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Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Medical marijuana and pain management Leslie Mendoza Temple, MD
Introduction Cannabis is one of the earliest known plants to be domesticated by humans, with evidence of its existence dating approximately 36 million years ago in central Asia. This plant grows easily in many conditions. Described simply, its ﬁbrous stems are used to make rope, paper, and cloth, its seeds and oil provide nourishment, and its ﬂowers create a controversial drug. As a recreational, medicinal, and even religious ceremonial substance, cannabis has endured a colorful and storied past, with one of the earliest formal records of medicinal purposes described in China in 2737 BC.1 Moving through the Industrial Age to the 20th century, Western physicians recommended cannabis for various ailments, starting in the mid-1800s. The height of physician-ordered cannabis prescribing reached its height around the late 19th–20th century. Pharmaceutical companies Merck, Bristol-Meyers, Burroughs-Wellcome, Squibb, Eli Lilly, and Parke-Davis marketed cannabis extracts. However, the sociopolitical climate turned the tides on cannabis starting in the 1920s with anti-alcohol legislation, ultimately leading to marijuana becoming outlawed in 1970. The passage of the Controlled Substance Act criminalized all cannabis possession regardless of the purpose, quantity, or context of its use. A more comprehensive history of cannabis use is elegantly described in the April 2015 edition of this publication, Disease-a-Month, by Greydanus and colleagues.1–4 The following review will relate speciﬁcally toward cannabis and pain management for the primary care clinician. In the 21st century, the sociopolitical tides have again turned, this time in favor of reinstating the legality and mainstream social acceptance of cannabis in the United States. To date, 23 states and the District of Columbia have legalized cannabis for medical use. Four states allow cannabis for legal recreational and medical use. This paradigm shift has sparked a great need for increased education on the potential beneﬁts and harms of this herb for both patient and physician.
The endocannabinoid system The endocannabinoid system (ECS) was a relatively recent discovery from the early 1990s. The ECS is a ubiquitous signaling system responsible for a variety of survival functions in all vertebrates. The actions “relax, eat, sleep, protect, and forget” neatly summarizes the various functions of the ECS, which are regulated by an array of receptors, ligands, and enzymes. These players interact from moment-to-moment to promote functions that the organism requires at http://dx.doi.org/10.1016/j.disamonth.2016.05.014 0011-5029/& 2016 Mosby, Inc.. All rights reserved.
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the time. The main players of the ECS are its receptors (CB-1 and CB-2), its ligands (anandamide “AEA” and 2-arachidonoylglycerol “2-AG”), and the signal-terminating enzymes (fatty acid amide hydrolase “FAAH” and monoacylglycerol lipase “MAGL”). Learning the distribution of CB-1 and CB-2 receptors in the body is important for the clinician in understanding the implications of cannabis or pharmaceuticals for the patient in pain. CB-1 receptors are G-protein coupled receptors located in the central and peripheral nervous systems, adipocytes, leukocytes, spleen, heart, lung, gastrointestinal tract, kidney, bladder, reproductive organs, skeletal muscle, bone, joints, and skin. Despite its nearly ubiquitous presence in the body, CB-1 expression is sparse to non-existent in the brainstem, medulla, and thalamus.5–8 The low receptor density of CB-1 in the brainstem and medulla may likely explain the low risk of mortality from respiratory depression from cannabis overdose.6 CB-2 receptors are found mostly in the immune system, and in lesser amounts in bone, liver, and nerve cells. CB-2 receptors modulate immune function primarily,9–27 with evidence that these receptors also have analgesic effects on induced nerve damage and pain in animal models.28–31
Phytocannabinoids The leaves and ﬂowering tops of the cannabis plant contains at least 489 distinct compounds from 18 different chemical classes, including over 60 different phytocannabinoids.32 Two of these phytocannabinoids are worth to be noted—THC (delta-9 tetrahydrocannabinol or Δ9-THC) and CBD (cannabidiol). THC and CBD have speciﬁc actions at these receptors and can make a difference in clinical outcomes and psychoactive effects, or the lack thereof. The female cannabis plant is harvested, dried, and processed to be consumed via oral (i.e., infused food, oil, tea, and hash) or inhalation (i.e., pipe, joint, and vaporizer) routes.
