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Intravenous Delta-9-Tetrahydrocannabinol to Prevent Postoperative Nausea and Vomiting: A Randomized Controlled Trial

Kleine-Brueggeney, Maren MD*; Greif, Robert MD, MME, FERC*; Brenneisen, Rudolf PhD; Urwyler, Natalie MD*; Stueber, Frank MD*; Theiler, Lorenz G. MD*

doi: 10.1213/ANE.0000000000000877
Anesthetic Pharmacology: Research Report

BACKGROUND: Evidence suggests that cannabinoids can prevent chemotherapy-induced nausea and vomiting. The use of tetrahydrocannabinol (THC) has also been suggested for the prevention of postoperative nausea and vomiting (PONV), but evidence is very limited and inconclusive. To evaluate the effectiveness of IV THC in the prevention of PONV, we performed this double-blind, randomized, placebo-controlled trial with patient stratification according to the risk of PONV. Our hypothesis was that THC would reduce the relative risk of PONV by 25% compared with placebo.

METHODS: With IRB approval and written informed consent, 40 patients at high risk for PONV received either 0.125 mg/kg IV THC or placebo at the end of surgery before emergence from anesthesia. The primary outcome parameter was PONV during the first 24 hours after emergence. Secondary outcome parameters included early and late nausea, emetic episodes and PONV, and side effects such as sedation or psychotropic alterations.

RESULTS: The relative risk reduction of overall PONV in the THC group was 12% (95% confidence interval, −37% to 43%), potentially less than the clinically significant 25% relative risk reduction demonstrated by other drugs used for PONV prophylaxis. Calculation of the effect of treatment group on overall PONV by logistic regression adjusted for anesthesia time gave an odds ratio of 0.97 (95% confidence interval, 0.21 to 4.43, P = 0.97). Psychotropic THC side effects were clinically relevant and mainly consisted of sedation and confusion that were not tampered by the effects of anesthesia. The study was discontinued after 40 patients because of the inefficacy of THC against PONV and the finding of clinically unacceptable side effects that would impede the use of THC in the studied setting.

CONCLUSIONS: Because of an unacceptable side effect profile and uncertain antiemetic effects, IV THC administered at the end of surgery before emergence from anesthesia cannot be recommended for the prevention of PONV in high-risk patients.

From the *Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, and University of Bern, Switzerland; and Department of Clinical Research, University of Bern, Bern, Switzerland.

Accepted for publication May 10, 2015.

Funding: This work was funded by an institutional research grant of the Department of Anaesthesiology and Pain Medicine, Bern University Hospital, Inselspital, Bern, Switzerland, and by a research grant of the Swiss Society of Anaesthesiology and Reanimation.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the American Society of Anesthesiologists annual meeting, Chicago, 2011.

Reprints will not be available from the authors.

Address correspondence to Lorenz G. Theiler, MD, Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital and University of Bern, Freiburgstrasse 1, CH-3010 Bern, Switzerland. Address e-mail to lorenz.theiler@insel.ch.

Postoperative nausea and vomiting (PONV) severely interferes with patient well-being. It occurs at a rate of 20% to 70%1–4 and can lead to dehydration and electrolyte imbalance, suture dehiscence, bleeding, or aspiration.

Risk factors for PONV are patient-related (female sex, nonsmoking status, history of motion sickness and PONV, young age), surgery-related (procedure, duration of surgery), or anesthesia-related (volatile anesthetics, nitrous oxide, neostigmine, opioids).5,6 Prophylactic and therapeutic administration of available antiemetics may reduce, but does not eliminate, PONV and has considerable side effects.7

Medicinal properties of cannabis sativa have been known for thousands of years. In more recent scientific studies, delta-9-tetrahydrocannabinol (d-9-THC or THC) and cannabidiol have become the focus of investigation.8–12 Recently, cannabinoids were legalized for medicinal purposes in several states of the United States. Indications include spasticity in multiple sclerosis and spinal cord injuries,13–16 analgesia,17,18 neuropathies linked to AIDS,19,20 neurological disorders,21–23 and gastrointestinal disease.24,25

