ASRA Pain Medicine Update

In the quest to alleviate suffering, the practice of pain management today is faced with major issues from different fronts, extending from the regulatory environment of opioids to the rising use of cannabis and cannabinoids for pain treatment. But with all the public attention on cannabis, what are we to believe? In the setting of the opioid epidemic, there has been a nationwide push to find analgesic alternatives that do not have the same addictive and lethal properties that opioid use elicits. Cannabis has been suggested as an efficacious, safer alternative or replacement for opioid analgesics.^[1],[2] However, the gap between these benefits and the scientific evidence for high-quality research (randomized control trials, multicenter clinical trials) remains wide, largely due to the national restrictions that have been placed on cannabis research. These limitations are largely related to its status as a schedule 1 substance with the Drug Enforcement Agency.^[3] This gap in knowledge is highlighted by the fact that this is one of the only times in U.S. history where a medication was determined efficacious for medical conditions, not by scientists nor researchers, but by the general public.^[4]

This is one of the only times in U.S. history where a medication was determined efficacious for medical conditions, not by scientists nor researchers, but by the general public.

When discussing the therapeutic components of cannabis, the major active substances thought to provide the most biologic effect are the phytocannabinoids delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). One theory suggests that these two components are the cannabinoids that are primarily responsible for cannabis’s analgesic properties. However, we must acknowledge that our understanding of the physiologic effect of these cannabinoids as well as the function of the endocannabinoid system as a whole is still primitive and requires more robust research in the basic science and clinical realm. Furthermore, there are more than 100 minor cannabinoids, terpenes, and flavonoids within the cannabis plant that have some evidence to support analgesic benefits.^[5],[6] Therefore, an alternative theory suggests that a more complicated interaction between all the numerous components of the cannabis plant play a role in analgesia via an “entourage effect.”^[7] In short, the exact mechanisms by which cannabis produces analgesic effects are still not clearly understood.

Cannabis has historically been used as a pain reliever dating back to ancient times.^[8] The presence of the endocannabinoid system in vertebrate species evolved approximately 600 million years ago, whereas the first signs of the plant species of cannabis originated only 25 million years ago.^[9] The main receptors that cannabis and cannabinoids physiologically impact are cannabinoid 1 receptors (CB1) and cannabinoid 2 receptors (CB2). CB1 receptors are located mainly in the brain and central nervous system while CB2 receptors are localized primarily in the periphery and associated with cells of immune function.^[10],[11] Because of the location of CB1 receptors in the brain, spinal dorsal horn, dorsal root ganglia, and peripheral afferent neurons, the analgesic effect of cannabis and cannabinoids is believed to be due to agonism of CB1 receptors.^[12] There is also a potential anti-inflammatory effect that is largely attributed to its effect on CB2 receptors which are located mainly in cells of immune function.^[12] Additional receptor targets of cannabinoids (ie, TRPV1) require further study to elicit their role in pain.^[12]

The current literature on cannabis and cannabinoids is limited and often conflicting. One review focusing on cannabis use for pain may assert benefits while another supports negative or no effects.^[12],[13] What is consistent in the reviews of chronic pain treatment is that cannabis does demonstrate analgesic benefit, mostly on neuropathic pain conditions, comparable with current neuropathic pain agents.^[14] However, many of the clinical trials in these review articles contained small sample sizes and had short duration treatment periods. Furthermore, there is little uniformity between studies in terms of cannabinoids used, dosages, concentrations, and modes of administration.^[14] While efficacy is one concern, another large consideration is safety of cannabis as a therapeutic agent. The COMPASS trial demonstrated that quality-controlled herbal cannabis use, as part of a monitored treatment program over one year, appears to have a reasonable safety profile with no increase in serious adverse events. Significant, non-serious adverse events were reported, the most common of which were headache, nasopharyngitis, nausea, somnolence, and dizziness.^[15] Unlike opioids, there are no cannabinoid receptors located in the ponto-medullary area which may explain the lack of evidence for cannabis causing the serious and lethal respiratory depression effect that is seen with opioids.^[16],[17]

As of today, 33 states and the District of Columbia have legalized cannabis in some form for medicinal use in certain health conditions.^[18],[19] Of these, 11 states and the District of Columbia have approved laws for the recreational use of cannabis, with Illinois becoming the most recent state to legalize recreational use of the plant.^[18] In accordance with these state law changes, there has been an unprecedented expansion of the types of cannabis and cannabinoid products (many of which have not been studied or researched) available to the public, even though cannabis remains illegal at the federal level.^[20] Largely because of these changes in law and public sentiment towards cannabis, we have seen greater acceptance of its use as both a medicinal and recreational drug.

