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Medical Uses of Marijuana

Medical Uses of Marijuana. John Woytowicz, MD University of New England School of Pharmacy UNE Pharmacy Convention October 13, 2017 Portland ME. Objectives. To review the Maine statue on marijuana To review the evidence based literature on the clinical use of medical marijuana

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Medical Uses of Marijuana

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  1. Medical Uses of Marijuana John Woytowicz, MD University of New England School of Pharmacy UNE Pharmacy Convention October 13, 2017 Portland ME

  2. Objectives To review the Maine statue on marijuana To review the evidence based literature on the clinical use of medical marijuana To develop an integrative medicine approach in the clinical application of medial marijuana

  3. State Statutes • 29 states: AK, AZ ,AR, CA, CO, CT, DE, FL, HI, IL, ME, MD, MA, MI, MN, MT, NV, NH, NJ, NM, NY, ND, OH, OR, RI, VT, WA, WV and DC. CA-1996, ME-1999/2010 • 18 states with legal cannabidiol (CBD): AL, DE, FL, GA, IN, IA, KY, MS, MO, NC, OK, SC, TX, UT, VA, WI, WY

  4. States that allow CBD products • Legislation allowing for low-THC, CBD-rich marijuana oil has been approved for limited use in 18 states. • Indications: treatment of epilepsy or seizures in seriously ill children, intractable muscle spasm, cancer, sickle cell anemia, Crohn’s disease, ALS, MS, mitochondrial disease and Parkinson’s disease

  5. Medical indications specified in state statutes Seizure disorder including epilepsy, intractable skeletal muscular spasticity, glaucoma, severe or chronic pain, severe nausea or vomiting, cachexia, or wasting syndrome resulting from AIDS/HIV or cancer, Amyotrophic lateral sclerosis (Lou Gehrig’s disease, Multiple sclerosis, terminal cancer, muscular dystrophy, inflammatory bowel disease (e.g. Crohn’s or ulcerative colitis), intractable muscle spasm, Hepatitis C, agitation from Alzheimer’s disease, Nail-Patella Syndrome, chronic or debilitating pain syndrome, intractable nausea, peripheral neuropathy, PTSD in NM, DE and ME (2013) Hospice in NM and ME (use in free standing hospice units)

  6. On-line resources www.procon.org Use for a comparison of medical marijuana statues across the nation. www.maine.gov/dhhs/dlrs/mmm/index./html Use to locate the forms to certify a patient for the use of medical marijuana and to obtain details about the Maine statute.

  7. Certification guidelines • Most states will or have established a review/oversight board usually comprised of physicians, health care clinicians, and the public to review new indications and special cases. • Pediatrics: most states limit its use on a case by case basis. • NPs allowed to certify patients in some states, in ME as of 2013

  8. Medical Indications Established in ME 1999 • Persistent nausea, vomiting, wasting syndrome of loss of appetite as a result of: AIDS, chemo and radiation therapy to treat cancer • Heightened intraocular pressure as a result of glaucoma • Seizures associated with a chronic, debilitating disease. e.g. epilepsy • Persistent muscle spasms associated with chronic debilitating disease. e.g. multiple sclerosis

  9. Referendum Nov. 2009 • Establishment of a dispensary for patients to purchase marijuana, 8 in Maine • Establishment of a bona-fide physician-patient relationship • Broader medical indications: - Crohn’s disease - Hepatitis C - Agitation from Alzheimer’s dementia - ALS, Nail-Patella syndrome - Intractable pain of greater than 6 months duration that has not responded to ordinary medical or surgical measures

  10. So What Are The Most Common Requests Before 2009 • Prior to 2009 muscle spasms…multiple sclerosis and injuries; and nausea, vomiting, cachexia from cancer often in the setting of chemotherapy • One request each for elevated IOP in glaucoma and Alzheimer’s dementia, and several for seizure disorders

  11. Requests Since Nov. 2009 • Chronic pain; usually trauma/injury to head, neck and back, fibromyalgia, chronic headaches, advanced arthritis • Crohn’s disease and other gastrointestinal disorders with persistent nausea, cachexia, anorexia often in the setting of cancer and chemotherapy, ulcerative colitis • Muscle spasm/spasticity due to numerous neurological conditions: e.g. MS, Freidrich’s ataxia, dystonia, Parkinson’s disease

  12. Summary: 2 Types of EC Receptors • CB1: mainly expressed in the brain/CNS. But also found in the lung, liver, kidneys and peripheral nerves. • CB2: mainly expressed in the immune system and hematopoietic cells, and found in smaller amounts as CB1 • Perhaps non-CB1/non-CB2 expressed in the brain • No CB Rc’s are found in the brainstem or heart

