Transcript Cannabinoids - An Emphasis on the Treatment of Chronic Pain

Cannabinoids An Emphasis on the Treatment of
Chronic Pain
Raea Dobson
BSc, BScPharm, ACPR
Clinical Pharmacist at the
Jim Pattison Outpatient Care and Surgery Centre
January 6th, 2015
Objectives
To understand the mechanism of action of cannabinoids for pain
To understand the applicability and limitations of the best available evidence
To identify appropriate indications for use (pain and non-pain), adverse effects,
and drug interactions
To understand the process of enrolling a patient to receive medical marijuana
Cannabinoids
A class of pharmacologically active compounds derived from Cannabis
plants that function in the endocannabinoid system
These compounds can be endogenous, herbal, or synthetic
The Cannabis sativa plant has had 525 compounds from several chemical
classes have been identified
At least 85 cannabinoids have been isolated
Psychoactive: Δ(9)-tetrahydrocannabinol (THC)
Analgesic + anti-inflammatory: Cannabidiol (CBD), cannabinol + THC
Drug Alcohol Depend. 2010 Nov 1;112(1-2):126-33
Available Products
Brand
Cesamet
Sativex
Cannabis (sativa, indica)
Content
Nabilone
(synthetic THC
analog)
Nambiximols
Hundreds of
(Cannabis-derived
compounds, including
compounds; THC:CBD) THC and CBD
Route
Oral tablet
Oromucosal spray
Inhaled, ingested
THC or CBD 0.25mg, 0.5mg, 2.7mg THC + 2.5mg CBD THC illicit = 0.2-30%
per dose
1mg caps
/ 100 μL spray
Usual Dose
1-2mg BID
4-12 sprays/day
~1 to 3 grams daily
Onset
60-90 mins
15-40 mins
3-10 mins
Duration
Up to 12 hrs
1 to 2 hrs
2 to 8 hrs
Cost
$1.17 - 0.5mg
$124.95/vial (10ml)
5$/gram
NOTE: dronabinol (Marinol) discontinued in 2012
Ther Clin Risk Manag 2008 Feb;4(1):245; eCPS; Lexi-comp; Health Canada website
Mechanism of Action
There are 2 identified cannabinoid receptors:
CB1 receptors (CB1Rs) - CNS
CB2 receptors (CB2Rs) - periphery
THC works as a partial agonist on both subtypes of receptors, but its
psychotropic activity is due to the effect on the CB1R.
CBD does not appear to bind to CB receptors, but does affect ion channels and
enzymes to modulate neuroinflammation. It may also potentiate the effects of
THC. It lacks psychoactive properties.
CNS Neurol Disord Drug Targets. 2009 December ; 8(6): 403–421.; eCPS; Lexi-comp
Mechanism of Action – CB1Rs
CB1Rs = mainly CNS, but also cardiac muscle, skeletal muscle, leukocytes, etc
Location of Receptors in CNS
Symptoms
Periaqueductal gray, rostral ventrolateral
Pain transmission +
medulla, spinal dorsal horn/dorsal root ganglion modulation
Chemoreceptor trigger zone
Nausea and vomiting
Cerebral cortex
Higher cognitive functioning
Nucleus accumbens
Reward center
Amygdala
Fear
Hippocampus, basal ganglia, cerebellum
Memory and coordination
CNS Neurol Disord Drug Targets. 2009 December ; 8(6): 403–421.; eCPS; Lexi-comp
Mechanism of Action – CB2Rs
CB2Rs are generally located in the periphery
1º: immune system (spleen, tonsils, thymus, mast cells, B- and T-cells,
natural killer cells, monocytes, and polymorphonuclear cells)
2º: bone, liver, some neural cells
They are involved in modulation of the humoral and cellular immune
responses to neuroinflammation
They may also have involvement in the central processes of anxiolysis,
anticonvulsion, and neuroprotection
CNS Neurol Disord Drug Targets. 2009 December ; 8(6): 403–421.; eCPS; Lexi-comp
Mechanism of Action for Pain
Incomplete and poorly characterized
Inactive phytocannabinoids require heating to trigger decarboxylation into
biologically active compounds. After this, they work similarly to endogenous
cannabinoids (e.g. anandamide, 2-arachidonoylglycerol)
Central
Peripheral
Released from depolarized postsynaptic neurons Stimulation of receptors on
to stimulate presynaptic CB1Rs in the PAG and
primary peripheral afferent
dorsal horns of the spinal cord
neurons (ascending pathway)
This retrograde signaling blocks descending
pathways by suppression of neurotransmitter
release (e.g. glutamate, 5-HT) via ↓ Ca/↑ K
Decrease inflammation via
stimulation of CB2Rs
CNS Neurol Disord Drug Targets. 2009 December ; 8(6): 403–421.; Chem.Biodivers. 4: 1770-1804.
