Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy
Cannabis has a long history of medicinal use. Cannabis‐based medications (cannabinoids) are based on its active element, delta‐9‐tetrahydrocannabinol (THC), and have been approved for medical purposes. Cannabinoids may be a useful therapeutic option for people with chemotherapy‐induced nausea and vomiting that respond poorly to commonly used anti‐emetic agents (anti‐sickness drugs). However, unpleasant adverse effects may limit their widespread use.
To evaluate the effectiveness and tolerability of cannabis‐based medications for chemotherapy‐induced nausea and vomiting in adults with cancer.
We identified studies by searching the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and LILACS from inception to January 2015. We also searched reference lists of reviews and included studies. We did not restrict the search by language of publication.
We included randomised controlled trials (RCTs) that compared a cannabis‐based medication with either placebo or with a conventional anti‐emetic in adults receiving chemotherapy.
Data collection and analysis
At least two review authors independently conducted eligibility and risk of bias assessment, and extracted data. We grouped studies based on control groups for meta‐analyses conducted using random effects. We expressed efficacy and tolerability outcomes as risk ratio (RR) with 95% confidence intervals (CI).
We included 23 RCTs. Most were of cross‐over design, on adults undergoing a variety of chemotherapeutic regimens ranging from moderate to high emetic potential for a variety of cancers. The majority of the studies were at risk of bias due to either lack of allocation concealment or attrition. Trials were conducted between 1975 and 1991. No trials involved comparison with newer anti‐emetic drugs such as ondansetron.
Comparison with placebo-People had more chance of reporting complete absence of vomiting (3 trials; 168 participants; RR 5.7; 95% CI 2.6 to 12.6; low quality evidence) and complete absence of nausea and vomiting (3 trials; 288 participants; RR 2.9; 95% CI 1.8 to 4.7; moderate quality evidence) when they received cannabinoids compared with placebo. The percentage of variability in effect estimates that was due to heterogeneity rather than chance was not important (I2 = 0% in both analyses).
People had more chance of withdrawing due to an adverse event (2 trials; 276 participants; RR 6.9; 95% CI 1.96 to 24; I2 = 0%; very low quality evidence) and less chance of withdrawing due to lack of efficacy when they received cannabinoids, compared with placebo (1 trial; 228 participants; RR 0.05; 95% CI 0.0 to 0.89; low quality evidence). In addition, people had more chance of 'feeling high' when they received cannabinoids compared with placebo (3 trials; 137 participants; RR 31; 95% CI 6.4 to 152; I2 = 0%).
People reported a preference for cannabinoids rather than placebo (2 trials; 256 participants; RR 4.8; 95% CI 1.7 to 13; low quality evidence).
Comparison with other anti‐emetics-There was no evidence of a difference between cannabinoids and prochlorperazine in the proportion of participants reporting no nausea (5 trials; 258 participants; RR 1.5; 95% CI 0.67 to 3.2; I2 = 63%; low quality evidence), no vomiting (4 trials; 209 participants; RR 1.11; 95% CI 0.86 to 1.44; I2 = 0%; moderate quality evidence), or complete absence of nausea and vomiting (4 trials; 414 participants; RR 2.0; 95% CI 0.74 to 5.4; I2 = 60%; low quality evidence). Sensitivity analysis where the two parallel group trials were pooled after removal of the five cross‐over trials showed no difference (RR 1.1; 95% CI 0.70 to 1.7) with no heterogeneity (I2 = 0%).
People had more chance of withdrawing due to an adverse event (5 trials; 664 participants; RR 3.9; 95% CI 1.3 to 12; I2 = 17%; low quality evidence), due to lack of efficacy (1 trial; 42 participants; RR 3.5; 95% CI 1.4 to 8.9; very low quality evidence) and for any reason (1 trial; 42 participants; RR 3.5; 95% CI 1.4 to 8.9; low quality evidence) when they received cannabinoids compared with prochlorperazine.
People had more chance of reporting dizziness (7 trials; 675 participants; RR 2.4; 95% CI 1.8 to 3.1; I2 = 12%), dysphoria (3 trials; 192 participants; RR 7.2; 95% CI 1.3 to 39; I2 = 0%), euphoria (2 trials; 280 participants; RR 18; 95% CI 2.4 to 133; I2 = 0%), 'feeling high' (4 trials; 389 participants; RR 6.2; 95% CI 3.5 to 11; I2 = 0%) and sedation (8 trials; 947 participants; RR 1.4; 95% CI 1.2 to 1.8; I2 = 31%), with significantly more participants reporting the incidence of these adverse events with cannabinoids compared with prochlorperazine.
People reported a preference for cannabinoids rather than prochlorperazine (7 trials; 695 participants; RR 3.3; 95% CI 2.2 to 4.8; I2 = 51%; low quality evidence).
In comparisons with metoclopramide, domperidone and chlorpromazine, there was weaker evidence, based on fewer trials and participants, for higher incidence of dizziness with cannabinoids.
Two trials with 141 participants compared an anti‐emetic drug alone with a cannabinoid added to the anti‐emetic drug. There was no evidence of differences between groups; however, the majority of the analyses were based on one small trial with few events.
