Cannabinoids and Hallucinogens for Neuropathic Pain and Headache

Educational Objectives

The goal of this program is to improve the diagnosis and treatment of pain. After hearing and assimilating this program, the clinician will be better able to:

1. Counsel patients requesting a prescription for medical marijuana about safety issues associated with cannabis.

2. Evaluate the safety and efficacy of hallucinogenic drugs used to treat pain.

Summary

Marijuana: term refers to Cannabis sativa and Cannabis indica; tetrahydrocannabinol (THC) most psychoactive compound among ≈130 cannabinoids in plant; acts at cannabinoid receptor type 1 (CB1) and CB2; CB1 induces effects in reward system involving nucleus accumbens and in kidney, liver, and lungs; CB2 may mediate complications in immune system; cannabis Schedule I drug (according to US Food and Drug Administration, medical use lacking, and risk for dependence high); prevalence of consumption within state increases when medical use legalized; effects — include hunger, relief of nausea, changes in blood pressure (BP; drug typically raises BP, but sometimes lowers it), and relief of tremor and possibly migraine; effects on cortex include disturbances in consciousness and perception, hallucinations, and delusions; drug may impair memory and coordination

Synthetic THC: dronabinol (Marinol) approved in United States for treatment of nausea induced by human immunodeficiency virus (HIV) infection; nabilone approved for nausea associated with cancer (and used off-label for HIV-induced nausea); drugs available outside United States include nabiximols (Sativex) and rimonabant (blocks cannabinoid receptor responsible for hunger)

Medical marijuana: study found 58% of patients who obtain marijuana from dispensary use it in lieu of prescription drugs; belief that herbal medications more effective and safer than prescribed drugs prevalent; patients report they use medical marijuana to treat pain, insomnia, muscle spasms, and anxiety; to relax; to stimulate appetite; and to relieve nausea and depression; purported benefits include relief of painful tonic spasms of multiple sclerosis (MS), peripheral neuropathy, dysesthetic limb pain, migraine, epilepsy, anxiety, depression, Alzheimer disease, Parkinson disease, addiction, arthralgias, nausea, poor appetite, inflammatory bowel disease, and glaucoma

Routes of administration: marijuana may be smoked, vaporized, or eaten; smoking releases toxins that may cause pulmonary disease; vaporization likely safer (does not appear to release toxins); eating marijuana does not produce toxins, but onset of effects slow; study found 67% of users of medical marijuana ingested drug daily (majority smoked it); effects vary based on strain; C sativa associated with euphoria and relief of stress; C indica induces relaxation and relief of pain; species often combined to customize effects

Regulatory status: medical marijuana not approved by US Food and Drug Administration or standardized; content varies with growing conditions; study found ≈75% of cannabidiol products purchased online mislabeled

Chronic pain: meta-analysis found marijuana induced ≥30% reduction in global chronic pain, but placebo favored in some studies; studies evaluating neuropathic pain (excluding patients with MS) found effect of cannabis modestly greater than placebo (duration of studies short); another study found that vaporized cannabis relieved central and peripheral pain (duration of study short)

Migraine: Goadsby et al proposed that patients with migraine may have deficiency of anandamide (interacts with endogenous cannabinoid receptor); however, active compounds in plant may not be correctly identified, and studies poorly designed

Safety: effects of medical marijuana on memory well documented; anxiety and psychosis reported; study found density of nucleus accumbens greater in children using marijuana; however, cognitive effects not quantified, patients studied took multiple drugs, and causation not proven; neurologic issues include reversible vasoconstrictive syndrome, stroke, headache on withdrawal, and cannabinoid hyperemesis syndrome (may be relieved by excessive bathing); drug may reduce testosterone levels and sperm count in men and decrease (or occasionally increase) sexual pleasure and alter menstrual cycle in women

Smoking marijuana: smoking marijuana more toxic to pulmonary system than smoking tobacco (eg, bronchitis, emphysema, lung cancer); increases BP, pulse rate, and risk for myocardial infarction (MI) 5-fold within 1 hr

