Chemotherapy Induced Nausea and Vomiting

Seriousness of medical condition(s)

Chemotherapy-induced nausea and vomiting are the most severe and troublesome symptoms for cancer patients receiving chemotherapy. Unresolved chemotherapy-induced nausea and vomiting can lead to metabolic disorders, dehydration, nutritional depletion and oesophageal tears, and can reduce patients’ daily functioning and quality of life and interfere with treatment schedules.

Who could benefit from this treatment?

Chemotherapy-induced nausea and vomiting refractory to current established therapies.

Clinical justification for using Medicinal Cannabis

a.      The medicinal cannabis’s suitability for the intended indication

b.      The medicinal cannabis’s efficacy and expected benefits

 

In 2017, the US National Academies of Sciences, Engineering, and Medicine have reviewed evidence and provided recommendations on the health effects of cannabis and cannabinoids

There is conclusive or substantial evidence that cannabis or cannabinoids are effective:

·         As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids) for refractory cases (Attal et al., 2010).

 

The TGA’s Guidance for the use of medicinal cannabis for the prevention or management of nausea and vomiting in Australia booklet makes the following recommendation:

“High-THC medicinal cannabis products can sometimes be effective for nausea and vomiting and should only be prescribed only after newer standard approved treatments have failed and where otherwise not contraindicated.”

 

This guidance mentions that studies have shown that Medicinal cannabis has some benefit, when compared to placebo, in treating Chemotherapy induced Nausea and Vomiting.

 

The following reviews also found strong evidence for the treatment of Chemotherapy induced Nausea and Vomiting:

·         Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review BMJ 2001;323:16

 

·         Effects of smoked cannabis and oral delta-9-tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: A review of state clinical trials. Musty, R and Rossi, R. Journal of Cannabis Therapeutics. (2001). 1: 29-42.

·         Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Meiri, E., Jhangiani, H., Vredenburgh, J. J., Barbato, L. M. and others. (2007). Curr.Med.Res.Opin. 23: 533-543

 

Medicinal Cannabis may be beneficial in treating nausea/vomiting in patients that are not receiving chemotherapy.

 

c. any unknown or expected adverse effects, risks and safety issues & d. related toxicology:

A systematic review by Whiting et al. (2015) stated in their conclusions that “Cannabinoids were associated with an increased risk of short-term adverse effects”.

According to the Guidance for the Use of Medicinal Cannabis in Australia: Overview, Therapeutics Good Administration (2017):

Cannabis is not appropriate for patients who:

• Are under the age of 25 (with the exception of intractable epilepsy or severe pain syndrome)

• Have a personal history or strong family history of psychosis

• Have a current or past cannabis use disorder, or active substance use disorder

• Have unstable respiratory or cardiovascular disease (including angina, peripheral vascular disease, cerebrovascular disease, arrhythmias)

• Are pregnant, planning to become pregnant, or breastfeeding

 

Cannabis should be authorized with caution in patients who:

• Smoke tobacco

• Have risk factors for cardiovascular disease

• Are heavy users of alcohol

• Are taking sedating medications or any other medication metabolized by the CYP450 pathway

• At risk or have liver disease

 

Drug Interactions – CYP P450 Enzyme System

THC and CBD are metabolized by Cytochrome P450 enzyme system, including CYP1A2, CYP2C9, CYP2D6, CYP2C19 and CYP3A4. Based on in vitro and animal studies with cannabis, there is a potential for interactions with the medications metabolized by the P450 enzymes (2C9, 2C19, 3A4). It’s notable, however, that the inhibitory effects in vitro and in animal models were only seen at exposures significantly higher than the maximum observed in clinical trials. For instance, in clinical trials were Sativex® has been taken concomitantly with other drugs metabolized by the Cytochrome P450 enzyme system, no clinically apparent drug-drug interactions have been seen in these trials at clinical doses. In an in vitro study with 1:1% (v/v) THC botanical drug substance (BDS) and CBD BDS, no relevant induction of the Cytochrome P450 enzymes was seen for human CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in human hepatocytes at doses of up to 1µM (314ng/mL) (Stout and Cimino, 2014).

