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Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics
Abstract
Chemotherapy-induced nausea and vomiting (CINV) is one of the most common symptoms feared by patients, but may be prevented or lessened with appropriate medications. Several antiemetic options exist to manage CINV. Corticosteroids, serotonin receptor antagonists, and neurokinin receptor antagonists are the classes most commonly used in the prevention of CINV. There are many alternative drug classes utilized for the prevention and management of CINV such as antihistamines, benzodiazepines, anticonvulsants, cannabinoids, and dopamine receptor antagonists. Medications belonging to these classes generally have lower efficacy and are associated with more adverse effects. They are also not as well studied compared to the aforementioned agents. This review will focus on dronabinol, a member of the cannabinoid class, and its role in CINV. Cannabis sativa L. (also known as marijuana) contains naturally occurring delta-9-tetrahydrocannibinol (delta-9-THC). The synthetic version of delta-9-THC is the active ingredient in dronabinol that makes dronabinol an orally active cannabinoid. Evidence for clinical efficacy of dronabinol will be analyzed in this review as monotherapy, in combination with ondansetron, and in combination with prochlorperazine.
... Dronabinol is synthetic tetrahydrocannabinol (THC) that has been US Food and Drug Administration (FDA) approved since 1985 to treat HIV/AIDS-induced anorexia and to treat patients who do not respond to conventional anti-emetics from the nausea and vomiting of chemotherapy [1,2]. Dronabinol activates the cannabinoid CB 1 receptor, stimulating appetite and provoking an anti-emetic response by reducing the emetic effects of endogenous neurochemicals like dopamine and serotonin [1,2]. ...
... Dronabinol is synthetic tetrahydrocannabinol (THC) that has been US Food and Drug Administration (FDA) approved since 1985 to treat HIV/AIDS-induced anorexia and to treat patients who do not respond to conventional anti-emetics from the nausea and vomiting of chemotherapy [1,2]. Dronabinol activates the cannabinoid CB 1 receptor, stimulating appetite and provoking an anti-emetic response by reducing the emetic effects of endogenous neurochemicals like dopamine and serotonin [1,2]. Over half of chemotherapy cycles adversely affected the quality of life for patients by inducing undesirable effects including nausea, vomiting, anorexia, nutrient depletion, and metabolic imbalances. ...
... Over half of chemotherapy cycles adversely affected the quality of life for patients by inducing undesirable effects including nausea, vomiting, anorexia, nutrient depletion, and metabolic imbalances. By using dronabinol alone or in combination with conventional anti-emetics like ondansetron and prochlorperazine, randomized clinical trials concluded that dronabinol helped prevent nausea and vomiting episodes [2]. Prescription THC activates the CB 1 to combat weight loss and wasting syndrome from HIV by increasing appetite [1]. ...
Introduction:
Dronabinol is approved in the USA for chemotherapy-induced nausea as well as vomiting and HIV-induced anorexia, while cannabidiol is primarily approved for childhood epileptic disorders Lennox-Gastaut and Dravet syndrome. The use pattern for these prescription cannabinoids in the USA is unknown. This study examined Medicaid claims for two FDA-approved prescription cannabinoids, dronabinol and cannabidiol, approved in 1985 and 2018, respectively, from 2016-2020 to better understand the pharmacoepidemiologic trends and distribution of these drugs in US Medicaid amidst the increasing use of non-pharmaceutical formulations of cannabis.
Methods:
The longitudinal study analyzed Medicaid prescription claims that were calculated by extracting the prescriptions on a state level from 2016 to 2020 for two cannabinoids, dronabinol and cannabidiol, where outcomes over each year were calculated. Outcomes were (1) the number of prescriptions for each state corrected for the number of Medicaid enrollees and (2) dronabinol and cannabidiol spending. Spending refers to the amount reimbursed by the state Medicaid program.
Results:
Dronabinol prescriptions per state decreased by 25.3% from 2016 to 2020, while cannabidiol prescriptions increased by 16,272.99% from 2018 to 2020. The spending on these drugs parallels that of their prescription trend with a 66.3% decrease in reimbursement for dronabinol ($5.7 million in 2020), whereas cannabidiol increased by +26,582.0% ($233.3 million in 2020). Dronabinol prescriptions, when corrected for the number of enrollees, in Connecticut were 136.4 times larger than in New Mexico, and seventeen states had zero prescriptions. Idaho's prescriptions of cannabidiol (27.8/10,000 enrollees) were significantly elevated relative to the national average and were 15.4-fold higher than Washington, DC (1.8/10K enrollees).