Self-Medication Rates
A 2012 cross-sectional study of 457 fibromyalgia pts found that 13% were selfmedicating with cannabinoids for pain
80% herbal marijuana, 24% prescription cannabinoids, 3% combo
A 2004 study found that 53% of British Columbians had tried cannabis at least
once in their lifetime
There have been ~26,000 authorized pts under Health Canada's Marihuana
Medical Access Program
Arthritis Care Res 2012 Aug;64(8):1202; CMAJ 2000 Jun 13;162(12):1685; http://www.hc-sc.gc.ca/ahc-asc/media/nrcp/_2012/2012-193-eng.php; http://communications.uvic.ca/releases/release.php?display=release&id=758
Indications
www.cannabis-med.org/studies/study.php
Currently >350 studies of various indications
Non-Pain-Related Trials
Non-Pain-Related Trials
SC = smoked cannabis, DR = dronabinol, NB = nabilone, SV = Sativex
Condition
Medication
Outcomes
Glaucoma
SC, po THC
~25% ↓ intraocular pressure
HIV-related anorexia
SC, DR
↑ appetite (38% vs 8%; NNT 3.3), ↓ nausea (20% vs
7%; NNT 8) , ↑ weight:1 .2kg (4 wks) to 1.8kg (1yr)
Chemo-related anorexia,
N/V
DR, po THC, 100% had ≥ 5% weight gain over 6 mos
po extract
Appetite ↑ 73% vs 69% (NNT 25)
Anorexia nervosa
po THC
Weight ↑ by ~4kg over 4 wks
IBS
DR
Reduced fasting motility in pts with diarrhea
Epilepsy
CBD
Insufficient info: May ↑or ↓ seizure freq.
Alzheimer Dementia
DR
“Insufficient evidence”: may improve behavioral
Sxs (e.g. agitation, “unusual behavior”)
ALS
DR, po THC
↑ sleep and appetite
Parkinson’s Disease
SC, NB, po
extract
1 trial↓ levodopa-induced dyskinesia
2 trials ↔levodopa-induced dyskinesia/tremor
Depression, anxiety
NB, po THC
No benefit
Non-Pain-Related Trials
SC = smoked cannabis, DR = dronabinol, NB = nabilone, SV = Sativex
Condition
Dystonia
Tourette’s
Asthma
Hepatitis C
Medication
Po CBD, NB
Po THC
Aero-THC, NB
SC
Multiple sclerosis Extract
Huntington’s
Disease
Po CBD
Outcomes
1 trial 20-50% ↓ dystonia; 1 trial: ↔
↓ motor and vocal tics, ↓ obsessive behaviors
Acute bronchodilation, chronic obstruction(smoked)
↓D/Cs of Hep-C meds: 5% vs 33%; NNT 4
↑ virologic response rates: 54% vs 18%; NNT 3
↓ post-Tx virologic relapse: 14% vs 61%; NNT 2
Fibrosis progression (OR 3.4)
Severe fibrosis (OR 2.5), steatosis (OR 2.1)
Muscle stiffness relief : 29.4% vs 15.7% (NNT 8)
↓ spasticity: 61% vs 46% (NNT 7)
↓ urgency, frequency, #/mL of incontinence eps
↔ tremor
↔ Huntington’s Sxs
Spinal cord injury Po THC, SC, NB ↓ spasticity sum score (8.92 vs 16.72)
Cancer-Related Pain Trials
Cancer-Related Pain Trials
Study Details
Outcomes
177 pts with mod-severe
cancer-pain despite optimal
Tx
NRS Pain (0-10):
SV vs P: -1.37vs-0.69 (clin. sig)
THC vs placebo: -1.01 vs -0.69 (NSS)
A multicenter (28),
randomized, double-blind
study of self-titrated Sativex
(THC:CBD) vs THC extract vs
placebo as oromucosal spray
> 30% pain ↓:
SV vs P: 43% vs 21% (NNT 4.5)
THC vs placebo: 23 vs 21% (NSS)
Max of 48 sprays per 24 hrs
(? dose achieved)
No change from baseline in background meds
across Tx groups or # of breakthrough doses
Duration: 14d
AEs: no serious AEs ; >10%: somnolence (13%, NNH
33), dizziness (12%, NNH 14), nausea (10%, NNH 33)
QoL (Quality of Life Questionnaire): ↔
J Pain Symptom Manage. 2010 Feb;39(2):167-79; Ann Emerg Med. 1996;27:485-489.
