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Medical Marijuana for Pain: Clinical Uses and Concerns Stephen J. Ziegler, PhD, JD Gregory T. Carter, MD, MS Stephen D. Passik, PhD

Disclosures  Stephen J. Ziegler, PhD, JD – Nothing to disclose

 Gregory T. Carter, MD, MS – Nothing to disclose

 Steven Passik, Ph.D

– Consultant/Independent Contractor: Ameritox, Cephalon, Covidien, Endo, Janssen, Millennium, Pharmacofore, Purdue Pharma, Quest; – Speaker's Bureau: Cephalon, Janssen, Millennium, Quest

Learning Objectives Describe the conflict between the federal Controlled Substances Act (CSA) and state laws which authorize medical marijuana for certain medical conditions Identify the clinical uses of medical marijuana Identify the clinical concerns stemming from the recommendation of medical marijuana by health care providers

Do State Medical Marijuana Laws Violate the Federal CSA?  Marijuana: Schedule I Substance (21 USC 821)  CSA: Prohibits aid and abet  17 States currently authorize (not all same; different laws, Regs, and for different conditions); CT in 2012 =17th state (Public Act 12-55).  Passed through direct or representative democracy (Popular Initiative)  Rx cannot be issued; only make “recommendation” in states So, are state laws in conflict?  Justice Department Memo (October 19, 2009)  Conant v. Walters (2002); 9th Circuit only (AZ, WA, HI, …)

Future of Medical Marijuana?

Clinical Uses of Medical Marijuana Gregory T. Carter, MD, MS

Cannabis  One of the oldest known psychoactive plants - first documented use as medicine > 5000 years ago in China  There are 3,000-year-old Egyptian mummies that contain cannabis traces (still active!)  Introduced into Western medicine in 1840’s by Dr. W.B. O’Shaughnessy  One of earliest cultivated non-food plants: – fiber for rope, seeds for oil and birdseed – mixture of leaves, stems, tops

Cannabis Meds Produced Commercially: Parke Davis 1920

What Happened?  Harry Anslinger: our first drug czar; had no formal medical training  Openly prosecuted doctors for over-prescribing, sending some to prison  Single-handedly created “Reefer Madness”: "How many murders, suicides, robberies, criminal assaults, holdups, burglaries and deeds of maniacal insanity it causes each year, especially among the young, can only be conjectured...No one knows, when he places a marijuana cigarette to his lips, whether he will become a joyous reveller in a musical heaven, a mad insensate, a calm philosopher, or a murderer...“ HJ Anslinger, 1932

The Laws Started to Change…  Fed Gov-appt commissions and Organizations issuing favorable statements: – Shafer Commission in 1972 – IOM in 1982 – NIH 1997 – ACP 2008 – AMA 2010

 All issued cautiously affirmative statements; currently 18 states have laws BUT no state may authorize MC clinical trials without federal approval

The Chemical Makeup of Cannabis.  Cannabinoids are terpenophenols in viscous resin produced in glands (trichomes) Delta-9-tetrahydrocannabinol (THC): most psychoactive, lesser therapeutic  Cannabidiol (CBD): analgesia; moderates effects of THC  Cannabinol (CBN): anticonvulsant  Tetrahydrocannabivarin (THCV): anti-inflammatory  Cannabichromene (CBC): mixed effects  Cannabicyclol (CBL): analgesic  Plus 80-100 other cannabinoids

Clinical Pharmacology Of Cannabis  Lipophilic; 95-99% protein bound; rapidly clearance from plasma via hydroxylation, oxidation, and conjugation; first-pass metabolism to 11-OH-THC  Elimination is slow: days to weeks; 20-35% found in urine; 6580% found in feces; stored in adipose  Fast absorption if vaporized; slower if PO or topical  No constipation or respiratory suppression  No LD50

How Does Cannabis Work  Endocannabinoid system is intricately involved in normal human physiology, specifically in the control of movement, pain, memory, mood, motor tone, and appetite, among others  Cannabinoid receptors are found in the brain and peripheral tissues  Dense receptor concentration in the cerebellum, basal ganglia, and hippocampus  Few cannabinoid receptors in the respiratory areas in brainstem

Clinical Uses Of Cannabis In Chronic Pain Neuropathic pain; Myofascial pain Sleep, mood, and appetite improvement Enhances effects of opioids and helps offset opioid side effects Helps with muscle spasms No constipation or respiratory suppression No LD50

In The Past 15 Years There have been 33 completed and published American controlled clinical trials with cannabis Compared with placebos or standard drugs, including sometimes dronabinol Assessed appetite stimulation, pain in HIV neuropathy and other types of chronic and neuropathic pain, spasticity in multiple sclerosis, weight loss in wasting syndromes, intraocular pressure in glaucoma, dyspnea in asthma, and emesis due to cancer chemotherapy

Cannabinoid Suppression of Pain  Analgesia: different mechanism than opiates, some synergy though  Spasticity: likely GABA mediated  Appetite enhancement: hippocampal?  Anti-emetic: cerebellar?  Elevated levels of the CB1 receptor are found in areas of the brain that modulate nociceptive processing  CB1 and CB2 agonists have peripheral analgesic actions  CBs may also exert anti-inflammatory effects  Analgesic effects not blocked by opioid antagonists

