(Clark) Cannabinoids for pain management (Revista++++)

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Volume 10 Supplement A • Autumn 2005
Pain Research
&Management
Cannabinoids for Pain Management
Guest Editor: Dr Alexander J Clark
Publication of this supplement sponsored by an
unrestricted educational grant from Valeant
The Journal of the Canadian Pain Society
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Pain Res Manage Vol 10 Suppl A Autumn 2005
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Autumn 2005
Volume 10 Supplement A
EDITORIAL
Cannabinoids for pain management: What is their role?
5A
Alexander J Clark, Mary E Lynch
REVIEWS
Preclinical science regarding cannabinoids as analgesics: An overview
7A
ME Lynch
Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive
and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the
presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and
evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that
cannabinoids exhibit significant potential as analgesics. This article presents an overview of the preclinical
science.
Pharmacokinetics of cannabinoids
15A
Iain J McGilveray
Delta-9-tetrahydrocannabinol (∆-9-THC) is the main psychoactive ingredient in cannabis (marijuana).
This review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol
and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC) and
nabilone.
Toxic effects of cannabis and cannabinoids: Animal data
23A
Pierre Beaulieu
This article reviews the main toxic effects of cannabis and cannabinoids in animals. Toxic effects can be
separated into acute and chronic classifications. Animal toxicity data, however, are difficult to extrapolate to
humans, and one should be very careful when interpreting the results and appying them to humans. The best
approach to human toxicology rests on the study of human data.
Cannabinoids for the treatment of pain: An update on recent
clinical trials
27A
Mark Ware, Pierre Beaulieu
Over the past five years, there has been a considerable increase in clinical research on cannabinoid use for a
range of pain syndromes. Cannabinoid products are becoming available for research and clinical use, and
pharmaceutical industry interest in the potential for cannabinoids in therapeutics is also gaining
momentum. This article summarizes recent clinical trial data in the field of pain management and suggests
that the potential for cannabinoid therapy for chronic pain states is encouraging.
Continued on page 4A
Pain Res Manage Vol 10 Suppl A Autumn 2005
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Autumn 2005
Volume 10 Supplement A
REVIEWS – CONTINUED
Safety issues concerning the medical use of cannabis and cannabinoids
31A
Mark A Ware, Vivianne L Tawfik
Safety issues are a major barrier to the use of cannabis and cannabinoid medications for clinical purposes.
In this article, the evidence behind major safety issues related to cannabis use is summarized, with the aim
of promoting informed dialogue between physicians and patients in whom cannabinoid therapy is being
considered. Caution is advised in interpreting these data, because clinical experience with cannabinoid
use is in the early stages.
Addiction and pain medicine
38A
Douglas Gourlay
The adequate cotreatment of chronic pain and addiction disorders is a complex and challenging problem for
health care professionals. There is great potential for cannabinoids in the treatment of pain; however, the
increasing prevalence of recreational cannabis use has led to a considerable increase in the number of
people seeking treatment for cannabis use disorders.
Guidelines for the use of cannabinoid compounds in chronic pain
44A
AJ Clark, ME Lynch, M Ware, P Beaulieu, IJ McGilveray, D Gourlay
The objective of this paper was to provide clinicians with guidelines for the use of cannabinoid compounds
in the treatment of chronic pain. Publications indexed from 1990 to 2005 in the National Library of
Medicine Index Medicus were searched through PubMed. A consensus concerning these guidelines was
achieved by the authors through review and discussion. A practical approach to the treatment of chronic
pain with cannabinoid compounds is presented.
DEPARTMENTS
Instructions to Authors
4A
47A
Pain Res Manage Vol 10 Suppl A Autumn 2005
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EDITORIAL
Cannabinoids for pain management: What is their role?
Alexander J Clark MD FRCPC1, Mary E Lynch MD FRCPC2
n the popular press, many Canadians claim to be using
herbal cannabis (marijuana) to control symptoms such as
pain, nausea, muscle spasm, anorexia and anxiety that may be
associated with diseases like AIDS/HIV, multiple sclerosis,
epilepsy and chronic pain. Surveys of patients with chronic
pain, multiple sclerosis and epilepsy suggest that approximately 10% to 12% of these patients are active cannabis
users, and up to 36% have tried using herbal cannabis or its
derivatives to control symptoms they experience with these
diseases (1-3).
On the other hand, the prescription cannabinoids available
have, to date, only limited use in the management of pain.
Neither nabilone (Cesamet, Valeant Canada limitée/Limited)
nor dronabinol (Marinol, Solvay Pharma Inc, Canada) have
pain as an indication according to the Canadian Compendium
of Pharmaceuticals and Specialties (4), while Sativex
(GW Pharma Ltd, United Kingdom) is only indicated for neuropathic pain in multiple sclerosis.
Although there is a large and growing preclinical literature
regarding potential therapeutic uses of cannabinoids, there are
few studies on the clinical efficacy of natural and synthetic
cannabinoids as analgesics. Previous available studies have
involved only small numbers of subjects and were often of limited quality (5).
