Medical Marijuana

Cannabis for Opioid Reduction in Chronic Pain Management?

Kim Dupree Jones PhD, FNP-BC, FAAN [email protected] [email protected] Objectives

 Dr. Jones has NIH and DoD funding regarding chronic pain and has received educational grant funding from Greenwich Biosciences Why this program?

 Patients keep asking, and using  Growing body of evidence  30 states and DC have some form of medical marijuana  9 states and DC have legalized marijuana for recreational use  The Oregon Medical Board: “A physician who recommends the medical use of marijuana should complete a minimum of three hours of category 1 continuing medical education related to medical marijuana”  NPs in at least 5 states including WA and CA can sign medical MJ forms OR and WA

 OREGON Decriminalized 1973 Medical legalized in 1998 Recreational legalized in 2014  WASHINGTON Medical legalized in 1998 Recreational legalized in 2012 (first, with Colorado) Oregon Medical Board, (OMB) April 2017

 A physician who recommends the medical use of marijuana should complete a minimum of three hours of category 1 continuing medical education related to medical marijuana.

 Ideally, this should be before the physician begins making recommendations for the medical use of marijuana to patients.

 Such a program should explain the proper use of marijuana, including the endo-cannabinoid system, pharmacology and effects of marijuana (e.g., distinction between cannabidiol [CBD] and tetrahydrocannabinol [THC]; methods of administration; and potential side effects or risks).

 PCP not ‘pot doctor’ Oregon Medical Board, (OMB) April 2017

 Physicians who recommend marijuana should closely follow the emerging evidence on the use of marijuana for therapeutic purposes and adopt consistent best practices.

 Physicians recommending marijuana for minors also should be keenly aware and up-to-date on the peer-reviewed literature regarding the effects of THC on children and young adults’ developing brains.  http://www.oregon.gov/omb/Topics-of- Interest/Pages/Medical-Marijuana.aspx Federal Law regarding cannabis

 Schedule I Controlled Substance:  “no currently accepted medical use and a high potential for abuse”.  Some examples of Schedule I drugs are heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), peyote, and 3,4-methylenedioxymethamphetamine (“Ecstasy”). Cannabis use at work

 The Federal Standard, i.e. zero tolerance, applies for all employees at OHSU and VA  OHSU – all employees

 Pre-employment testing

 For cause (e.g. performance, injury) testing  VA

 Those with direct patient contact

 Pre-employment testing, random testing, for cause testing

 Those without direct patient contact

 For cause testing  What about your employer? Cannabis Pharmacology

Adapted from: Joseph Bubalo PharmD, BCOP, BCPS Assistant Professor of Medicine Oncology Clinical Pharmacy Specialist OHSU Hospital and Clinics Marijuana

 Cannabis sativa – flowering herbal plant

 Also refers to indica species

 Originated in Asia, now grown nearly world wide

DeVane CL Pharmacotherapy 2013;33(10):1009-1011 Cannabinoids

There are over 100, these are the major ones: Delta-9-tetrahydrocannabinol (THC) • Major psychoactive component in cannabis • Naturally occurs in concentrations anywhere from 0.5 – >20% depending on cannabis strain Cannabidiol (CBD) • Lacks any noticeable intoxicating effects • Has low affinity for endogenous cannabinoid receptors • Increases the action of/exposure to THC Cannabinol (CBN) • Responsible for the sedative effects of cannabis • May also have antibacterial, bone growth stimulation, and skin healing effects

National Cancer Institute Jones G, et al. Br J Pharmacol. 1972;45:375-7. Zuardi AW, et al. Psychopharmacology. 1982;76:245-50. Cannabinoid receptors

Two cannabinoid receptors

1. CB1 - identified in 1988 • Located in central nervous system and peripheral nerves • Activation produces classic marijuana-like effects on psyche and circulation

2. CB2 - identified in 1993  Located on B lymphocytes and natural killer cells  Possible role in immunity

Abrams DI, et al. Clin Pharmacol Ther. 2015;97(6):575-86. UW Alcohol & Drug Abuse Institute www.medicinalgenomics.com Cannabis pharmaceuticals

Dronabinol (Marinol®) . Synthetic ∆9-THC in sesame oil

. Activates cannabinoid receptors CB1 and CB2; has approximately equal affinity for each, but efficacy is less at CB2 receptors

