Irritable Bowel Syndrome

Seriousness of medical condition(s)

IBS is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Bloating, distension and disordered defecation are commonly associated features.

IBS represents the most common referral to Gastroenterologists.  IBS is diagnosed into three categories:

  • IBS with diarrhea predominance (IBS-D)
  • IBS with constipation predominance (IBS-C)
  • IBS-mixed/alternating (diarrhea & constipation) (IBS-M)

 

Cause can be due to disorders of the brain-gut axis (anxiety/stress), microbiome or food intolerance/allergy.

First line treatments include lifestyle changes & stress management, dietary modification and symptomatic treatments for pain, spasms, diarrhea, constipation and flatulence.  There are no approved medications specifically indicated to treat IBS.

Cannabinoid receptors CB1 and CB2 are present in the gastrointestinal tract and have been shown in invitro studies to play a role in gastric motility.  CB1 receptors are prevalent in the myenteric and submucosal neurons (1) whilst CB2 receptors are predominantly found in inflammatory and epithelial cells of the GI tract (2,3).  Studies to date have most clearly shown interaction through inhibition of intrinsic cholinergic mechanisms that result in inhibition of motility.

Human physiologic studies support a role for Medicinal Cannabis in IBS-D and IBS-M(8).  Clinical studies are needed to support routine use in IBS.  Medicinal Cannabis products will be considered when standard of care medications for IBS have failed.

Who could benefit from this treatment?

Patients diagnosed with IBS-D and IBS-M with ongoing symptoms not adequately resolved with standard of care medications.

Clinical justification for using Medicinal Cannabis

A large body of evidence exists demonstrating that the safety profile of cannabis is acceptable, with side effects that are generally tolerable and short-lived. The therapeutic dose of THC:CBD is highly variable between individuals and it is therefore important that patients are able to control their dose in order to get an adequate therapeutic response whilst avoiding intolerable side effects (Alexander et al).

 

Tilray THC10:CBD10 oil was evaluated in an open-label, single centre pharmacokinetic study. Healthy volunteers (n=12) were administered 1ml THC/CBD Oral Solution (total dose: 10 mg THC, 10 mg CBD) and blood samples taken periodically over the following 24h post dose. Tilray THC/CBD Oral Solution (total dose: 10 mg/10 mg THC/CBD) was found to be safe and well tolerated with no reported serious AE’s.  Please refer to Tilray Clinical Information Dossier attached.

The efficacy of cannabinoids in the management of chronic pain has been well established.  A comprehensive review published by the US National Academies of Science and Medicine in 2017 concluded that there is substantial evidence that cannabis is an effective treatment for

chronic pain in adults (National Academies of Sciences).  The TGA guidance document published in December 2017 that medicinal cannabis was more likely than placebo to produce 30% and 50% reductions in pain scores and more likely than placebo to produce a significantly greater reduction in pain intensity ratings (TGA).

The European Pain Federation (EFIC) position paper on appropriate use of cannabis‐based medicines and medical cannabis for chronic pain management (2018) states that medicinal cannabis can be considered as third line therapy for chronic neuropathic pain and as an individual therapeutic trial in chronic non-neuropathic pain, if all established treatments have failed (Hauser et al, 2018).

 

Human studies in gastric motility are limited but suggest potential therapeutic benefit.

 

In a double-blind, randomized study, 30 healthy volunteers were randomly assigned to receive dronabinol and a non-selective cannabinoid receptor agonist, 5 mg b.i.d. or placebo for three doses assessing GI function. There was an overall retardation of gastric emptying with Dronabinol which was more pronounced in females than in males.

 

Wong et al compared the effects of dronabinol and placebo on colonic motility and sensation in patients with IBS (Wong et al, 2011).  Seventy-five individuals with IBS (35 with IBS with constipation [IBS-C], 35 with IBS-D, and with 5 IBS-alternating [IBS-A]) were randomized to either a single dose of placebo, 2.5 mg or 5.0 mg dronabinol. Left colonic compliance, motility index (MI), tone, and sensation, during fasting and after a meal were assessed.

 

In all patients, dronabinol decreased fasting proximal left colonic MI, compared with

placebo, decreased fasting distal left colonic MI, and increased colonic compliance.  The effects of

dronabinol were greatest in patients with IBS-D or -A. Dronabinol did not alter sensation or tone.  The authors concluded that in patients with IBS-D or -A, dronabinol reduces fasting colonic motility (Wong et al, 2011).

 

Unknown or expected adverse effects, risks and safety issues & 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

 

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

Abdominal Pain- Buscopan, Mebeverine, Codeine

Diarrhoea- Loperamide + Diphenoxylate, Codeine

Constipation- PEG 3350 plus electrolytes (Movicol), Pysillium Husk, Metamucil, Lactulose

Why is medicinal cannabis appropriate for use?

Medicinal cannabis products will be considered for treatment when:
– standard of care medications have been trialed to maximally tolerated dose without acceptable symptom relief or functional improvements.
– Patient is unable to tolerate standard of care medications
– Standard of care medications are contraindicated.
The medicinal cannabis will not be used as sole treatment of condition. Chronic conditions often require polypharmacy to manage and are difficult to treat. In this way, the medicinal cannabis will act as an adjuvant. Tolerability and efficacy of adjuvants must be trialed in individual patients.
As above

References

  • Australian Therapeutic Goods Administration. Guidance for the use of medicinal cannabis in the treatment of chronic non-cancer pain in Australia Version 1, December 2017.  https://www.tga.gov.au/node/769205.
  • Duncan M, Mouihate A, Mackie K, et al. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats. Am J Physiol Gastrointest Liver Physiol. 2008; 295:G78–G87. [PubMed: 18483180]
  • 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.
  • Häuser, W, Finn, DP, Kalso, E, et al. European Pain Federation (EFIC) position paper on appropriate use of cannabis‐based medicines and medical cannabis for chronic pain management. Eur J Pain.. 2018; 22: 1547– 1564. https://doi.org/10.1111/ejp.1297
  • https://www.tga.gov.au/medicinal-cannabis-guidance-documents
  • Izzo AA, Camilleri M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut. 2008; 57:1140–1155. [PubMed: 18397936]
  • National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. https://doi.org/10.17226/24625

  • 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.
  • Wong BS, Camilleri M, Busciglio I, et al. Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology. 2011;141(5):1638‐47.e477. doi:10.1053/j.gastro.2011.07.036
  • Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008; 153:263–270. [PubMed: 17906675]