Pharmaceutical cannabinoids THC only Dronabinol is synthetic delta-9 tetrahydrocannabinol (Δ9-THC) in sesame oil, marketed as Marinols. Dronabinol has been available since the mid-1980s for anorexia associated with weight loss in patients with AIDS and nausea and vomiting associated with cancer chemotherapy. Dronabinol comes in 2.5, 5, and 10 mg capsules, and dosing can range from 2.5 to 40 mg per day. Nabilone is a synthetic analogue of Δ9-THC, marketed as Cesamets, indicated only for nausea and vomiting associated with cancer chemotherapy in patients where conventional antiemetic treatments have failed. Nabilone dosage varies from 0.2 to 6 mg per day. THC and CBD Nabiximols is a botanical cannabis oromucosal spray containing approximately equal ratios of Δ9-THC, CBD, other cannabinoids, terpenoids, and ﬂavonoids ﬂavored with peppermint oil, marketed as Sativexs. Each 100 μL spray contains 2.7 mg Δ9-THC and 2.5 mg CBD. Nabiximols are indicated for relief of spasticity in multiple sclerosis in 27 countries (not including the United States). The drug is currently in phase 3 clinical development in the United States as a treatment for patients with inadequately controlled cancer pain despite the use of optimized chronic opioid therapy. Approximately 1–16 sprays per day may be used.33 CBD only Epidiolexs is a liquid plant-derived CBD for severe infantile-onset, drug-resistant pediatric epilepsy.33
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The endocannabinoid system, pain, and inﬂammation Anti-inﬂammation and cannabinoids In vitro, the anti-inﬂammatory activities of THC have shown twice the potency of hydrocortisone and 20 times that of aspirin.34 Co-ingesting cannabinoids and COX-2 inhibitors may, in theory, synergistically inhibit prostaglandin and enhance endocannabinoid activity. The combination may produce greater pain relief compared to using either agent alone.35 Tolerance is a main unwanted development with all analgesic drugs, including cannabinoids, and COX-2 inhibition may prolong cannabinoid analgesia.36 Takeda et al.37 demonstrated that CBDA (the acid form of CBD found in fresh cannabis leaves) is a potent and selective inhibitor for COX-2 in vitro. Ruhaak et al. studied six cannabinoids from Cannabis sativa and their effects on prostaglandin production—delta-9 tetrahydrocannabinol (Δ9-THC), delta-9 tetrahydrocannabinolic acid (Δ9-THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), and cannabigerolic acid (CBGA). The cannabinoids inhibited cyclo-oxygenase enzyme activity in human colon cell cultures.38 However, more clinical studies are needed to test whether a synergistic effect on inﬂammation and pain can be observed reliably in humans. Opioids and cannabinoids Cannabinoids may have an opioid-sparing effect, providing analgesia while allowing the patient to use a lower dose of opioids for overall pain control. Preclinical data shows a solid amount of evidence to support this theory, while clinical data shows preliminary evidence of this effect. The cannabinoid and opioid systems share similar biological effects like sedation, hypotension, hypothermia, inhibition of gastrointestinal motility and locomotor activity, and anti-nociception. Cannabinoid and opioid receptors are distributed in an overlapping manner in the nervous system, which may inﬂuence spinal level modulation of peripheral pain inputs. Both the types of receptors share similar signal transduction pathways and are both located on pre-synaptic membranes. Hence, signiﬁcant crosstalk occurs between the cannabinoid and opioid systems.39–41 Animal studies have shown additive or synergistic effects of combining opioid medications (morphine and codeine) with THC at acute or subeffective doses.42–47 Human trials have shown some positive or mixed results. Abrams et al.48 studied patients with chronic non-cancer pain on stable doses of morphine or oxycodone. A signiﬁcant augmentation effect was found after participants vaporized cannabis three times a day for 5 days while also taking twice daily morphine or oxycodone. Narang et al.49 demonstrated an additive effect on pain relief from dronabinol (10 and 20 mg) for patients with chronic pain who were also taking opioids. Other studies showed pain reduction with nabiximols (THC:CBD extract) in poorly controlled opioid-treated cancer pain. However, no statistically signiﬁcant changes in decreased opioid dosing were noted in the study patients.50,51
Clinical evidence of cannabinoids for pain management In 1997, the Ofﬁce of National Drug Control Policy funded a study by the Institute of Medicine to evaluate the scientiﬁc evidence for medicinal cannabis and its risk/beneﬁt proﬁle.52 The literature for cannabinoids in acute and chronic pain primarily features pharmaceutical derivatives of THC and/or CBD, with a smaller proportion of studies looking at whole-plant cannabis extracts. The varying levels of scientiﬁc rigor and power in studies looking at cannabis for pain management and other conditions is a source of political and social controversy. Since 1970, cannabis has been a Schedule I drug in the United States, creating signiﬁcant barriers to researching its efﬁcacy in various medical conditions.
