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.
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).
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).
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).
Anesthesia Times and Pain
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.
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).
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.
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.
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.
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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© 2015 International Anesthesia Research Society
48. Dexter F. Wilcoxon-Mann-Whitney test used for data that are not normally distributed. Anesth Analg. 2013;117:537–8