Discussion about EBM of Medical Marijuana use

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Discussion about EBM of Medical Marijuana use

• Weiping Mei, MD
• Reviewer David Thom, MD, PhD
• Special thanks Julie Haugen

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History

• The earliest well-documented evidence of cannabis
  use was 4000 BCE (carbon-14 dating) in China
• In Ancient Egypt, Greece, evidence of cannabis
  use for medical purpose
• In 1964, tetrahydrocannabinol, or THC, the main
  component of cannabis, was isolated and
  synthesized in Israel by Raphael Mechoulams
  team.
• In 1972, the National Institute on Drug Abuse
  (NIDA, UAS) began funding studies on cannabis
  with the intent of demonstrating its deleterious
  effect
• Deleterious effect gynaecomastia, chromosome
  damage, addiction and cognitive deterioration
• pathophysiological benefits also noted
  musculoskeletal and neuropathic analgesic,
  anti-inflammatory, immunomodulatory, antiemetic,
  appetite stimulant
• In Oct.1986, FDA approved the synthetic THC,
  dronabinol, the identical to the natural
  compound, manufactured and placed in a seasame
  oil capsule
• In 1988, a cannabinoid receptor (CB1) was found
  in brain, and in 1992, anandamide, the first
  central endogenous cannabinoid, was
  characterized. Subsequently, a peripheral
  receptor (CB2) was discovered on immune cell.
• In 1996, California passed the compassionate Use
  Act, which allows the use of smoked marijuana for
  a variety of medical conditions including HIV
  disease and its complications

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Background

•         More than 400 chemicals in marijuana,
  and at least 60 are cannabinoids. The principal
  active constituent is THC. Others include
  delta-8-THC, cannabinol (CBN), and cannabidiol
  (CBD)
•        In UK, the leading indication for
  clinical cannabis investigation is the treatment
  of pain and spasm in multiple sclerosis. In USA,
  interesting AIDS and cancer chemotherapy are
  paramount. Other use glaucoma, spinal cord
  spasticity.
•         Effectiveness of THC was usually
  correlated to the onset of a high or
  intoxicated feeling.
•         Side-effect
• CNS distortion of reality, euphoria, dysphoria,
  changes in coordination and concentration,
  hallucinosis, depersonalization, paranoia.
  Specific associate with crude marijuana
  concentration, motor coordination, memorization,
  memory retrieval, ability to sort unimportant
  information all adversely affected
• Cardiac tachycardia and hypotension
• Respiratory impair lung function

4
Clinical Questions

• Does medicinal cannabis improve appetite in HIV
  patient with wasting syndrome?
• Does smoking marijuana more effective than oral
  THC in HIV patient with wasting syndrome?
• In patient with pain, does medicinal cannabis
  provide symptom control?

5
Evidence

• Database searched Cochrane library, PubMed
• Search term medicinal cannabis or connabinoids,
  tetrahydrocannabino (THC), marijuana

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Cochrane Library

• No systematic review/meta-analysis result
  available yet, only two protocols
• The medical use of cannabis for reducing
  morbidity and mortality in patient with HIV/AIDS
  (in progress)
• Botanical medicine for low-back pain only review
  data from orally ingested, not smoked (in
  progress)

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CENTRAL Database

• Cannabis Use in HIV for pain and other medical
  symptoms1 2005
• Ø      The study was done in UK. The outpatient
  clinic provided a walk-in service as well as
  pre-arranged appointments, including pharmacy and
  phlebotomy sections. All patients entering the
  clinic were asked to verbally consent to
  participate in the study.
• Ø      Sample size 523, users n143, non-users
  n380, 107 (75) were current users. Smoking was
  the single route of administration in 101 (71),
  and was combined with eating and drinking the
  plant in 39 (27) ingestion was the only route
  in 3 (2).
• Ø      Patients reported improved appetite (97),
  muscle pain (94), nausea (93), anxiety (93),
  nerve pain (90), depression (86), and
  paresthesia (85). Many cannabis users (47)
  reported associated memory deterioration.