Trials have evaluated cannabinoids for the prevention of nausea and vomiting in oncologic patients,26,27 and dronabinol (synthetic d-9-THC) is approved in the United States as an antiemetic for patients receiving chemotherapy. A review concluded that, despite low oral cannabinoid dosage, there was a modest antiemetic efficacy in oncologic patients.28 The following side effects were noted: sensation of “high,” drowsiness, sedation, somnolence, euphoria, dizziness, dysphoria, depression, hallucination, paranoia, and hypotension. However, patients overwhelmingly preferred cannabinoids over other antiemetics.28

Very little is known about cannabinoids and PONV. Current guidelines29 do not support the use of cannabinoids for the prevention of PONV, based on a small study using oral synthetic THC.30 This study, which included 53 women, found a similar incidence of PONV in patients receiving oral nabilone (a synthetic THC derivative) or metoclopramide.30 In contrast, a retrospective study31 showed a marked relative risk reduction of 75% for PONV with a combination of preoperative oral dronabinol (the pure isomer of d-9-THC) and rectal prochlorperazine. Both studies on THC and PONV used low-dose oral cannabinoids.

Pharmacokinetic profiling of THC in volunteers revealed that oral THC undergoes an extensive first-pass metabolism and that plasma peaks highly vary interindividually while IV administration results in more predictable plasma concentrations.32

We therefore intended to conduct a prospective, double-blind, randomized, placebo-controlled trial to evaluate the clinical value of IV THC for the prevention of PONV. Because other used drugs result in a relative risk reduction of 25%,1 our hypothesis was that THC would reduce the relative risk for PONV in the first 24 hours postoperatively by 25% compared with placebo.

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METHODS

We obtained approval from the local ethics committee (Kantonale Ethikkommission, Postfach 56, 3010 Bern, approval number KEK-240/07). In Switzerland, THC is only legal within controlled clinical trials. Therefore, we obtained approval from the appropriate authorities, including the Swissmedic (Swiss Agency for Therapeutic Products, Notification Number 2008 DR3086) and the Federal Office of Public Health (Bundesamt für Gesundheit, decree number AB-8/5-BetmG–08.002953). All patients gave written informed consent to participate. The study was registered through the international trial register ClinicalTrials.gov (Identifier NCT00695487) and performed at the Inselspital, Bern University Hospital in Bern/Switzerland from July 2008 to November 2009. Data were collected before surgery on the ward, during anesthesia in the operating rooms, and after surgery in the postanesthesia care unit (PACU) and on the ward.

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Subject Selection, Inclusion, and Exclusion Criteria

Patients aged 18 to 70 years, ASA physical status I to III scheduled for elective open and laparoscopic gynecological surgery or breast surgery with a planned duration of at least 60 minutes under general anesthesia were included. These types of surgery have a high risk for PONV.1 Exclusion criteria were ambulatory surgery, pregnancy, breastfeeding, obesity (body mass index >35 kg/m2), history of drug abuse other than THC, current (within 30 days) cannabis consumption, antipsychotic or antiemetic medication, preoperative nausea and vomiting, psychiatric disorders, central nervous system disease, severe heart disease, vertebrobasilar artery insufficiency, vestibular disease, cytostatic therapy, and renal or liver malfunction.

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Study Substances and Preparations, Dosage, and Randomization

The THC injection solution (1 mg/mL) was prepared according to Naef et al.,32 following good manufacturing practice. THC solution and placebo (NaCl 0.9%) were provided in identical ampules that were numbered. Their content was only known to RB, who was not involved in the clinical part of the study. Quality control was performed by the producer (Bichsel Pharmacy, Interlaken, Switzerland) and by RB at the Department of Clinical Research, University of Bern.

Block randomization to THC or placebo and stratification according to sex and smoking status33 was performed in blocks of 10. We used computer-generated randomization in sealed opaque envelopes, containing the number of the ampule that was to be administered. Envelopes were opened after induction of anesthesia. The volume corresponding to 0.125 mg/kg THC (maximum of 10 mg) or the same volume of placebo was taken from the ampule and administered IV over 15 minutes, 15 minutes before the estimated end of surgery. This dose of THC was based on the recommended dose of oral nabilone for the treatment of nausea during chemotherapy.34 The patient and all involved personnel were blinded with respect to ampule content.

