Cannabinoids are compounds present in the Cannabis plant that bind to cannabinoid receptors and exert pharmacologic effects that stimulate appetite, act as antiemetics, and have analgesic effects. Cannabinoids approved for use in the United States include dronabinol and nabilone. Cannabis compounds studied for symptom management in patients with cancer have been in oral forms, oral spray, or ingested through smoking. It should be noted that not all Cannabis formulations or methods of ingestion necessarily provide the same effects and results.
Recommended for Practice
Cotter, J. (2009). Efficacy of crude marijuana and synthetic delta-9-tetrahydrocannabinol as treatment for chemotherapy-induced nausea and vomiting: A systematic literature review. Oncology Nursing Forum, 36, 345–352.doi: 10.1188/09.ONF.345-352
To determine if oral synthetic tetrahydrocannabinol (THC) and smoked marijuana are effective in the treatment of chemotherapy-induced nausea and vomiting (CINV), and to evaluate the side effects and patient preferences for treatment
Databases searched were MEDLINE (1966–present), CINAHL (1982–present), and the Cochrane Library. A search of article reference lists also was performed.
Search keywords were nausea, vomiting, cancer, chemotherapy, cannabis, marijuana, and dronabinol.
Studies were included in the review if they
- Reported on human clinical trials.
- Involved treatment with smoked marijuana or oral synthetic THC for CINV.
- Were in English.
The author retrieved 18 relevant citations, 10 of which were clinical trials and included in the review. The author evaluated the quality of the reference based on strength of evidence, study design, sample size, and purpose. Specific criteria were not described.
- A total of 929 patients were involved across the 10 included studies.
- Sample sizes ranged from 15 to 214.
- Subjects had a variety of diagnoses and were receiving various types of chemotherapy.
- Six studies involved the use of chemotherapy that was of moderate to high emetogenic potential.
- Two studies evaluated the efficacy of oral synthetic THC versus placebo. In both studies, THC was significantly better than placebo at reducing CINV (p < 0.001).
- A one-group study tested crude marijuana; 78% of patients reported it to be moderately or highly effective. However, 18 patients dropped out of the study because they did not accept the smoking route of administration.
- Three studies examined oral synthetic THC versus phenothiazines. Two of these studies found that THC was significantly more effective in controlling CINV (p < 0.05) while the third found no difference. Timing and dosages differed across studies. In one study, patients who took THC reported significantly more sedation, incoordination, and feelings of being high than those receiving compazine or placebo.
- One study found that the combination of THC and antiemetics was most successful in mitigating severity and duration of CINV.
- In one study of smoked marijuana versus phenothiazines, no differences were found between groups.
- In a comparison of oral THC versus smoked marijuana, both were found to be effective with no significant differences found between these approaches.
- One study compared oral THC versus 5-HT3 receptor antagonists (RAs) in a randomized, controlled, double-blind design. All patients received a standard antiemetic protocol of dexamethasone and ondansetron prior to chemotherapy and then were randomly assigned to also receive THC, placebo, or other drugs alone or in combination. All drugs were more effective than placebo, but no significant differences were found between those who took the THC and the other medication groups.
- A number of these studies had small sample sizes, and one lacked a control group.
- Both oral THC and smoked marijuana were found to be more effective than placebo and as equally effective as other commonly used antiemetics in controlling CINV.
- Oral THC appears to be as effective as smoked marijuana.
- THC was associated with more side effects (sedation, lack of coordination, and feeling “high”).
- Some patients found the inhalation route for marijuana use to be unacceptable.
- Some patients may not be able to tolerate the harsh smoke, and, because crude marijuana may contain bacteria or fungi, concerns exist for immunocompromised patients.
- Cannabinoids appear to have value as adjuvant medication, and the evidence supports their use for mitigation of CINV. They appear to be most effective in combination with other antiemetics.
Nurses need to review potential sides effects. Individual patients can have differing concerns as a result of other problems or preferences. Oral THC may be the best option for use among patients with cancer.