An overview of the rapidly developing basic science relevant to potential analgesic actions of cannabinoids (6), which
includes a review of the endogenous cannabinoid system; evidence of antinociceptive, antihyperalgesic and anti-inflammatory actions; and a review of the pharmacokinetics of
cannabinoids (7) is presented in this special issue. Reviews of
the current literature assist in understanding the possible toxic
effects (8), safety (9) and risks of addiction (10) of cannabinoids. As with all pharmacologically active agents, currently
available cannabinoids are associated with adverse effects, and
it is important to be aware of these effects as clinicians begin to
consider these agents in the treatment of pain. Examples
include effects on drowsiness, attention and cognition, the
possibility of exaggerating existing psychoses or provoking others long-term, postural hypotension and tachycardia.
I
Further understanding the roles of the cannabinoid receptors (CB1 and CB2) and the development of new cannabinoid
receptor agonists will allow us to maximize the analgesic efficacy and minimize the side effects caused by the cannabinoids.
Development of novel agonists, which do not cross the bloodbrain barrier, alternative methods of delivery (ie, transdermal,
buccal, rectal, etc), and further elaboration of ways to manipulate the endogenous cannabinoid system are all exciting areas
of research that will lead to compounds exhibiting greater efficacy, and potentially fewer adverse effects. However, it will
likely be several years before such compounds will be clinically available and, right now, we need to be familiar with the currently available compounds.
The purpose of the present supplement to Pain Research &
Management is to provide Canadian clinicians and researchers
with comprehensive reviews of the current basic and clinical
science regarding cannabinoids, along with up-to-date reviews
of the literature relevant to safety, toxicity and the risk of
addiction related to cannabinoids.
The authors of the present supplement have developed an
algorithm for use by clinicians in the assessment and treatment
of chronic pain when cannabinoid compounds are considered.
In addition, guidelines for the use of the two oral cannabinoid
compounds that are currently available by prescription in
Canada are provided. It is not possible to make recommendations about the buccal administered cannabinoid compound
because information is limited.
The use of smoked herbal cannabis should be discouraged;
there is significant controversy regarding this route of delivery.
There is no question that smoking is toxic, but can patients
limit their risk by minimizing the dose? Do the benefits outweigh the risks in some cases? The answers to these questions
await further study and, until inexpensive, safer and efficient
methods of delivery are available, it is probable that some
patients with pain and other symptoms will seek relief by
smoking cannabis. Others may receive existing preparations
for off-label use.
It is the goal of the present supplement to assist clinicians,
researchers and policy makers with these issues.
1Chronic
Pain Centre, Calgary Health Region, and Department of Anesthesia, University of Calgary, Calgary, Alberta; 2Pain Management Unit,
Queen Elizabeth II Health Sciences Centre, and Departments of Psychiatry and Anesthesia, Dalhousie University, Halifax, Nova Scotia
Correspondence and reprints: Dr Alexander J Clark, Chronic Pain Centre, Calgary Health Region, 160–2210 2nd Street SW, Calgary, Alberta
T2S 3C3. Telephone 403-943-9900, fax 403-209-2955, e-mail john.clark@calgaryhealthregion.ca
Pain Res Manage Vol 10 Suppl A Autumn 2005
©2005 Pulsus Group Inc. All rights reserved
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Editorial
DECLARATION OF INTEREST: This series of articles has been
supported by an unrestricted grant from Valeant Canada
limitée/Limited. The grant enabled a symposium to be held in
Montreal, Quebec on June 4, 2004 and facilitated preparation of the
manuscripts. The Editor-in-Chief of the Journal, Dr Harold Merskey,
participated in the symposium. The participants and authors wish to
acknowledge the support provided.
REFERENCES
1. Ware MA, Doyle CR, Woods R, Lynch ME, Clark AJ. Cannabis use
for chronic non-cancer pain: Results of a prospective survey. Pain
2003;102:211-6.
2. Clark AJ, Ware MA, Yazer E, Murray TJ, Lynch ME. Patterns of cannabis
use among patients with multiple sclerosis. Neurology 2004;62:2098-100.
3. Gross DW, Hamm J, Ashworth NL, Quigley D. Marijuana use and
epilepsy: Prevalence in patients of a tertiary care epilepsy center.
Neurology 2004;62:2095-7.
6A
4. Compendium of Pharmaceuticals and Specialties. Ottawa:
Canadian Pharmacists Association, 2005.
5. Ware M, Beaulieu P. Cannabinoids for the treatment of pain:
An update on recent clinical trials. Pain Res Manage
2005;10(Suppl A):27A-30A.
6. Lynch ME. Preclinical science regarding cannabinoids as
analgesics: An overview. Pain Res Manage
2005;10(Suppl A):7A-14A.
7. McGilveray IJ. Pharmacokinetics of the cannabinoids. Pain Res
Manage 2005;10(Suppl A):15A-22A.
8. Beaulieu P. Toxic effects of cannabis and cannabinoids:
Animal data. Pain Res Manage
2005;10(Suppl A):23A-26A.
9. Ware MA, Tawfik VL. Safety issues concerning the medical use of
cannabis and cannabinoids. Pain Res Manage
2005;10(Suppl A):31A-37A.
10. Gourlay D. Addiction and pain medicine. Pain Res Manage
2005;10(Suppl A):38A-43A
Pain Res Manage Vol 10 Suppl A Autumn 2005
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REVIEW
Preclinical science regarding cannabinoids
as analgesics: An overview
ME Lynch MD FRCPC
ME Lynch. Preclinical science regarding cannabinoids as
analgesics: An overview. Pain Res Manage 2005;10(Suppl A):
7A-14A.