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CENTRAL Database (cont)

• Initial experiences with medicinal extracts of
  cannabis for chronic pain results from 34 N of
  1 study2 2004
• Ø      12 week period study, use sublingual spray
  route for administration.
• Ø      After the initial open label period, the
  THC, CBD, and the 11 mixture were used in
  randomized, double-blind, placebo controlled
  crossover trial.
• Ø      Study patients kept a daily diary of their
  worst two symptoms, each measured with a standard
  10cm visual analogue scale (VAS).
• Ø      Results extracts which contained THC
  proved most effective in symptom control.
  THCCBD and THC were both significantly better
  than placebo (plt0.05 and lt0.01). Quality of
  sleep all three were significantly better than
  placebo, but not duration of sleep. Decreased
  GHQ28 and BDI score.
• Ø      Side effect most common is dry month,
  other drowsiness, euphoria/dysphoria, dizziness,
  panic and anxiety infrequent, hallucination in
  one patient.

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CENTRAL Database (cont)

• Lack of analgesic efficacy of oral
  delta-9-tetrahydrocannabinol in postoperative
  pain3 2003
• Ø      40 women undergoing elective abdominal
  hysterectomy.
• Ø      It was a double-blind, placebo-controlled,
  single-dose trial.
• Ø      There were no significant differences in
  mean (SD) VAS pain scores before and after
  medication.

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CENTRAL Database (cont)

• Efficacy of two cannabis based medicinal extracts
  for relief of central neuropathic pain from
  brachial plexus avulsion results of a randomised
  controlled trial4 2004
• Ø      48 patients with intractable symptoms
  entered a baseline period of 2 weeks, followed by
  three, 2-week treatment periods during each of
  which they received one of three oromucosal spray
  preparations.
• Ø      These were placebo and two whole plant
  extracts of Cannabis sativa L. GW-1000-02
  (Sativex), containing Delta(9)tetrahydrocannabinol
  (THC)cannabidiol (CBD) in an approximate 11
  ratio and GW-2000-02, containing primarily THC.
• Ø      The mean pain severity score during the
  last 7 days of treatment failed to fall by the
  two points defined in their hypothesis. But the
  measures of sleep showed statistically
  significant improvements.

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CENTRAL Database (cont)

• The analgesic effect of oral delta-9-tetrahydrocan
  nabinol (THC), morphine, and a THC-morphine
  combination in healthy subjects under
  experimental pain conditions5 - 2003
• Ø      20 healthy volunteers, randomized,
  placebo-controlled, double-blinded, crossover
  study
• Ø      THC 20 mg, Morphine 30 mg, THC-morphine
  (20mg, 30mg) combination
• Ø      Pain test heat, cold, pressure, single
  and repeated transcutaneous electrical
  stimulation. Also monitor reaction time,
  side-effects, and vital
• Ø      Result THC did not significantly reduce
  pain. In the cold and heat tests it even
  produced hyperalgesia. No analgesic effect
  resulted in the pressure and heat teat neither,
  with THC nor THC-morphine.
• Ø      Psychotropic and somatic side-effects
  (sleepiness, euphoria anxiety, condusion, nausea,
  dizziness, etc) were common, but usually mild.

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PubMed Clinical Queries

• The effects of cannabinoids on the
  pharmacokinetics of indinavir and nelfinavir8
  (from UCSF Dr. Abrams group) 2002
• Ø      smoking marijuana allows for easier
  titration and has been reported to be more
  effective than oral THC.
• o     Further search THC in marijuana cigarettes
  reaches the bloodstream rapidly. With usual
  doses, the onset the high(acute intoxication)
  is 6-12 min, with max effects 15-30 minutes after
  the first puff, last 2-4 hours. Orally
  administered THC is slowly and erratically
  absorbed, giving blood levels that increase only
  gradually over four to six hours after
  administration.

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PubMed Clinical Queries

• Are cannabinoids an effective and safe treatment
  option in the management of pain? A qualitative
  systematic review6 2001 BJM
• o     20 randomized controlled trials were
  identified, 9 used for this review (222
  patients). 5 trials related to cancer pain, 2 to
  chronic non-malignant pain and 2 to acute
  postoperative pain.
• o     Oral route administration for cannabinoids
  was used.
• o     Conclusion cannabinoids are no more
  effective than codeine in controlling pain and
  have depressant effects on the central nervous
  system. In acute postoperative pain they should
  not be used. For treating spasticity and
  neuropathic pain need further valid randomized
  controlled studies.

