By Yoel H. Sitbon, PhD
Opioids are a class of drugs found in the Papaver Somnuferum plant, and are among the most potent pain-relieving medications, prescribed when the pain cannot be resolved using over-the-counter pain medications. Because of their euphoric-like effects, they are often associated with a high risk of dependance, which can lead to overdose and death if abused. This resulted in the opioid crisis, a major health problem in the United States, bearing a consequent human death toll and a significant economic burden. While pharmacological and non-pharmacological treatments are available and help at alleviating withdrawals symptoms, they can sometimes be misused. As such, alternative therapies are being investigated, and evidence suggest that medical cannabis may be potential target to treat opioid dependence.
Opioids are a class of drugs found in the Papaver Somnuferum plant, most known as the opium poppy plant.1 Opioids are among the oldest and most potent pain-relieving medications and are usually prescribed when the pain is very severe and cannot be resolved using over-the-counter pain medications. However, they are commonly associated with a high risk of dependence which can lead to overdose and death. Dependence refers to a state that develops from extended drug usage, which can result in withdrawal symptoms including (for the case of opioids) restlessness, muscle and bone pain, insomnia, diarrhea, vomiting, cold flashes with goose bumps and involuntary leg movements.2,3
Opioids interact with opioid receptors, comprised of four types: μ receptors (MOR), κ receptors (KOR), δ receptors (DOR), and nociceptin receptors (NOR), expressed in the central and peripheral nervous system (CNS, PNS).4-6 Opioids come in different types ranging from prescription opioids (e.g., Vicodin®, Oxycontin® or Percocet®), synthetic opioids (e.g., fentanyl) and the illegal drug heroin, all having high risk of abuse if not taken properly, specifically due to the fact they produce euphoric-like effects.
The opioid crisis has become a devastating and increasing problem in the world, and particularly in the United States, which started in the late 1990s due to an increasing number of opioids being prescribed. This drove to a widespread and misuse of these addictive medications leading to high overdose and death rate over the years.7 This crisis is categorized into three waves depending on the type of opioids abused (1990s: prescription opioids, 2010: heroin, and 2013: fentanyl), leading to an estimated number of 450,000 deaths from opioid overdose.8 Between June 2019 and May 2020, more than 80,000 Americans died from drug-involved overdose (illicit drugs and prescription options) and this number spiked even more during the COVID-19 pandemic.9 This crisis not only bears a significant human death toll, but it also has a huge economic burden of $78.5 billion per year ranging from healthcare costs, substance abuse treatment costs and criminal justice involvement.10
Treatments for opioid dependence are categorized into two main therapeutic avenues: pharmacological and non-pharmacological approaches. As of today, there are four pharmacological agents available: naloxone, naltrexone, buprenorphine, and methadone, with the latter two being the most widely prescribed for opioid disorder treatment.11 These can help alleviate withdrawal and craving symptoms but may still be associated with misuse and overdose risks.12 Reducing the opioid dose and the duration of the medication prescribed have also been encouraged by health care providers as means to reduce dependence.13 Non-pharmacological treatments include cognitive-behavioral therapy (CBT), shown to be effective in treating various psychological disorders, and contingency management (CM), rarely used by healthcare providers despite providing promising results.14,15 While these approaches may provide some opioid dependence relief, the development of alternative therapies is rising. As such, increasing evidence suggest medical cannabis may be a potential target to treat opioid dependence.
The cannabis plant has been used as a medicinal plant for decades and contains more than 500 active ingredients including the most studied phytocannabinoids: cannabidiol (CBD) and tetrahydrocannabinol (THC).16 While the latter is associated with euphoric-like effects or feelings of being high, both compounds interact with the endocannabinoid system (ECS), composed of cannabinoid receptor 1 and 2 (CB1, CB2), distributed throughout the body.17 Similar to opioid receptors, CB1 receptors are also found at high concentrations in areas of the brain responsible for pain, reward and withdrawal.18 With the increasing number of US states legalizing cannabis for recreational and medical purposes and due to its analgesic properties, investigating its potential for opioid dependence represent an interesting avenue.
