The Use of Cannabinoids in Pain

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The Use of Cannabinoids in Pain

• Allan Gordon MD
• Neurologist and Director
• Wasser Pain Management Centre
• Mount Sinai Hospital

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Pot eases peripheral neuropathy pain, U.S. study
shows

• SAN FRANCISCO Smoking marijuana eased
  HIV-related pain in some patients in a small
  study that nevertheless represented one of the
  few rigorous attempts to find out if the drug has
  medicinal benefits.
• The Office of National Drug Control Policy, part
  of the administration of President George W.
  Bush, quickly sought to shoot holes in the
  experiment.
• The study, conducted at San Francisco General
  Hospital from 2003 to 2005 and published Monday
  in the journal Neurology, involved 50 patients
  suffering from HIV-related foot pain known as
  peripheral neuropathy. There are no drugs
  specifically approved to treat that kind of pain.

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• Three times daily for nearly a week, the patients
  smoked marijuana cigarettes machine-rolled at the
  National Institute of Drug Abuse, the only legal
  source for the drug recognized by the federal
  government.
• Half the patients received marijuana, while the
  other 25 received placebo cigarettes that lacked
  the drug's active ingredient, tetrahydrocannabinol
  .
• Scientists said the study was the first one
  published that used a comparison group, which is
  generally considered the gold standard for
  scientific research.

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• Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H,
  Press S, Kelly ME, Rowbotham MC, Petersen
  KL.Related Articles, Links Cannabis in painful
  HIV-associated sensory neuropathy a randomized
  placebo-controlled trial.Neurology. 2007 Feb
  1368(7)515-21.

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• Fifty patients completed the entire trial.
• Smoked cannabis reduced daily pain by 34
• Greater than 30 reduction in pain was reported
  by 52 in the cannabis group and by 24 in the
  placebo group .
• The first cannabis cigarette reduced chronic pain
  by a median of 72 vs 15 with placebo .
• Cannabis reduced experimentally induced
  hyperalgesia to both brush and von Frey hair
  stimuli but appeared to have little effect on the
  painfulness of noxious heat stimulation.

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Rationale for Cannabis-Derived Drugs

• A Canadian survey of patients with neuropathic
  pain found that 73 suffer from inadequate pain
  control (Gilron Bailey, Can J Anaesth, 2003)
• While there are some effective treatments for
  neuropathic pain of peripheral origin there are
  relatively few treatments for central neuropathic
  pain
• An estimated 15 of people with MS use cannabis
  for symptom relief (Clark et al., Neurol, 2004)

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Epidemiology of medical use of cannabis

• 2 of Canadian population use cannabis for
  medical purposes (Ogborne 2000)
• Prospective prevalence studies done in
• HIV/AIDS 25 (Sidney 2001, Prentiss 2004)
• MS 15 (Clark et al 2004, Page et al 2003)
• CNCP 10 (Ware et al 2003)

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Cannabis use by patients with IBDSimon Lal,
Manijeh Ryan, Sabrina Tangri, Mark S Silverberg,
Allan Gordon, A Hillary Steinhart. APS April
2007

• 100 patients with ulcerative colitis (UC mean
  age 33 (range 18-80) 66 female) and 191 patients
  with Crohns disease (CD mean age 33.5 (range
  18-71) 105 female) attending the outpatient
  clinic
• Completed a questionnaire concerning current and
  previous cannabis use, socio-economic factors,
  disease history, and medication use and QOL.

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• A comparable proportion of UC and CD patients
  reported lifetime (51) UC vs. (48) CD or
  current (12) UC vs. (16) CD use of cannabis.
• For lifetime cannabis users
• 14/43 (33) UC and 40/80 (50) CD patients had
  used it to relieve IBD-related symptoms
  including
• abdominal pain 93 UC vs. 95 CD
• diarrhea 64 UC vs. 23 CD and
• reduced appetite 86 UC vs. 70 CD).

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• Patients were more likely to use cannabis for
  symptom relief if
• they had a history of abdominal surgery (29/48
  (60) vs. 24/74 (32) p0.002),
• chronic analgesic use 29/41 (71) vs. 25/81 (31)
  
• alternative/complimentary medicine use 36/66
  (55) vs. 18/56 (32)
• a lower IBDQ (QOL) score

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Ware et al. Pain Res Manage 20027(2)95-99
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Applications received per month for Authorization
to Possess under the Medical Marijuana Access
Regulations December 2005
http//www.hc-sc.gc.ca/dhp-mps/marihuana/stat/2005
/dec_e.html
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COMPASS Study

• Multicentre, open label study of herbal cannabis
  in patients with chronic non-cancer pain
• 500 patients 1500 Control
• In progress