Survol des données précliniques sur les
propriétés analgésiques des cannabinoïdes
Modern pharmacology of cannabinoids began in 1964 with the isolation
and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and
antihyperalgesic effects of cannabinoid agonists in animal models of acute
and chronic pain; the presence of cannabinoid receptors in pain-processing
areas of the brain, spinal cord and periphery; and evidence supporting
endogenous modulation of pain systems by cannabinoids has provided
support that cannabinoids exhibit significant potential as analgesics. The
present article presents an overview of the preclinical science.
C’est en 1964 qu’est née la pharmacologie moderne des cannabinoïdes,
quand on a isolé et partiellement synthétisé le delta-9-tétrahydrocannabinol, principal agent psychoactif de la plante appelée cannabis. Depuis
lors, les puissants effets antinociceptifs et antihyperalgésiques des agonistes des cannabinoïdes dans des modèles animaux de douleur aiguë et
chronique, la découverte de récepteurs des cannabinoïdes dans les zones
du cerveau, de la moelle épinière et du système nerveux périphérique
responsables de la perception de la douleur et les preuves à l’appui d’une
modulation endogène des stimuli douloureux par les cannabinoïdes confirment leur important potentiel analgésique. Le présent article propose
une vue d’ensemble des données précliniques.
Key Words: Cannabinoid opioid interactions; Cannabinoid receptors;
Cannabinoids; Chronic pain; Endocannabinoids
erbal cannabis has been used for centuries for medicinal
and recreational purposes, but it has only been in the past
40 years that scientists have been able to elucidate the molecular basis of cannabinoid action.
Modern pharmacology of cannabinoids began in 1964
when the major psychoactive constituent of cannabis, delta-9tetrahydrocannabinol (∆-9-THC), was isolated in pure form,
its structure elucidated and later synthesized (1). Since then,
the endogenous cannabinoid (endocannabinoid) system has
been described, stimulating the development of a range of
novel cannabinoid receptor agonists and antagonists (2).
These developments have attracted renewed interest in the
cannabinoids as potential therapeutic agents. In less than five
years there have been over 1500 citations on MEDLINE
regarding cannabinoids, and the rate of publications in the
field is growing rapidly (Figure 1).
Areas of inquiry include the potential role of cannabinoids in
pain, antiemesis, appetite modulation, antispasticity, neuroprotection, anti-inflammatory action, tumour suppression, antioxidant activity, immune modulation, glaucoma, sexual dysfunction
and addiction control. The present paper will focus on the preclinical literature regarding cannabinoids and pain. There are
already a number of excellent reviews on this topic (2-7), and the
current article will present an overview of the field.
H
ENDOCANNABINOID SYSTEM
The first crucial step in elucidating the molecular basis of
cannabinoid action was achieved in 1988. At that time, a
radiolabelled potent synthetic cannabinoid was found to bind
to brain membranes in a highly specific and selective manner,
exhibiting features that were characteristic of receptor binding
(8). Within a short time, the cannabinoid receptor (now called
CB1) was discovered and cloned from rat and human brain (9).
Three years later, a second cannabinoid receptor (CB2) was
discovered and cloned (10). Since then, researchers around
the world have mapped the location of CB1 and CB2 receptors,
identified a probable third receptor, and described additional
endocannabinoids as well as mechanisms and sites of action.
Distribution of cannabinoid receptors
CB1 receptors are found in particularly high concentrations
within the central nervous system; indeed, CB1 receptors are
10 times more abundant than mu opioid receptors in the brain
(11). CB1 receptors are also present in peripheral neurons and
in non-neuronal tissues. The distribution of cannabinoid
receptors has been examined by several methods (12-14). High
levels of CB1 receptors have been found in the hippocampus,
basal ganglia, hypothalamus, cerebellum, areas of the cerebral
cortex and the nucleus accumbens, with implications for memory, coordination, feeding, higher cognitive function and
reward. Most important for pain are moderately abundant concentrations located within the periaqueductal gray (PAG) of
the midbrain, the rostral ventrolateral medulla (RVM), superficial layers of the spinal dorsal horn and dorsal root ganglion,
from which they are transported to the peripheral and central
terminals of the primary afferent neuron (Figure 2). These
locations are important in descending pain modulation, spinal
processing of pain and peripheral pain perception. Additional
areas include the hypothalamus and the pituitary gland (temperature regulation, endocrine and reproductive function), the
Pain Management Unit, Queen Elizabeth II Health Sciences Centre, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia
Correspondence: Dr Mary Lynch, Pain Management Unit, Queen Elizabeth II Health Sciences Centre, 4th Floor Dickson Centre, Room 4086,
Halifax, Nova Scotia B3H 1V7. Telephone 902-473-6428, fax 902-473-4126, e-mail mary.lynch@dal.ca
Pain Res Manage Vol 10 Suppl A Autumn 2005
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Lynch
Figure 1) Number of PUBMED citations per five-year period regarding ‘cannabinoid’ and ‘cannabis’ research
amygdala (emotional response and fear), the brainstem
(arousal) and the nucleus of the solitary tract (nausea and
vomiting) (2,12,15-21) (Figure 2).
There are low levels of cannabinoid receptors in brainstem
cardiopulmonary centres, which probably accounts for the
high safety margin of the cannabinoids (5). The identification
of receptors in the areas described above is consistent with the
behavioural effects produced by cannabinoids.
