Why Are We So Reluctant To Embrace Cannabis And Its Derivatives For Pain Control?

Derek Anselmo, DPM, coauthored this DPM Blog.

The opioid crisis in our country is reaching epidemic proportions. In 2015, there were over 52,000 drug overdoses reported in the U.S. and greater than 40 percent were directly related to prescription opioid use.¹

In 1995, Purdue Pharma introduced OxyContin to the market and by 2002, the company had funded over 20,000 educational programs encouraging long-term use of the extended release hydrocodone drug.² In fact, a retrospective review of the literature from this time period reveals papers advocating for the use of opioid analgesics and claiming physicians were underutilizing opioids, maintaining that any fear that prescribing them would lead to addiction was irrational.³

This led to the adoption of a much more liberal paradigm in non-cancer pain management that disseminated through specialties and residency training programs. The result was a modern philosophy of both ambulatory and inpatient pain management in which one considers prescription opioids a first line standard of care. The podiatric profession has not been immune as well.

Cannabis plants contain over 400 chemical compounds and 60 different cannabinoids. The two main compounds of clinical interest that act on the central nervous system are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the former being the main psychoactive agent. Through a pathway known as the endocannabinoid system, THC binds directly to CB1 receptors in the brain and other tissues and releases a powerful psychoactive metabolite. Cannabidiol stimulates activity in both CB1 and CBD2 receptors without actually binding to them.⁴ This enables the cellular response while competitively inhibiting THC binding to CB1 and thus producing less metabolite.⁵ This mitigates side effects and counteracts the psychological effect of THC while enabling other therapeutic responses such as the inhibition of proinflammatory cytokines and antioxidant action greater than that of vitamins A and E6.

Medical grade cannabis is genetically engineered to have higher cannabidiol to THC ratios than strains people use for recreational purposes. Cannabinoids act in a similar fashion to opioids with a key difference being that cannabinoids are not active in the brainstem, making them considerably safer to use.⁷

Researchers have well described the valuable clinical effects of cannabinoids to treat a multitude of conditions. In a systematic review, Lynch and Campbell identified 18 randomized control trials comparing placebo to cannabinoids for the management of chronic pain, finding that 15 studies showed a significant reduction in pain.⁸ Studies have shown cannabinoids to be effective in treating pain symptoms associated with multiple sclerosis, HIV/AIDS, migraines, side effects from chemotherapy and pediatric epilepsy to name a few.^9–13

However, it is important to note that although there is a plethora of research regarding the implications of cannabinoids for chronic pain conditions, there is a relatively miniscule amount of studies that investigate their use for acute pain and, in particular, orthopedic perioperative pain. Given the current opioid abuse epidemic, prescribing practices and estimations that as many as 75 percent of heroin users had their first opioid experience from a prescription, it is almost alarming that there have not been large scale trials investigating the potential applications of cannabinoids in our postoperative pain management protocols.¹⁴

Is It Time To Rethink The Classification Of Cannabis As A Schedule I Substance?

A major factor in our dearth of understanding when it comes to medical cannabis is the paradoxical sphere in which cannabis resides in our country. While you can get medical marijuana with a prescription in almost 30 states and use it recreationally in eight states, the federal government still considers it a Schedule I substance. That means if researchers wish to initiate a study with cannabis, they need authorizations from the Drug Enforcement Agency (DEA), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH). The marijuana in this hypothetical study would need to come from a single farm at the University of Mississippi and be stored in a specialty vault with a high-tech security system.

With these limitations and consideration of the staff that would be needed to monitor such a program and maintain compliance with regulations, a large-scale study would be prohibitively expensive for anyone outside of a large academic center with a massive grant. Furthermore, the cannabis available for study would be limited in its chemical profile and may not have the ideal ratio of THC to CBD for the indication of interest, meaning that a study from an approved academic center may be irrelevant when applied to what a patient would get from marijuana purchased at a dispensary.

Given the current legal climate, it is of little surprise that a large share of the literature regarding the clinical applications of medical cannabis and cannabis derivatives comes from outside of the United States. The Health and Medicine Division of the National Academies of Sciences recently issued a position paper that makes several suggestions to support and improve the cannabis research agenda.¹⁵ The committee recommends focusing on basic science work to improve understanding of the pharmacodynamics, modes of delivery and dosing, and further considering this data in the context of different populations and conditions. The paper suggests the implementation of uniform nomenclature, research methods, surveillance and statistical reporting methods to improve study quality.

The most impactful strategy suggested may be the simple removal of barriers to research such as declassification of cannabis as a schedule I substance.¹⁵ Also impactful, according to the study, would be the establishment of a joint Centers for Disease Control and Prevention (CDC)/NIH/FDA/private industry-funded expert committee to produce evidence-based reports that characterize the obstacles to cannabis research and propose strategies for the development of infrastructure needed to conduct this comprehensive research agenda.

