Topical Capsaicin & Cannabinoid Hyperemesis Syndrome

Background Information: Cannabinoid Hyperemesis Syndrome (CHS) is characterized by the chronic use of cannabis paired with nausea, recurrent vomiting episodes and diffuse abdominal pain.¹ The pathophysiology of CHS remains unclear and large systematic reviews of the literature have recommended up to 9 differing mechanisms as to why it occurs.² The duration of cannabis use in CHS also widely varies with the majority of patients reporting daily use and beginning use early in life.² In addition to the history of frequent cannabis use, patients’ self-reported relief of symptoms following hot showers or baths helps distinguish CHS from other cyclic vomiting syndromes. Treatment typically involves cessation of cannabis use however the authors of this randomized controlled pilot study wished to investigate the use of topical capsaicin cream when compared to placebo.

Paper: Dean D, et al. A Pilot Trial of Topical Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome. Academic Emergency Medicine. 2020. PMID: 32569429

Clinical Question:

• What is the safety and efficacy of topical capsaicin cream for vomiting from suspected cannabinoid hyperemesis syndrome in the emergency department?

What They Did:

• Randomized double-blind placebo-controlled pilot trial performed at a single urban academic trauma center with approximately 100,000 annual ED visits
• Enrollment occurred between December 2017 and July 2019 by research team members present in the ED 7 days a week from 8am to midnight (and not during holidays)
• Eligible patients were randomized to one of the following two groups
  • Treatment Group: 5 g of topical 0.1% capsaicin cream
  • Placebo Group: moisturizing cream
• Both creams were de-identified, had no scent and were packaged similarly
• An ED nurse applied the study medication cream to the abdomen in a uniform manner
• Patients in both groups continued to receive conventional therapy determined by the treating physician independent of study enrollment
• Nausea was assessed using previously validated visual analog scales (VAS)
• Research team members remained at bedside for first 60 minutes to assess any immediate adverse events related to the study medication
• Original protocol excluded patients who received any anti-emetics, halfway through the trial this exclusion criteria was removed due to the difficulty in obtaining consent and enrolling symptomatic patients prior to receiving standard therapy, however nausea still needed to be present to be enrolled

Inclusion Criteria:

• All adult patients (age ≥ 18 years)
• Presenting with suspected exacerbation of CHS and had active vomiting or nausea in the ED

Exclusion Criteria:

• Minors (< 18 years old)
• Pregnant patients
• Those with allergy to capsaicin or hot peppers
• Resolution of nausea prior to randomization
• Outpatient use of prescription antiemetics within the past 24 hours (Removed halfway through the trial)
• Acute infectious or surgical abdominal conditions
• Inability to provide informed consent

Outcomes:

Primary

• Patients’ reported nausea on VAS at 30 minutes following study medication application

Secondary

• Patients’ reported nausea and percent change from baseline at 60 minutes
• Disposition status (ie. Admission vs Discharge)
• Whether patients had complete relief of nausea (VAS = 0)
• Need for rescue antiemetic medication

Results:

• A total of 611 patients were screened and a total sample size of 30 participants were enrolled
• 17 patients (56.7%) in the capsaicin group and 13 patients (43.3%) in the placebo group
• Of the 12 patients randomized after the protocol change, three in the capsaicin arm and four in the placebo arm received an antiemetic prior to randomization

Critical Results:

• Only one patient randomized to the treatment group had no prior cannabis use
• Only one patient did not tolerate the treatment drug due to skin irritation
• Only one patient in the placebo group reported a repeat ED visit for recurrent vomiting
• No additional adverse events were reported
• There was a statistically significant reduction in mean nausea score at 60 minutes in the experimental group compared to the placebo
• Higher proportion of capsaicin group patients had complete resolution of nausea
• In the treatment group there was a statistically significant reduction in mean nausea score at 60 minutes compared with placebo

Strengths:

• Although a pilot study, this is one of the first randomized control trials looking at capsaicin as a treatment in CHS. Prior literature is limited to case reports and retrospective studies
• Detailed plan to investigate safety profile (ie. researchers sat at the bedside for 60 minutes after study drug application to monitor for adverse effects)
• Patients in both groups still received conventional therapy
• Assessed the need for rescue antiemetic therapy and made that a secondary outcome
• Incorporated a 30-day follow-up to assess for additional skin-related adverse events and for repeat ED or hospital visits
• Treatment physicians, research team members, and patients were blinded to study drug allocation
• Chose a 3cm VAS difference as clinically meaningful endpoint because in the literature 2.1cm has been identified as clinically meaningful
• There were no patients lost to follow up once allocated to treatment arms