The first CB2 receptors were cloned not from brain, but
from a human immune cell line (12); thus, it was apparent
from the beginning that the cannabinoid system extended
beyond the nervous system. Since that time, studies have
demonstrated the presence of CB2 receptors throughout the
immune system (22,23).
This work has established the current model for cannabinoid receptors, with CB1 primarily located in brain and associated structures such as the pituitary gland and peripheral
nervous tissues, and CB2 primarily located in the reproductive
and immune systems (2,23). Recently, CB2 receptor-like
immunoreactivity has been described in the rat brain in neuronal patterns supporting possible broader central nervous system roles for the CB2 receptor (24).
Endocannabinoids
Until the end of the 20th century, only two major endocannabinoids, anandamide (N-arachidonoyl-ethanolamine
[AEA]) and 2-arachidonylglycerol (2-AG) had been discovered (25-27). Since then, additional endocannabinoids have
been identified (28). These include noladin ether, virodhamine (O-arachidonoyl-ethanolamine) and N-arachidonoyl
dopamine (NADA) (29-31), as well as others that are in the
process of being identified.
To qualify as an endocannabinoid, the agent must exhibit
activity at cannabinoid receptors. The endocannabinoids
vary in their activity at the receptor depending on the type of
intracellular event measured (32). AEA, NADA and noladin
are more selective for CB1, virodhamine appears to prefer
CB2 and 2-AG is equipotent for both CB1 and CB2 (28). In
addition to CB1 agonist activity, AEA binds to the vanilloid
receptor (29). NADA also exhibits activity at vanilloid
receptors (now called transient receptor potential vanilloid 1
receptors) and appears to be pronociceptive (28).
Palmitoylethanolamide (PEA) is not strictly an endocannabinoid, but has cannabinomimetic properties, including analgesic effects, which in vivo are antagonized by the
CB2 receptor antagonist SR144528 (7) (Table 1).
8A
Figure 2) Location of cannabinoid receptors (CB1) in the areas of the
nervous system that are important for pain transmission and modulation. PAG Periaqueductal gray; RVM Rostral ventrolateral medulla
Biosynthesis and inactivation of endocannabinoids
Endocannabinoids are biosynthesized via a phospholipiddependent pathway (Figure 3). The metabolic pathway for
AEA and 2-AG have been identified; the detailed biosynthesis of the more recently discovered endocannabinoids is currently being worked out (28). The balance of evidence
supports that AEA and 2-AG are synthesized and released on
demand following physiological and pathological stimuli such
as neuronal depolarization and the presence of bacterial
lipopolysaccharides, possibly depending on calcium-dependent
remodelling of phospholipid precursors. After biosynthesis,
AEA and 2-AG are immediately released into the extracellular space. The release, disposition and potential recycling of
endocannabinoids is not well understood. Research groups are
pursuing various lines of inquiry, including identification of a
putative transporter, uptake via caveolin-mediated endocytosis
and passive diffusion. Inactivation of AEA and 2-AG occurs
via fatty acid amide hydrolase (FAAH) and monoacylglycerol
lipase, respectively (4,6,28,33).
CANNABINOID PHARMACOLOGY,
MECHANISMS AND SITES OF ACTION
There are several chemical classes of cannabinoid receptor
agonists. These are the ‘classical’ cannabinoid ∆-9-THC, the
‘nonclassical’ cannabinoid CP55,940, the aminoalkylindole
WIN55,212-2, the ‘eicosanoid’ cannabinoid AEA, and additional fatty acid ethanolamides and esters that act as endocannabinoids (2,4). As with the endocannabinoids, there is
variability regarding the activity of cannabinoid ligands at the
receptor. For example, ∆-9-THC and CP55,940 exhibit equal
affinity for CB1 and CB2, whereas WIN55,212-2 exhibits modest selectivity for CB2 (2). Table 1 presents further detail
regarding endogenous, naturally occurring and synthetic
cannabinoids and their activity at receptors known to date.
Signal transduction at the CB1 receptor
Both cannabinoid receptor types are embedded in the cell membrane and are coupled to G proteins, negatively to adenylyl
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TABLE 1
Cannabinoid agonists and antagonists*
Naturally occurring cannabinoids
Endogenous cannabinoids
Agent
Action
∆-9-THC
CB1 and CB2 agonist
Comments
Main psychoactive constituent of cannabis
Cannabidiol
Unknown mode of action
Nonpsychoactive constituent of cannabis
Anandamide
CB1 partial agonist
Also binds to TRPV1
2-Arachidonylglycerol
CB1 and CB2 agonist
Noladin
CB1
N-arachidonoyl dopamine
CB1 and TRPV1 agonist
Virodhamine
CB2 partial agonist
Pronociceptive
CB1 antagonist
Acts like a CB2 agonist with analgesic
Palmitoylethanolamide
effects antagonized by CB2 antagonist
but does not bind to CB2 receptors
Synthetic cannabinoids
Nabilone
CB1 and CB2 agonist
Available by prescription in Canada
Synthetic ∆-9-THC (dronabinol;
CB1 and CB2 agonist
Available by prescription in Canada
Marinol [Solvay Pharma Inc, Canada])
CP55,940
CB1 and CB2 agonist
WIN55,212-2
CB1 and CB2 agonist
AM1241
CB2 agonist
HU-210
CB1 and CB2 agonist
High-potency agonist
HU-211
Not active at cannabinoid receptors
Neuroprotective
SR141716A
CB1 antagonist
Inverse agonist activity
SR144528
CB2 antagonist
Inverse agonist activity
AM251
CB1 antagonist
AM630
CB2 antagonist
*This is not an exhaustive list. ∆-9-THC Delta-9-tetrahydrocannabinol; CB1 Cannabinoid receptors found primarily in the nervous system; CB2 Cannabinoid receptors found primarily in peripheral tissues and immune system; TRPV1 Transient receptor potential vanilloid 1
cyclase and positively to mitogen-activated protein kinase
(2,6,7). CB1 receptors are coupled to ion channels through
G proteins, positively to A-type and inwardly rectifying potassium channels and negatively to N-type and P/Q-type calcium
channels and to D-type potassium channels (2). Activation of
either receptor will result in inhibition of adenylyl cyclase
activity resulting in a decrease in the production of cyclic
AMP (cAMP) and cellular activities dependent on cAMP,
with opening of inwardly rectifying potassium channels resulting in decreased cell firing and closing of calcium channels
resulting in decreased release of neurotransmitters (Figure 4).
