EVIDENCE FOR CLINICAL EFFICACY OF DRONABINOL IN CINV
Dronabinol was approved by the US Food and Drug Administration (FDA) in 1985 for the treatment of CINV in patients who have failed to respond adequately to conventional antiemetic treatment.7
The endogenous cannabinoid system is an important pathway involved in the emetic response. Cannabinoids can prevent chemotherapy-induced emesis by acting at central CB1 receptors by preventing the proemetic effects of endogenous compounds such as dopamine and serotonin.8 In addition, by acting as an agonist to CB1, cannabinoids used as a treatment results in an antiemetic effect.9 Cannabinoids have been used effectively for treating CINV since 1985.10
A meta-analysis evaluated a total of 1,366 patients with 30 randomized clinical trials between 1975 and 1996.10 Three different cannabinoids were evaluated among the 30 trials, with 16 trials investigating nabilone, 13 investigating dronabinol, and one investigating intramuscular levonantradol. The controls included prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alizapride, and placebo. The data showed that cannabinoids were more effective with completely controlling CINV than the active comparators or placebo in all the trials (number needed to treat [NNT] =6 for nausea and NNT =8 for nausea). In patients receiving a low or highly emetogenic chemotherapy regimen, cannabinoids were similar in efficacy of complete control of CINV versus the control; however, in patients receiving moderate emetogenic risk chemotherapy regimens, cannabinoids performed better than the control.
The three cannabinoids resulted in greater adverse drug effects compared to the controls.10 There was a significant increase in the number of patients who withdrew from the studies due to intolerable adverse drug effects in 19 of the 30 trials. The increased adverse drug effects were described as being beneficial or harmful. The beneficial adverse effects included sensation of a “high”, euphoria, drowsiness, sedation, and somnolence. The harmful adverse effects included dysphoria, depression, hallucination, and paranoia. Cannabinoids also increased the risk of arterial hypotension (>20% decrease in blood pressure from baseline) in patients. This meta-analysis showed that one in eleven patients would stop chemotherapy treatment if taking a cannabinoid for antiemesis compared to no patients discontinuing treatment if prescribed another antiemetic.
Rocha et al’s11 meta-analysis evaluated 13 randomized clinical trials. Five trials included dronabinol, six included nabilone, and two included levonantradol. Ten of the trials used prochlorperazine as a comparator, with the remaining using alizapride, chlorpromazine, or domperidone. Dronabinol’s ability for antiemetic efficacy was determined to show statistical significance over the comparator (P=0.03, NNT =3.4). The difference in antiemetic efficacy with nabilone or levonantradol compared to controls was not statistically significant (P=0.21 and P=0.60, respectively).
Patients in the cannabinoids group reported paranoid delusions, hallucinations, dysphoria, and depression.11 These adverse drug effects occurred exclusively in the cannabinoids group. Other adverse drug effects such as a “high” sensation, sleepiness, sedation, and euphoria occurred more frequently and more intensely in the cannabinoids group. However, only 30% of the 400 patient dropouts were due to toxicities.
Dronabinol in combination with ondansetron
Meiri et al8 conducted a randomized, double-blind, placebo-controlled, parallel group trial that enrolled 64 patients receiving moderate or highly emetic chemotherapy.8 The objective of this study was to determine if 4 days after chemotherapy, adding dronabinol to a prophylactic regimen for acute CINV and continuing treatment either alone or in combination with ondansetron can help prevent delayed CINV. The four parallel groups were dronabinol monotherapy (D; n=17), ondansetron monotherapy (O; n=17), combination with dronabinol and ondansetron (D + O; n=16), and placebo (n=14). Patients in all four groups received dexamethasone 20 mg PO (by mouth) and ondansetron 16 mg intravenous prechemotherapy on day 1. In the three active treatment groups, patients also received dronabinol 2.5 mg PO both prechemotherapy and postchemotherapy on day 1. Day 2 consisted of fixed doses with dronabinol 2.5 mg PO four times daily and/or ondansetron 8 mg PO twice daily in the respective groups. Days 3–5 were flexible dosing days, with patients being allowed to take dronabinol 2.5–5 mg PO four times a day and/or ondansetron 4–8 mg PO twice daily depending on tolerability. In the placebo group, a placebo was matched with the doses of dronabinol and/or ondansetron. In all groups, patients were provided with rescue medications consisting of metoclopramide PO, prochlorperazine PO, and prochlorperazine suppository to be used on days 1–8 for intolerable nausea and vomiting or retching after the maximum prescribed study doses.
In this trial, there were more females (37 out of 61 patients, 61%) compared to males (24 out of 61 patients, 39%).8 The two most common cancer diagnoses were breast cancer (26 out of 64 patients, 41%) and non-small-cell lung cancer (14 out of 64 patients, 22%). Among all four groups, 29 patients (45%) took all of the appropriate study medications in the correct dosages over the 5-day trial period. A total response was defined as no vomiting and/or retching, intensity of nausea less than 5 mm on a 100 mm visual analog scale (VAS), and no rescue medications. VAS is ranked from 0 to 100 mm, with 0 mm meaning no nausea and 100 mm meaning intractable nausea. For day 1 results, the three active treatment groups were combined and compared to the placebo group. The total response during active treatment on day 1 for the combined active treatment (CAT) group was 79% compared to 40% for the placebo group. For days 2–5, the total response for the D, O, D + O, and placebo groups were 54%, 58%, 47%, and 20%, respectively. The percentage of patients without nausea on day 1 in CAT group was 79% and in the placebo group 38%. For days 2–5, the percentages were 71%, 64%, 53%, and 15% in the D, O, D + O, and placebo groups, respectively. The reported VAS for nausea intensity was 7.65 in the CAT group and 30.67 in the placebo group. For days 2–5, the VAS was 10.1 in the D group, 24 in the O group, 14.3 in the D + O group, and 48.4 in the placebo group. Overall, the complete response rate was 62% in the D group, 58% in the O group, 60% in the D + O group, and 20% in the placebo group. In addition, the active treatment groups reduced the number of vomiting episodes to zero and decreased the duration of vomiting and retching to 0 hours by days 4 and 5. The duration of nausea was comparable between all four groups. On the flexible dosage days, the median dosage in the D group was 20 mg/d of dronabinol, 16 mg/d of ondansetron in the O group, and 17.5–20 mg/d of dronabinol and 12–16 mg/d of ondansetron in the D + O group. Rescue medications were used in all four groups (24% in D, 31% in O, 12% in D + O, and 43% in placebo groups).
Treatment-emergent adverse drug effects were reported in all four groups, with the largest percentage in the ondansetron group.8 Adverse drug effects were reported in 82% in the D group, 88% in the O group, 71% in the D + O group, and 50% in the placebo group. The percentage of patients who permanently discontinued a study medication because of a treatment-emergent adverse drug effect was 6% in the D group, 13% in the O group, 18% in the D + O group, and no patients in the placebo group.