Conclusions:
The prescriptions of pharmaceutical-grade tetrahydrocannabinol decreased while those of cannabidiol increased. This study also identified pronounced state-level variation in cannabinoid prescribing to Medicaid patients. State formularies and prescription drug list variation may contribute to the drug reimbursements in Medicaid, though further research is needed to identify the health policy or pharmacoeconomic origins of these disparities.
... However, both the FDA and EMA have approved the use of drugs that contain individual cannabinoids (Whiting et al., 2015). Some examples include Epidiolex, a purified form of CBD used for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome (Sekar and Pack, 2019) (FDA and EMA-approved) or Dronabinol (FDA-approved)-a synthetic THC used as an appetite stimulant in AIDS-related cachexia (Badowski and Yanful, 2018) and for alleviating chemotherapy-induced nausea and vomit in cancer patients (May and Glode, 2016). Another area of interest is the treatment of post-traumatic stress disorder (PTSD) in military personnel with THC or nabilone (Sholler et al., 2020). ...
... Oncology practice guidelines for clinicians, NCCN and ASCO include the indication of Nabilone and Dronabinol for nausea and vomiting refractory to conventional therapy. 2.5-5 mg oral solution Dronabinol should be used every 4-6 h 1-2 mg of Nabilone can be used twice daily as rescue therapy (May and Glode, 2016). ...
Cannabis enjoyed a “golden age” as a medicinal product in the late 19th, early 20th century, but the increased risk of overdose and abuse led to its criminalization. However, the 21st century have witnessed a resurgence of interest and a large body of literature regarding the benefits of cannabinoids have emerged. As legalization and decriminalization have spread around the world, cancer patients are increasingly interested in the potential utility of cannabinoids. Although eager to discuss cannabis use with their oncologist, patients often find them to be reluctant, mainly because clinicians are still not convinced by the existing evidence-based data to guide their treatment plans. Physicians should prescribe cannabis only if a careful explanation can be provided and follow up response evaluation ensured, making it mandatory for them to be up to date with the positive and also negative aspects of the cannabis in the case of cancer patients. Consequently, this article aims to bring some clarifications to clinicians regarding the sometimes-confusing various nomenclature under which this plant is mentioned, current legislation and the existing evidence (both preclinical and clinical) for the utility of cannabinoids in cancer patients, for either palliation of the associated symptoms or even the potential antitumor effects that cannabinoids may have.
... 4 Delayed phase is more common and severe than the other phases manner and is resistant to antiemetic treatment. 5 According to NCCN guidelines, standard antiemetic agents for patients receiving moderate and high emetogenic chemotherapy include 5-HT3 antagonists, dexamethasone, NK1 RAs, and olanzapine. However, NK1 RAs and olanzapine were added for patients receiving high emetic risk chemotherapy. ...
Objective:
To evaluate the effects of tetrahydrocannabinol (THC):cannabinoid (CBD) (1:1) oil in reducing chemotherapy-induced nausea and vomiting (CINV) in gynecologic cancer patients who received moderate-to-high emetogenic chemotherapy.
Material and method:
This was a randomized, double-blinded, crossover and placebo-controlled trial. The study was conducted at the Gynecologic Oncology Units, Bhumibol Adulyadej Hospital (BAH), Royal Thai Air Force, Bangkok, Thailand, between August and November 2022. Participants had gynecologic cancer and received moderate-to-high emetogenic chemotherapy. Subjects were randomized and divided into two groups (A and B) based on the block of four randomization method. In the first cycle, groups A and B received THC:CBD extract oil 1:1 (TCEO) and placebo before chemotherapy administration. In the second cycle, groups A and B received placebo and TCEO before chemotherapy administration. Both groups received per protocol antiemetic medication during chemotherapy. Nausea score and side effects were recorded.