Limitations:

• Small sample size leading to wide confidence intervals in the primary outcome
• CHS diagnosis was dependent on clinical suspicion from the treating team
• Although cannabis use was quantified, this was not assessed in relation to the study medication. Current criteria defining cannabis use in the literature was not published when this study occurred
• Study performed at a single institution increases potential for type 1 errors, limits generalizability and external validity
• 90% of patients were African Americans, thus further limiting generalizability
• Baseline nausea severity was not balanced between the two groups
• Unblinding may have occurred when research team members had to warn patients about the potential side effect of skin irritation
• Higher proportion of patients in the placebo group received an antiemetic medication prior to randomization which may have added to further bias
• Study not powered adequately to assess adverse events

Discussion:

• The 30- and 60-minute outcome assessment times were based on clinical experience with capsaicin.  The medication has a fairly rapid effect (<30min) but can have a delayed maximum effect (60min). The 30-minute time frame may have been too short.  There was no previous evidence to help guide the decision to use this as the primary outcome
• The authors justify their use of 0.1% capsaicin cream by stating it’s the highest available concentration over-the-counter
• Although the authors justified their need for a protocol change, these are never a good sign in research studies as they have the potential to introduce confounding variables and serve to complicate data analysis. With an already small sample size, it’s possible that the antiemetic given to the 7 patients enrolled after the protocol change may have unintentionally skewed the data
• Patients did not consent to participate for one of two reasons:
  • Disbelief that cannabis use could be the cause of their symptoms (In my experience this is hands-down the most frequent reason and results in a lengthy and much needed educational discussion with patients)
  • Disinterest in an investigational drug when they already felt so ill
• Interestingly all patients had no prior experience with capsaicin cream when enrolled. Although likely due to chance, this served to help the study by eliminating any external biases the patients may have regarding the study medication
• A lower baseline of nausea severity in experimental group than the placebo group may have biased the results falsely towards the placebo. Additionally, more patients in the placebo group receiving an antiemetic before randomization compared to the capsaicin group also biases the results in favor of the placebo group.
• No patients in the trial received rescue antiemetic medication within 30 minutes of study drug application
• As of now, 11 states allow the use of recreational marijuana and 47 of 50 states allow the use of medical marijuana. Michigan being one of the 11 states is also where this study occurred. The authors recognize that this may have made patients less hesitant in disclosing information related to their cannabis use and more prone to participate in the trial.
• Lastly, there are still many unknowns related to the exact mechanism of capsaicin in this specific clinical setting. It is theorized that capsaicin acts by impacting central regulation of nausea and vomiting through a potent transient receptor potential vaniloid-1 receptor (TRPV1) that is responsible for the sensation of heat and similar to the reason these patients find relief with hot showers.^3,4

Author’s Conclusions:

• In this pilot trial, the application of topical capsaicin cream was associated with a significant reduction in nausea at 60 minutes but not at 30 minutes and provided more complete relief of nausea.

Our Conclusion:

• Although a pilot study with a small sample size and several methodological flaws, this trial helps investigate additional therapies for CHS outside of conventional treatments. Given the low risk of adverse effects and ability to provide more complete relief of nausea, capsaicin has a promising role in CHS and more specifically was found to reduce nausea at 60 minutes. Additional studies performed on a larger more diverse patient population and at more than a single academic institution are warranted

Clinical Bottom Line:

• Widespread availability, low cost, low adverse effect profile and ability to reduce nausea at 60 minutes are all factors that favor the use of capsaicin cream in the treatment of patients with CHS. Although not statistically significant, there were trends toward higher proportion of patients with complete nausea relief, overall rates of vomiting and need for rescue medications again favoring the capsaicin arm. Due to this study being underpowered, major conclusions cannot be drawn however this pilot trial provides direction for planning larger scale, adequately powered, clinical trials on this topic.

REFERENCES:

1. Dean D, et al. A Pilot Trial of Topical Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome. Academic Emergency Medicine. 2020. PMID: 32569429
2. Sorensen CJ, et ak. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment-a systematic review. J Med Toxicol 2017; PMID: 28000146
3. Richards JR. Cannabinoid hyperemesis syndrome: a disorder of the HPA axis and sympathetic nervous system? Med Hypotheses 2017; PMID: 28571820
4. Richards JR, et al. Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment. Clin Toxicol (Phila) 2018; PMID: 28730896

 Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srreziae)