The overall effect is that of cellular inhibition. This is very
much like the mechanism of action of the opioids. The
cannabinoids and opioids have similar actions but involve different systems. The CB1 receptor antagonist SR141716A prevents the analgesic effects of THC but not of morphine (34),
whereas naloxone, an opioid antagonist, blocks the analgesic
effect of morphine but not of THC and its analogues (35).
Thus, with regard to signal transduction at the CB1 receptor, cannabinoids exhibit actions very much like the morphine
group of drugs, but are able to act independently. The cannabinoid system is larger and occupies more areas than the opioid
system, with the implication that the cannabinoid system may
have wider potential therapeutic applications.
Endocannabinoid signalling in the brain
In contrast to classical neurotransmitters, investigators have identified that endocannabinoids are able to function as retrograde
synaptic messengers (36). In this case, the endocannabinoid is
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Tissue damage
Phospholipids
Phosphatidic
acid
phospholipase A2
phospholipase C
Arachidonic acid
phosphohydrolase
Dopamine
diacylglycerol lipase
cyclo-oxygenase
(COX 1, 2, 3)
N-acyltransferase
lipo-oxygenase
2-AG
N-acylphosphatidyl-ethanolamine
specific phospholipase D
Leukotrienes
Anandamide
AEA
Prostaglandins
Prostacyclin
Thromboxane
NADA
Noladin
Virodhamine
Biosynthetic pathway known
Biosynthetic pathway details to be identified
Figure 3) Biosynthesis of endocannabinoids in the context of the
arachidonic acid pathway following tissue damage. 2-AG 2-arachidonylglycerol; AEA N-arachidonoyl-ethanolamine; NADA N-arachidonoyl dopamine
synthesized and released from the postsynaptic neurons to travel
backwards across the synapse, activating CB1 on presynaptic
axons and then suppressing neurotransmitter release. This
capacity for ‘working backwards’ is directly relevant to pain
modulation.
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Figure 4) Signal transduction mechanisms at the cannabinoid receptor
found primarily in the nervous system (CB1). Activation of the receptor
stimulates coupling to the G protein with activation of mitogen-activated
protein (MAP) kinase and inhibition of adenylyl cyclase with decreased
production of cyclic (c)AMP. The G protein also directly couples the
CB1 receptor negatively to N- and Q/P-type voltage-dependent calcium
(Ca2+) channels and positively to A-type and inwardly rectifying potassium
channels (K+A and K+ir, respectively). Thus, there is enhanced outward
K+ current resulting in decreased cell firing, and closing of Ca2+ channels
resulting in decreased release of neurotransmitters, resulting in an overall
effect of cellular inhibition. PKA Protein kinase A. Adapted from reference 80
Supraspinal sites of action
It has been demonstrated that cannabinoids act at multiple
levels in the modulation of nociceptive or pain-related transmission (2,4,5). Intracerebroventricular administration of
cannabinoids (37) suppresses tail-flick responses and spinal
nociceptive responses (17). Direct brain injections into areas
involved in descending inhibition of spinal nociceptive neurons elicits antinociceptive effects; these areas include the
PAG in the midbrain, the RVM and the noradrenergic
nucleus A5 in the medulla (38-40). Furthermore, microinfusion with the cannabinoid agonist WIN55,212-2 directly into
the RVM in rats leads to increased ‘off-cell’ activity with
increased tail-flick latencies, indicating that cannabinoids act
directly within the RVM to affect off-cell activity (41).
Additionally, cannabinoids have been shown to decrease noxious stimulus-evoked firing of nociceptive neurons in the ventral posterolateral nucleus of the thalamus as well as the RVM,
with the latter being a demonstrated CB1 effect (4).
Through a series of experiments involving animal behaviour (tail flick) and extracellular single unit recordings from
RVM neurons, along with administration of specific cannabinoid and opioid agonists and antagonists, it has been demonstrated that cannabinoids produce analgesia through the same
brainstem circuit used for opioid analgesia. The use of an opioid is not required for the cannabinoid to produce this effect
(42). In addition, both systemic and intracerebroventricular
administration of cannabinoids have been shown to decrease
noxious heat-evoked activity of wide dynamic range (WDR)
neurons in a manner sensitive to spinalization, indicating a
supraspinal site of action and descending modulation of WDR
neurons (17).