Davis, M.P. (2008). Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opinion on Investigational Drugs, 17(1), 85-95.doi: 10.1517/135437126.96.36.199
Keywords searched were cannabinoids, nabilone, nausea, pain, tetrahydrocannabinol, and vomiting.
This was a review of published English literature, including reviews, meta-analysis, and treatment trials from 1975–1997 on using cannabinoids to control or prevent chemotherapy-induced nausea and vomiting (CINV), with very few trials found after 1997. From this review, 30 randomized control trials were found that looked at cannabinoids to control or prevent CINV. Overall, the trials received low scores for adequacy of randomization, blinding design, and description of withdrawal. Three cannabinoids were studied: nabilone (16), dronabinol (13), and levonantradol (1). The medications were compared to prochloperazine (12), placebo (10), metochlorpramide (4), chlorpromazine (2), domperidone (2), alizapride (1), thiethylperazine (1), and haloperidol (1). Twelve studies involved various scoring systems. No clear separation existed between acute and delayed CINV.
The trials included 1,760 patients, with 394 excluded.
- Nabilone was found to be superior to placebo, domperidone, and prochlorperazine but not metoclorpramide.
- Cannabinoids did not add to the benefits of 5-HT3 receptor antagonists.
- Side effects were greater for nabilone than prochloperazine in these studies, but patients preferred nabilone to prochloperazine.
- The major limitation of these studies was the grading of response and the inability to differentiate between acute and delayed CINV.
- The adequacy of randomization, blinding design, and description of withdrawal were insufficient.
- The time period for the review was limited to 1975–1997. From 1997–present, many changes in managing CINV have occurred.
- The databases of the search were not indicated.
Cannabinoids, like nabilone, may have a role in reducing delayed or refractory CINV, but more evidence is needed.
Keeley, P.W. (2009). Nausea and vomiting in people with cancer and other chronic diseases. BMJ Clinical Evidence, 2406.
To determine the effects of treatments for nausea and vomiting either as a result of the disease or its treatment in adults with cancer and other chronic diseases
Databases reviewed searched were MEDLINE, Embase, and the Cochrane database. Harm alerts from the Food and Drug Administration (FDA) and the United Kingdom regulatory agency also were reviewed.
No separate description of the volume of literature evaluated or the specific evaluation process was provided. The Grading of Recommendations Assessment, Development and Evaluation (GRADES) system was used for rating the evidence, and these results were provided. The literature review was completed as of April 2008.
The study reported on 13 randomized, controlled trials (RCTs), representing more than 14,000 patients with cancer. These included studies of nausea and vomiting as a result of disease or treatment.
Results indicated that 5-HT3 RAs + dexamethasone was beneficial.
The following were identified as likely to be beneficial.
- 5-HT3 RAs + corticosteroid with radiotherapy-induced nausea and vomiting
- Aprepitant added to conventional regimens
- Metoclopramide for chemotherapy-induced nausea and vomiting (CINV)
- Venting gastrostomies
Cannabinoids were identified as being a tradeoff between benefit and harm.
The following were determined to have unknown effectiveness.
- 5-HT3 receptor antagonists (RAs) for radiation-induced nausea and vomiting
- Benzodiazepines for CINV
- Although no evidence was identified, and, at this writing, there was a stated drug safety alert on haloperidol, this review identified haloperidol as likely to be beneficial. It is unclear how this can meet this category.
- Results cited tended to focus on vomiting episodes and did not address the symptom of nausea.
- Results were a mix of symptoms from the disease itself or treatment, so differentiation of applicability was not always clear.
- Some aspects of the search strategy were unclear.
- Some interventions stated that no RCTs or systematic reviews were found, so no evidence was provided; however, in other areas, observational studies and consensus opinions were cited as supporting evidence.
- Inclusion and exclusions were not stated.
- No information was included on nonpharmacologic interventions in combination with antiemetic regimens.
