Endometriosis

Seriousness of medical condition(s)

Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help.

Who could benefit from this treatment?

Patients diagnosed with Endometriosis with ongoing symptoms not adequately resolved with standard of care medications.

Clinical justification for using Medicinal Cannabis

Recent studies in a rat model and women showed that sensory and sympathetic nerve fibres sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain (Dmitrieva et al, 2010).

 

Medicinal cannabis is an alternative that shows efficacy as an analgesic adjuvant for pain in relation to endometriosis with safety improvements over commonly used therapies. CBD and THC act on cannabinoid receptors on central and peripheral neurons and animal models illustrate the association between CB1 and CB2 receptors and pain development, however the exact mechanism of pain modulation is unknown (Lee et al, 2018) The viability of medicinal cannabis in humans is shown by clinical trials and observational data which suggests efficacy in reducing pain and the use of opioids (Lee et al, 2018).

 

Although THC has analgesic properties, caution should be taken when using THC to treat endometriosis, as CB1 receptor antagonists like THC may increase cell migration in the disease (McHugh et al, 2012). Cannabinoid receptor GPR-18 appears responsible for the migration of endometrial tissue in endometriosis and, in cell studies, is activated by THC. Fortunately, it appears to be inhibited by CBD, therefore it is advised that women with endometriosis avoid THC-only cannabis products in favour of products with at least 3:1 ration of CBD to THC (McHugh et al, 2012).

 

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

Analgesics/Opioids: Paracetamol, Codeine, Oxycodone, Fentanyl, Morphine, Buprenorphine and Pethidine

Non-steroidal anti-inflammatory drugs: Ibuprofen,

Naproxen sodium, Diclofenac, Indomethacin, and

Ketoprofen

Why is medicinal cannabis appropriate for use?

Medicinal cannabis products will be considered for treatment when:

  • standard of care medications have been trialled 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 may not be used as sole treatment of condition. The medicinal cannabis may act as an adjuvant. Tolerability and efficacy of adjuvants will be trialled in individual patients.

References

  • Dmitrieva, N., Nagabukuro, H., Resuehr, D., Zhang, G., McAllister, S. L., McGinty, K. A., Mackie, K., & Berkley, K. J. (2010). Endocannabinoid involvement in endometriosis. Pain151(3), 703–710. https://doi.org/10.1016/j.pain.2010.08.037
  • https://www.tga.gov.au/medicinal-cannabis-guidance-documents
  • Lee, G., et al., Medical cannabis for neuropathic pain. Current pain and headache reports, 2018. 22(1): p. 8.
  • McHugh, D., Page, J., Dunn, E., & Bradshaw, H. B. (2012). Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. British journal of pharmacology165(8), 2414–2424. https://doi.org/10.1111/j.1476-5381.2011.01497.x
  • 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.