10A
Spinal sites of action
Several investigators have demonstrated that cannabinoids
also inhibit pain by a direct spinal action (16,43-49). These
observations are consistent with labelling studies exhibiting
the presence of cannabinoid receptors in the dorsal horn of the
spinal cord. For example, cannabinoids can act at spinal CB1
receptors to inhibit capsaicin-sensitive fibres in lumbar dorsal
horn slices and to decrease noxious stimulus-evoked firing of
WDR neurons (16,48). Additional evidence supports that
activation of the spinal CB1 receptor can decrease N-methylD-aspartate receptor activation, potentially by inhibiting glutamate release into the spinal cord (49).
Intrathecal injection of (methyl-6-phenylethynyl) pyridine,
a selective metabotropic glutamate-5 receptor antagonist,
reversed the antihyperalgesic effect of intrathecal WIN55,212-2
in a rat loose ligation sciatic nerve model (50).
These data suggest that the antihyperalgesic effect of
cannabinoid agonist WIN55,212-2 is mediated through an
interaction with spinal metabotropic glutamate-5 receptors
(50). In addition, there is growing support that cannabinoids
modulate spinal noradrenergic and opioid systems (see ‘Opioid
system’ section) (4).
Peripheral cannabinoid action
Cannabinoids also act in the periphery. The endocannabinoids
AEA and PEA have been found in the skin in concentrations
five- to 10-fold higher than in brain or plasma in the rat (50).
Evidence supports the presence of CB1 receptors on central
and peripheral terminals of primary afferent neurons (2).
A number of studies have demonstrated a peripheral antinociceptive action for cannabinoid agonists in preclinical
models (50-53); both CB1 (51,53) and CB2 receptor agonists
(52) exhibit peripheral antinociceptive action.
Peripheral application of cannabinoids has also been demonstrated to reduce hyperalgesia and inflammation in preclinical
models of neuropathic and inflammatory pain (51). Furthermore,
it has been demonstrated that topical application of cannabinoid agonist (WIN55,212-2) enhances the antinociceptive
effect of topical morphine via a CB1-mediated effect; in addition, spinally ineffective doses of WIN55,212-2 potentiate the
antinociceptive effects of topical morphine (54).
ENDOGENOUS PAIN MODULATION
There is growing support that endocannabinoids participate in
endogenous pain modulation. Supraspinally, in the PAG, it has
been demonstrated that administration of cannabinoid antagonists produces hyperalgesia and blocks the analgesia produced
by electrical stimulation of the dorsal PAG (47,55).
Furthermore, using microdialysis in the PAG along with liquid
chromatography/mass spectrometry, it was established that the
analgesia produced by electrical stimulation or by injection of
the chemical irritant formalin into the hind paws of anesthetized rats was associated with the release of AEA in the
PAG (56), supporting that either pain itself or electrical stimulation leads to the release of AEA, which then acts on
cannabinoid receptors in the PAG to inhibit nociception.
Spinally, it has been demonstrated that hypoactivity of the
spinal cannabinoid system has been associated with N-methylD-aspartate-dependent hyperalgesia (49).
There is also support for peripheral control of pain initiation by endocannabinoids. Gas chromatography/mass spectrometry measurements indicate that the levels of AEA and
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PEA in the skin are enough to cause tonic activation of local
cannabinoid receptors. Furthermore, the CB1 antagonist
SR141716A and the CB2 antagonist SR144528 prolong and
enhance pain behaviour produced following formalin injection. This work supports participation of endocannabinoids in
the intrinsic control of pain initiation at peripheral sites (50).
CANNABINOIDS AND INTERACTIONS
WITH OTHER SYSTEMS
Monoaminergic/noradrenergic systems
There is evidence suggesting the involvement of monoaminergic
systems in cannabinoid-induced antinociception. The serotoninergic neurotoxin 5,7-dihydroxytryptamine and the dopaminergic
neurotoxin 6-hydroxydopamine both reduce the antinociceptive
effect of cannabinoids in animal models. In these studies, noradrenergic involvement could not be ruled out due to the lack of
pretreatment with a noradrenergic uptake inhibitor.
Intrathecal administration of yohimbine (an alpha-2adrenergic antagonist) blocked antinociceptive effects of ∆-9THC. In contrast, intrathecal injection of the nonspecific
serotonin antagonist, methysergide, did not reduce ∆-9THC-induced antinociception, nor did serotonin depletion
by p-chlorophenlyalanine, suggesting a lack of serotonin
involvement in cannabinoid antinociception. Similarly, the
alpha1-antagonist phenoxybenzamine failed to block cannabinoid antinociception. Taken together, these data support a role
for the spinal noradrenergic system in cannabinoid-induced
antinociception (3).
Opioid system
Studies have determined that the analgesic effect of THC is, at
least in part, mediated through delta and kappa opioid receptors.
THC administered intrathecally has been shown to release
endogenous opioids that stimulate delta and kappa receptors
(57). Delta antagonists do not interfere with cannabinoid
antinociception. Dynorphin antisera and the selective kappa
antagonist nor-binaltorphimine block THC-induced antinociception; this antagonism is specific to antinociception and
occurs at the spinal level. Furthermore, dynorphin A (1-8) antiserum and antisense to the kappa-1 receptor antagonized the
effect (2,3). In addition, a bidirectional cross tolerance of ∆-9THC and CP55,940 to kappa agonists has been demonstrated in
the tail-flick test (58). Thus, the preponderance of data supports
a role for kappa and delta opioid receptors in the mediation of a
component of cannabinoid antinociception (57).