Machado Rocha, F.C., Stefano, S.C., De Cassia Haiek, R., Rosa Oliveira, L.M., & Da Silveira, D.X. (2008). Therapeutic use of cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: Systematic review and meta-analysis. European Journal of Cancer Care, 17, 431–443.doi: 10.1111/j.1365-2354.2008.00917.x
To use a systematic literature review and meta-analysis to evaluate interventions using Cannabis sativa in the treatment of chemotherapy-related nausea and vomiting
Databases searched were MEDLINE, Embase, PsycINFO, LILACS, and the Cochrane Collaboration Controlled Trials Register (12-2006).
Searched keywords were Medical Search Headings (MeSH) therapeutics, drug therapy, chemical and pharmacologic phenomena, neoplasms, antineoplastic and immunosuppressive therapy, marijuana abuse, cannabis, randomized controlled trials, and clinical trials.
Studies were included in the review if they
- Were randomized clinical trials (RCTs).
- Involved people with any type of cancer receiving chemotherapeutic treatment of low-, moderate-, or high-emetic potential.
- Were published in peer-reviewed journals.
- Evaluated pharmacologic interventions based on substances derived from Cannabis sativa or smoked Cannabis.
Studies were excluded from the review if they involved patients receiving radiotherapy.
The initial search yielded 12,749 papers. After scanning titles for inclusion, 735 abstracts were evaluated. Of these, 96 papers were reviewed and a final sample of 30 RCTs were included in the review. RCTs that were appropriate for meta-analysis numbered 13. Studies were rated for quality using the Cochrane Manual for methodological quality evaluation in terms of bias risk.
- A final sample of 30 studies was included in the systematic review, and 13 studies were included in meta-analysis.
- Sample sizes varied among studies, with only six studies involving more than 100 patients.
- Across studies, the total sample size was 1,719.
- Two studies comparing dronabinol to placebo showed a trend favoring dronabinol, but it was not significant (p = 0.10).
- In five studies comparing dronabinol to neuroleptics, dronabinol was significantly better than the comparisons (relative response [RR] = 0.67, p = 0.03).
- In six studies comparing nabilone to neuroleptics, no significant differences were found.
- Four studies comparing levonantradol to neuroleptics showed no differences.
- In 18 studies composed of 1,138 patients, participants had a significant preference for cannabis (RR = 0.33, p < 0.00001).
- All of the studies had low or only moderate risk of bias.
- Patients taking cannabinols had a higher number of collateral effects and tended to have higher symptom intensity.
- Most patients preferred cannabis-based treatment when asked about their preferred drug.
- Different cannabis derivatives demonstrated different effectiveness when compared to standard treatment used at the time.
- Newer and more effective approaches for management of nausea and vomiting have emerged in practice since these studies were conducted.
- Comparative effectiveness of cannabis derivatives versus these approaches is unknown.
- If patients do not respond to antiemetics or they experience increased emesis after taking antiemetics, increased dosage or frequency of administration is not recommended.
- Because cannabinoids appear to act through different mechanisms than other drugs, they may be effective for people with nausea and vomiting that does not respond to other management approaches.
- Clinical trials comparing cannabinoids to modern antiemetics are warranted.
Research Evidence Summaries
Duran, M., Perez, E., Abanades, S., Vidal, X., Saura, C., Majem, M., … Capella, D. (2010). Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. British Journal of Clinical Pharmacology, 70, 656–663.doi: 10.1111/j.1365-2125.2010.03743.x
To evaluate the effect, toleration, and pharmacokinetics of dose titration of cannabis oral spray added to standard therapy to control chemotherapy-induced nausea and vomiting (CINV) in patients receiving a moderately emetogenic regimen
Intervention Characteristics/Basic Study Process:
- Patients were eligible if they had experienced more than 24 hours of CINV despite standard antiemetic treatment after receiving one day of moderately emetogenic chemotherapy (MEC).
- Standard antiemetics included corticosteroids, 5-HT3 antagonists, or metoclopramide.
- The Cannabis-based medicine (CBM) used was a mixture of tetrahydrocannabinol (THC) and cannabidiol 1:1 (Sativex®), with other cannabinoid derivatives, delivered in an oral spray.
- Patients were randomly assigned to the Cannabis spray (CBM) or a placebo, which was designed to match the appearance, smell, and taste of the active formula.
