Crawling through the Weeds: Searching through the haze and smoking out the truth regarding medical marijuana effects.

Rita Agarwal MD, FAAP, FASA and Elliot Krane MD, FAAP

Today’s PAAD is an excellent and comprehensive evaluation of the medicinal marijuana literature by world experts in the topic, including pediatric anesthesiologist and pain specialist Dr. Elliot Krane. Even though Elliot is an author of the paper, I’ve asked him and Rita Agarwal to review it for us in the PAAD.  Elliot and Rita are frequent contributors to the PAAD and Rita is our primary pain reviewer.  I’ve included several other reviews in the reference list.(1-3)  29+ States have legalized medicinal and/or recreational marijuana so many of the issues discussed in today’s PAAD will become increasingly important to your practices.   Myron Yaster MD

Original article

Moore RA, Fisher E, Finn DP, Finnerup NB, Gilron I, Haroutounian S, Krane E, Rice ASC, Rowbotham M, Wallace M, Eccleston C. Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews. Pain. 2021 Jul 1;162(Suppl 1):S67-S79. PMID: 32804833

If you believe the hype, marijuana, cannabis, and cannabis-based products are good for just about everything that that ails you: ALS, cancer, chronic and acute pain, diabetes, brain damage, autism, ADHD, Alzheimer’s, anxiety, OCD, depression.  You get the idea, a little cannabis and all will be better.

And while marijuana and many cannabis based products remain illegal in the United States, a majority of States (29 and counting) have legalized medicinal and some have legalized recreational marijuana use. In most of these States, children are allowed to use medicinal marijuana products with parental consent and physician recommendation. Because marijuana remains a DEA class I drug, little formal academic research with this family of drugs has been possible.  As a result, the few studies that have been done are of low quality and there have been few formal studies in pediatrics.  Most children who do use marijuana based products for medical purposes use them for chronic pain, seizures or cancer or chemotherapy related nausea.(4,5). Flannery et al have written an excellent review on the perioperative management of children who are using medicinal marijuana.(6) 

There are 4 FDA-approved cannabinoid-based medications in production. Dronabinol is a synthetic THC that is used for cancer induced nausea and vomiting. Nabilone is a synthetic THC  also used for nausea and vomiting. Nabiximol (Sativex) is a plant derived THC and CBD compound in a 10:1 ratio used for neuropathic pain and spasticity, but it is not FDA approved for use in the USA. Cannabidiol (Epidiolex) is plant derived CBD used for the management of seizures in Lennox Gastaut, Dravet’s syndrome and for other patients with intractable seizures. 

Most products used in marijuana dispensaries contain both THC and CBD in varying ratios. Physicians recommending cannabinoids usually start with a recommendation for a high CBD product, adding THC containing products if the patient is unresponsive to the CBD product.(7)  In the U.S., the quality and purity of these compounds is not well controlled and there is considerable variability between manufacturers and between batches of product from the same manufacturer. At least one country, Switzerland, strictly controls the composition and purity of marijuana products and studies from that country will be interesting to follow.(5)

In 2018, the International Association for Study of Pain (IASP) established a Presidential Task Force on Cannabis and Cannabinoid Analgesia. Today’s PAAD is part of the output of the Task Force, numbering 8 papers in total, and sought to provide a summary of the published pain treatment RCTs of cannabinoids, cannabis, and cannabis-based medications (CBM).  They evaluated studies of patients with acute or chronic pain including adolescents and children, who had received any type of cannabinoid product, by any route of administration. The primary outcomes were a reduction in pain of 30 % (moderate improvement) to 50 % (substantial improvement) as well as several secondary outcomes, such as improvements in physical or emotional functioning, global impression of improvement, and sleep duration and quality.