 

Potential drug interactions

Increasing THC concentration:

Examples of inhibitors:

– Antidepressants (e.g. Fluoxetine, Fluvoxamine)

– Proton Pump Inhibitors (e.g. Omeprazole)

– Cimetidine

– Macrolides (Clarithromycin, Erythromycin)

– Antimycotics (e.g. Itraconazole, Fluconazole, Ketoconazole, Miconazole)

– Calcium Antagonists (e.g. Diltiazem, Verapamil)

– HIV protease inhibitors (e.g. Ritonavir)

– Amiodarone

– Isoniazid

– Grapefruit juice

 

Increasing CBD concentration:

– Metabolized by CYP 2C19 and CYP 3A4

– Bioavailability could be increased by many of the same substances as for THC

 

Decreasing THC and CBD concentration:

• CYP 2C9 and 3A4 Inducers accelerate THC and CBD metabolism

• Examples of inducers:

– Rifampicin

– Primidone

– Carbamazepine

– Phenobarbital

– Phenytoin

– Rifabutin

– Saint John’s Wort

 

Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen in the study by Gaston et al (2017) on interactions between cannabidiol (Epidiolex®) and commonly used antiepileptic drugs. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with supraphysiological doses of CBD (e.g. 1000mg/kg).

 

·         Caution with blood thinners like Warfarin, Heparin, Clopidogrel (Plavix)

·         Additionally, pharmacodynamic interactions should be expected between cannabis and drugs with sympathomimetic activity (tachycardia, hypertension), central nervous system depressants (drowsiness, ataxia), and drugs with anticholinergic effects (tachycardia, drowsiness).

 

Many of these drug interactions can be mitigated in complex patients with polypharmacy by slowly titrating cannabis.

Approved treatments for this medical condition

Currently available pharmacological treatments include:

  • Dopamine antagonists
  • Phenothiazines
  • Antihistamines
  • 5HT3 antagonists
  • Other agents (e.g. Steroids, benzodiazepines, anticholinergic)

Why is medicinal cannabis appropriate for use?

Medicinal cannabis will only be trailed after an approved therapeutic good/s have been trailed and failed due to ineffective response or undesirable effects.

 

Chemotherapy-induced nausea and vomiting (CINV) remains a significant cause of morbidity in oncology patients despite the best current antiemetic prophylaxis. Cancer patients rate nausea the most distressing side effect of chemotherapy.

The Multinational Association of Supportive Care in Cancer (MASCC) has published guidelines which recommend a standardised regimen of a 5-HT3 receptor antagonist, with dexamethasone, and for most regimens an NK-1 antagonist for optimal antiemetic prophylaxis of moderate or high emetic risk (https://www.mascc.org/antiemetic-guidelines). However, even among patients receiving guideline-consistent antiemetic prophylaxis, contemporary observational studies of moderate or highly emetogenic chemotherapy found that 46%–70% experienced significant nausea and 9%–37% experienced vomiting (Aapro et al., 2012). A double-blind randomised trial of nabiximols for secondary prevention of CINV found substantial efficacy, high patient acceptability and manageable side effects (Duran et al., 2010). In this study, patients who experienced CINV after moderately emetogenic chemotherapy, despite prophylaxis with a guideline-consistent antiemetic regimen, were randomised to nabiximols or placebo. Substantial efficacy was observed, with complete response in 71% vs 22%, (difference 49%, [95% CI 1% to 75%]), absence of delayed emesis in 71% vs 22% and nausea in 57% vs 22%, however no difference in acute nausea or vomiting.

 

The addition of medicinal cannabis to standard guideline-based antiemetics will improve the control of CINV, leading to improved quality of life.

References

  • Aapro M, Molassiotis A, Dicato M, et al. The effect of guideline consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol 2012;23:1986–92.
  • Allan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K, et al. Systematic review of systematic reviews for medical cannabinoids. Pain, nausea and vomiting, spasticity, and harms. Can Fam Physician 2018; 64:e78-94.
  • Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113-e88.
  • Duran M, Pérez E, Abanades S, et al. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol 2010;70:656–63.
  • Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Sep;58(9):1586-1592. doi: 10.1111/epi.13852. Epub 2017 Aug 6. PMID: 28782097.
  • https://www.tga.gov.au/medicinal-cannabis-guidance-documents
  • Meiri EJhangiani HVredenburgh JJBarbato LMCarter FJYang HMBaranowski V. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin.2007 Mar;23(3):533-43.
  • Ryan J. Treatment of Chemotherapy-Induced Nausea in Cancer Patients. Eur Oncol. 2010 ; 6(2): 14–16
  • Smith LA1Azariah FLavender VTStoner NSBettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev.2015 Nov 12;(11):CD009464. doi: 10.1002/14651858.CD009464.pub2.
  • Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015;313(24):2456-73. Errata in: JAMA 2016;315(14):1522, JAMA 2015;314(21):2308, JAMA 2015;314(5):520, JAMA 2015;314(8):837.