Nabilone (Cesamet®) . Mimics THC; synthetic cannabinoid receptor agonist that binds both CB1 and CB2 receptors

Nabiximols (Sativex®) Not available in the USA . 1:1 THC and CBD mixture; stimulates both cannabinoid receptors CB1 and CB2. 80 mg nabiximols/mL (27 mg THC, 25 mg CBD, + others =56 mg total cannabinoids) Cannabidiol (Epidiolex®) FDA approved, awaiting DEA scheduling . Purified cannabidiol from cannabis plants in a 100 mg/mL oral solution

Nabilone [package insert] Nabiximols [package insert] Epidiolex monograph Greenwich biosciences 2017 Dronabinol [package insert] Objectives

 Describe the clinical pharmacology and pharmacodynamics of cannabis and its active components  Discuss evidence regarding cannabis and cannabinoids for chronic pain  Understand potential adverse effects of cannabis and cannabinoids  Overview the data on the role of cannabis in opioid reduction Contemporary Approach to Classifying Pain

Neuropathic Pain ‘Centralized’ Pain / Nociceptive Pain (Central & Peripheral) Sensory Hypersensitivity

■ Inflammation or ■ Damage or dysfunction ■ Characterized by central mechanical damage of peripheral nerves disturbance in pain in tissues processing (diffuse ■ Responds to both hyperalgesia/allodynia) ■ NSAID, opioid peripheral (NSAIDs, responsive opioids, Na channel ■ Responsive to blockers) and central neuroactive compounds ■ Responds to (TCA’s, neuroactive altering levels of procedures compounds) neurotransmitters pharmacological involved in pain ■ Classic examples therapy transmission ■ Acute pain due to ■ Classic examples ■ Classic examples injury ■ Diabetic neuropathic ■ Fibromyalgia ■ Osteoarthritis pain ■ Irritable bowel ■ Rheumatoid arthritis ■ Post-herpetic syndrome ■ Cancer pain Mixed or Complexneuralgia Pain States■ TMD ■ Thalamic or MS pain ■ Tension headache The Health Effects of Cannabis and Cannabinoids: Current State of Evidence and Recommendations for Research

http://nap.edu/24625

National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research. Washington, DC: The National Academies Press. National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research. Washington, DC: The National Academies Press. JAMA. 2015;313(24):2456-2473. 28 pain studies/ 2454 patients

13 nabiximols 5 nabilone 4 smoked THC 3 THC oromucosal spray 2 dronabinol 1 vaporized cannabis (2 doses) 1 ajuvenic acid capsules 1 oral THC

JAMA. 2015;313(24):2456-2473. Design: Half parallel, Half cross-over Odds Ratio indicate 30% or greater improvement in pain with cannabinoid compared to placebo

Abrams 2007 dose 3.56% THC One 0.9 g cig 3/daily

Smoked cannabis reduced daily pain by 34% compared to 17% reduction in placebo (p = 0.03)

JAMA. 2015;313(24):2456-2473. Whiting conclusions

 Meta-analysis including 79 randomized controlled trials of cannabis across a broad range of conditions  Most evaluated prescription cannabinoids (dronabinol, nabilone, nabiximols)  moderate-quality evidence to support the use of cannabinoids for the treatment chronic neuropathic or cancer pain (smoked THC and nabiximols)  Limitations- short study length, differing outcome measures, lack of blinding, crossover trials were not included in analysis

Whiting et al. JAMA. 2015;313(24):2456-2473. Lynch conclusions

 22 of 29 RCT’s demonstrated significant analgesic effect  Modest treatment effects  Mean duration of treatment was 2.8 weeks

Lynch et al., 2015,J NeuroImmune Pharm  “…daily doses of 2.5 to 10 mg of dronabinol, 1 to 4 mg of nabilone, and 8.3 sprays of nabiximols when administered over 2 to 15 weeks are associated with analgesic benefit compared to placebo at 2 weeks or more after initiation of treatment…”

11 RCTs for 1219 neuropathic pain patients: dronabinol (1+), nabilone (2+/1-) or nabiximols (2+/5-)

ANESTHESIA & ANALGESIA November 2017, 125(5): 1638-1652 Inhaled Studies - Neuropathic Pain Inhaled Studies - Neuropathic Pain

J of Pain 2015, (16)12 Inhaled Studies - Neuropathic Pain

Dose= cumulative THC /24hr J of Pain 2015, (16)12 Inhaled Studies- Andreae conclusions

This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment.