Over 7000 studies were screened. Only thirty-six were included in the final review. The remainder were disqualified for failing to meet inclusion criteria: randomized controlled studies (RCTs) with a control arm of any type-- placebo, pharmacologic, or non-pharmacologic pain therapy, in patients with any kind of pain. The authors worked diligently to accurately extract the data and identify any risk of bias. The analyzed studies in this review evaluated patients with neuropathic pain (13 studies), cancer pain (6), acute pain after surgery (4), pain due to multiple sclerosis (10), chronic prostatitis/chronic pelvic pain, carpal tunnel syndrome, and back pain (1 each)  

None of the studies were considered to have a low risk of bias and most were rated as having low or very low quality of evidence.  The authors go on to say that “The current available evidence provides us with no confidence that a defined cannabinoid, cannabis, or CBM product, at a defined dose, using a defined route of administration, reduces pain intensity in any condition, nor do we fully understand the long-term implications of taking cannabinoids, cannabis, and CBM”.  They conclude that while Cannabis-based medication CBM) may work for a small number of patients, considerably more high quality, RCT trials are needed.

Notwithstanding the disappointing lack of high-quality evidence to support the use of cannabinoids in pain management, it should be noted that decades of laboratory research of cannabinoids demonstrate them to be significantly analgesic in multiple animal models in multiple species.(3)

Laboratory science has identified biologically active molecules in the cannabis plant and has identified and localized CB receptors in the CNS and body (it is notable that CB receptors are the most numerous and widely distributed of all the G-protein coupled receptors in the CNS!). In addition to the compelling animal science, there are many case reports, anecdotal experiences and case series that report analgesia in humans, although of course the plural of anecdote is not data.

The summary conclusion of the Task Force states, “Overall, numerous knowledge gaps exist across preclinical, clinical, and regulatory aspects of cannabinoid research. Collaborative, multidisciplinary, and rationalized research efforts across the translational spectrum to address the gaps identified by the task force can catalyse the development and delivery of safe and effective medicines to treat pain.”(3) The chair of the task force, Andrew Rice, Professor of Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London summed up the state of affairs as follows: “While IASP cannot endorse the general use of cannabinoids for treatment of pain at this time, we do not wish to dismiss the lived experiences of people with pain who have found benefit from their use.”

References

1.          Fisher E, Moore RA, Fogarty AE, Finn DP, Finnerup NB, Gilron I, Haroutounian S, Krane E, Rice ASC, Rowbotham M, Wallace M, Eccleston C. Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. Pain 2021;162:S45-s66.

2.          Finn DP, Haroutounian S, Hohmann AG, Krane E, Soliman N, Rice ASC. Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies. Pain 2021;162:S5-s25.

3.          Haroutounian S, Arendt-Nielsen L, Belton J, Blyth FM, Degenhardt L, Di Forti M, Eccleston C, Finn DP, Finnerup NB, Fisher E, Fogarty AE, Gilron I, Hohmann AG, Kalso E, Krane E, Mohiuddin M, Moore RA, Rowbotham M, Soliman N, Wallace M, Zinboonyahgoon N, Rice ASC. International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management. Pain 2021;162:S117-s24.

4.          Woo JJ, van Reekum EA, Rosic T, Samaan Z. Children and Youth Who Use Cannabis for Pain Relief: Benefits, Risks, and Perceptions. Adolesc Health Med Ther 2020;11:53-61.

5.          Zürcher K, Dupont C, Weber P, Grunt S, Wilhelm I, Eigenmann DE, Reichmuth ML, Fankhauser M, Egger M, Fenner L. Use and caregiver-reported efficacy of medical cannabis in children and adolescents in Switzerland. Eur J Pediatr 2021.

6.          Flannery KM, D'Souza G, Agarwal R. Perioperative Management of the Pediatric Patient on Medicinal Marijuana: What Anesthesiologists Should Know. Anesth Analg 2019;129:1339-43.

7.          Bhaskar A, Bell A, Boivin M, Briques W, Brown M, Clarke H, Cyr C, Eisenberg E, de Oliveira Silva RF, Frohlich E, Georgius P, Hogg M, Horsted TI, MacCallum CA, Müller-Vahl KR, O'Connell C, Sealey R, Seibolt M, Sihota A, Smith BK, Sulak D, Vigano A, Moulin DE. Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process. J Cannabis Res 2021;3:22.