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Vincent Vinciguerra, MD; Terry Moore, MSW; Eileen Brennan, RN ABSTRACT. A prospective pilot study of the use, of Inhalation marijuana as an antiemetic for cancer chemotherapy was conducted. Fifty-six patients who had no Improvement with standard antiemetic agents were treated and 78% demonstrated a positive response to marijuana. Younger age and prior marijuana exposure were factors that predicted response to treatment. Toxicity was mild and consisted primarily of sedation and xerostomia. This preliminary trial suggests the usefulness of Inhalation marijuana as an antiemetic agent. Because of the lack of a randomized placebo control group, the precise role of this agent is unclear. Further studies should include derivatives of this substance in combination with standard effective drugs to control chemotherapy-induced nausea and vomiting. (New York State Journal of Medicine, October 1988; 88: 525 - 527) From the Don Monti Division of Oncology. Department of Medicine, North Shore University Hospital, Manhasset, NY, and the Department of Medicine, Cornell University Medical College, New York, NY. Address correspondence to Dr Vinciguerra, Chief, Division of Oncology/Hematology, North Shore University Hospital, 300 Community Dr, Manhasset. NY 11030. Supported in part by the Don Monti Memorial Research Foundation, Community Clinical Oncology Program (CCOP) grant #CA-35379, and the New York State Department of Health. A great deal of clinical information has recently been generated concerning the efficacy of various antiemetics agents for patients treated with cancer chemotherapy. (1-3). Without effective control of nausea and vomiting, patient compliance with potentially curative chemotherapy programs diminishes, compromising not only quality but quantity of life. Effective new chemotherapeutic agents could never be successfully tested in clinical trials if they possessed potent emetic side-effects. Although a number of agents have recently been found to be active, including metoclopramide, (4,5) haloperidol, (6) dexamethasone, (7) and lorazepam, (8) the need to introduce newer agents and combination antiemetic therapy may be necessary for continued control of symptoms. Also, complete control of nausea and vomiting during anticancer treatment must take into account not only the physical effects but also the psychological ones. Control of anxiety through behavior modification and relaxation is an effective antiemetic treatment of anticipatory nausea and vomiting. (9) Natural and synthetic cannabinoids are known to be effective antiemetic agents. (10-12) Delta-9-tetrahydrocannabinol (THC) has been found to be superior to prochlorperazine. (13) Also, patients who are refractory to standard antiemetic agents have significant reduction in nausea and vomiting with oral THC. (14) There is little information on the efficacy of inhalation marijuana aside from anecdotal reports from patients who obtained the drug privately. As a part of a New York State Department of Health program, North Shore University Hospital conducted a preliminary study of the use of inhalation marijuana as an antiemetic agent for cancer chemotherapy. The purpose of this study was to evaluate the efficacy of inhalation marijuana for patients refractory to standard agents, to identify patient characteristics to predict response, and to evaluate toxicity and patient acceptance of this form of treatment. METHODS Patients with histologically confirmed malignancies who were actively receiving chemotherapy were entered into the protocol. Eligibility criteria included: 18 years of age or older, refractoriness to conventional antiemetic agents, and absence of severe cardiac or psychiatric disease. Patients had to agree not to drive or operate heavy machinery or a motor vehicle for at least 12 hours after the last dose of marijuana. Central nervous system depressants including alcohol were prohibited during the administration of marijuana. Marijuana cigarettes were supplied by the National Institute on Drug Abuse (NIDA) to the New York State Department of Health. All patients were instructed on standard smoking procedures. The patient inhales deeply, holds the inhalation for ten seconds, and then exhales. After waiting 10 to 15 seconds, the cycle is repeated. The total dose is completed within five minutes. A flame-proof holder was available to permit delivery of nearly all of the cigarette appropriate to the patient's dosage. The dose schedule, which was calculated to the nearest one-fourth cigarette; was 5 mg THC/m2, starting 6-8 hours prior to chemotherapy and every 4-6 hours thereafter, for a total dose of four doses per day on each day of chemotherapy (one cigarette = 10.8 mg THC). In order to prevent cigarettes from drying out and causing harsh smoke, patients were instructed to keep the cigarettes in the refrigerator or humidified. This was a nonrandomized study where patients served as their own controls. Patients were asked to self-rate their status by completing a patient evaluation form after each therapeutic episode. Nausea was graded on a scale from 1 (none) to 4 (severe), vomiting was graded from 1 (none) to 5 (10+ times), appetite was graded from 1(none) to 5 (above normal), and physical state was graded from 1 (very weak) to 4 (above normal), and mood was graded from 1 (very depressed to 5 (very happy). Based on the degree of nausea, vomiting, food intake, physical state, and over-all mood, patients rated the overall effectiveness of marijuana as none, moderately effective, and very effective. Physician investigators were approved by the Hospital's Patient Qualification Review Board. Physicians utilized the official New York State triplicate prescription form as their research order for medication. Informed consent was obtained from all patients and the procedures followed were approved by an institutional research committee. RESULTS Seventy-four patients entered the study and 56 were evaluable. Eighteen patients who had initially agreed to be treated with marijuana later decided not to participate. Eighteen patients rated the marijuana very effective (34%) and 26 patients rated it moderately effective (44%) for an overall response rate of 78% (44/56). Twelve patients (22%) noted no benefit.