  13. Physiology of EC RC’s • CB1: antiemetics and appetite stimulants…..agonists like tetrahydrocannabinol (THC) and nabilone. Suppressions of muscle spasms/spasticity in MS and spinal cord injury. Relief of chronic pain, lowering intraocular pressure and preventing bronchospasm. • CB1 antagonists might suppress appetite and play a role in the management of schizophrenia or disorders of cognition and memory

  14. Phamacokinetics • Inhaled THC causes maximum plasma levels within minutes, psychotropic effects begins within seconds. Maximum levels after 15-30 minutes before tapering down over 2-3 hours in most people. • Oral ingestion have a longer active duration of 4-12 hours.

  15. Available forms of medical marijuana • Dried herb used to smoke or vaporize • Edibles: cookies, candy, butter or ghee • Young green tips of plant: fresh or dried used in cooking to make spaghetti sauce, for instance, or steep as a tea. • Liquid extracts: “glycerine” based contain both active THC and CBD or “alcohol” or “tincture” contains only active CBD • Topical salves

  16. Multiple Sclerosis • Interesting group of studies. Most studies show variable results from medical marijuana when measured against the Ashworth scale used to assess muscle spasm • Remarkably, most studies note that patients report improved function in ADLs, control of pain related to muscle spasm, and improved sleep (Vaney C, etal. Mult Scler. 2004 Aug;(10):417-24)

  17. CBD reduces inflammation in viral model of Multiple Sclerosis • Modifies the deleterious effects of inflammation in TMEV-demyelinating disease. • Decreases the transmigration of leukocytes by downregulating the expression of vascular cell adhesion molecules, chemokines and proinflammatory cytokines (IL-1beta and attenuates activation of microglia. (Mecha M, etal. Cannibidiol provides long-lasting protection against deleterious effects of inflammation in a viral model of MS. Neurobiol Dis 2013 Jul 11:59C:141-150)

  18. Cytoprotection mediated through endocannabinoidrecepetors. • Immune cells mainly have CB2, and less CB1 • Expression of CB1 and CB2 altered by inflammation. • Decreased production of pro-inflammatory cytokines • Suppression of mitogen-induced cell proliferation, migration, Antigen presentation and trafficking into inflamed tissues are regulated via CB2 • Suppression of auto-reactive T cells controlled by CB2 • Neuro-protective action on neurons controlled by CB1 • MS cannabinoid-mediated neuroprotection may be more important than immunosuppression in chronic stages of MS. ( Delago E, etal and Kozela E, etal)

  19. Treatment of Spasticity • Randomized, placebo-controlled trials, as well as longer-term open-label extensions, show a clear cut improvement in spasticity in patients refractory to other therapies, with a good tolerability and safety profile (Oreja-Guevara C. Treatment of spasticity in multiple sclerosis: a new perspective regarding the use of cannabinoids. Rev Neurol. 2012 Oct 1;55(7): 4210430. ) • 300 pts who were previously refractory to treatment showed clear improvement in sleep quality, bladder function control and mobility (Flachenecker P. Expert Rev Neurother 2013 Feb;13 (3suppl 1): 15-19)

  20. Multiple Sclerosis • Data from 300 patients showed that Sativex provided relief of MS-related spasticity in the majority of patients who were preciously resistant to treatment. • Clear improvements in associated symptoms of sleep quality, bladder function control and mobility. (Flachenecker P. Expert Rev Neurother.2013 Feb;13 (3 Suppl 1):15-9)

  21. MS: Neuropathic Pain • Sativex: Phase I-III studies in 2000 subjects demonstrate marked improvement in sleep parameters in patients with wide variety of pain conditions including MS, peripheral neuropathic pain, intractable cancer pain, and RA with acceptable adverse event profile. Sativex is an inhaled form of marijuana marketed in Canada and Europe. (Russo EB, etal Chem Biodivers. 2007 Aug;4(8) 1729-43)

  22. Neurodegenerative Disorders • Further study of the endocannabinoid system especially by antagonists of the CB1 receptors or inhibition of EC metabolism may play significant role for treatment in neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and multiple sclerosis. (Basavarajappa BS etal Mini Rev Med Chen. 2009 Apr;9(4):448-62)

  23. Overall Benefit in MS • Cannibis may slow the neurodegenerative process • Boost the immune • Reduce spasm and spasticity • Improve urinary incontinence