There is also some evidence supporting a possible role for
mu opioid receptors in the enhancement of morphine antinociception by THC. Both naloxone and SR141716A (CB1-specific
antagonist) block the enhanced antinociception due to the
combination of low-dose THC and morphine, supporting both
CB1 and mu opioid roles in the synergy (57). Thus, the current
literature supports the possible involvement of all three major
opioid receptor subtypes involved in some part in the enhancement of opioids by THC (57).
It has been demonstrated that cannabinoids can act synergistically with the opioid receptor agonists in the production of
antinociception in animal models of acute pain (2,4). This
synergy has been demonstrated in numerous studies, using several routes of administration (4), and the synergy works both
ways, with cannabinoids enhancing opioid antinociception
and morphine enhancing cannabinoid antinociception. Full
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isobolographic analysis has substantiated the greater than additive effect necessary to identify synergy (57).
Following chronic dosing, upregulation of opioid receptor
protein in the spinal cord has been observed in combinationtreated animals and may play a role in retention of efficacy of
the drug combination. Short-term administration of low-dose
THC with morphine in mice attenuated opioid tolerance without the loss of the antinociceptive effect. Further prolonged
exposure to a cannabinoid agonist failed to result in downregulation of delta opioid receptors in vitro. Taken together, these
results support that cannabinoids can alter opioid tolerance
(57). Thus, data support a synergistic effect of cannabinoids and
opioids and a possible role for cannabinoids in situations of opioid tolerance.
CANNABINOIDS AND PAIN
Cannabinoids exhibit antinociceptive and antihyperalgesic
effects in models of acute and chronic pain
Preclinical work reveals that cannabinoids block pain responses
in virtually every pain model tested. One of the earliest studies
was performed by Dixon (59), who demonstrated that
cannabis was able to suppress canine reactions to pinpricks. In
models of acute or physiological pain, cannabinoids are effective against thermal, mechanical and chemical pain and are
comparable with opioids in potency and efficacy (5).
In models of chronic pain, cannabinoids exhibit greater
potency and efficacy in both inflammatory (60) and neuropathic pain (61). Because cannabinoids are also able to affect
motor systems, it is important to establish that the slowed reactions of animals in pain tests are not because of slowed motor
activity rather than pain inhibition. In electrophysiological
studies, it has been concluded that cannabinoids produce
profound suppression of cellular nociceptive responses with no
suppression of the low threshold mechanoreceptive neurons
(5). These experiments include suppression of neurophysiological responses to all types of nociceptive stimuli tested, suppression of windup (a model of central sensitization observed
in chronic pain) and suppression of increased spontaneous firing following injection of the inflammatory agent complete
Freund’s adjuvant (2,5,17,18,62-65). Thus, there is significant
evidence that cannabinoids exhibit antinociceptive and antihyperalgesic effects in models of acute and chronic pain.
Of further importance to chronic pain is the fact that upregulation of CB1 receptors (within the ipsilateral superficial dorsal
horn of the spinal cord in rats following chronic constriction
injury of the sciatic nerve) has been demonstrated. This
enhanced the effects of a cannabinoid agonist (WIN55,212-2)
on both thermal hyperalgesia and mechanical allodynia, supporting that upregulation of spinal cannabinoid receptors following peripheral nerve injury may contribute to the effects of
exogenous cannabinoids in neuropathic pain (66). Furthermore,
repeated administration of WIN55,212-2 given subcutaneously
reversed the development of hyperalgesia that normally develops in chronic constriction of the sciatic nerve in rats (67), supporting that cannabinoids may play a role in prevention of
neuropathic pain if given early after nerve injury.
Nonpsychoactive cannabinoids targeting pain
There is significant interest in the development of synthetic
cannabinoids without psychotropic activity (68-70). Ajulemic
acid (also called CT-3) is a synthetic analogue of ∆8-THC-11-oicacid, one of the endogenous transformation products of THC.
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Figure 5) Cannabinoid influences on peripheral nerve activity with tissue injury and inflammation. 5-HT 5-hydroxytryptamine; CB1
Cannabinoid receptors found primarily in nervous system; CB2
Cannabinoid receptors found primarily in peripheral tissues/immune
system; CGRP Calcitonin gene-related peptide; NGF Nerve growth
factor; NO Nitric oxide; trk A High affinity NGF receptor. Figure
adapted from reference 71
In preclinical studies, ajulemic acid has been found to exhibit
potent analgesic, antiallodynic and anti-inflammatory activity;
however, it binds to CB1 receptors and has been found to cause
sedation in mice (70). Cannabidiol (CBD) is a nonpsychoactive cannabinoid present in cannabis that does not bind to
cannabinoid receptors; it has also been demonstrated that
CBD inhibits FAAH and blocks the reuptake of AEA, thus
enhancing extracellular levels of AEA (71). Investigators have
developed synthetic analogues to CBD in a search for a nonpsychoactive, nonsedating agent. HU-320 (CBD-dimethyl-heptyl-7oic acid) is a novel synthetic cannabinoid acid that has been
demonstrated to exhibit strong anti-inflammatory and immunosuppressive properties while demonstrating no psychoactive
effects (70).