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Anesthesia

Anesthetic management was standardized. Premedication was with midazolam 7.5 mg. To avoid the influence of propofol on endocannabinoid levels,35 thiopental (4–5 mg/kg), rocuronium (0.6 mg/kg), and fentanyl (1–2 µg/kg) were used for induction. Anesthesia was maintained with fentanyl and sevoflurane or desflurane in 30% oxygen and 70% air. Routine reversal of muscle relaxation with glycopyrrolate 0.5 mg and neostigmine 2.5 mg was performed at the end of surgery. Body temperature was controlled and maintained around 36°C.

Ventilation was set to maintain end-tidal carbon dioxide at 35 to 40 mm Hg and oxygen saturation of >95%. Patients were tracheally extubated when clinical signs of full recovery were present and spontaneous respiratory function was restored (tidal volume >6 mL/kg, ETCO2 <50 mm Hg). All patients received patient-controlled analgesia with fentanyl postoperatively for the first 24 hours. This limited opioid use to fentanyl and allowed for exact quantification during the entire anesthetic and postanesthetic period.

In case of PONV, rescue medication was provided if either significant nausea persisted for >15 minutes, if >2 episodes of vomiting occurred, or at the request of the patient. The first rescue antiemetic was tropisetron 2 mg or ondansetron 4 mg, and the second rescue antiemetic was dexamethasone 4 mg.29

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Measurements and Outcome Parameters

We recorded patient characteristics (sex, age, body mass index, etc.) and risk factors for PONV, such as history of PONV, motion sickness, and smoking history. A preoperative diagnostic interview using a standardized checklist was used to exclude psychiatric disorders. Data regarding PONV and all other outcome parameters were collected by investigators unaware of the patients’ group assignment, ensuring the double-blind characteristic of this trial.

Primary outcome parameter was the incidence of PONV over 24 hours postoperatively (overall PONV). We defined PONV as vomiting, retching, significant nausea (numeric rating scale [NRS] ≥4), and/or the need for rescue medication.36–39 For all parameters, “zero” on the 11-point numeric rating scale indicated the absence of the symptom, while “ten” indicated the maximum. Early PONV was defined as PONV within the first 2 hours and late PONV as PONV within 2 to 24 hours after emergence.33Vomiting was defined as forceful expulsion of gastric contents and retching as an active attempt to vomit without expulsion of gastric contents. Retching and vomiting were summarized as emetic episodes.40Nausea was defined as the desire to vomit without the presence of muscular movements. A value ≥4 on the NRS was defined as the presence of significant nausea.36,38,39 Emetic episodes, nausea, the severity of nausea, and administration of antiemetic rescue medication were evaluated as secondary outcome parameters. All data were recorded every 15 minutes for the first hour, every 30 minutes for up to 6 hours postoperatively and at 12, 18, and 24 hours after emergence from anesthesia.

The primary hypothesis was that THC would reduce the relative risk for overall PONV in the first 24 hours postoperatively by 25% compared with placebo. Overall PONV was defined as the presence of PONV at any time during the 24 hours postoperatively.

Other secondary outcome parameters included the time period from the end of surgery to emergence, as well as the duration of PACU stay. To objectively assess the patients’ need for treatment in the PACU, we used the modified Aldrete score.41 Postoperative pain and analgesic consumption were assessed. Side effects included heart rate, assessed by the study personnel, and acute somatic and psychotropic effects subjectively graded by the patients at 1 and at 2 to 3 hours after emergence using an NRS. These included sedation, confusion, sleepiness, dizziness, lethargy, euphoria, anger, anxiety, aggression, changes in the inner or exterior perception, hallucinations, unusual thoughts and ideas, dry mouth, headaches, and respiratory or cardiac problems.32 The day after surgery, patients were asked whether they would choose the same anesthesia again.

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Sample Size Calculation and Statistical Analysis

On the basis of our previous study, we expected a PONV event rate of about 60% in the control group.3 Expecting a clinically relevant relative risk reduction of 25%1 with the use of THC, we calculated a sample size of 304 patients necessary to achieve a power of 0.8 with a 2-tailed α level of P = 0.05. We planned to include a total of 320 patients to compensate for dropouts. For recalculation of the sample size and for the evaluation of safety and side effects, a first interim analysis was planned after inclusion of 40 patients. We stratified smoking status and sex according to the PONV risk factors.33