  24. Management of Chronic Pain • Cannabinoids act synergistically with opioids and act as opioid sparing agents allowing for lower doses and fewer side effects form chronic opioid therapy. (Elikottil J, etal J Opioid Manag. 2009 Nov-Dec;5(6): 341-57)

  25. Synergy with opiate use • Medical cannabis use was associated with a 64% decrease in opioid use (n=118), decreased number and side effects of medications, and improved quality of life (45%). • Cross-sectional retrospective survey of 244 medical cannabis patients with chronic pain. Patrons at a medical cannabis dispensary in MI. ( Boehnke KF, etal. J Pain. 2016 Mar 18. pii: S1526-5900(16)00567-8)

  26. Different Types of Pain • Various forms of medicinal cannabis have provided mostly positive response for patients with different types of pain: neuropathic, chronic, post-operative, that related to fibromylagia, rheumatoid arthritis, multiple sclerosis and cancer. (Borgelt, LM, etal. The Pharmacologic and Clinical Effects of Medical Cannabis. Pharmacotherapy. vol 33, no 2, 2013195-209)

  27. Opioid and Cannabinoid Intereactions • Recent studies indicate that opioid and cannabinoid antinocioception may have additive or even synergistic antinocioceptive effects • Clinically this may enhance analgesic effects with lower doses and consequently fewer undesirable side effects. (Desroches J, Beaulieu P. Curr Drug Targets 2010 Apr;11(4):462-73)

  28. Synergy Between Cannibis and Opioids • The combination of THC in low, non-psychoactive doses with opioids has a synergistic effect and reduces the opioid tolerance effects. (Karst M, Wippermann S. Expert Opin Investig Drugs. 2009 Feb: 18(2):125-33) Synergistic interactions between cannabinoid and opioid receptors show potential reduction in drug-seeking behavior and opiate sparing effects. ( Leung L. J Am Board Fam Med. 2011 Jul-Aug;24(4):452-62)

  29. Chronic Pain Management • Meta-analysis of RCTs: Cannabis was most effective for neuropathic pain over placebo. • The most prominent adverse effects were related to the CNS and GI systems. • (Aviram J, etal. Efficiacy of cannabis-based medicines for pain management: A systematic review and meta-analysis of randomized controlled trials. Pain Physician.2017 Sep;20(6):E755-E796.)

  30. Chronic Pain • The route of delivery of cannabis is important as the bioavailability and metabolism are very different for smoking vs oral/sublingual routes. • Some studies support the use of cannabinoids for some cancer, neuropathic, spasticity, acute pain, and chronic pain conditions. • ( Jensen B, etal. Medical marijuana and Chronic Pain. Curr Pain Headache Rep. 2015 Oct;19(10):50)

  31. Adjuvant Pain Relief in Cancer patients with chronic uncontrolled pain • Forms of cannabinoids: nabiximols (Sativex) • Advanced cancer patients with chronic pain unalleviated by optimized opioid therapy • Nabiximols was statisically superior to placebo on 2 of 3 quality of life instruments. • ( Lichtman AH, etal. Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as adjuvant therapy in advance cancer patients with chronic unalleviated pain. J Pain Symptoms Manage. 2017 Sep 15)

  32. Cannabinoids for Medical Use • 79 trials ( 6462 participants) • 4 judged as low risk of bias • Conclusion: compared to placebo • 1. cannbinoids were associated with a greater average number of patients showing complete nausea and vomiting response,

  33. continued • 2.reduction in pain • 3. greater average reduction in numerical rating scale pain assessment and average reduction in the Ashworth spasticity scale (Whiting PF etal. Cannabinoids for Medical Use: A systematic Review and Meta-analysis. JAMA> 2-73) Jun 23-30: 313(24):2456015

  34. Adverse Effects • Dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, hallucinations (Whiting PF etal. Cannabinoids for medical use: A systematic review and meta-analysis, JAMA 2015 Jun 23-30;313(24) 2456-73.)