Results:
A total of 60 cases were recruited. After exclusion, 54 cases were included in the study. The mean age of participants was 54.4 years. The mean body mass index (BMI) was 26.5 kg/m2. Fifty-nine (21/54) percent cases were the advanced stages of cancer. The nausea score of TCEO and placebo groups were 2.11 and 2.99, respectively (P < 0.05). More than half of the participants (36/54) reported dizziness and sedation side effects. Dry mouth, confusion, anxiety, and palpitation of both groups were comparable.
Conclusion:
The cannabinoid extract (THC:CBD) was an appropriate adjuvant agent to reduce CINV in patients with gynecologic cancer who received high-emetogenic chemotherapy. Dizziness and sedation were the major side effects.
... However, harmful side effects occurred more often with the administration of cannabinoids which includes dizziness, hallucination, paranoia, arterial hypotension, euphoria, sedation, or drowsiness. [31] The downside of it was that patients given cannabinoids were more likely to redraw. Two prescription cannabinoids approved by FDA are available, dronabinol (synthetic ∆ 9 -THC) and Nabilone (a THC congener). ...
The use of cannabis for medical purposes has been a subject for discussion for so many years. Cannabis as a source of medical treatment first came to light in the 19th century. However, origins of cultivation of marijuana as a medical plant can be traced back to thousands of years. Attempts to completely legalize the use of cannabis for medical purposes are strongly contested in many places due to some of its negative effects on users physically, psychologically, and socially. This review is aimed to discuss the mechanism of action and pharmacogenetics of cannabinoids to elucidate its uses as medicine as well as negative effects. Online searches on the following database: Google Scholar, PubMed, Biomed Central, and SciELO were done. An attempt was made to review articles with keywords such as cannabis, cannabinoid receptors, genes, and medical marijuana. This review has highlighted with evidence the importance of genomic profiling to prevent side effects associated with predisposing genes for the benefit of patients who are medical candidates for medicinal cannabis use. Medical profiling via cannabinoid gene expression studies of patients who are medical candidates of cannabis could prevent the negative effects associated with its use.
... For example, while THC and THC-based medications are themselves associated with drowsiness (Issa, Narang, Jamison, et al., 2014;Schimrigk, Marziniak, Neubauer, et al., 2017;May & Glode, 2016), research has suggested that cannabis high in cannabidiol (CBD) produces particularly strong sedating effects (Crippa et al., 2004;Pearce et al., 2014;Zhornitsky & Potvin, 2012). We have argued (Johnson, 2020;Johnson, 2022) that the sedating properties of alcohol and drugs, not just the intoxicating properties, are understudied agents of crash risk, and accordingly, in earlier research investigated both THC and CBD as predictors of driving impairment. ...
Background:
β-myrcene, one of the most common terpenes found in cannabis, has been associated with sedation. We propose that β-myrcene contributes to driving impairment even in the absence of cannabinoids.
Aim:
To conduct a double-blind, placebo-controlled crossover pilot study of the effect of β- myrcene on performance on a driving simulator.
Method:
A small sample (n=10) of participants attended two experimental sessions, one in which they were randomized to receive 15 mg of pure β-myrcene in a capsule versus a canola oil control. Each session, participants completed a baseline block and three follow-up blocks on a STISIM driving simulator.
Results:
β-myrcene was associated with statistically significant reductions in speed control and increased errors on a divided attention task. Other measures did not approach statistical significance but fit the pattern of results consistent with the hypothesis that β-myrcene impairs simulated driving.
Conclusions:
This pilot study produced proof-of-principle evidence that the terpene β-myrcene, an agent commonly found in cannabis, can contributes to impairment of driving-related skills. Understanding how compounds other than THC affect driving risk will strengthen the field's understanding of drugged driving.
The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics targeting the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atropisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retain─and in some cases, strengthen─affinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex endocannabinoid system.
Study objectives:
The potential sedative effect of dronabinol and the high expression of cannabinoid receptors on the hypoglossal motor nuclei makes this agent a good candidate for obstructive sleep apnea (OSA) pharmacotherapy, to be tested with atomoxetine, a noradrenergic reuptake inhibitor that reduced OSA severity in combination with oxybutynin. Here we tested the effect of atomoxetine 80 mg plus dronabinol (Ato-Dro) at two different doses (5 and 10 mg) vs. baseline and atomoxetine alone in a two-center, open-label, dose-escalating trial. The primary outcome was the effect of Ato-Dro vs. baseline on OSA severity (apnea-hypopnea index, AHI4). Safety of the combination and subjective outcomes were also assessed.
