Medical Cannabis in the Era of an Opioid Epidemic

Educational Objectives

The goal of this program is to improve the therapeutic use of cannabis. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize medical conditions for which evidence supports treatment with cannabis.

2. Identify adverse events associated with cannabis products.

3. Select patients most likely to benefit from cannabis products.

Summary

History: study found that majority of oncologists recommend using cannabis; prescribing based largely on data obtained from patients (scientific data lacking); cannabis used as therapeutic agent for centuries; manufactured by pharmaceutical companies as tinctures at turn of 20th century; in 1937, US Marihuana Tax Act passed, and American Medical Association stated that more research on cannabis necessary; cannabis banned by federal government; in 1970, US Food and Drug Administration (FDA) classified cannabis as schedule I drug but advocated for research (obstructed by schedule I status); recent liberalization of use began because treatment of AIDS-related cachexia lacking; in 1996, California legalized medical use of cannabis without substantiation by medical data (based on referendum); legalization of medical and recreational use followed in many states; only 3 states deny all access; choice of products wider when recommended by physician compared with recreational use

Legal status: US Supreme Court granted physicians right to recommend cannabis; possession of <50 cannabis plants or <50 kg of cannabis flower not subject to charges of drug trafficking; physicians typically influenced by legal concerns in discussions of cannabis with patients; legal status continuously changing and varies by state

Medical evidence: in 2017, National Academies of Science, Engineering, and Medicine stated that despite increased use of cannabis and changing policies at state level, conclusive evidence regarding short- and long-term health effects (harms and benefits) remains elusive; rigor of research varies widely; conclusions influenced by biases for and against use; theoretical benefits — compounds biologically similar to cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) produced endogenously; interact with mu-opioid system, serotonin receptors in brain, and immune system; type 1 cannabinoid (CB1) receptors found primarily in central nervous system; type 2 cannabinoid (CB2) receptors found peripherally; THC strong agonist of CB1 receptor (explains psychoactive properties); CBD has stronger affinity for CB2 receptor (psychoactive effects attenuated); interactions with endocannabinoid system not elucidated; use of term cannabis rather than marijuana encourages medical legitimacy; plant species include Cannabis sativa and Cannabis indica; THC and CBD most widely studied compounds in cannabis and most similar to endogenous cannabinoids

Regulated pharmaceutical products: dronabinol (Marinol) — synthetic THC; liquid version available (Syndros); plant-based product containing only CBD (Epidiolex) — well-controlled trial found that administration of CBD in children with intractable seizure disorders decreased number of seizures; because of favorable results, FDA expanded access; prohibitive cost limits use (even in patients with insurance coverage); nabiximols (Sativex) — first regulated product containing plant-based THC (not legal in US); contains equal ratio of THC and CBD; C indica — contains higher levels of CBD; C sativa — contains higher levels of THC; hemp plant — contains <0.03% THC and CBD in lower amounts; extraction of cannabinoids more difficult; dispensing cannabinoids — approved for 15 to 20 medical conditions (depending on state); in Pennsylvania, opioid use disorder added as approved condition to combat opioid epidemic (medical evidence lacking)

Clinical trials: single US randomized placebo-controlled trial — performed in 2007 in patients with neuropathic pain (variety of causes); based on subjective rating scale, study found cannabis cigarettes helpful during time of use; reparative effects lacking; trial of nabiximols (Sativex; ratio of THC to CBD 1:1) — nabiximols administered in patients with central and peripheral neuropathic pain; found subjective improvement in pain over 5-wk period; UK study in cancer patients receiving opioids — found decreased level of pain in patients taking nabiximols and plant-based THC compared with placebo over 2-wk period; patients in experimental arms used fewer opioids; study in mice — found that CBD administered rectally decreased inflammation in experimentally induced Crohn disease; CBD acts on peripheral CB2 receptors and modulates inflammation; may be more effective in inflammatory pain syndromes

Clinical uses: cannabinoids most commonly prescribed for pain, spasticity associated with multiple sclerosis, nausea, cancer, epilepsy, and degenerative neurologic conditions; cachexia — cannabinoids enhance appetite; data on weight gain lacking; epilepsy — data suggest efficacy of CBD, especially in children with refractory seizure disorders; study by Devinsky et al (2016) found average decrease in incidence of seizures 54%; replacement for opioids — safety profile for cannabis wider than for many other medications; lethal dose much higher; population-based studies found that rates of overdose caused by opioids lower in states that legalized recreational use of cannabis; causality not established; factors that could contribute to decreased rates of overdose include increase in awareness of risk for overdose, decrease in number of prescriptions for opioids, and increase in access to treatment of substance abuse; even in states with most permissive cannabis laws, rates of overdose not higher; rate of admissions for treatment of substance abuse decreased after legalization of cannabis; cannabis most widely used illegal drug; in 2017, 250 million individuals worldwide estimated to use cannabis