J of Pain 2015, (16)12 No synthetics. Only plant based products Conclusion: low-strength evidence that cannabis preparations with precisely defined THC:CBD content (most in a 1:1 to 2:1 ratio) have the potential to improve neuropathic pain but insufficient evidence in PTSD patient populations.  AUTHORS' CONCLUSIONS: (16 studies with 1750 participants)  “The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes”

Mucke, M et al.Cochrane Database Syst Re v. 2018 Mar Cannabis-based medicines for chronic neuropathic pain in adults. Ongoing pain trials Clinical Trials.Gov

 Sickle cell: vaporized: 4.7% THC and 5.1% CBD vs. Placebo  Neuropathic pain: Cannabis oil: 20% THC, 40 mg per 70 kg  HIV-NP: 3 doses of vaporized CBD+THC  2 Advanced cancer pain:100 μl oromucosal spray 2.7 mg THC/2.5 mg CBD vs. placebo  Lung cancer: smoked high CBD/low THC: 15.76% CBD and 3.11% THC vs. placebo Ongoing pain trials Clinicaltrials.gov continued

 Ulcerative colitis: oral capsule both CBD and THC, up to 250 mg twice daily vs. placebo  “Seriously Ill”: smoked high CBD/low THC: 15.76% CBD and 3.11% THC vs. placebo  Knee OA: 5 doses vaporized vs. placebo  Low back pain: vaporized: 3.5% THC vs. dronabinol vs. placebo  Spinal cord injury: Vaporized: 3.5% THC vs. 7.0% THC vs. placebo Ongoing pain trials Clinical Trials.Gov

 Describe the clinical pharmacology and pharmacodynamics of cannabis and its active components  Discuss evidence regarding cannabis and cannabinoids for chronic pain  Overview the data on the role of cannabis in opioid reduction  Understand potential adverse effects of cannabis and cannabinoids Can cannabis be used to reduce opioid use in people with chronic pain? Michigan medical marijuana dispensary data (n=244) suggests that medical cannabis use in pain patients was associated with a 64% reduction in opioid use and a 45% improvement in QOL.  “Using quarterly data on all fee-for-service Medicaid prescriptions in the period 2007–14, we tested the association between those laws and the average number of prescriptions filled by Medicaid beneficiaries. We found that the use of prescription drugs in fee- for-service Medicaid was lower in states with medical marijuana laws than in states without such laws in five of the nine broad clinical areas we studied. If all states had had a medical marijuana law in 2014, we estimated that total savings for fee-for-service Medicaid could have been $1.01 billion.”

May 2017  There is increasing debate about the use of cannabis for medical purposes, including chronic non-cancer pain (CNCP)  In 1514 people prescribed opioids for CNCP, 16% had used cannabis for pain (survey)  A quarter reported that if they had access to cannabis, they would use it for pain relief  Those using cannabis for pain were younger, with greater pain severity and interference  They had been prescribed opioids for longer and were on higher opioid doses  Users report greater pain relief in combination with opioids than when opioids are used alone  In an open‐label study (n=274) of medicinal cannabis use for patients with chronic pain over a 6‐month period, patients reported improved pain severity and interference, but more striking was that 44% of those on opioids had discontinued opioid treatments

 (Haroutounian et al., 2016) “Our findings suggest that a substantial fraction of patients at a pain clinic may wish to engage in voluntary opioid tapering. Our data challenge common notions that patients taking high-dose opioids will fail outpatient opioid tapers or that duration of opioid use predicts taper success. Combining patient education about the benefits of opioid reduction with a plan that reduces opioids more slowly than current tapering algorithms with close clinician follow-up may help patients engage and succeed in voluntary outpatient tapering.” Clinical trial underway

 2.4 million NIDA grant to Albert Einstein College of Medicine, Inc. Fordham University & Columbia University. 250 HIV+ person observational, prospective, cohort study. Jan 1, 2018- June 30, 2022 Objectives

 Effect vs adverse effect- yes  Serious adverse events- no  Cancer- no  Heart disease & CVA- case studies only  Mental and cognitive health (addiction, dependence, psychosis, schizophrenia)- some evidence  Accidents- when combined w other substances