Methods:
15 OSA patients received progressively increasing Ato-Dro doses (dose escalation was performed every week, starting from Ato-Dro 40-2.5 mg, then 80-5 mg and finally 80-10 mg). A clinical, in-lab polysomnography was performed at baseline, on Ato-Dro 80-5 and Ato-Dro 80-10 mg.
Results:
Ato-Dro 80-10 mg did not significantly reduce AHI4 and hypoxic burden and yielded limited clinical benefit vs. baseline and atomoxetine alone. However, Ato-Dro 80-5 mg did improve OSA severity (ΔAHI=8.3[0.3, 16.3] events/h; mean[CI]; Δhypoxic burden=37.7[12.5, 62.7] %min/hr) and multiple subjective outcomes vs. baseline and/or atomoxetine alone. Ato-Dro administration was characterized by several potentially harmful side effects and treatment discontinuation in 1/3 of cases.
Conclusions:
Ato-Dro 80-5 mg might be useful to reduce OSA severity and led to subjective improvement in those who could tolerate the combination. However, given the numerous side effects and the exploratory nature of this open-label study, our results warrant further validation in larger trials.
Clinical trial registration:
Registry: ClinicalTrials.gov; Identifier: NCT05101122; Title: Study for Efficacy and Dose Escalation of AD313 + Atomoxetine (SEED) (SEED); URL: https://clinicaltrials.gov/ct2/show/NCT05101122.
This paper aims to evaluate the anti-emetic efficacy of cannabinoids in cancer patients receiving chemotherapy using a systematic review of literature searched within electronic databases such as PUBMED, EMBASE, PSYCINFO, LILACS, and ‘The Cochrane Collaboration Controlled Trials Register’. Studies chosen were randomized clinical trials comprising all publications of each database until December 2006. From 12 749 initially identified papers, 30 fulfilled the inclusion criteria for this review, with demonstration of superiority of the anti-emetic efficacy of cannabinoids compared with conventional drugs and placebo. The adverse effects were more intense and occurred more often among patients who used cannabinoids. Five meta-analyses were carried out: (1) dronabinol versus placebo [n = 185; relative risk (RR) = 0.47; confidence interval (CI) = 0.19–1.16]; (2) Dronabinol versus neuroleptics [n = 325; RR = 0.67; CI = 0.47–0.96; number needed to treat (NNT) = 3.4]; (3) nabilone versus neuroleptics (n = 277; RR = 0.88; CI = 0.72–1.08); (4) levonantradol versus neuroleptics (n = 194; RR = 0.94; CI = 0.75–1.18); and (5) patients' preference for cannabis or other drugs (n = 1138; RR = 0.33; CI = 0.24–0.44; NNT = 1.8). The superiority of the anti-emetic efficacy of cannabinoids was demonstrated through meta-analysis.
Chemotherapy-induced nausea and vomiting (CINV) in cancer patients are common symptoms most feared by patients. The aim of this study was to analyze the impact of CINV associated to moderate/highly emetogenous chemotherapy regimens on patients' quality of life (QoL).
Open, multicenter, prospective observational study was performed. Each patient filled out a patient diary for each cycle from the day before chemotherapy and for the next 5 days that included the number of emetic episodes, the intensity of nausea, and QoL evaluation (functional living index-emesis questionnaire).
Data from 202 consecutive patients from nine university hospitals were collected, but only data from 160 were analyzed (79.2 %). Most of the participants (70 %) were women with a mean age of 50 years (SD 1.2 years). The most frequent cancer site was breast (44 %) followed by lung (16 %) and 76.3 % were receiving highly emetogenous chemotherapy. Despite the use of antiemetic prophylaxis, patients experienced significant nausea and vomiting during 31 % (3.2 % during acute, 15.0 % during delayed phase, and 13.2 % during both phases) and 45.1 % (5.1 % only during the acute phase, 23.5 % only during the delayed phase and 16.5 % during both phases) of the cycles, respectively, having 44.5 % (nausea) and 39.3 % (emesis) of the cycles an impact on patients' QoL.