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PubMed Clinical Queries

• The Lancet - Cannabinoids for treatment of
  spasticity and other symptoms related to multiple
  sclerosis (CAMS study) multicentre randomized
  placebo-controlled trial7 - 2003
• 630 stable multiple sclerosis and muscle
  spasticity participants, 33 UK centers, 15 weeks
• Oral cannabis extract, delta-9-tetrahyrocannabinol
  or placebo
• Measure Ashworth scale (spasticity scores), a
  timed 10 m walk, Rivermead mobility index,
  patient-reported spasticity and pain
• Findings no difference in Ashworth score, but
  there is objective improvement in mobility and
  patient opinion of the improvement in pain.

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Comments

•         From random trials data, the results
  seem mix. Need more study on administration
  routes (smoking, sublingual spray route,
  suppository, oral) and dosing
•         Gap between patients subjective report
  and scientific measurement
•         Side effects short term and long term
  exposure
•         Since there is a central endogenous
  cannabinoid in our brain, there is a hope in
  future a possible synthetic cannabinoid, that has
  the only beneficial effects, not unwanted
  psychoactivity, may will be available

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Citations

• 1)Cannabis Use in HIV for Pain and Other Medical
  Symptoms
• Emily Woolridge MB BS, BSc, Simon Barton MB BS
  (Distinction), BSc, FRCP (Ed), FRCP (London),
  Jonathon Samuel
• BSc, Jess Osorio BSc, Andrew Dougherty BSc and
  Anita Holdcroft MB ChB, MD, FRCA Magill
  Department of Anesthesia, Imperial College London
  (E.W., A.H.), and HIV/GUM Services (S.B., J.S.,
  J.O., A.D.), Chelsea and Westminster Hospital,
  London, United Kingdom Accepted 28 July 2004. 
  Available online 23 April 2005.
• 2) Initial experiences with medicinal extracts of
  cannabis for chronic pain results from 34 'N of
  1' studies.Notcutt W, Price M, Miller R, Newport
  S, Phillips C, Simmons S, Sansom C.Department of
  Anaesthesia, James Paget Hospital, Lowestoft
  Road, Great Yarmouth, Norfolk, NR31 6LA, UK.
  Anaesthesia 2004 May59(5)440-52
• 3) Lack of analgesic efficacy of oral
  delta-9-tetrahydrocannabinol in postoperative
  pain.Buggy DJ, Toogood L, Maric S, Sharpe P,
  Lambert DG, Rowbotham DJ.Mater Misericordiae
  Hospital, Dublin, Ireland.Pain 2003 Nov 106
  (1-2)169-72
• 4) Efficacy of two cannabis based medicinal
  extracts for relief of central neuropathic pain
  from brachial plexus avulsion results of a
  randomised controlled trial.Berman JS, Symonds
  C, Birch R.Royal National Orthopaedic Hospital,
  Brockley Hill, Stanmore, Middlesex HA7 4LP, UK.
  johathan.berman_at_rnoh.nhs.uk Pain 2004 Dec 112
  (3)299-306
• 5) The analgesic effect of oral
  delta-9-tetrahydrocannabinol (THC), morphine, and
  a THC-morphine combination in healthy subjects
  under experimental pain conditions.Naef M,
  Curatolo M, Petersen-Felix S, Arendt-Nielsen L,
  Zbinden A, Brenneisen R.Department of Clinical
  Research, University of Bern, Murtenstrasse 35,
  CH-3010 Bern, Switzerland. Pain 105 (2003) 79-88

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Citations

• 6) BMJ vol 323 July7 2001
• Are cannabinoids an effective and safe treatment
  option in the management of pain? A qualitative
  systematic review
• FA Campbell, MR Tramer, D Carroll, DJ Reynolds,
  RA Moore, HJ McQuay
• 7) The Lancet vol 362 nov 8, 2003 P1517-1526
• Cannabinoids for treatment of spasticity and
  other symptoms related to multiple sclerosis
  (CAMS study) multicentre randomized
  placebo-controlled trial
• J Zajcek, P Fox, J Snaders, D Weight, J Vickery,
  A Nunn, A Thompson
• UK MS research group