 Overdose- no (LD50 estimated to be 1500 pounds smoked in 15 minutes)  Red flags in higher risk patients- yes Cannabinoid effects

Activation of cannabinoid system causes four groups of psychological effects

 Affective: euphoria and easy laughter

 Sensory: temporal and spatial perception alterations and disorientation

 Somatic: drowsiness, dizziness, and motor incoordination

 Cognitive: confusion, memory lapses, and difficulty concentrating

UW Alcohol & Drug Abuse Institute 1 year prospective cohort study 256 active subjects (2.5 gm/d median cannabis dose/12.5% THC) 216 controls (no cannabis)

Primary outcome: Serious and non-serious adverse events & secondary safety outcomes (CBC, chem panel, endocrine) pulmonary & neurocognitive function

Exploratory outcome: pain COMPASS trial results

 Most common serious adverse events (SAEs) in cannabis group were abdominal pain, intestinal obstruction, and nephrolithiasis  Most common non-SAEs in cannabis group somnolence, amnesia, cough, nausea, dizziness, euphoric mood, hyperhidrosis, and paranoia

Cannabis group Control group At least 1 28 patients (13%) 42 patients (19%) OR = 0.64 SAE 95% CI 0.38- 1.04 Incidence rate 4.61 events/person- 2.85 events/person-year IRR = 1.64 of non-SEAs year 95% CI 1.35- 1.99

Ware et al. J Pain. 2015 Sep 16  no association between lung CA and cannabis after adjusting for tobacco use

 habitual cannabis users were much more likely than nonhabitual or never users to be tobacco smokers (86.3% vs. 64.0%, p < 0.001). Similarly, tobacco smokers were more likely than never smokers to use cannabis habitually (13.8% vs. 4.3%, p < 0.001).

Zhang,et al 2015. International Journal of Cancer 136(4):894–903 Dependence

 Fewer scientists consider MJ addictive, especially when ingested orally rather than inhaled; dependence is common in some as the brain develops a tolerance to cannabinoids

 Dependence develops in 9-10% of cannabis users

 Risk much lower than nicotine (32%), heroin (23%), cocaine (11%), and alcohol (15%), and equivalent to anxiolytics

 Physiologic withdrawal after long term use is common

Abrams and Weil. Interactive Oncology, 2nd ed. Wilkinson ST JAMA 2014;311:2377-2378 Meta-analysis (32 trials): Suicidal behaviors, mania, psychosis & cognitive effects

Strength of evidence

Nugent 2017 Annals of Int Med Dose-response relationship between cannabis exposure & psychosis

66, 816 participants

Marconi et al 2016 Schizophr Bull 42(5) Schizophrenia

“Self medication with cannabis is an unlikely explanation for the association observed”

Zammit et al 2002 BMJ 325: 1199 Pain conclusions

 Pain is common. Many of our patients use cannabinoids  For most qualifying conditions, approval has relied on low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion  Most chronic illness trials evaluated prescription cannabinoids (dronabinol, nabilone, nabiximols)  Moderate-quality evidence to suggest that cannabinoids (including smoked THC and nabiximols) may be beneficial for the treatment of chronic neuropathic, ‘centralized pain’ or cancer pain  Results of studies with individual cannabinoids (e.g., THC or CBD) cannot be extrapolated to inhaled marijuana and vice versa  Optimal dose is unknown, particularly for smoked cannabis

 No RCT level data currently available on other cannabis products available in dispensaries (e.g., shatter, wax, oil) or by plant name

 Non RCT data indicate that cannabis access may be associated with reduced opioid use Safety conclusions

 Cannabinoids are associated with adverse effects, most of which are not serious  Little risk for lung cancer; vaping may confer lower risks than smoking  Multiple published case studies regarding CVD/CAD risk, but no serious AEs in controlled trials  Dose dependent relationship between cannabis and psychosis and schizophrenia, particularly with adolescent/young adult exposure  Less habit forming than nicotine and ‘hard drugs’ but dependence risk is real (~9%), likely higher in adolescents  Prenatal exposure is problematic  Children & pets are at risk. Keep cannabis stored in a lock box  Prescribers should communicate risk and benefits as with any medication  Concentrates (shatter, dab…) are recreational not medical  Need studies in higher risk subgoups (older adults with chronic illnesses)