The results of the study confirm the detrimental effect of CINV on patients' QoL despite the use of antiemetic prophylaxis (5HT(3) receptor antagonist, steroids, and dopamine receptor antagonists). It is mandatory to intensify the detection of CINV in order to improve the management of these important, albeit frequent, side effects of cancer treatments.
This review provides background information on chemotherapy-induced nausea and vomiting (CINV) classification and pathophysiology and reviews various antiemetic agents for CINV prophylaxis, including corticosteroids, serotonin receptor antagonists (5-HT3 RAs), tachykinin NK1 receptor antagonists (NK1 RAs), and olanzapine. Other less commonly used agents are briefly discussed. Practical considerations are reviewed as well, including emetogenicity of chemotherapeutic regimens, patient-specific risk factors for CINV, principles of CINV management, health economics outcome research, and quality of life. Available data on the newly FDA-approved antiemetic combination netupitant/palonosetron (NEPA) is also reviewed. Prevention of CINV is an important goal in managing patients with cancer and is especially difficult with respect to nausea and delayed CINV. Corticosteroids are a mainstay of CINV prophylaxis and are usually given in combination with other therapies. The 5-HT3 RA palonosetron has shown increased efficacy over other agents in the same class for prevention of delayed emesis with moderately emetogenic chemotherapy and NK1 RAs improve emesis prevention in combination with 5-HT3 RAs and dexamethasone. Olanzapine has shown efficacy for CINV prophylaxis and the treatment of breakthrough CINV. The new combination therapy, NEPA, has been shown to be efficacious for the prevention of acute, delayed, and overall CINV. Risk factors that have been identified for CINV include gender, age, and alcohol intake. It is important to assess the emetogenicity of chemotherapy regimens as well as the potential impact of patient risk factors in order to provide adequate prophylaxis. Acute and delayed CINV are severe, burdensome side effects of chemotherapy; however, new data on prevention and the discovery of new agents can further improve CINV control.
As of March 2015, 23 states and the District of Columbia had medical marijuana laws in place. Physicians should know both the scientific rationale and the practical implications for medical marijuana laws.
To review the pharmacology, indications, and laws related to medical marijuana use.
The medical literature on medical marijuana was reviewed from 1948 to March 2015 via MEDLINE with an emphasis on 28 randomized clinical trials of cannabinoids as pharmacotherapy for indications other than those for which there are 2 US Food and Drug Administration-approved cannabinoids (dronabinol and nabilone), which include nausea and vomiting associated with chemotherapy and appetite stimulation in wasting illnesses.
Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence. Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications.
Medical marijuana is used to treat a host of indications, a few of which have evidence to support treatment with marijuana and many that do not. Physicians should educate patients about medical marijuana to ensure that it is used appropriately and that patients will benefit from its use.
Background. In 1999 the Institute of Medicine (IOM) issued a report entitled Marijuana and Medicine (Joy, Watson and Benson, 1999). It recommended the development of cannabinoid drug delivery systems which might be effective for nausea, vomiting and AIDS wasting syndrome, among other chronic disorders. The report went on to recognize that patients should be allowed to smoke marijua- na if they failed to achieve relief from approved symptoms that could be relieved by cannabinoid drugs with rapid onset. Recommended criteria of the report included: access to marijuana within 24 hours of submission by a physician, supervision that allows for assessment of treatment effectiveness, and an oversight strategy comparable to an institutional review board. In this context a review of previously un- published state-run clinical trials with Cannabis sativa (marijuana and/ or ∆9-tetrahydrocannabinol capsules) to test efficacy in reducing nau- sea and vomiting following cancer chemotherapy is warranted. The impetus for these studies came from individual state legislatures re- sponding to constituents' claims that smoking marijuana reduced or blocked nausea and vomiting. Methods. Technical reports were obtained from 6 states which had
Before the introduction of the serotonin receptor antagonists (5-HT3 receptor antagonists) in the early 1990s, limited effective options were available to prevent and treat chemotherapy-induced nausea and vomiting (CINV). In 1985, the FDA approved 2 cannabinoid derivatives, dronabinol and nabilone, for the treatment of CINV not effectively treated by other agents. Today, the standard of care for prevention of CINV for highly and moderately emetogenic chemotherapy is a 5-HT3 receptor antagonist, dexamethasone, with or without aprepitant or fosaprepitant. With the approval of safer and more effective agents, cannabinoids are not recommended as first-line treatment for the prevention of CINV and are reserved for patients with breakthrough nausea and vomiting. Because of medical and legal concerns, the use of marijuana is not recommended for management of CINV and is not part of the NCCN Clinical Practice Guidelines in Oncology (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, its use remains legally and therapeutically controversial.
Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of chemotherapy, but it may be prevented or mitigated with medications. Uncontrolled CINV can lead to reduced quality of life and can result in increased costs (due to health care utilization and missed work). We prospectively assessed the prevalence and burden of CINV in a US population.
Final analysis was performed on 178 patients, beginning chemotherapy during 2007-2008 at oncology specialty settings. Patients kept a diary recording use of antiemetic medications just before the start of chemotherapy and use of antiemetic medications, health care resources, and episodes of nausea and vomiting during the 5 days following. In addition, they completed a Functional Living Index-Emesis (FLIE) questionnaire and a Work Productivity and Assessment Inventory-Nausea and Vomiting assessment, to determine the impact of CINV on daily functioning and on work productivity, respectively. Physicians independently recorded prescribed medications and health care utilization.
Of the patients, 61.2% reported experiencing CINV (34.3% with acute CINV and 58.4% with delayed CINV). Based on the FLIE assessment, 37.2% of all patients reported reduced daily functioning, and of those with poorly managed CINV, about 90% reported a significant impact on daily functioning. Total costs due to CINV were on average $778.58 per patient from the day of administration through the 5 days following the first cycle of chemotherapy; patients with more severe CINV typically had higher costs.
CINV remains a significant problem among US patients, suggesting a need for more effective prophylaxis use in clinical practice.
Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.
Fifteen patients with osteogenic sarcoma receiving high-dose methotrexate chemotherapy were studied in a randomized, double-blind, placebo-controlled trial of oral and smoked delta-9-tetrahydrocannabinol (THC) as an antiemetic. Each patient served as his or her own control. Fourteen of 15 patients had a reduction in nausea and vomiting on THC as compared to placebo. Delta-9-tetrahydrocannabinol was significantly more effective than placebo in reducing the number of vomiting and retching episodes, degree of nausea, duration of nausea, and volume of emesis (P less than 0.001). There was a 72% incidence of nausea and vomiting on placebo. When plasma THC concentrations measured less than 5.0 ng/mL, 5.0 to 10.0 ng/mL, and greater than 10.0 ng/mL, the incidences of nausea and vomiting were 44%, 21%, and 6%, respectively. Delta-9-tetrahydrocannabinol appears to have significant antiemetic properties when compared with placebo in patients receiving high-dose methotrexate.
Dronabinol (Marinol, Roxane Laboratories, Columbus, OH) and prochlorperazine were tested alone and in combination in a randomized, double-blind, parallel group, multicenter study. Patients were randomized to receive either 1) dronabinol 10 mg every 6 hr plus placebo; 2) placebo plus prochlorperazine 10 mg every 6 hr; or 3) dronabinol and prochlorperazine, each 10 mg every 6 hr. Antiemetic treatment was begun 24 hr prior to and continued for 24 hr after the last dose of chemotherapy; all was given orally. Only 29% of patients in group 3 versus 47% in group 1 and 60% in group 2 experienced nausea after chemotherapy. In addition, the median duration per episode and severity of nausea were significantly less with combination therapy. Vomiting occurred after chemotherapy in 41%, 55%, and 35% of patients in groups 1, 2, and 3, respectively. The median duration per episode of vomiting was 1 min in group 3 versus two in group 1 and four in group 2. Side effects, primarily CNS, were more common in group 1 than in group 2; addition of prochlorperazine to dronabinol appeared to decrease the frequency of dysphoric effects seen with the latter agent. The combination was significantly more effective than was either single agent in controlling chemotherapy-induced nausea and vomiting.