Adverse effects: wide availability of products high in THC necessitates that physicians be familiar with adverse effects and discuss them with patients; include dizziness, panic attacks, tachycardia (may trigger angina), and falls; THC associated with anxiety and dysphoria, paranoia, disruptions in short-term memory, discoordination, and sleepiness; in patients using cannabis regularly, repeated admissions to hospital for nausea and vomiting not likely associated with cyclical vomiting syndrome; discontinuation of cannabis definitive treatment; physical addiction absent; lifetime risk for psychological dependence ≈9%; risk for problematic use and dependence highest in individuals aged ≤25 yr

Cannabis as “gateway drug”: study from 6 European countries found that in children aged <16 yr, use of cannabis ≥1 time/wk associated with higher rates of use of other illicit drugs, physical and psychosomatic symptoms, academic failure, and delinquency; in individuals aged ≥18 yr who used cannabis frequently, rate of use of other illicit drugs not higher; in individuals aged 16 to 18 yr, association with use of other illicit drugs unclear

Mental health disorders: use of cannabis strongly discouraged; even in patients with well-controlled schizophrenia or bipolar disorder, risk for psychotic episode high (may be related to discontinuation of antipsychotic medication); in patients with schizophrenia who regularly use cannabis, yearly rate of hospitalization for psychotic episode 42% compared with 17% in patients not using cannabis

Pulmonary function and infection: 2018 meta-analysis found that short- and long-term use of cannabis not associated with changes (eg, progression of restrictive or obstructive disease); however, authors considered evidence insufficient to reach definitive conclusions; in immunocompromised patients, risk for aspergillosis eliminated by administration of cannabis by vaporization; many cases of overwhelming pulmonary infection reported in immunocompromised patients who smoked cannabis

Geriatric use: patients aged ≥65 yr fastest growing subset using cannabis; survey of oncology practices found rate of use of cannabis in patients ≥60 yr ≈33%; majority of patients do not voluntarily inform physicians of use

Drug interactions: cannabinoids metabolized by cytochrome P450 pathway; THC induces and CBD inhibits pathway; formulations combining THC and CBD attenuate drug interactions; hemorrhagic and thromboembolic complications of antiplatelet agents reported in patients using THC alone or CBD alone

Contraindications: absolute contraindications include psychosis and unstable psychiatric conditions; caution warranted in older patients with severe arrhythmia or other severe cardiac condition; cannabinoids can induce hypotension and tachycardia (especially in cannabinoid-naive patients)

Study from Israel: included >2700 patients aged ≥65 yr; found cancer-related symptoms most common indication for use of cannabinoids (eg, pain, chemotherapy-induced nausea and vomiting; 60% of all prescriptions); second most common indication low back pain; previous use of cannabis reported in ≈25%; at 6-mo follow-up, majority of patients reported improvement in symptoms; significant number of patients (not majority) discontinued or decreased use of other medications (eg, benzodiazepines, sleep aids, antiemetic drugs)

Role of physicians: encourage medicalization of cannabis; ask patients whether they use cannabis products; inform patients about appropriate use; provide specific recommendations; study of unregulated hemp-based CBD products found that concentration of cannabinoids 40% to 400% higher than advertised; independent validation of contents required for regulated cannabis products; discuss cost with patients (insurance coverage lacking)

Readings

Devinsky O et al: Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 2016 Mar;15(3):270-8; Ghasemiesfe M et al: Marijuana use, respiratory symptoms, and pulmonary function: a systematic review and meta-analysis. Ann Intern Med 2018 Jul 17;169(2):106-115; Lee G et al: Medical cannabis for neuropathic pain. Curr Pain Headache Rep 2018 Feb 1;22(1):8; Wilsey B et al: Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013 Feb;14(2):136-48; Wilsey B et al: A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008 Jun;9(6):506-21; Wilson M et al: Cannabis use moderates the relationship between pain and negative affect in adults with opioid use disorder. Addict Behav 2018 Feb;77:225-231.

Disclosures

For this program, the following has been disclosed: Dr. Worster reported nothing to disclose. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Worster was recorded at the 42nd Annual Eastern Shore Medical Symposium, cosponsored by Sidney Kimmel Medical College at Thomas Jefferson University, Office of Continuing Professional Development, and the University of Delaware, Division of Professional and Continuing Studies, and held June 17-21, 2019, in Rehoboth Beach, DE. For information about upcoming CME conferences presented by the University of Delaware, please visit www.pcs.udel.edu. The Audio Digest Foundation thanks the speakers and sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM664601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.