A P value <0.05 was considered statistically significant. The incidence of PONV and other binary data were analyzed using χ2, or Fisher exact test, if >20% of expected values were <5. We tested continuous data for normal distribution using Q-Q plots and Shapiro-Wilk W test and equality of variance using variance ratio test and Levene test. In addition, residuals from the Student t tests were tested using Q-Q plots and Shapiro-Wilk W test to confirm normal distribution. Continuous data are presented as mean with SD and were analyzed using independent Student t test if normally distributed. Data that were not normally distributed are presented as median with 25th and 75th percentile and analyzed using Mann-Whitney U test. To control for the possible influence of anesthesia time on overall PONV, we performed a multivariable logistic regression analysis, including treatment group and anesthesia time with flexible restricted cubic splines. Odds ratios (ORs) and 95% confidence intervals (95% CI) were obtained using exact logistic regression as implemented in Stata. Relative risk reductions with 95% CI were calculated as (1 minus risk ratio) using the cohort study command (“cs”) in Stata. Survival curves were evaluated with the log rank test and Cox proportional hazards regression analysis. Data were analyzed using Stata V.13.1 (StataCorp, College Station, TX).

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RESULTS

Table 1

Table 1

Figure 1

Figure 1

As per protocol, an interim analysis was performed after inclusion of 40 patients. This analysis revealed considerable, clinically unacceptable side effects in the THC group. Furthermore, possible antiemetic effects were potentially less than the expected clinically relevant 25% relative risk reduction. Therefore, we discontinued the study, and all data represent 40 patients (39 females and 1 male). Because of risk-stratified block randomization, 19 patients received THC and 21 received placebo. A diagram with patient flow is shown in Figure 1. Demographic data, types of surgery, risk factors, and the risk score for PONV32 did not differ between the groups (Table 1). Surgery and anesthesia were significantly longer in the placebo group, possibly putting this group at a higher risk for PONV. All patients who were randomized (n = 40) received THC or placebo according to randomization, and all were followed up for 24 hours (no dropouts). Thus, analysis was performed with data from all 40 randomized patients.

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Postoperative Nausea and Vomiting

For our primary outcome variable, the overall incidence of PONV during 24 hours postoperatively, there was no statistically significant difference between the placebo and the THC group (71% vs 63%, P = 0.58; Table 2). The relative risk reduction of PONV with THC was 12%, with a 95% CI of −37% to 43%. Because anesthesia and surgery time differed significantly between the groups, we also performed logistic regression analysis. Calculation of the effect of treatment group on overall PONV in the logistic regression with anesthesia time gave an OR of 0.97 (95% CI, 0.21 to 4.43, P = 0.97). Calculation of the effect of treatment group on overall PONV in the logistic regression with surgery time gave an OR of 0.99 (95% CI, 0.22 to 4.55, P = 0.99). The P values for interaction between time and treatment group were 0.93 for anesthesia time and 0.94 for surgery time. There was less late PONV in the THC group, but this did not reach significance (P = 0.46).

Table 2

Table 2

Nausea was similar between both groups. There was a statistically nonsignificant relative risk reduction of 39% for late nausea (P = 0.27) and a statistically nonsignificant increase in the relative risk of 74% for emetic episodes (P = 0.12) in the THC group (Table 2).

Antiemetic rescue medication was administered in 62% (n = 13) of placebo patients and 53% (n = 10) of THC patients (P = 0.55, χ2 test). All patients who received an antiemetic first received a 5HT3-antagonist, which if necessary was followed by dexamethason. Dexamethason was given in 24% (n = 5) of placebo patients and in 26% (n = 5) of THC patients (P = 1.00, Fisher exact test). Median time from tracheal extubation to rescue medication was similar between the groups (P = 0.56).

Figure 2

Figure 2

Kaplan-Meier survival curves for PONV, nausea, emetic episodes, and antiemetics are shown in Figure 2. Test statistics did not show any statistically significant differences (PONV P = 0.65, nausea P = 0.59, emetic episodes P = 0.16, antiemetics P = 0.69).

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Anesthesia Times and Pain

Table 3

Table 3

Emergence time did not differ between groups (Mann-Whitney U test: P = 0.16; Table 3).a There was no difference in the duration of the PACU stay, and the difference in the time to achieve the criteria for discharge from the PACU missed significance (P = 0.06; Table 3). The highest pain scores did not differ between the groups (Table 3). Median fentanyl consumption (patient controlled analgesia) was lower up to the first 4 hours (median: placebo 30 versus THC 0 μg/h, P = 0.03) in the THC group and similar thereafter.

