CANNABIS AND PAIN. Debra Kimless, M.D. Medical Director, ForwardGro MAOP Annual Meeting September 14, 2018

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1 CANNABIS AND PAIN Debra Kimless, M.D. Medical Director, ForwardGro MAOP Annual Meeting September 14, 2018

4 FDA APPROVAL: PREGABALIN, DULOXETINE, MILNACIPRAN FOR FIBROMYALGIA PREGABALIN, DULOXETINE FOR NEUROPATHIC PAIN ALL OTHER RECOMMENDED MEDICINES ARE OFF-LABEL USE

5 HOW SUCCESSFUL ARE THESE MEDICATIONS? 50% People treated with PREGABALIN experienced a 30% reduction in pain versus placebos that experienced 19% reduction in pain. People treated with DULOXETINE experienced 49% reduction in pain as compared with placebo that received 32% reduction in pain A larger number of patients using MILNACIPRAN (25%) than placebo (19%) had at least a 30% reduction in pain

6 SIDE EFFECTS: DULOXETINE : asthenia, constipation, diarrhea, dizziness, drowsiness, fatigue, hypersomnia, insomnia, nausea, sedation, headache, and xerostomia. Other side effects include: agitation, erectile dysfunction, nervousness, psychomotor agitation, tension, vomiting, abdominal pain, anorexia, decreased appetite, decreased libido, hyperhidrosis, abnormal orgasm, suicide

7 PREGABALIN : infection, ataxia, blurred vision, constipation, diplopia, dizziness, drowsiness, fatigue, headache, peripheral edema, tremor, weight gain, visual field loss, accidental injury, and xerostomia. Other side effects include: abnormal gait, abnormality in thinking, amnesia, arthralgia, asthenia, cognitive dysfunction, confusion, edema, neuropathy, sinusitis, speech disturbance, vertigo, visual disturbance, myasthenia, amblyopia, increased appetite, and twitching, disorientation, confusion, anxiety, serotonin syndrome in combo with SSRI s

8 MILNACIPRAN : hypertensive crisis, constipation, dizziness, headache, hot flash, nausea, and insomnia. Other side effects include: hypertension, increased heart rate, migraine, palpitations, skin rash, vomiting, anxiety, increased pulse, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, hyperhidrosis, and xerostomia

11 United States, in particular, acetaminophen accounts for more than 50% of overdose-related acute liver failure

15 National Overdose Deaths Number of Deaths Involving All Drugs 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 Total Female Male 63,632 72,306 Source: National Center for Health Statistics, CDC Wonder

16 AVERAGE ER VISIT COSTS $ MILLION DOLLARS PER DAY!!!!!!

20 Biochemical Mechanisms of Pain Control by Cannabinoids (endogenous or exogenous) Serotonergic Dopaminergic Anti-inflammatory Cannabinoid-Opioid Interactions Periaqueductal Gray Matter NMDA/Glutamate Receptors Substance P Synergy/Entourage Effect

21 MULTI-MODAL MECHANISMS FOR MODULATING PAIN The ECS is active in tonic fashion in control of pain ECS functions in nociceptive areas of CNS Integrative control of pain in PAG VPL where CBs 10-fold more potent than morphine in WDR neurons mediating pain 21

22 MULTI-MODAL MECHANISMS FOR MODULATING PAIN ECS active in spinal cord pain mechanisms including NMDA, wind-up, and allodynia ECS also active in periphery on pain, inflammation, hyperalgesia Homeostasis of Activators and Sensitizers through both CB1 and CB2 22

23 Analgesic and Anti-inflammatory Compounds in Cannabis Tetrahydrocannabinol (THC) Cannabidiol (CBD) Tetrahydrocannabinolic acid (THCA) Cannabidiolic acid (CBDA) Beta Caryophyllene Plus many others 23

24 CANNABINOID-OPIOID SYNERGY Both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord Cannabinoids may interact with delta and kappa receptors Adding a cannabinoid to opioid therapy may lead to greater pain relief at lower opioid doses and less adverse effects 24

25 Cannabinoids Mechanisms of action are distinct from opioids THC and CBD have analgesic efficacy in animal models Mechanisms are due to activity at CB 1 and CB 2 receptors (THC), and at TRPV 1 receptors (CBD). CBD has anti-inflammatory properties in vitro Opioid efficacy related to activity at mu opioid receptors CB receptors are scarce in cardiorespiratory centres in contrast to opioid receptors SO NO OVERDOSE DEATHS FROM CARDIORESPIRATORY ARREST!!!!! BUT Cannabinoids enhance release of endogenous opioids CB receptors may co-localise with mu opioid receptors AND No evidence of clinically relevant adverse drug-drug interaction between cannabinoids and opioids

28 LD 50 IBUPROFEN: 636mg/kg CAFFEINE :192mg/kg NICOTINE: 50 mg/kg HEROIN: 22 mg/kg It would take a 70kg man to smoke 1,500 lbs in a 15 minutes time period to die Francis L. Young, Administrative Law Judge for the US Drug Enforcement Administration (DEA) wrote in his Sep. 6, 1988 decision in a case attempting to reschedule marijuana so that it can be prescribed by physicians:

29 Potential Warnings with Cannabis use: TACHYCARDIA HTN SOMNOLENCE HYPEREMESIS EUPHORIA ALTERED TIME PERCEPTION/PARANOIA, HALLUCINATIONS TOLERANCE