Quality of the evidence-The trials were generally at low to moderate risk of bias in terms of how they were designed and do not reflect current chemotherapy and anti‐emetic treatment regimens. Furthermore, the quality of evidence arising from meta‐analyses was graded as low for the majority of the outcomes analysed, indicating that we are not very confident in our ability to say how well the medications worked. Further research is likely to have an important impact on the results.
Cannabis‐based medications may be useful for treating refractory chemotherapy‐induced nausea and vomiting. However, methodological limitations of the trials limit our conclusions and further research reflecting current chemotherapy regimens and newer anti‐emetic drugs is likely to modify these conclusions.
Lesley A Smith, Fredric Azariah, Verna TC Lavender, Nicola S Stoner, Silvana Bettiol
Plain language summary
Cannabis‐based medicine for nausea and vomiting in people treated with chemotherapy for cancer
Background-As many as three‐quarters of people who receive chemotherapy experience nausea (feeling sick) and vomiting (being sick), which many find distressing. While conventional anti‐sickness medicines are effective, they do not work for everyone, all of the time. Therapeutic drugs based on the active ingredient of cannabis, known as THC (delta‐9‐tetrahydrocannabinol), have been approved for use as anti‐sickness medicines in some countries.
Review question-This review evaluated how well cannabis‐based medicines work for treating nausea and vomiting due to chemotherapy treatment in people with cancer, and what the side effects were.
Main findings-This review of 23 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) found that fewer people who received cannabis‐based medicines experienced nausea and vomiting than people who received placebo (a pretend medicine). The proportion of people who experienced nausea and vomiting who received cannabis‐based medicines was similar to conventional anti‐nausea medicines. However, more people experienced side effects such as 'feeling high', dizziness, sedation (feeling relaxed or sleepy) and dysphoria (feeling uneasy or dissatisfied) and left the study due to the side effects with cannabis‐based medicines, compared with either placebo or other anti‐nausea medicines. In trials where people received cannabis‐based medicines and conventional medicines in turn, overall people preferred the cannabis‐based medicines.
Quality of the evidence-The trials were of generally of low to moderate quality and reflected chemotherapy treatments and anti‐sickness medicines that were around in the 1980s and 1990s. Also, the results from combining studies on the whole were of low quality. This means that we are not very confident in our ability to say how well the anti‐sickness medicines worked, and further research reflecting modern treatment approaches is likely to have an important impact on the results.
Cannabis‐based medicines may be useful for treating chemotherapy‐induced nausea and vomiting that responds poorly to commonly used anti‐sickness medicines.
Lesley A Smith, Fredric Azariah, Verna TC Lavender, Nicola S Stoner, Silvana Bettiol
Implications for practice
The widespread use of cannabis‐based medicines for management of nausea and vomiting with chemotherapy is unlikely due to the adverse effects they cause. However, cannabinoids are a useful adjunctive treatment to consider for people on moderately or highly emetic chemotherapy that are refractory to other anti‐emetic treatments, when all other options of therapy have been tried. Consideration needs to be made of the adverse effect profile of the cannabinoids, and how the adverse effects may be exacerbated with other concurrent anti‐emetic treatments, as well as the age of the person. This systematic review will be valuable evidence for clinicians and future development of international guidelines to summarise the evidence available.
Implications for research
Adequate study design is important for anti‐emetic studies, ideally using a double‐blind trial design that is stratified for known prognostic factors, such as gender, age, alcohol intake, previous experience of chemotherapy, emetic potential of chemotherapy and a person's susceptibility to motion sickness (De Mulder 1992; Olver 1992a; Olver 1992b; Pater 1984). It is preferable for people to be chemotherapy naive and receiving the same chemotherapy regimens, or, if that is not possible, to receive those of the same emetogenicity as classified by international guidelines. Uniform anti‐emetic regimens should be used, when comparing an adjunctive anti‐emetic being added to the regimen in one arm (Rhodes 1984). Studies that compare the use of newer anti‐emetics that have efficacy for treating refractory nausea and vomiting (olanzapine and palonosetron) with cannabinoids would also be informative. It is difficult to compare anti‐emetic studies (Martin 1992), due to the variation in anti‐emetic doses, routes of administration, time periods of assessment of nausea and vomiting, assessment of episodes of nausea and vomiting, and any additional anti‐emetics that may have been administered. It also needs to be clear whether acute or delayed (or both) nausea and vomiting is being assessed, and there is also a variation in the definitions of complete response across studies, which impacts on comparing studies (Pater 1984). In the original anti‐emetic trials, assessment of nausea and vomiting has been inconsistent where no reliable and valid measures have been used, which also impacts on their analysis and interpretation (Pater 1984; Rhodes 1984).
While cross‐over trials are attractive to evaluate this type of therapy, they are susceptible to loss of participants if not all cross‐over to the second and subsequent phases of the trial. Following recommendations of the CONSORT (Consolidated Standards of Reporting Trials) statement for cross‐over studies would improve interpretation of such studies.