Non-Cancer Pain Trials
Common Themes
Small sample sizes
Unclear randomization, allocation
Blinding maintained?
Variable doses and substances used (not standardized)
Many crossover trials – pros? cons?
Do not track co-morbid conditions or interventions that may
confound response
Selective reporting (efficacy, safety)?
Variable outcome use has disallowed meta-analyses from being
performed!
Short trial duration
HIV Neuropathy
Study
Double-blind, placebo-controlled, randomized crossover trial
Patients
34 outpts with HIV-associated distal sensory predominant
polyneuropathy (≥5/10 pain) refractory to ≥ 2 analgesic classes
Exclusions
Current substance use (including cannabis and cannabinoids),
previous intolerance to cannabinoids
Intervention Smoked cannabis 4% (1-8% THC) QID Standardized smoking
+ pre-study analgesic regimen
technique
PRN dosing adjustment –
Comparator Smoked placebo cannabis QID
analgesia + side effects
+ pre-study analgesic regimen
Outcomes
1º: change in pain intensity (Descriptor Differential Scale, VAS)
2º: disability, mood, QoL, adverse effects
Duration
7 weeks total:
1 week wash-in + 5 days Tx (placebo or cannabis) + 2 week wash-out
+ 5 days Tx (placebo or cannabis) + 2 weeks wash-out
HIV Neuropathy – Baseline Characteristics
Male
100%
Caucasian
75%
Age
48.8 ± 6.8 years
HIV History
Infected for > 5 years
Combination 93%
ARV therapy (72% exposed to neurotoxic ARVs - didanosine or stavudine)
Previous
96%
cannabis use Generally remote (> 1 year = 63%)
Concomitant Opioids (64%), NSAIDs or acetaminophen (36%), tricyclic
medications antidepressants (29%), anticonvulsants (64%)
Descriptor Differential Scale
2 X 12 item scales
Summary score: 0-20 points
MCID = ??
HIV Neuropathy – Efficacy Results
# of
6 (i.e. full data 1: psychosis, 2: cough, 3: diarrhea, 4: unexpected
dropouts for 28 pts)
personal commitment, 5: lost to follow--up, 6 – +
toxicology screen
Efficacy
Descriptor Differential
Scale
Baseline: 11.1 (9.1 – 13.7)
∆: -3.3 points with active Tx
0 with placebo
≥ 30% Reduction in Pain
(cannabis vs placebo)
46% vs 18%
NNT 3.6
Visual Analog Scale
(100mm)
(cannabis vs placebo)
-17mm vs -4mm
Sickness Impact Profile
Similar improvements in total mood,
Profile of Mood States
physical disability and quality of life
Brief Symptom Inventory (data not shown)
HIV Neuropathy - Efficacy
W/I = wash-in, W/O = wash-out, PCB = placebo, CNB = Cannabis
HIV Neuropathy – Safety Results
Not quantified (except for tachycardia)
Reported as:
Difficulty concentrating, fatigue, sedation/sleepiness, increased duration of
sleep, thirst, reduced salivation
Greater side effect frequency and severity with Cannabis vs placebo
Changes in HR/BP were asymptomatic and resolved spontaneously
↑ HR of ≥ 30 beats/min within 30 min of a smoking session were more
frequent with cannabis (46% vs 4% - NNH 2.4).
Detection by clinician?
Changes in viral load and CD4 counts did not differ
Serious adverse effects were not specified
HIV Neuropathy - Appraisal
Strengths
Weaknesses
Randomized, placebo controlled
Small sample size - more sensitive to bias +
confounding
Generalizable pt population
Tracked co-interventions
Utilized an individualized dosing
strategy to optimize outcomes
Performance/detection bias:
-Most pts receiving Cannabis could guess
their Tx allocation
-Physiological monitoring?
