The management of chemotherapy-induced nausea and vomiting (CINV) has improved over the past 20 years. Before the introduction of 5-hydroxytryptamine (5-HT3) receptor antagonists, treatment options were limited to less-effective and more-toxic agents, such as cannabinoids and neuroleptics. The principle goal of antiemetic therapy is to prevent acute and delayed CINV.1 In 1991, ondansetron was the first 5-HT3 receptor antagonist approved for CINV and changed how patients undergoing chemotherapy were managed, treated, and studied. The addition of the neurokinin-1 (NK-1) receptor antagonists and new-generation 5-HT3 receptor antagonists (palonosetron) have further improved control of delayed nausea and vomiting.
CINV can be separated into several categories: acute, delayed, anticipatory, and breakthrough.1,2 Acute CINV usually occurs within a few minutes to several hours after the chemotherapy is given, and resolves within approximately 24 hours. Delayed CINV occurs more than 24 hours after chemotherapy treatment. Acute CINV is managed through prevention using a 2 or 3 drug combination. Delayed CINV is prevented with effective treatment of acute CINV and the addition of aprepitant to the antiemetic regimen. Palonosetron, a new-generation 5-HT3 receptor antagonist, is also effective at preventing delayed CINV. Anticipatory CINV occurs before the patient even receives the chemotherapy dose, and benzodiazepines are recommended for its treatment. Breakthrough nausea and vomiting occurs despite appropriate antiemetic treatment or requires additional antiemetic rescue medications.
Breakthrough CINV continues to be a concern because it can be difficult to treat. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis recommend using an agent from a class other than the one used to prevent acute and delayed CINV (available in this issue; to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).1 Several agents are recommended, including cannabinoids, haloperidol, metoclopramide, olanzapine, phenothiazines, and benzodiazepines, for the management of breakthrough nausea and vomiting that target the various neuroreceptors. The NCCN Guidelines recommend synthetic cannabinoids, dronabinol, and nabilone as treatment options for breakthrough nausea and vomiting caused by chemotherapy. ASCO guidelines recommend cannabinoids be reserved for patients intolerant of or refractory to 5-HT3 receptor antagonists, NK-1 receptor antagonists, and dexamethasone.3 The Multinational Association of Supportive Care in Cancer states that cannabinoids can be considered for refractory nausea and vomiting and as a rescue antiemetic.4
In the mid-1980s, synthetic orally administered cannabinoids were approved for the treatment of CINV. With the approval of safer and more-effective medications, the use of these agents with a lower therapeutic index, such as cannabinoids, is not recommended as first-line treatment for prevention of CINV and should be reserved for patients refractory to or intolerant of standard antiemetics.
The use of medical marijuana is very controversial and is not part of the NCCN Guidelines for Antiemesis. Although patients may like to pursue this treatment option in states that have approved the use of marijuana for medical purposes, prescribers and patients must remember that marijuana use is still illegal according to federal law.
Chemotherapy-induced emesis may be the result of several neurotransmitters activating receptors on the chemoreceptor trigger zone, vomiting center, and gastrointestinal tract. The neuroreceptors involved in emesis include serotonin (5-HT3) and dopamine receptors. Acetylcholine, corticosteroid, histamine, cannabinoid, opiate, and NK-1 receptors are also involved in the emetic response. These receptors may also be drug targets for antiemetic therapy. The 2 known cannabinoid receptors are CB1 and CB2. In contrast with the receptors listed earlier, blocking of CB1 and CB2 results in emesis. Cannabinoids act as an agonist on the CB1 receptors, resulting in their pharmacologic effect.5 Parker et al.6 provides a more detailed review of the mechanism of action of cannabinoids in the regulation of nausea and vomiting.
Delta-9-tetrahydrocannabinol (THC) is the major psychoactive component of cannabis and has been shown to have antiemetic properties. Studies with dronabinol and nabilone were performed in the 1970s and 1980s, before the approval of 5-HT3 receptor antagonists, and often included a placebo arm, which is something that would not occur today. Their side effect profile and the availability of safer and more-effective agents for CINV prevention have limited the use of oral cannabinoids.
Tramer et al.7 published a meta-analysis on the use of cannabinoids for CINV control. The investigators screened 198 reports and analyzed data from 30 randomized controlled studies from 1975 to 1997; 16 studies were with nabilone, 13 with dronabinol, and 1 with intramuscular levonantradol. Of the 30 studies, 10 used a placebo as the comparator, and prochlorperazine was prescribed in 12 trials. Other antiemetic controls included metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Of the 30 studies, 25 were crossover designs. The authors found that cannabinoids were more effective with moderately emetogenic chemotherapy regimens than all of the active controls, but were not more effective with very high or low emetogenic regimens. When asked, patients preferred the cannabinoid over the control antiemetic. More side effects were associated with the cannabinoid treatment, and patients were more likely to withdraw from therapy. Beneficial side effects, such as euphoria, a “high” sensation, drowsiness, sedation, or somnolence, were observed in the cannabinoid arms. However, harmful events, such as dysphoria, depression, hallucinations or paranoia, and arterial hypotension (> 20% decrease in blood pressure), were also more common.
Rocha et al.8 published a meta-analysis on data from 13 studies of cannabinoids versus another antiemetic. In 10 studies, the comparator was prochlorperazine. None of the studies compared the cannabinoid with a 5-HT3 receptor antagonist. The analysis showed that dronabinol was better than prochlorperazine. Nabilone was not superior to the neuroleptic antiemetics studied. They also reviewed 18 studies for patient preference. Patients preferred cannabinoid therapy over control. Side effects were more problematic in the cannabinoid arms. The side effects occurred more frequently and were more intense in patients receiving cannabinoids than the control. Paranoid delusions, hallucinations, dysphoria, and depression were almost exclusively associated with cannabinoid therapy. Some of the side effects were considered beneficial, such as a high sensation, sleepiness, sedation, and euphoria.
Ettinger DS, Armstrong DK, Barbour S et al. . NCCN Clinical Practice Guidelines in Oncology for Antiemesis. Version 1, 2012. Available at: http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed January 31, 2012.
Kris MG, Hesketh PJ, Somerfield MR et al. . American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24:2932–2946.
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