Final Notes

A recent Gallup Poll indicated 64 percent of Americans think marijuana should be legal for recreational use while 93 percent of respondents in a Quinnipiac poll feel medical marijuana should be legal.^16,17 Despite the increasingly pro-cannabis opinions of constituents, many elected officials are still reluctant to support pro-cannabis legislation at the state and federal levels. Part of the issue is that many lawmakers are still grossly misinformed about the evidence surrounding both recreational and medical marijuana use, including Attorney General Jeff Sessions, who continually cites marijuana as being a gateway drug although research has overwhelmingly debunked that myth.^18–20

The sad reality is that according to the data, the real gateway drug is a doctor’s prescription pad.

In our practice, we try to employ a multimodal pain management approach that includes the use of preoperative regional blocks, liposomal bupivacaine, cold compression therapy and patient education as an adjunct to opioid therapy. Given the persistent increase in prescription opioid abuse, it is vital that we explore all possible pain management modalities. The FDA currently approves two medications with synthetic THC analogues, dronabinol (Marinol, AbbVie) and nabilone (Cesamet, Meda Pharmaceuticals), for treating nausea and weight loss associated with HIV/AIDS and cancer chemotherapy. Some research has investigated the potential of these medications for chronic pain and postoperative pain with varying effects.^21,22 However, it is important to note that these studies only considered one synthetic cannabinoid each.

On June 25, the FDA approved the first marijuana-based pharmaceutical after a unanimous vote by the advisory committee early this year. Epidiolex (Greenwich Biosciences), a CBD-heavy formula indicated for pediatric epilepsy, could usher in a new era of thinking with regard to medical marijuana and cannabis research policy. The hope is that this will prove to be a catalyst for high quality research into other applications for cannabis derivatives.

We do not currently understand the potential cannabis may have in helping to lessen our reliance on prescription opioids to treat acute and chronic pain, but unless serious changes occur in federal and state policy and in our paradigms as physicians, we never will.

References

1. Rudd R, Aleshire N, Zibbell J, Matthew Gladden R. Increases in drug and opioid overdose deaths-United States, 2000-2014. Am J Transpl. 2016;16(4):1323-1327.

2. Government Accounting Office. OxyContin abuse and diversion and efforts to address the problem. J Pain Palliat Care Pharmacother. 2004;18(3):109-113.

3. Morgan J. American opiophobia. Adv Alcohol Substance Abuse. 1985;5(1-2):163-172.

4. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2(6):241-254.

5. McPartland J, Duncan M, Di Marzo V, Pertwee R. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737-753.

6. Roques B, Fournié-Zaluski M, Wurm M. Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nature Reviews Drug Discovery. 2012;11(4):292-310.

7. Lynch M, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011;72(5):735-744.

8. Whiting P, Wolff R, Deshpande S, et al. Cannabinoids for medical use. JAMA. 2015;313(24):2456.

9. Page S. Cannabis use as described by people with multiple sclerosis. Can J Neruol Sci. 2003;30(3):201-205.

10. Ellis R, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2008;34(3):672-680.

11. Robbins M, Tarshish S, Solomon S, Grosberg B. Cluster attacks responsive to recreational cannabis and dronabinol. Headache. 2009;49(6):914-916.

12. Chang A. Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. Ann Intern Med. 1979;91(6):819.

13. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurology. 2016;15(3):270-278.

14. Cicero T, Ellis M, Surratt H, Kurtz S. The changing face of heroin use in the United States. JAMA Psychiatry. 2014;71(7):821.

15. National Academies of Sciences, Engineering, and Medicine. The Health Effects Of Cannabis And Cannabinoids: The Current State Of Evidence And Recommendations For Research. First Edition. The National Academies Press, Washington, DC, 2017, pp. 395-398.

16. McCarthy J. Record-high support for legalizing marijuana use in U.S. Gallup. Available at https://news.gallup.com/poll/221018/record-high-support-legalizing-marijuana.aspx . Published Oct. 25, 2017.

17. Quinnipiac University Poll. Available at https://poll.qu.edu/national/release-detail?ReleaseID=2539 . Published April 26, 2018.

18. Substance Abuse and Mental Health Services Administration. Behavioral health trends in the United States: results from the 2014 national survey on drug use and health. Available at https://www.samhsa.gov/datahttps://s3.amazonaws.com/HMP/hmp_ln/imported/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf .

19. Tarter R. Predictors of marijuana use in adolescents before and after licit drug use: examination of the gateway hypothesis. Am J Psychiatry. 2006;163(12):2134.

20. Kleinig J. Ready for retirement: the gateway drug hypothesis. Subst Use Misuse. 2015;50(8-9):971-975.

21. Svendsen K, Jensen T, Bach F. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004;329(7460):253.

22. Buggy D, Toogood L, Maric S, Sharpe P, Lambert D, Rowbotham D. Lack of analgesic efficacy of oral δ-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1):169-172.