Used a confusing tool for efficacy
Assessed blinding maintenance
Similar NNT to that found in
another, similar study of HIV
inpatients
Used smoked Cannabis – optimal?
Placebo – content?
No quantification of adverse effects
Short duration of Tx
Other Pain Conditions
SC = smoked cannabis, DR = dronabinol, NB = nabilone, SV = Sativex
Condition
Medication
Outcomes
“Neuropathic pain”
SC vs placebo
Improved VAS versus placebo
SV vs placebo
NNT 9 for 30% and 50% reductions in pain
Diabetic neuropathy
Multiple sclerosis
NB vs placebo
NNT 2 for 30% reduction in pain
NNT 4 for 50% reduction in pain
NB vs gabapentin
NB and gabapentin had similar VAS reductions
SC vs placebo
Clin sig reduction in VAS for SC vs placebo
DR vs placebo
NNT 3.5 for 50% reduction of pain with DR
Rheumatoid Arthritis SV vs placebo
Clin sig reduction in VAS
Fibromyalgia
NB vs placebo
Clin sig reduction in VAS, borderline
improvements in QoL over 4 weeks
Post-surgical/
Traumatic pain
po THC, NB vs
placebo
No stat sig differences in VAS. Evidence does not
support use.
Safety - Side Effects
CNS
Euphoria (5-38%), dysphoria (1-10%), dizziness (3-59%), relaxation,
drowsiness (7-66%), memory or cognitive dysfunction (<1%), timedistortion (3%), loss of inhibitions, ↓ focus (3-12%), intensification of
sensory experiences (3%), withdrawal Sxs, addiction, dependence,
ataxia (13-14%), hallucinations (<1%), ?psychosis
HEENT
Scleral redness,↓ IOP, facial flushing, stomatitis, head/neck CA?
Resp
Cough (OR 2; 3%), wheeze (OR 2.98), dyspnea (8%), pharyngitis,
asthma, COPD, pneumonia (7%), ? lung CA
CV
Tachycardia (1-46%), ↑BP, ↓BP (5-8%), arrhythmias (<1%), MI (<1%)
GI/GU
↑ appetite (2-4%), xerostomia (8-36%), N/V/abdominal pain (3-12%),
diarrhea (6%), urinary tract infections (10%)
Other
↑ motor vehicle accidents (<1%), falls (3%)
Most AEs depend on dose, product, route of administration, and pt population!
Addiction Potential
The National Addiction Research Center in the USA performed an
epidemiological study on the relative addictiveness of 5 substances
based on pt surveys.
Of those who tried the substance at least once, these are the %s that
eventually met criteria for addiction to that substance:
Nicotine (32%)
Heroin (23%)
Cocaine (17%)
Alcohol (15%)
Cannabis (9%)
Dependence and Withdrawal
Cannabis dependence (physical or psychological) and cannabis withdrawal are
included in the DSM-V.
Incidence: dependence can develop in ~10% of chronic users
Withdrawal
“Common”: Irritability, aggression, anxiety, restlessness, insomnia,
anorexia/weight loss
“Less common”: depression, chills, sweating, shakiness, GI pain
Onset: 1-2 days post-discontinuation
Peak: 2-6 days
Full resolution: 1-2 weeks
The Big “Draw”
No reported deaths due to overdose
Reason:
No CB-receptors in the medulla = no effect on breathing
The LD50 for marijuana in humans is estimated to be ~70 g of THC
~10mg bioavailable THC per joint = 7000 joints (short period) =
~$35,000
Safety vs Tobacco
Many of the same carcinogens are found between tobacco
smoke and marijuana smoke
Cannabis smoking results in 3-fold higher levels of tar, and 5-fold
higher levels of carbon monoxide exposure
Due to marijuana smokers typically smoking fewer units per day
vs a tobacco smoker, this discrepancy could even out
Drug Interactions
Additive adverse effects when used in combination with sedatives, hyponotics, alcohol,
antihypertensives, sympathomimetics, etc
THC+CBD: substrates of CYP1A2, 2C9, 2D6, 2C19, 3A4, and highly protein- bound but to
date there are only case reports of clinically-relevant DIs (e.g. Warfarin)
56 yo M on warfarin x 11 yrs admitted with UGIB + INR 10.41. Given 4U FFP and 10mg
vitamin K. Discharged 7 days post-admission with INR 1.8
15 days later, readmitted with epistaxis/brusing + INR 11.55. Treated again.