Characteristics of responding and nonresponding patients are listed in Table I. While no statistically significant differences were noted between responders and nonresponders with regard to sex, type of diagnosis, prior radiation therapy, prior oral THC treatment, incidence of euphoria, or smoking history, it is important to remember that the sample sizes were small, making interpretation of differences difficult. Patients who responded to marijuana cigarettes were more likely to be younger, median age 40 vs 54 for nonresponders, and had prior marijuana exposure, 52% vs 17% (p= 0.06). The most common diagnoses for this group of patients were breast cancer, lymphoma, lung cancer, colon cancer, ovarian cancer, testicular cancer, sarcoma, acute leukemia, and myeloma. The most common emetic chemotherapeutic agents were cyclophosphamide, doxorubicin, cis-platinum, procarbazine, methotrexate, dacarbazine, and streptozocin, given either singly or in combination. Four of seven patients treated with cis-platinum responded favorably to marijuana cigarettes. Toxic side effects included sedation in 88%, dry mouth in 77%, dizziness in 39%, and confusion in 13%. Anxiety, headache, and fantasizing were also seen but were less common. There was no toxicity in 13% of patients (Table II).
DISCUSSION The results of this prospective study suggest that inhalation marijuana is active in controlling nausea and vomiting resulting from chemotherapy. Marijuana benefited patients who were treated with a wide range of chemotherapeutic agents including drugs which have considerable emetogenic potential. A prior report by Chang et al (15) documented effectiveness of oral THC and inhaled marijuana against high-dose methotrexate, which normally has mild gastrointestinal toxicity. While most experience indicates that THC is generally ineffective against cis-platinum-induced emesis, benefit was seen in a small number of patients treated in our program with this agent. Since this was a single arm, nonrandomized, outpatient program, this study lacks a controlled placebo group. Nevertheless, the patients acted as their own controls, having previously failed standard antinausea medications. They evaluated marijuana based on their subjective rating of the severity of nausea, vomiting, appetite and food intake, mood, and physical state after chemotherapy treatment. A placebo-controlled, randomized inpatient study which quantitates all emetic episodes would obviously provide objective and precise information. (16) Failure to respond to oral THC does not preclude benefit from inhaled marijuana. Twenty-nine percent of patients who failed oral THC responded to the cigarette form. This is not unexpected, since only 5-10% of orally administered THC is absorbed, whereas inhaled marijuana has a five-to tenfold greater bioavailability. (17) Clearly, oral THC is an effective treatment for chemotherapy-induced emesis. Most studies have demonstrated THC to be better than placebo and comparable to prochlorperazine. Patient characteristics were evaluated to identify factors which would predict response to marijuana. There were no significant differences between responders and nonresponders with regard to sex, diagnosis, prior radiation therapy, prior THC ingestion, induced euphoria, and history of cigarette smoking. The only factors that approached significance were young age and prior marijuana intake. Unlike the experience with oral THC, experiencing a euphoric high was not a prerequisite to obtaining the antiemetic effect with marijuana. (20) The mechanism of the antiemetic action of cannabinoids is unknown. Inhibition of prostaglandin and cyclic adenosine monophosphate has been suggested. Its major action is more likely related to its effect on the brain, as marijuana causes central nervous system depression and impairment of brain function. At the cellular level, cannabinoids interfere with the synthesis of nucleic acids and chromosome proteins. (21) Some of the problems encountered in this study which could influence interpretation of the results were the low patient accrual and the fact that nearly 25% of patients who initially consented refused to receive