Vaporization Of Cannabis: Safe Alternative To Smoking  Cannabinoids vaporize at 285 °F (140 °C). Vaporization most effective at 338 °F (170 °C); START LOW; GO SLOW; 2-3 inhalations, stop, wait ten minutes  Do not need to be high to get pain relief

Other Ways To Use Medicinal Cannabis? Ingestion: Takes about an hour to get effects so harder to dose but lasts longer Transdermal? Yes! Works well as a liniment Injectable: NO  high levels of both THC and CBD = strong, energizing effect, typical of Sativa

 Low THC and high CBD = more relaxing, sleep-inducing, typical of Indica  Some cannabinoids, including Cannabinol (CBN), Cannabichromene (CBC) and Cannabicyclol (CBL) are not psychoactive but are therapeutic.  CBD, CBN, CBC all moderate THC effects

Clinical Concerns Stephen D. Passik, PhD


References  Aggarwal SK, Carter GT, Sullivan MD, Morrill R, ZumBrunnen C, Mayer JD. HealthRelated Quality of Life and Symptom Relief in a Sample of Chronically Ill Medical Cannabis Patients in Urban Washington State. Quality of Life Research (in-press).  Aggarwal SK, Carter GT, Zumbrunnen C, Morrill R, Sullivan M, Mayer JD. Psychoactive substances and the political ecology of mental distress. Harm Reduction Journal, 2012; 9(1):4.  Aggarwal SK, Carter GT. Cannabinoids and Neuroprotection. In: Holland J, (ed.) The Complete Guide to Cannabis: Its Role in Medicine, Science, Politics, and Culture (2011), Rochester, VT. Park Street Press; pp. 295-311.  Aggarwal SK, Carter GT, Sullivan MD, Morrill R, ZumBrunnen C, Mayer JD. Characteristics of patients with chronic pain accessing treatment with medicinal cannabis in Washington State. Journal Opioid Management, 2009; 5(5):257-286.

References  Aggarwal SK, Carter GT, Sullivan MD, Morrill R, ZumBrunnen C, Mayer JD. Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. Journal Opioid Management, 2009; 5(3):153-168.  Aggarwal SK, Kyashna-Tocha M, Carter GT. Dosing Medical Marijuana: Rational Guidelines on Trial in Washington State. Medscape General Medicine, 2007; 9(3):52.  Aggarwal S, Carter GT, Steinborn J. Clearing the air: What the latest Supreme Court decision regarding medical marijuana really means. American Journal Hospice Palliative Care, 2005; 22(5):327-329.  Baumrucker S, Mingle P, Harrington D, Stolick M, Carter GT, Oertli KA. Medical marijuana and organ transplantation: drug of abuse, or medical necessity? American Journal of Hospice and Palliative Medicine, 2011; 27(7):494-9.

References  Carter GT, Flanagan A, Earleywine M, Abrams DI, Aggarwal SK, Grinspoon L: Cannabis in palliative medicine: improving care and reducing opioid-related morbidity. American Journal of Hospice and Palliative Medicine, 2011; 28(5):297303.  Carter GT, Abood ME, Aggarwal SK, Weiss MD. Cannabis and amyotrophic lateral sclerosis: practical and hypothetical applications, and a call for clinical trials. American Journal of Hospice and Palliative Medicine, 2010; 27(5):347-56.  Carter GT, Mirken B. Medical marijuana: politics trumps science at the FDA. Medscape General Medicine, 2006; 8(2):46.  Carter GT, Ugalde VO. Medical marijuana: emerging applications for the management of neurological disorders. Physical Medicine and Rehabilitation Clinics of North America, 2004; 15(4):943-954.

References  Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medical marijuana: rational guidelines for dosing. IDrugs, 2004; 7(5):464-470.  Carter GT, Rosen BS. Marijuana in the management of amyotrophic lateral sclerosis. American Journal Hospice Palliative Care, 2001; 18(4):264-70.  Cohen PJ. Medical Marijuana 2010: It’s Time to Fix the Regulatory Vacuum. Journal of Law, Medicine & Ethics, 2010; 38 (3): 654-666.  Conant v. Walters, 309 F.3d 629 (2002, CA 9) (cert denied Oct. 14, 2003).  Gieringer DH, Rosenthal E, Carter GT (eds): Marijuana Medical Handbook: Practical Guide to Therapeutic Uses of Marijuana. Quick American Press, Oakland, CA, 2008

References  Institute of Medicine. Marijuana and Medicine: Assessing the Science Base (1999), National Academies Press, Washington, D.C.  Martin M, Rosenthal E, Carter GT. Medical Marijuana 101 (2011), Quick American Press, Oakland, CA.  Murphy JB. The Legal Implications of Medical Marijuana. Practical Pain Management, 2011; 11 (6): 111-113.  Passik SD, Tickoo S. Medical Marijuana Is a Trojan Horse That Pain Physicians Should Refuse to Accept. OncLive, 2011 (available at:  Spillane JF. Debating the Controlled Substances Act. Drug and Alcohol Dependence, 2004; 76: 17-29.

Medical Marijuana of Pain: Clinical Uses and Concerns  

Stephen Ziegler, PhD, JD Gregory T. Carter, MD, MS Stephen D. Passik, PhD

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