- On the first day of treatment, subjects received up to 3 sprays within a two-hour period following chemotherapy administration. If no signs of intoxication were seen after the first spray, a second and third were given after 30 minutes and 120 minutes.
- Patients were advised to increase home dose until day four, with up to 8 sprays within any four-hour period, every 24 hours.
- Blood samples were collected at several time points for the pharmacokinetic analysis.
- The study consisted of 16 participants.
- Median age was 50 with a range of range 34–76 years.
- The majority of participants were female (94%).
- Most patients had breast cancer.
- All patients had received one cycle of chemotherapy and were enrolled in the following cycle that included MEC agents. All had good performance status.
- Exclusion criteria were current use of illicit drugs or alcohol abuse, radiation therapy to abdomen or pelvis within one week, or cannabinoid use within 30 days prior to enrollment.
They study was conducted at multiple outpatient settings in Barcelona, Spain.
Phase of Care and Clinical Applications:
All patients were in active treatment.
This was a randomized, double-blind, placebo-controlled, parallel, phase-II trial.
Complete response was defined as no vomiting and a mean nausea score of ≤ 10 mm.
Partial response was defined as vomiting 1-4 times daily and a mean nausea score of ≤ 25 mm on a 100-mm visual analogue scale (VAS).
The following additional measurement instruments were used.
- Morrow Assessment of Nausea and Vomiting (MANE) questionnaire for frequency and duration of nausea and vomiting
- Functional Living Index-Emesis (FOIE) patient daily diary for recording of adverse events
- Daily structured telephone interview
- The mean number of daily sprays during the four days after chemotherapy was 4.81 in the CBM group, equivalent to 12.9 mg of THC.
- In the CBM group, 6 out of 7 patients tolerated dose titration. One patient discontinued treatment because of anxiety, somnolence, visual hallucinations, and confusion. These symptoms disappeared after three hours.
- Somnolence, dry mouth, and fatigue were the most common adverse events in both groups.
- In the delayed period, complete response was higher in the CBM group (71.4%) than in the placebo group (22.2%).
- In the acute period, no difference was found between the groups.
- A larger percentage of patients in the CBM group had no delayed emesis (71.4%) or nausea (57.1%) than in the placebo group (22.2%).
- Plasma concentrations showed a wide variability across subjects and suggested that patients following a repeat-administration schedule accumulate CBM active compound over time, despite the relatively short half-life of the active compounds.
The addition of this formulation of Cannabis to standard antiemetic treatment appears to improve control of delayed nausea and vomiting with MEC.
- The sample size was extremely small.
- The standard antiemetic regimen was less than what is currently recommended; however, it did follow recommendations at the time of the study.
- No discussion of the use of or need for rescue medications was provided.
- Other research has shown effectiveness of Cannabis compounds for CINV.
- The addition of Cannabis compounds to other antiemetic regimens may be specifically helpful in patients with refractory CINV, and it may be most helpful with delayed nausea and vomiting.
- The delivery system of an oral spray provides an alternative that may be helpful. Further research in the use of this formulation is warranted.
Meiri, E., Jhangiani, H., Vredenburgh, J.J., Barbato, L.M., Carter, F.J., Yang, H.M., Baranowski, V. (2007). Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Current Medical Research and Opinion, 23(3), 533-543.doi: 10.1185/030079907X167525
To compare the effectiveness of dronabinol alone or in combination with ondansetron versus ondansetron alone for delayed, chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) in multiple cancer centers
Intervention Characteristics/Basic Study Process:
- The study took place over five days.
- Participants were randomized to four treatment groups: dronabinol alone, ondansetron alone, combination with both drugs, and placebo.
- Standard pretreatment medications, fixed doses on day 2, and flexible doses days 3-5 were administered.
- Participants were assessed based on patient telephone diary entries. Each morning, patients reported symptoms from the previous day via the Interactive Voice Response System.
- The study consisted of 64 participants, aged 18 years or older, with a malignancy that did not involve bone marrow.
- Participants were undergoing chemotherapy regimens and had performance statuses of 0–2 at screening. They could be receiving concurrent radiation except to the abdomen and changing regimens with last antiemetics seven days prior to study enrollment.