treatment. Reasons for patients' refusal to participate included physician and patient bias against smoking, harshness of smoke from the cigarettes, and preference for oral THC capsules. The major objection was related to the social stigma attached to the use of marijuana. Many patients rejected the idea of "smoking pot" at home and exposing their children to the implications of this type of medication. Should this therapy become available in a different vehicle of administration, patient acceptance would significantly improve. Our results demonstrate that inhalation marijuana is an effective therapy for the treatment of nausea and vomiting due to cancer chemotherapy. A randomized, controlled trial would, however, be necessary to accurately define the exact role of this drug. Toxic effects are well tolerated and the availability of a parenteral form would improve patient utilization of this agent. Future antiemetic protocols should include the active ingredient of marijuana in combination with current effective agents. Acknowledgments. The authors thank Rosemarie Galderisi and Annie Middleton for their assistance. REFERENCES 1. Seigel LJ, Longo DL: The control of chemotherapy-induced emesis. Ann Intern Med 1981; 95: 352-359. 2. Frytak S, Moertel CG: Management of nausea and vomiting in the cancer patient. JAMA 1981; 245: 393-396. 3. Bakowski MT: Advances in anti-emetic therapy. Cancer Treat Rev 1984; 11: 237-256. 4. Meyer BR, Lewin M, Drayer DE, et al: Optimizing metoclopramide control of cisplatin-induced emesis. Ann Intern Med 1984; 100: 393-395. 5. Kris MG, Gralla RJ, Tyson LB, et al: Improved control of cisplatin-induced emesis with high-dose metoclopramide, and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 225 patients. Cancer 1985; 55: 527-534. 6. Neidhart JA, Gagen M, Young D, et al: Specific antiemetics for specific cancer chemotherapeutic agents: Haloperidol versus benzquinamide. Cancer 1981; 47: 1439-1443. 7. Cassileth PA, Lusk EJ, Torri S, et al: Antiemetic efficacy of dexamethasone therapy in patients receiving cancer chemotherapy. Arch Intern Med 1983; 143: 1347-1349. 8. Bishop J, Oliver I, Wolf M, et al: Lorazepam: A randomized, double blind, crossover study of a new antiemetic in patients receiving cytotoxic chemotherapy and prochlorperazine. J Clin Oncol 1984; 2: 691-695. 9. Morrow GR: Clinical characteristics associated with the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy treatment. J Clin Oncol 1984; 2: 1170-1176. 10. Laszlo J: Tetrahydrocannabinol: From pot to prescription [editorial]. Ann Intern Med 1979; 91: 916-918. 11. Stack P: The pharmacologic profile of nabilone: A new antiemetic agent Ca Treat Rev 1982; 9 (suppl B): 11-16. 12. Frytak S, Moertel CG, O'Fallon J, et al: Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. Ann Intern Med 1979; 91: 825-830. 13. Sallan SE, Cronin C, Zelen M, et al: Antiemetics in patients receiving chemotherapy for cancer. A randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 1980; 302: 135-138. 14. Lucas VS, Laszlo J: Delta-9-tetrahydrocannabinol for refractory vomiting induced by cancer chemotherapy. JAMA 1980; 243: 1241-1243. 15. Chang AE, Shilling D, Stillma RC, et al: Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. Ann Intern Med 1979; 91: 819-824. 16. Carey MP, Burish TG, Brenner DE: Delta-9-tetrahydrocannabinol in cancer chemotherapy: Research problems and issues. Ann Intern Med 1983; 99: 106-114 17. Nahas GG: Current status of marijuana research. Symposium on marijuana held July 1978 in Reims, France. JAMA 1979; 242: 2775-2778. 18. Poster DS, Penta JS, Bruno S, et al: Delta-9-tetrahydrocannabinol in clinical oncology. JAMA 1981; 245: 2047-2051. 19. Citron ML, Herman TS, Vreeland F, et al: Antiemetic efficacy of levonantradol compared to delta-9-tetrahydrocannabinol for chemotherapy-induced nausea and vomiting. Ca Treat Rev 1985; 69: 109-112. 20. Ungerleider JT, Andrysiak T, Fairbanks L, et al: Cannabis and cancer chemotherapy. Cancer 1982; 50: 636-645. 21. Council on Scientific Affairs: Marijuana. Its health hazards and therapeutic potentials. JAMA 1981; 246: 1823-1827. |
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