A study published in 2018 examining 21 years of data showed that medical cannabis legalization was associated with a reduction in the number of prescriptions of Schedule III opioids (e.g., codeine) but not of Schedule II opioids (e.g., Oxycontin® or Percocet®) as well as a reduction in Medicaid annual spending on opioid prescription.19 Along those lines, a decrease in opioid-related hospitalizations (opioid dependence, abuse or overdose) and deaths was found in states in which medical cannabis was legalized.20,21 A study done in 2017 showed that patients taking opioids were more likely to reduce their opioids use and reported that cannabis was even more effective at reducing pain levels along with fewer unwanted side effects.22 While smoking was the most common method of ingestion, no further information was available to determine the THC vs CBD content. Similar observation was noted in Piper et al., in which over 75% of regularly opioids users reduced their use since they started medical cannabis.23 A study performed by a group in Canada showed a negative association between frequent cannabis use and frequent illicit opioid use among people who use drugs for chronic pain, suggesting it may serve as an alternative substitute for illicit opioid use.24 More specifically, they found that people who used cannabis every day had 50% lower odds of using opioids compared to cannabis non-users.
In addition, animal studies indicate that the combined use of THC and MOR agonists can have additive or synergistic effects on reducing pain sensation while preventing physiological dependence.25,26 A double-blind, placebo-controlled study showed that combination of a lower dose of a frequently prescribed opioid analgesic, oxycodone, and THC, led to a reduction of pain responses but this also led to an increase in positive subjective ratings related to oxycodone.27
Other animal studies reported that CBD may have beneficial effects in reducing drug-related memories associated with drug-seeking behavior, which may suggest it can be used as a replacement compound to treat drug dependence.28,29 Another investigation published in 2019 aimed at determining the potential of CBD in previous heroin users in reducing cue-induced craving and anxiety which are two critical features of addiction and dependence. Using a double-blind randomized placebo-controlled trial, the team found that administration of low and high dose of CBD led to a significant reduction in the above parameters and in anxiety at 1-2 hours, 24 hours and 7 days after CBD ingestion compared to placebo control.30 CBD administration also led to a reduction in physiological measures (e.g., increased heart rate and cortisol levels) induced by drug cues while no adverse events were noted in this group, suggesting CBD may be a good alternative to treat opioid dependence. Currently, there are two ongoing clinical trials: one aiming at determining the safety, efficacy, and tolerability of a novel drug, APH-150, CBD encapsulated in biodegradable polymer nanospheres, as a pharmacotherapy for opioid dependence, and one testing whether medical marijuana use by adults on high-dose chronic opioid therapy for chronic non-cancer pain is associated with reduced opioid dose and improved pain severity.31,32
In the United States, the opioid epidemic is recognized as an evolving and alarming crisis that needs to be properly addressed to reduce opioid dependence, overdose and ultimately death. While several interventions are available to treat opioid dependence, these are often associated with side effects and relapse and as such, novel therapeutic avenues are being investigated. One of which is the use of medical cannabis, specifically targeting two of the most investigated molecules, THC and CBD. Studies have shown that not only does medical cannabis may reduce opioid use, but they also demonstrated a decrease in pain-related symptoms along with fewer side effects. While these findings may shine new lights onto the treatment of opioid dependence, there remains additional work to be performed. As such, despite presenting a lower risk of dependence compared with opioids, patients being prescribed medical cannabis should be guided on a safe initiation and titration by medical experts to avoid risks of cannabis use disorder. A recent study outlined recommendations on how to best self-administer medical cannabis and taper opioids in patients with chronic pain to better educate these individuals.33
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- Mollereau C, Parmentier M, Mailleux P, et al. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 1994;341(1):33-8. DOI: 10.1016/0014-5793(94)80235-1.
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- Morone NE, Weiner DK. Pain as the fifth vital sign: exposing the vital need for pain education. Clin Ther 2013;35(11):1728-32. DOI: 10.1016/j.clinthera.2013.10.001.
- Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2020. (Assessed on May 25th 2021http://wonder.cdc.gov.).
- Ahmad F.B. RLM, Sutton P. Provisional Drug Overdose Death Counts. (Assessed May 25th 2021https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm).
- Florence CS, Zhou C, Luo F, Xu L. The Economic Burden of Prescription Opioid Overdose, Abuse, and Dependence in the United States, 2013. Med Care 2016;54(10):901-6. DOI: 10.1097/MLR.0000000000000625.
- Wakeman SE, Larochelle MR, Ameli O, et al. Comparative Effectiveness of Different Treatment Pathways for Opioid Use Disorder. JAMA Netw Open 2020;3(2):e1920622. DOI: 10.1001/jamanetworkopen.2019.20622.
