 1996;27(4):485-9. (In eng). DOI: 10.1016/s0196-0644(96)70238-x.

5.           Cooper SA, Desjardins PJ, Turk DC, et al. Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain 2016;157(2):288-301. (In eng). DOI: 10.1097/j.pain.0000000000000375.

6.           Smith SM, Dworkin RH, Turk DC, et al. Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations. Pain 2020;161(11):2446-2461. (In eng). DOI: 10.1097/j.pain.0000000000001952.