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Cancer pain Clinical studies for cancer pain and cannabinoids comprise the highest number of human studies.53 Portenoy and colleagues studied nabiximols in a randomized, double-blind, placebocontrolled, graded dose study in patients with advanced cancer and opioid-resistant pain. Participants in the low-dose (1–4 sprays daily) and medium-dose (6–10 sprays daily) groups reported less pain compared to placebo and less sleep disruption, with greater tolerability compared to the high-dose group (11–16 sprays daily).50 Chronic non-cancer pain Cannabinoids have been shown to be potentially effective for chronic non-cancer pain in a 2011 systematic review of randomized trials.54 In all, 15 of 18 qualiﬁed studies showed signiﬁcant pain reduction from cannabinoids involving 766 study participants between 2003 and 2010. Sleep also improved in several trials for chronic neuropathic pain, multiple sclerosis, rheumatoid arthritis, and neuropathic pain from brachial plexus avulsion.55–58 Treatment effects were generally modest, with an average treatment duration of 2.8 weeks (range: 6 h–6 weeks). Adverse events were well tolerated and mild. Cannabis dosing Dosing whole-plant cannabis extracts, whether in oral or inhaled form, is highly individualized. Dose titration is more clear-cut with the inhaled (vaporized or smoked) form compared to the oral ingested route.59 For ﬁrst time use, patients should start at a very low dose. For inhalation, the intake should be slow, waiting several minutes between puffs. For edible cannabis products, patients should wait 30–60 min between bites to avoid overdosing. A typical joint contains between 500 and 1000 mg of cannabis whole-plant matter, weighing an average of 750 mg. The Δ9-THC content varies between 7.5 and 225 mg. Approximately 25% of the total available amount of Δ9-THC in a joint is absorbed systemically.59–61 The rest of the cannabinoids are combusted or lost in side-stream smoke. Vaporization of heated cannabis creates less combustion products than smoked cannabis, and may theoretically confer less risk to cardiovascular and pulmonary function. Orally consumed cannabis is more difﬁcult to dose based on individual gastrointestinal motility, drug absorption, quantity of cannabis consumed, and the liver’s ﬁrst pass effect, although the lung effect is bypassed. Orally consumed cannabis effects are longer lasting, yet take longer time to manifest their effects (30–60 min). Various studies in the peer-reviewed literature suggest that a majority of surveyed participants using medicinal cannabis took 10–20 g per week (inhaled or edible forms) or approximately 1000–3000 mg of cannabis, or 1.3–4 cigarettes per day.59,62,63 Side effects Most adverse events are not serious with respect to medical or recreational cannabis use. The most serious events in a systematic review by Wang et al.64 included relapse of multiple sclerosis, cannabis hyperemesis syndrome, and urinary tract infection. Non-serious adverse events include dizziness (most common), fatigue, dry mouth, nausea, sleepiness, euphoria, vomiting, disorientation, confusion, loss of balance, and hallucination.65 Paranoia, psychosis, anxiety, depersonalization, worsened short-term memory, impaired judgment and driving, and appetite stimulation with weight gain (unless desired) are additional risks that can be serious but transitory until the drug is cleared. Long-term use of cannabis in adolescents may be associated with a decline in intelligence quotient, and is discouraged in adolescents under 18 years of age before full brain maturation.66
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Indications for medical cannabis use in pediatric patients however, may confer greater beneﬁt compared to risk in the young patient with persistent, intractable seizures. The estimated human lethal dose of intravenous THC is 30 mg/kg, or 2100 mg in a 70 kg person,67 although there has been no documented evidence of death exclusively attributable to cannabis overdose to date.