- Sansone RA, Sansone LA. Buprenorphine treatment for narcotic addiction: not without risks. Innov Clin Neurosci 2015;12(3-4):32-6. (https://www.ncbi.nlm.nih.gov/pubmed/25973324).
- Dowell D HT, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep. 2016;2016;65(No. RR-1):1–49. DOI:http://dx.doi.org/10.15585/mmwr.rr6501e1external
- McHugh RK, Hearon BA, Otto MW. Cognitive behavioral therapy for substance use disorders. Psychiatr Clin North Am 2010;33(3):511-25. DOI: 10.1016/j.psc.2010.04.012.
- Prendergast M, Podus D, Finney J, Greenwell L, Roll J. Contingency management for treatment of substance use disorders: a meta-analysis. Addiction 2006;101(11):1546-60. DOI: 10.1111/j.1360-0443.2006.01581.x.
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- Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258(5090):1946-9. DOI: 10.1126/science.1470919.
- Scavone JL, Mackie K, Van Bockstaele EJ. Characterization of cannabinoid-1 receptors in the locus coeruleus: relationship with mu-opioid receptors. Brain Res 2010;1312:18-31. DOI: 10.1016/j.brainres.2009.11.023.
- Liang D, Bao Y, Wallace M, Grant I, Shi Y. Medical cannabis legalization and opioid prescriptions: evidence on US Medicaid enrollees during 1993-2014. Addiction 2018;113(11):2060-2070. DOI: 10.1111/add.14382.
- Shi Y. Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever. Drug Alcohol Depend 2017;173:144-150. DOI: 10.1016/j.drugalcdep.2017.01.006.
- Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med 2014;174(10):1668-73. DOI: 10.1001/jamainternmed.2014.4005.
- Reiman A, Welty M, Solomon P. Cannabis as a Substitute for Opioid-Based Pain Medication: Patient Self-Report. Cannabis Cannabinoid Res 2017;2(1):160-166. DOI: 10.1089/can.2017.0012.
- Piper BJ, DeKeuster RM, Beals ML, et al. Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. J Psychopharmacol 2017;31(5):569-575. DOI: 10.1177/0269881117699616.
- Lake S, Walsh Z, Kerr T, et al. Frequency of cannabis and illicit opioid use among people who use drugs and report chronic pain: A longitudinal analysis. PLoS Med 2019;16(11):e1002967. DOI: 10.1371/journal.pmed.1002967.
- Williams J, Haller VL, Stevens DL, Welch SP. Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception. Eur J Pharmacol 2008;584(1):78-86. DOI: 10.1016/j.ejphar.2007.12.035.
- Kazantzis NP, Casey SL, Seow PW, Mitchell VA, Vaughan CW. Opioid and cannabinoid synergy in a mouse neuropathic pain model. Br J Pharmacol 2016;173(16):2521-31. DOI: 10.1111/bph.13534.
- Cooper ZD, Bedi G, Ramesh D, Balter R, Comer SD, Haney M. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology 2018;43(10):2046-2055. DOI: 10.1038/s41386-018-0011-2.
- Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology (Berl) 2004;175(3):360-6. DOI: 10.1007/s00213-004-1825-7.
- Viudez-Martinez A, Garcia-Gutierrez MS, Navarron CM, et al. Cannabidiol reduces ethanol consumption, motivation and relapse in mice. Addict Biol 2018;23(1):154-164. DOI: 10.1111/adb.12495.
- Hurd YL, Spriggs S, Alishayev J, et al. Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial. Am J Psychiatry 2019;176(11):911-922. DOI: 10.1176/appi.ajp.2019.18101191.
- Exploratory Dose Ranging Study Assessing APH-1501 for the Treatment of Opioid Addiction. (Assessed on May 25th 2021https://www.clinicaltrials.gov/ct2/show/NCT03813095?term=opioid+dependence+CBD&draw=2&rank=1).
- Evaluation of Medical Cannabis and Prescription Opioid Taper Support for Reduction of Pain and Opioid Dose in Patients With Chronic Non-Cancer Pain. (Assessed on May 25th 2021https://www.clinicaltrials.gov/ct2/show/NCT04827992term=opioid+dependence+cannabis&recrs=abdf&draw=2&rank=4).
- Sihota A, Smith BK, Ahmed SA, et al. Consensus-based recommendations for titrating cannabinoids and tapering opioids for chronic pain control. Int J Clin Pract 2020:e13871. DOI: 10.1111/ijcp.13871.