  35. Cannabinoids and The Gut • EC-Rc’s are involved in the regulation of food intake, nausea and emesis, gastric secretions and gastroprotection, GI motility, ion transport, visceral sensation, intestinal inflammation and cell proliferation in the gut. (Izzo AA, Sharkey KA. Pharmacol Ther. 2010 Apr:126(1):21-38. Epub 2010 Feb 1)

  36. Crohn’s Disease • The endocannabinoid system influences the GI tract through the CB1 receptors located in the enteric nervous system and in sensory terminals of vagal and spinal neurons and regulate neurotransmitter release, CB2 receptors are mainly distributed in the immune system. The EC system conveys protection to the GI tract through regulation of inflammation, and gastric and enteric secretion. (Massa F etal J Endocrinol Invest. 2006;29(3 suppl):47-57)

  37. Cannabis as a Steroid Sparing Alternative • 21 patients (mean age 41+/- 14 yrs, 13 men who did not respond to therapy with steroids, immunomodulators, anti-TNK alpha agent) assigned randomly to 2 groups cannabis, BID, cigarettes with 115 mg delta9-THC and placebo containing cannabis flowers from which THC was extracted. Disease activity and laboratory tests were assessed during 8 weeks of treatment and then Q 2 weeks. (Naftali T, etal. Cannabis induces a clinical response in patients with Crohn’s disease: A prospective placebo-controlled study. ClinGastroenterolHepatol. 2013 May 4, s1543-3565(13)00604-6)

  38. Results • Complete remission 5/11 in cannabis group & 1/10 in placebo group. (P=.43) • Clinical response 10/11 in cannabis group & 4/10 in placebo group (P=.028) • 3 patients from cannabis group weaned from steroid dependency • Cannabis group: improved appetite and sleep, no serious side effects.

  39. Overall • Although the primary endpoint of the study (induction of remission) was not achieved, a short course (8 weeks) of THC-rich cannabis produce significant clinical, steroid free benefits to 10 to 11 patients with active Crohn’s disease compared with placebo, without side effects.

  40. Chemotherapy-Induced Nausea and Vomiting • Cannabinoids are more effective than placebo and comparable to antiemetics like prochlorperazine and ondansetron. (Cotter J. Oncol Nurs Forum. 2009 May 1;36(3):345-352)

  41. Which Anti-Emetic is Best? • A review of anti-emetic efficacy of cannabinoids in cancer patients receiving chemotherapy. • 30 studies • The superiority of the anti-emetic efficacy of cannabinoids compared with conventional drugs was demonstrated through meta-analysis. (Machado Rocha FC, et al. Eur J Cancer Care(Engl). 2008 Sep;17(5):431-43. Epub 208 Jul 8)

  42. Glaucoma • Recent review by the American Society of Glaucoma indicated that marijuana does lower IOP for 3-4 hours, effect is short lasting requiring frequent use every 3-4 hours. Therefore, the ASG does not recommend it for the treatment of glaucoma due to its short duration of effectiveness. (Jampel H. J Glaucoma. 2010 Feb; 19(2):75-6)

  43. A Note of Caution • As efficacy and tolerability is not completely understood it is important that cannabinoids not be considered as the first-line therapies for which there are other choices. (Turcotte D, etal Expert OpinPharmacother. 2010 Jan;11(1):17-31) Is this still true today?

  44. Side Effects • Dry mouth (xerostomia), large doses may exacerbate vomiting. Tachycardia, hypo or hypertension, syncope, palpitations, vasodilatation. • May affect motor coordination, reaction time, and visual perceptions. • May exacerbate panic disorders, hallucinations, flashbacks, depression, and other emotional disturbances. • Chronic use may cause laryngitis, bronchitis, sexual dysfunction, abnormal menstruation.

  45. Interactions with Drugs • Competes with barbiturate metabolism and may increase drug levels. • Might exacerbate CNS depressants. • One case of hypomania reported with disulfiram and fluoxetine. • May increase the metabolism of theophylline. • Using more than 2 oz a week, may increase INR.

  46. Mental Health Co-Morbidities • Medical literature shows significant support for its use with anxiety, agoraphobia, social anxiety disorders depression, and PTSD • The literature creates some doubt rather than solid support for DSM diagnoses especially ADHD, bipolar, psychosis, and schizophrenia • Increasing body of evidence in “harm reduction” literature that cannabis can help with alcohol abuse, and opiate addiction and withdrawal. • Once again a multidisciplinary or integrative approach is most effective.

  47. Incidence of Schizophrenia in Adolescents • Growing concern that “synaptic pruning” is influenced by endocannabinoids(Freund TF, etal. Role of endogenous cannabinoids in sympatic signaling. Physiol Rev 2003:83:1017-66) • Cannabis interferes with adolescent neurodevelopment especially of the hippocampus and the cerebellum (AshtariM, etal. Medical temporal structures and memory function in adolescents with heavy cannabis use.. J Psychiatri Res 2011;45:1055-66) • Continuous use of cannabis in schizophrenics is associated with more severe psychosis. (Foti DJ, etal Cannabis Use and the course of schizophrenia: 10-year follow-up study. Am J Psychiatry 2010; 167: 987-63)

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