There is an abundance of optimism and promise that cannabis and its multiple components have the potential to be tailored to specific pain conditions and provide analgesia without opioid use. However, as physicians, we must be cautious in our recommendation of this drug until we have a strong scientific foundation to stand on. Although cannabis might be considered relatively safe when compared to opioids,^[15],[21] there have been significant adverse events related to cannabis administration that have been well documented in the literature. These adverse outcomes have included possible precipitation of a myocardial infarction,^[22] short-term memory loss,^[23] worsening of psychological disease,^[24] and development of respiratory condition (chronic bronchitis).^[25] Additional studies evaluating cannabis use in pain management are required to determine the true safety and efficacy profile of this medication, ideal mode of administration, and drug-drug interactions as well as its effects in specific patient populations such as the pregnancy, geriatric, and pediatric populations. In addition, longer-term monitoring for functional outcomes are needed, and future studies will need to address issues around standardization of dose, various types of cannabinoids and effective concentrations, and modes of administration as well as its role in specific pain phenotypes. 

References

1. Barlowe TS, Koliani-Pace JL, Smith KD, Gordon SR, Gardner TB. Effects of medical cannabis on use of opioids and hospital visits by patients with painful chronic pancreatitis. Clin Gastroenterol Hepatol. 2019;17(12):2608-9.e1. https://doi.org/10.1016/j.cgh.2019.01.018
2. Vyas MB, LeBaron VT, Gilson AM. The use of cannabis in response to the opioid crisis: a review of the literature. Nurs Outlook. 2018;66(1)56-65. https://doi.org/10.1016/j.outlook.2017.08.012
3. United States Drug Enforcement Administration. The controlled substances act. https://www.dea.gov/controlled-substances-act. Accessed July 8, 2020.
4. Hurd YL. Cannabidiol: swinging the marijuana pendulum from ‘weed’ to medication to treat the opioid epidemic. Trends Neurosci. 2017;40(30):124–7. https://doi.org/10.1016/j.tins.2016.12.006
5. Xiao X, Wang X, Gui X, Chen L, Huang B. Natural flavonoids as promising analgesic candidates: a systematic review. Chem Biodivers. 2016;13(11):1427–40. https://doi.org/10.1002/cbdv.201600060
6. Guimarães AG, Quintans JSS, Quintans LJ Jr. Monoterpenes with analgesic activity-a systematic review. Phytother Res. 2013;27(1):1-15. https://doi.org/10.1002/ptr.4686
7. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344–64. https://doi.org/10.1111/j.1476-5381.2011.01238.x
8. Abel EL. Marihuana: The First Twelve Thousand Years. New York, NY: Plenum Press; 1980.
9. McPartland JM, Norris RW, Kilpatrick CW. Coevolution between cannabinoid receptors and endocannabinoid ligands. Gene. 2007;397(1-2):126-35. https://doi.org/10.1016/j.gene.2007.04.017
10. McPartland JM, Guy GW, DiMarzo V. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One. 2014;9(3):e89566. https://doi.org/10.1371/journal.pone.0089566
11. Russo EB, McPartland JM. Cannabis is more than simply delta(9)-tetrahydrocannabinol. Psychopharmacology (Berl). 2003;165(4):431-4. https://doi.org/10.1007/s00213-002-1348-z
12. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389-462. https://doi.org/10.1124/pr.58.3.2
13. Nielsen S, Sabioni P, Trigo JM, et al. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology. 2017;42(9):1752–65. https://doi.org/10.1038/npp.2017.51
14. Lee G, Grovey B, Furnish T, Wallace M. Medical cannabis for neuropathic pain. Curr Pain Headache Rep. 2018;22(1):8. https://doi.org/10.1007/s11916-018-0658-8
15. Ware MA, Wang T, Shapiro S, Collet J-P, COMPASS study team. Cannabis for the management of pain: assessment of safety study (COMPASS). J Pain. 2015;16(12):1233-42. https://doi.org/10.1016/j.jpain.2015.07.014
16. Pickering EE, Semple SJ, Nazir MS, et al. Cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety. Chron Respir Dis. 2011;8(2):109-18. https://doi.org/10.1177/1479972310391283
17. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87(5):1932-6.
18. State marijuana laws in 2019 map. Governing. www.governing.com/gov-data/safety-justice/state-marijuana-laws-map-medical-recreational.html. Published June 25, 2019. Accessed July 8, 2020.
19. Kim H, Kim S-H. Framing marijuana: how u.s. newspapers frame marijuana legalization stories (1995–2014). Prev Med Rep. 2018;11:196–201. https://doi.org/10.1016/j.pmedr.2018.07.003
20. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: National Academies Press; 2017. https://doi.org/10.17226/24625
21. Centers for Disease Control and Prevention. Data overview - the drug overdose epidemic: behind the numbers. https://www.cdc.gov/drugoverdose/data/. Accessed July 8, 2020.
22. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation. 2001;103(23):2805–9. https://doi.org/10.1161/01.cir.103.23.2805
23. Broyd SJ, van Hell HH, Beale C, Yucel M, Solowij N. Acute and chronic effects of cannabinoids on human cognition—a systematic review. Biol Psychiatry. 2016;79(7):577-67. https://doi.org/10.1016/j.biopsych.2015.12.002
24. Bioque M, Tseng H-H, Mizrahi R. Stress response in cannabis users and psychosis. In: Preedy VR. Handbook of Cannabis and Related Pathologies. Cambridge, MA: Academic Press; 2017.
25. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10(3)239–47. https://doi.org/10.1513/AnnalsATS.201212-127FR