Pulmonary effects: smoke usually held in lungs after inhalation for prolonged time (smoking marijuana associated with obstructive lung disease and greater exposure to “tar” than smoking tobacco); 5-fold increase in carboxyhemoglobin level in smokers of marijuana may contribute to heart disease; smoking marijuana and cigarettes has synergistic effect; smoking marijuana does not cause respiratory depression

Cardiovascular effects: patients may die of MI after smoking marijuana (even in absence of coronary artery disease); MI related to smoking marijuana associated with higher mortality rate than MI due to other causes

Immune system: risk higher for tuberculosis, Neisseria meningitidis infection, and possibly sexually transmitted diseases, fatty liver, and cancers

Psychiatric disorders: marijuana does not increase risk of developing anxiety disorder, but anxiety may be symptom of withdrawal; patients who smoke marijuana may be self-treating unrecognized psychiatric disorders; risk for psychosis 40% higher in users of marijuana and 200% higher in heavy users; outcome poor in patients with schizophrenia

Pregnancy: maternal use associated with impaired motor, social, and cognitive skills in offspring; low birth weight, preterm delivery, and childhood leukemia; marijuana excreted in breast milk (amount may be clinically insignificant)

Substance abuse: tolerance may develop; withdrawal may precipitate anger, aggression, irritability, depression, loss of control, anorexia, vivid dreams, anxiety, depression, headache, and muscle tension; lifetime risks for dependence 32% for nicotine, 23% for heroin, 17% for cocaine, 15% for alcohol, and 9% for marijuana

Drug interactions: marijuana lipophilic; metabolism extensive (primarily by way of cytochrome P450 3A4); cannabis interacts with grapefruit juice, eletriptan, and other drugs; drinking grapefruit juice potentiates effect

Psilocybin: prodrug of psilocin found in some mushrooms; typical dose 1 to 2 g (10-25 mg psilocybin); duration of effect ≈5 hr; patients may have disinhibition and visual hallucinations; drug agonist at 5-HT2 receptor; potential for abuse low

Lysergic acid diethylamide (LSD): subhallucinogenic doses previously used to treat headache; may be effective for migraine and anxiety; psychiatric adverse effects reported in patients with headache; binds to serotonin receptors

Methysergide: previously marketed as preventive agent for migraine and cluster headaches; no longer manufactured because of adverse effect of retroperitoneal fibrosis; hallucinations found at high doses; closely related to LSD; other adverse effects include pleuropericardial and subendocardial fibrosis; in uncontrolled Internet study of 53 patients with cluster headache, 22% reported methysergide helpful

2-bromo-lysergic acid diethylamide: form of LSD without hallucinogenic properties studied by Halpern et al; drug no longer manufactured

Ketamine: study compared intranasal ketamine with midazolam in patients with migraine with prolonged aura; found ketamine reduced duration, but not severity, of aura; in study of 5 patients with hemiplegic migraine, ketamine found to reduce severity and duration of symptoms

Readings

Akerman S et al: Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: implications in migraine. J Neurosci 2013 Sep 11;33(37):14869-77; Aviram J, Samuelly-Leichtag G: Efficacy of cannabis-based medicines for pain management: a systematic review and meta-analysis of randomized controlled trials. Pain Physician 2017 Sep;20(6):E755-96; Bonn-Miller MO et al: Labeling accuracy of cannabidiol extracts sold online. JAMA 2017 Nov 7;318(17):1708-9; Gilman JM et al: Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. J Neurosci 2014 Apr 16;34(16):5529-38; Karst M et al: The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series. Cephalalgia 2010 Sep;30(9):1140-4; Mücke M et al: Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018 Mar 7;3:CD012182; Wilsey B et al: Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013 Feb;14(2):136-48.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Green presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Green was recorded at the 31st Annual Practicing Physician’s Approach to the Difficult Headache Patient, presented by the Diamond Headache Clinic Research and Education Foundation and Presence Saint Joseph Hospital and held February 16-19, 2018, in Carlsbad, CA. For information on future educational opportunities from the Diamond Headache Clinic Research and Education Foundation, please visit dhc-fdn.org. 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:

IM653802

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.