Legal landscape The most common conditions treated in medical cannabis eligible states are cancer, HIV/ AIDS, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, and cachexia or severe nausearelated conditions.68 It is noteworthy that between 1999 and 2010, 13 states in the United States, which have had medical cannabis laws experienced a 24.8% lower mean annual opioid overdose mortality rate compared with states lacking medical cannabis laws. The mortality reduction effect strengthened over time.69 More human clinical trials are necessary to better understand the efﬁcacy of medical cannabis for the many conditions that are now legal for cannabis treatment in 23 states. In these states, the local health departments are charged to consider adding new medical conditions for eligibility by their constituents. Many of the conditions are considered with a focus on compassionate use for intractable, severe cases (i.e., amyotrophic lateral sclerosis), even if the scientiﬁc evidence base for cannabis use in the particular condition is weak. With the clinical evidence largely in a preliminary phase for most of these conditions, there will be a continued strong need to study the efﬁcacy and safety of medical cannabis for years to come. References 1. Zuardi AW. History of cannabis as a medicine: a review. Braz J Psychiatry. 2006;28(2):153–157. 2. McPartland JM, Guy GW. The evolution of cannabis and coevolution with the cannabinoid receptor: a hypothesis. In: Guy PJ, Whittle BA, Robson PJ, eds. The Medicinal Use of Cannabis and Cannabinoids. London: Pharmaceutical Press; 2004:71–101. 3. Bostwick MJ. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. 2012;87(2): 172–186. 4. Greydanus DE, Kaplan G, Baxter LE, Patel DR, Feucht CL. Cannabis: the never-ending, nefarious nepenthe of the 21st century: what should the clinician know? Dis Mon. 2015;619(4):113–176. 5. Fine PG, Rosenfeld MJ. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med J. 2013;4(4): e0022. 6. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87 (5):1932–1936. 7. Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003;83(3): 1017–1066. 8. Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol. 2004;2(4):305–314. 9. Teixeira D, Pestana D, Faria A, Calhau C. Modulation of adipocyte biology by delta(9)-tetrahydrocannabinol. Obesity. 2010;18:2077–2085. 10. Greineisen WE, Turner H. Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists. Int Immunopharmacol. 2010;10:547–555. 11. Jean-Gilles L, Gran B, Constantinescu CS. Interaction between cytokines, cannabinoids and the nervous system. Immunobiology. 2010;215:606–610. 12. Rice W, Shannon JM, Burton F, Fiedeldey D. Expression of a brain-type cannabinoid receptor (CB1) in alveolar Type II cells in the lung: regulation by hydrocortisone. Eur J Pharmacol. 1997;327:227–232. 13. Shmist YA, Goncharov I, Eichler M, Shneyvays V. Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production. Mol Cell Biochem. 2006;283:75–83. 14. Wright K, Rooney N, Feeney M, Tate J. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005;129:437–453. 15. Marquez L, Suarez J, Iglesias M, Bermudez-Silva FJ. Ulcerative colitis induces changes on the expression of the endocannabinoid system in the human colonic tissue. PLoS One. 2009;4:e6893. 16. Linari G, Agostini S, Amadoro G, Ciotti MT. Involvement of cannabinoid CB1- and CB2-receptors in the modulation of exocrine pancreatic secretion. Pharmacol Res. 2009;59:207–214. 17. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126:21–38.
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