Found to have been smoking marijuana for depression during these times
Counseled to stop – no more bleeding episode in the following 9 months
Additional monitoring for pts with drugs that may theoretically interact!
Ann Pharmacother 2009;43:1347-53; eCPS; Lexi-comp
Precautions and Contraindications
Hypersensitivity (absolute contraindication)
Prior negative experience with cannabinoids
Personal or family history of psychotic disorders (e.g. schizophrenia) and other severe or
uncontrolled mood disorders
Patients <25 years old
Active cardiac ischemia, arrhythmias, active HTN, severe HF
Severe respiratory disorders (inhaled cannabinoids)
Severe immunosuppression
Severe liver, kidney dysfunction
Patients with a history of substance abuse
Patients currently taking sedative-hypnotic medications
Pregnancy and lactation, potential for pregnancy
Sativex: allergy to propylene glycol, ethanol (50% v/v), or peppermint
Caution in those with a history of alcoholism
Legality
Old vs New
MMAR
MMPR
Dates Effective
Until March 31, 2014
After April 1st, 2014
Product
Single strain from 1 supplier
via Health Canada (THC 12.5%)
or self-grown seeds
Free market via licensed
producers regulated through
Health Canada (no seeds)
Application
Specific criteria and diagnoses No indication required.
sent to Health Canada, who
Eligibility decided by
decided patient’s eligibility.
prescriber. Sent directly to
licensed producer.
Time to complete ~20 minutes
form(s)
~2 minutes
Green Card
Provided?
No
Yes
MMRP - the “New” System
http://www.hc-sc.gc.ca/dhp-mps/marihuana/info/med-eng.php
MMPR
The patient contacts licensed producers for product and pricing information
List of licensed producers can be found here:
http://www.hc-sc.gc.ca/dhp-mps/marihuana/info/list-eng.php
They then register with the licensed producer of their choice
The licensed producer will send the patient their requested product via mail
The amount sent is a maximum of 150g, or a 30 day supply of the amount
stipulated by the prescriber (whichever is less)
MMPR – the “New” System
BC requirements:
Pharmaceutical cannabinoids should generally be trialed first
Review of Pharmanet prior to application
Have the patient sign a written consent form* (Table 2)
Document that patient was informed of risks/benefits, that other treatments were tried
Advise patients to avoid driving for at least 4 hours after inhalation, 6 hours after
ingestion, and 8 hours after either method if the patient experiences euphoria**
Patient information handout: http://www.hc-sc.gc.ca/dhpmps/alt_formats/pdf/marihuana/info/cons-eng.pdf
Assess the patient’s risk of addiction using a standardized tool* (Table 4)
CANNOT authorize via telemedicine
Review efficacy and tolerability q3months
http://www.cfpc.ca/uploadedFiles/Resources/_PDFs/Authorizing%20Dried%20Cannabis%2
0for%20Chronic%20Pain%20or%20Anxiety.pdf
Other Information to Convey to
Patients
Start low, go slow - 1 inhalation, wait 4 hours. TID-QID is reasonable
Inhale slowly over 5 seconds, hold breath for 10 seconds, exhale slowly
Do not take more than recommended, or give product to others
Vaporizing is preferred to smoking
Take smoked cannabis in a well-ventilated, private, calm place and do not
expose other family members to smoke
Self-monitor mood and alter HCP if any changes
Store in a secure area
All patients should be monitored for abuse and misuse
Compassion Clubs
Unlicensed organizations that provide an assortment of cannabis products to their
customers (e.g. Many varieties of cannabis, smokables, edibles, etc)
Not recognized by Health Canada
Local police allow these Clubs to run as long as they are maintaining a certain
level of appropriateness
Clubs may request the medical practitioner provide them with the pts diagnosis
and/or a recommendation prior to supplying the pt with product
The pt must consent to this release of information (form filled out by the pt)
This form is supplied by the Club and must be filled out and faxed back to the Club
by the medical practitioner
Unanswered Questions
How truly efficacious and safe are cannabinoids?
Does the crude plant material of marijuana have different effects
from synthetic cannabinoids?
Should we permit or encourage smoking of marijuana? Why is Health
Canada only allowing a supply of this modality to our patients?
How do we get around the stigmas of prescribing this to our patients
when it may benefit them, and how to we help them to avoid
stigmatization themselves?
Questions?