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Side Effects

Median heart rate in the THC and the placebo group did not differ at the time of THC administration (P = 0.46), 5 minutes after THC administration (P = 0.17), or 15 minutes (P = 0.68) and 30 minutes (P = 0.85) after tracheal extubation (Mann-Whitney U test).

Side effects differed significantly between groups: 6 THC patients (32%) but no placebo patients were too sedated to perform the evaluation of psychotropic side effects at 1 hour after emergence (P = 0.007, Fisher exact test). At 2 to 3 hours after emergence, 3 THC patients (16%) but no placebo patients were too sedated to do so (P = 0.10, Fisher exact test). In the group of patients in whom evaluation was possible, THC patients were more confused 1 hour after emergence (median NRS 5 vs 0; P = 0.001), as subjectively graded by the patient on a numeric rating scale. Other potential side effects such as sleepiness, dizziness, lethargy, euphoria, anger, anxiety, aggression, changes in the inner or exterior perception, hallucinations, unusual thoughts and ideas, dry mouth, headaches, and respiratory or cardiac problems subjectively perceived and graded by the patient were low and did not differ between the groups. No difference was seen between the groups at 2 to 3 hours after emergence.

Four patients in the THC group experienced pronounced side effects, such as extreme and sustained mood swings or anxiety, including one patient who was fighting and screaming when waking up. In the placebo group, only 1 patient experienced anxiety. Ninety percentage of the placebo patients and 79% of the THC patients would choose to have the same anesthesia again (P = 0.40, Fisher exact test).

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DISCUSSION

This study aimed to investigate the preventive effect of IV THC on PONV in a high-risk population. If IV cannabinoids proved to be effective, the logical follow-up study would then have been to define a minimal effective dose. However, the study was stopped because of the results of a planned reassessment after enrollment of 40 patients. IV THC, even at a relatively high dose of 0.125 mg/kg, had a negligible effect on PONV but instead showed substantial side effects that are not tolerable in the perioperative setting.

Although there is evidence regarding the use of THC as a preventive measure against chemotherapy-induced nausea and vomiting,28 evidence regarding its perioperative use was scarce and limited by low numbers,30 antiemetic comedication,31 and retrospective analysis.31 In the available studies, synthetic oral cannabinoids were used, and results were conflicting, ranging from a relative risk reduction of 75% compared with standard procedure31 to a 4% relative risk augmentation compared with metoclopramide.30 The dosage (dronabinol 5 mg and nabilone 2 mg) was low for antiemetic effects and psychotropic side effects, and it was stated that the negative results were possibly caused by underdosing.30 Contrary to oral application, IV cannabinoids, as used in the present study, have a much more predictable pharmacokinetic effect.32

Because our initial sample size calculation had to rely on very vague data, we recalculated the necessary sample size after inclusion of 40 patients. This recalculation showed that a much higher than originally expected number of patients (1008 instead of 304) had to be included for the primary outcome parameter PONV. For significant late nausea, which showed the highest potential benefit of THC, the necessary sample size was still 258. Our results show that the magnitude of a PONV-preventing effect of THC, if indeed there were one, would be much less than the clinically relevant relative risk reduction of 25%.1 The number needed to treat for PONV was 12, but the 95% CI was large, corresponding to an absolute risk reduction ranging from 37% to −21%. In addition, we found a statistically nonsignificant increase of emesis with a number needed to harm only 4. Recent literature supports the possible pro-emetic characteristics of THC.43 The controversial findings of both anti- and pro-emetic effects of THC and the high necessary sample sizes make it highly unlikely that we would have found a clinically relevant PONV-protective effect of THC (i.e., a 25% relative risk reduction), if we had continued the study.

Reported side effects of cannabinoids are dose-dependent and usually disappear within 2 hours.32,34,42 Holdcroft states that side effects are insignificant compared with commonly used drugs like nonsteroidal analgesics.44 We assumed that peak effects would have passed at emergence. However, sedation in the THC group was pronounced: THC-treated patients showed longer times to emergence, higher sedation scores after emergence, and had almost statistically significant longer times until PACU discharge criteria were met. Although this might be acceptable for an inpatient setting in chemotherapy-induced nausea and vomiting, it impedes the perioperative use, particularly in an outpatient setting. Fentanyl consumption, as measured by patient-controlled analgesia, was significantly lower in the THC group for the first hours after surgery, which can also be explained by sedation. In addition, moderate coanalgesic effects of THC are possible.45 Psychotropic side effects were unpredictable in both quantity and quality. Hence, patient satisfaction varied enormously from “best anesthesia ever” to “worst experience in my life.”