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Observations

• People get high on marijuana even when given
  therapeutically
• May affect QOL, sleep rather than pain
• Large drop out rate in Toronto group
• Requires rigorous management

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Therapeutic options

• Nabilone (Cesamet)
• Dronabinol (Marinol)
• Cannabis-based medicine (Sativex)
• Herbal cannabis (MMAR)

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Synthetic THC Oral Cannabinoids

• Narcotics prescription
• Nausea, vomiting with chemotherapy, anorexia
  associated with HIV/AIDS
• Cesamet (Nabilone) (0.5, 1 mg)
• purified synthetic cannabinoid
• nitrogen analogue to THC
• T1/2 8-12 hrs
• Marinol (dronabinol) (2.5, 5 mg)
• Delta-9-THC
• T1/2 4-6 hrs
• metabolites long T1/2

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Molecular Structure?9-THC vs Nabilone
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Rx Cannabinoid Profile Summary
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Recent RCT results MS
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Cannabinoids in MS
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Cannabinoids and Pain Pathways
Adapted from Di Marzo 2001
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THCCBD 11

• Extracts of 2 Cannabis sativa L strains
• Equal amounts of
• Tetranabinex high-THC strain
• 27 mg/mL ?-9 THC
• Nabidiolex high-CBD strain
• 25 mg/mL CBD
• Buccal spray
• Ethanol/propylene glycol vehicle
• 2.7 mg THC and 2.5 mg CBD per spray
• Therapeutic dose
• High inter-patient variability
• Administered on self-titration regimen

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Pharmacokinetics Cannabis
Cannabis clinical effects by route of
administration compared with THCCBD 11
Grotenhermen F (2003), Sativex Product Monograph
(2005)
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Clinical Review Rog et al, 2005

• Objective
• Compare efficacy and tolerability of THCCBD 11
  with placebo
• Adjunctive therapy in central neuropathic pain
• Patient population
• Adult MS patients with central pain
• Dysesthesia, painful spasm
• 85 screened
• 66 randomized
• THCCBD 11 (n34) and placebo (n32)

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Clinical Review Rog et al, 2005
Study design
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Clinical Review Rog et al, 2005

• Method
• Continuation of existing analgesics
• Self-titration of study medication to maximum 48
  sprays daily
• 11-point numerical rating scale (NRS-11) to
  measure pain and sleep disturbance
• Randomization
• Placebo and treatment groups comparable
• Patient disposition
• 64 patients completed study
• 2 patients withdrew from treatment group
• Mean daily sprays
• THCCBD 11 9.6
• Placebo 19.1
• Outcomes
• Primary Change in neuropathic pain severity
  (NRS-11)
• Secondary Change in sleep disturbance due to
  pain (NRS-11)
• Patients global impression of change (PGIC)

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Clinical Review Rog et al, 2005
Pain scores at end of randomized treatment phase
7.00
p 0.005
6.00
N 34
N 32
5.00
N 32
4.00
Mean NRS-11 pain score
N 32
3.00
2.00
1.00
0.00
Baseline
On treatment
Scale 0 No pain 10 Worst possible pain
THCCBD 11
Placebo
Active vs placebo
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Clinical Review Rog et al, 2005
Sleep scores at end of randomized treatment phase
6.00
5.00
p 0.003
N 34
4.00
N 32
N 32
Mean NRS-11 sleep score
3.00
2.00
N 32
1.00
0.00
Baseline
On treatment
Scale 0 Did not disrupt sleep 10 Completely
disrupts sleep, unable to sleep due to pain
THCCBD 11
Placebo
Active vs placebo
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Clinical Review Rog et al, 2005
Patients global impression of change
30
25
20
Number of patients
15
10
5
0
No change
Much worse
Total improved
Much improved
Total worsened
Minimally worse
Very much worse
Minimally improved
Very much improved
Category
THCCBD 11
Placebo
P0.005 vs placebo
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Clinical Review Rog et al, 2005
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Clinical Review Rog et al, 2005

• Summary
• THCCBD 11 effectiveness demonstrated
• Central pain associated with MS
• Pain-related sleep disturbance
• Adjunctive analgesic
• Study provided additional comparative data for
  NPS vs traditional NRS used for pain measurement

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Recent studies

• Diabetic peripheral neuropathy
• Allodynia in NeP
• Upcoming trial in cancer pain

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Considerations relating to cannabinoids

• Long history of medicinal use
• 36 of multiple sclerosis patients may have tried
  it or use cannabis
• Prudent prescribing recommended
• Importance of risk assessment, boundary setting
• Follow-up for effectiveness, side effects,
  compliance