- For women, a negative pregnancy test at baseline was required.
- Diagnoses involved primary malignancy of the brain, spinal cord, or nervous system; brain metastases; severe brain trauma or surgery; leukemias; or lymphomas.
- Patients who had used marijuana within 30 days or antiemetics within 7 days were excluded from the study.
The study was conducted at multiple cancer centers.
This was a randomized, double-blind, placebo-controlled, parallel-group study.
The following measurement instruments were used.
- Visual analog scale (VAS)
- Total response
- Intensity of nausea
- Eastern Cooperative Oncology Group (ECOG) performance status
- McCorkle Symptom Distress Scale
Difficulties in enrollment led to early termination of this study.
- The efficacy of dronabinol alone was comparable with ondansetron for the treatment of delayed CINV in patients with cancer receiving HEC or MEC.
- Combination therapy with dronabinol and ondansetron was not more effective than either agent alone.
- Patients had difficulties with potential for randomization to placebo when receiving HEC or MEC.
- Early discontinuation of the study reduced the number of participants enrolled in each treatment group.
- The population was heterogeneous.
- No control chemotherapy treatment was used.
- The majority of patients had breast or lung cancer.
National Comprehensive Cancer Network. (2012). NCCN Clinical Practice Guidelines in Oncology: Palliative Care [v.2.2012]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf
Purpose & Patient Population:
The objective of the guidelines is to provide palliative care practice guidelines for patients with cancer, facilitating the appropriate integration of palliative care into oncology practice.
Type of Resource/Evidence-Based Process:
These are consensus-based guidelines.
Phase of Care and Clinical Applications:
Included in the guidelines are multiple phases of care with palliative care applications.
Guidelines & Recommendations:
The NCCN made recommendations on the following symptoms.
Nutritional support, including enteral and parenteral feeding, should be considered. Appetite stimulants such as megestrol acetate and corticosteroids can be used when appetite is an important aspect of quality of life.
Chemotherapy-Induced Nausea and Vomiting (CINV)
Recommendations include prochlorperazine, haloperidol, metoclopramide, or benzodiazepines. Adding 5-HT3 receptor agonists, anticholinergics, antihistamines, corticosteroids, antipsychotics, and cannabinoids also can be considered. Palliative sedation can be considered as a last resort.
Increase fluid intake, dietary fiber, and physical activity. Opioid-induced constipation should be anticipated and treated prophylactically with laxatives.
Pharmacologic interventions include opioids or benzodiazapines. Scopolamine, atropine hyoscyamine, and glycopyrrolate are options to reduce excessive secretions.
Do not reduce opioid dose for symptoms such as decreased blood pressure or respiratory rate. Palliative sedation can be considered for refractory pain.
For refractory insomnia with no underlying physiologic cause, pharmacologic management includes diazepam, zolpidem, and sedating antidepressants. Cognitive behavioral therapy may be effective. If present, restless leg syndrome can be treated with ropinirole.
- Recommendations are predominantly consensus- rather than evidence-based.
- Recommendations are generally based on low-level evidence.
- Recommendations regarding CINV seem particularly out of date and are not in concert with current evidence.
Recommendations provide expert opinion/consensus-level suggestions for management of various symptoms. Many recommendations, such as those for CINV, do not agree with current evidence in these areas.
Roila, F., Herrstedt, J., Aapro, M., Gralla, R.J., Einhorn, L.H., Ballatori, E., … ESMO/MASCC Guidelines Working Group. (2010). Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: Results of the Perugia consensus conference. Annals of Oncology, 21(Suppl. 5), v232–v243.doi: 10.1093/annonc/mdq194
Type of Resource/Evidence-Based Process:
This Perugia consensus panel was composed of 10 committees that reported findings to a 23-member expert panel from 10 different countries. The panel determined level of evidence and made changes in 2004 guidelines if evidence supported a greater than 10% increase in benefit. Updates were approved by the European Society of Medical Oncology (ESMO) Guidelines Working Group. All author relationships were reported. The panel used MEDLINE and other databases, which were not specified.