Several limitations must be noted: First, because the study was stopped after the first interim analysis, the number needed to treat and relative risk reduction show a large CI. However, we believe that the data are clear and important for clinicians and researchers who are planning to evaluate CB1 agonists to prevent PONV. Indeed, according to the clinical trials database (http://clinicaltrials.gov; NCT02115529), at least 1 center is starting a study evaluating oral nabilone for the prevention of PONV.

Second, the ideal THC dose for PONV is unknown. The amount of THC that is absorbed from a THC-containing cigarette highly varies with smoking style.34,46 Doses of up to 10 mg have been used for clinical studies.46 Four to 8 mg oral nabilone have been used for the treatment of chemotherapy-induced nausea and vomiting.34 We chose to use a dose of 0.125 mg/kg (maximum 10 mg) to optimize the drug effect and decrease the likelihood of underdosing. It is theoretically possible that THC shows a pro-emetic effect at high doses, even though this seems to be more of an issue in chronic use.43,47 Third, side effects are dose-dependent,32,34,46 and our study showed marked psychotropic side effects. Because effects such as pain reduction may be attributed to sedation from THC, an active placebo, such as a benzodiazepine, could have helped to better differentiate these findings.

Also, a different timing of the drug application might have changed outcomes. The 2 previous studies on perioperative THC applied the drug before induction of anesthesia and showed differing results.30,31 Because the pharmacokinetics of IV THC show a short half-life,32 we chose to administer the THC toward the end of surgery to have an antiemetic effect at the time of emergence. An application before induction might reduce PONV to a greater extent, but this is unknown.

By chance, anesthesia and surgery times were longer in the placebo group, possibly putting this group at higher risk for PONV.29 Indeed, the odds of overall PONV changed from an OR of 0.69 (95% CI, 0.15 to 3.15, P = 0.58) in the crude analysis to an OR of 0.97 (95% CI, 0.21 to 4.43, P = 0.97) when adjusting for the difference in anesthesia time between the treatment groups by logistic regression.

Many patients who were screened to participate in the study received regional anesthesia, were pregnant, >70 years old, had a planned short surgical procedure of <60 minutes, or received neurologically active drugs like antidepressants or sleep medication, and could therefore not be included.

Time to emergence is influenced by a variety of factors, such as respiratory settings, depth of anesthesia, and intensity of pain stimuli. Because we did not control for these factors, time to emergence has to be interpreted with caution.

In conclusion, IV d-9-THC at 0.125 mg/kg was found ineffective as a preventive measure against PONV and instead produced unpredictable psychotropic and sedative side effects impeding its use in the perioperative setting.

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DISCLOSURES

Name: Maren Kleine-Brueggeney, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Maren Kleine-Brueggeney has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Robert Greif, MD, MME, FERC.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Robert Greif has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Rudolf Brenneisen, PhD.

Contribution: This author helped design the study and was responsible for the study drug and blinding.

Attestation: Rudolf Brenneisen approved the final manuscript.

Name: Natalie Urwyler, MD.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Natalie Urwyler has seen the original study data and approved the final manuscript.

Name: Frank Stueber, MD.

Contribution: This author helped conduct the study and analyze the data.

Attestation: Frank Stueber has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Lorenz G. Theiler, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Lorenz G. Theiler has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

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ACKNOWLEDGMENTS

The authors thank all anesthesiologists who participated in the study. Special thanks to Marco Eschenmoser, University Institute of Pharmaceutics (ISPI, University Hospital Bern, Switzerland), for his support with the study drug, and to Marcel Zwahlen, PhD, Institute of Social and Preventive Medicine, University of Bern for his help with the statistical analysis.

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FOOTNOTE

a In a sensitivity analysis, we checked several of the common transformations of the parameter “emergence time.” Square root transformation showed a normal distribution for both the tetrahydrocannabinol and the placebo group. Comparison of the square root of “emergence time” by the Student t test with unequal variances gave a P value of 0.053. Thus, there was no statistically significant difference in emergence time between the groups regardless of the statistical method used. For further reference, see Dexter.48
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