Empirical Medicine of the 19 th Century Combined morphine, cannabis, and capsicum Provided a phyto-opioid, phytocannabinoid, and phytovanilloid in one preparation Affected the 3 known endogenous

30 Empirical Medicine of the 19 th Century Combined morphine, cannabis, and capsicum Provided a phyto-opioid, phytocannabinoid, and phytovanilloid in one preparation Affected the 3 known endogenous biochemical systems mediating pain: endorphin/enkephalin, endocannabinoid, vanilloid Arguably may have provided better outpatient pain relief than is currently available in the 21 st century 19 th century physicians noted ability of cannabis to produce opiate sparing, reduce morbidity, and treat opiate withdrawal EBR

31 National Academies of Sciences, Engineering, and Medicine: Health and Medicine Division 2017 Report, 440 pages Full text available free:

32 There is conclusive or substantial evidence that cannabis or cannabinoids are effective: For the treatment of chronic pain in adults (cannabis) (4-1) As anti-emetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids) (4-3) For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids) (4-7a) There is moderate evidence that cannabis or cannabinoids are effective for: Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis (cannabinoids, primarily nabiximols) (4-19)

33 CANNABIS FOR PAIN Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS), Mark Ware et al, Journal of Pain December Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) inthe treatment of pain caused by rheumatoid arthritis D. R. Blake et al, Rheumatology, Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis, David J. Rog et al, Neurology, Cannabis in painful HIV-associated sensory neuropathy: A randomized placebocontrolled trial, D. Abrams et al., Neurology, Given the choice, patients will reach for cannabis over prescribed opioids, University of British Columbia, 2017

35 Noyes, R., Jr., Brunk, S. F., Avery, D. A. H., & Canter, A. C. (1975). The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther, 18(1),

36 WHAT ABOUT CBD????

37 CBD 1. IS THE SECOND MOST ABUNDANT CANNABINOID 2. CONSIDERED NON-INTOXICATING 3. HAS A MULTI-MODAL MECHANISM OF ACTION 4. CURRENTLY, SCIENCE IDENTIFIED MORE THAN 65 MOLECULAR TARGETS 5. STILL BEING INVESTIGATED

38 CBD DOESN T BIND TO CB1 OR CB2 RECEPTORS MODULATES NON-CANNABINOID RECEPTORS AND ION CHANNELS ACTS THROUGH RECEPTOR-INDEPENDENT PATHWAYS

39 CBD AND NON-CANNABINOID RECEPTORS 1. ACTIVATES 5-HT1A SERATONIN RECEPTORS: FOR ANTI- ANXIETY ADDICTION MITIGATION, APPETITE MODULATION, SLEEP, PAIN, NAUSEA AND VOMITING 2. TRPV1 VANILLOID (CAPSAICIN) RECEPTORS: MEDIATES PAIN PERCEPTION, INFLAMMATION, TEMPERATURE REGULATION 3. GPR55 RECEPTOR: CBD IS AN ANTAGONIST. MODULATES BP, AND BONE DENSITY (INHIBITS OSTEOCLAST FUNCTION), INHIBITS CANCER CELL PROLIFERATION

40 CBD AND NON-CANNABINOID RECEPTORS (continued) 4. PPAR (peroxisome proliferator activated receptors) CBD IS AN AGONIST WHICH HAS A CANCER CELL ANTI-PROLIFERATIVE EFFECT, INDUCES TUMOR REGRESSION IN SOME CANCERS, MAY DEGRADE AMYLOID-BETA PLAQUE, MODULATES METABOLISM AND MAY PLAY A ROLE IN DIABETES (MAY REDUCE INSULIN RESISTENCE)

41 REUPTAKE INHIBITOR 1. RECENTLY REPORTED: FABPs ESCORT ENDOCANNABINOIDS INTO A CELL 2. ONCE INSIDE THE CELL EC GET BROKEN DOWN 3. CBD COMPETES FOR FABPs allowing for more circulating EC This is thought to be the mechanism of action for CBD and Brain Protection, antiseizure.

42 REUPTAKE INHIBITOR (continued) 1. ADENOSINE REUPTAKE INHIBITOR BY CBD WHICH INCREASES BRAIN ADENOSINE LEVELS. 2. CONFERS ANTI-INFLAMMATORY/ANTI- ANXIETY EFFECTS, ALONG WITH CARDIOVASCULAR FUNCTION.

43 ALLOSTERIC MODULATOR 1. POSITIVE: ON THE GABA RECEPTOR, WHICH AMPLIFIES ANXIOLYTIC EFFECTS OF GABA 2. NEGATIVE: ON THE CB1 RECEPTOR, MODULATES THE INTOXICATING EFFECTS OF THC

44 WHAT WOULD NIDA DO?

48 November 09, 2017

51 WEIGHING RISKS V. BENEFITS WHICH DO YOU CHOOSE?

Medical Marijuana Martin P. Eason MD, JD Associate Chief of Staff for Education Mountain Home VA Medical Center. Disclosure.

Medical Marijuana Martin P. Eason MD, JD Associate Chief of Staff for Education Mountain Home VA Medical Center Controversies in Pain Management Conference Johnson City, TN November 13, 2015 Disclosure