Guidelines & Recommendations:
Emetogenicity of agents:
- As new agents are developed, often limited recording of common toxicities is provided in order to accurately reflect emetogenic potential.
- Increased use of oral agents and chronic oral administration creates issues regarding whether emetogenicity is defined by a single dose or a full course, and chronic use has blurred the lines between acute and delayed chemotherapy-induced nausea and vomiting (CINV).
- The authors provided an updated list of chemotherapy agents and levels of emetogenicity. Classification of oral agents was provided on the basis of a full course of treatment.
Prevention of acute CINV:
- Minimal risk: No routine prophylaxis
- Low risk: Day 1—dexamethasone or 5-HT3 receptor antagonists or dopamine receptor antagonist
Moderate emetogenic chemotherapy (MEC)
- With anthracycline: Day 1—5-HT3 receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—aprepitant
- Without anthracycline: Day 1—palonosetron + dexamethasone; days 2 and 3—dexamethasone
- Highly emetogenic chemotherapy (HEC): Day 1—5-HT3 receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—dexamethasone + aprepitant; day 4—dexamethasone
- Although studies have shown effectiveness of casopitant, the producer discontinued regulatory filings, so this was not recommended for use.
- All 5-HT3 receptor antagonists were found to show the same efficacy. More studies are needed to determine if palonosetron is more effective with cisplatin-based therapies.
Prevention of delayed CINV:
- Aprepitant should be used to prevent delayed CINV.
- Whether dexamethasone is as effective or if the combination of dexamethasone and aprepitant would be more effective is not known. The optimal dose and duration of dexamethasone is not defined.
- Prevention with multiple-day cisplatin was not clear. Aprepitant + dexamethasone for acute and dexamethasone for delayed CINV was recommended. The possible role of neurokinin 1 (NK1) was not clear.
Refractory CINV and rescue:
- Maximally effective prophylaxis should be used.
- The addition of cannabinoids, olanzapine, and nonpharmacologic interventions could be considered.
Prevention of anticipatory CINV:
- The best way to prevent this learned response is maximum effective control of acute and delayed CINV.
- Anticipatory CINV is difficult to control with medication.
- Benzodiazepines are the only drugs identified as effective, but efficacy tends to decrease as chemotherapy continues.
Prevention of CINV with high-dose chemotherapy:
- Complete protection is currently only achieved in a minority of patients.
- Current standard is dexamethasone + 5-HT3 receptor antagonists.
- Evaluation of the addition of aprepitant is needed.
Radiation-induced nausea and vomiting:
- Risk level and antiemetic guidelines are provided.
- Generally, prophylaxis with 5-HT3 receptor antagonists + dexamethasone and rescue with 5-HT3 receptor antagonists are recommended.
Antiemetics in children:
- All pediatric patients receiving MEC or HEC should receive prophylaxis with 5-HT3 and dexamethasone. Optimal dosing requires further study.
- No studies have evaluated approaches for prevention of anticipatory CINV.
- Metoclopramide, phenothiazines, and cannabinoids have shown only moderate efficacy.
The guidelines provide a clear set of recommendations and review of the relevant evidence strength assessed for various cancer treatment scenarios.
A complete listing of databases used for evidence retrieval was not provided.
Control of emesis has markedly improved in recent years; however, nausea remains a challenge and future research should shift attention to this aspect. Current trials generally define complete response end points that exclude consideration of the experience of nausea rather than vomiting. Trials suggest that some agents are more effective for acute vomiting, others are more effective for delayed vomiting, and some may be more effective for nausea. Identification of these differences and incorporation into the rationale for treatment needs to continue.
Further research is needed in the areas of prevention with high-dose chemotherapy and stem cell support, combined chemotherapy and radiation therapy, and anticipatory nausea and antiemetic use in children. Practitioners need to be aware of the impact of oral therapy and chronic oral chemotherapy treatment on current approaches to antiemetic treatment, timing, and definitions of acute and delayed CINV. Practitioners also need to be aware that current chemotherapy risk determination does not apply to combined radiotherapy and chemotherapy.