Anti-inflammatory and peripheral antihyperalgesic effects
of cannabinoids
Following tissue injury or inflammation with disruption in
normal tissue integrity and migration of various cells (eg,
immune and mast cells, platelets), a diversity of chemical
mediators are produced or released locally. These mediators
then activate peripheral sensory nerve endings. Some will
activate the sensory nerve directly; others will sensitize the
nerve to other stimuli or exert regulatory effects on the sensory neuron, inflammatory cells and adjacent sympathetic
nerves (Figure 5) (72).
There is evidence that CB1 and CB2 receptors are present
peripherally, and the mechanisms for synthesizing, releasing
and inactivating endocannabinoids are present during inflammation (7).
CB1 agonists exhibit a direct effect on the sensory nerve
terminal itself to inhibit release of calcitonin gene-related peptide (51) and inhibit sensitizing effects of nerve growth factor
12A
(NGF) (7). Peripheral administration of AEA attenuates
hyperalgesia and edema via a CB1 receptor mechanism and
inhibits capsaicin-evoked plasma extravasation into the hindpaw (51).
Local analgesic actions of directly and indirectly acting
agonists for CB2 receptors, expressed on mast cells and
inhibiting mast cell function, have also been demonstrated
(50,52). CB2 receptor mechanisms may play a particularly
prominent role in inflammatory pain (7). Both CB2 and
high-affinity NGF receptors (trkA) have been identified on
mast cells, and mast cells amplify the NGF signal during
inflammation (7). There is increasing evidence that PEA (a
CB2 agonist) attenuates this amplification. PEA accumulates
in inflamed tissue, is synthesized by leukocytes, prevents mast
cell degranulation and suppresses inflammatory hyperalgesia
and edema (7). Furthermore, it has been demonstrated that
neutrophil migration is diminished by endocannabinoids in
models of inflammatory pain. In addition, cannabinoids attenuate nitric oxide production from stimulated macrophages via
a CB2 receptor-mediated action (7), and have also been
demonstrated to have profound and complex effects on
cytokine production (73).
A CB2 selective agonist (AM1241, administered intraperitoneally) suppressed development of intradermal capsaicininduced thermal and mechanical hyperalgesia and allodynia;
this was reversed by a CB2 antagonist (SR144528) but not by
a CB1 antagonist (SR141716A). Also, AM1241 suppressed
thermally and mechanically evoked hyperalgesia and allodynia
following local administration to the capsaicin ipsilateral paw
but had no effect on the contralateral (untreated) paw. These
data provide evidence that actions at CB2 receptors are sufficient to normalize nociceptive thresholds and produce
antinociception in persistent pain states (74).
In animal models of inflammmatory pain, local administration of AEA, PEA and synthetic cannabinoids have been
repeatedly demonstrated to attenuate behavioural responses to
proinflammatory substances including subcutaneous formalin,
capsaicin and complete Freund’s adjuvant (7). A recent study
(75) found that nabilone, a cannabinoid agonist available by
prescription in Canada, reduced edema and associated hyperalgesia following carrageenan injection into the paw. It has also
been demonstrated that AEA causes inhibition of interleukin-2
secretion in activated splenocytes via a mechanism involving
both cyclooxygenase-1 and cyclooxygenase-2 (76). Old antiinflammatory analgesic drugs such as indomethacin and flurbiprofen activate CB1 receptors via a decrease in FAAH
degradation and, therefore, an increase in AEA concentration,
suggesting the potential for a cannabinoid mechanism of
action contributing to their effects (77).
Visceral pain conditions
Manipulation of CB1 receptors can alter sensory processing
from the gut; brain integration of the brain-gut axis; extrinsic
control of the gut; and intrinsic control by the enteric nervous
system (78).
The upper gastrointestinal tract is strongly influenced by
CB1 receptor activation on central vagal pathways, whereas
intestinal peristalsis can be modified by CB1 receptor activation in the absence of extrinsic input (78). Endocannabinoids
(AEA and PEA) attenuate viscera-visceral hyperreflexia,
spinal Fos expression and the referred hyperalgesia in a model
of cystitis that shares features of interstitial cystitis; the effects
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of AEA are predominantly CB1 receptor-mediated and the
effects of PEA are predominantly CB2 receptor-mediated (7).
CB1-deficient mice or wild-type mice administered CB1
antagonists exhibit increased inflammation following
intrarectal administration of proinflammatory substances
(eg, 2,4-dinitrobenzene sulphonic acid [DNBS]). Treatment
with a cannabinoid agonist or genetic ablation of FAAH
protected against the development of DNBS-induced colitis.
Electrophysiological recordings from circular smooth muscle
cells 8 h after the administration of DNBS revealed spontaneous action potentials in CB1-deficient mice but not in wildtype littermate colons, indicating early CB1-mediated control
of inflammation-induced irritation of smooth muscle cells.
DNBS treatment increased the percentage of myenteric neurons expressing CB 1 receptors, suggesting enhanced
cannabinoid signalling during colitis. This work supports
evidence that CB1 receptors mediate intrinsic protective signals that counteract proinflammatory responses and indicates the endocannabinoid system is a promising target for
the treatment of gastrointestinal disorders with excessive
inflammatory responses (79).
The future of cannabinoid research
The present review has focused on cannabinoid research relating to pain applications. As presented in the introduction, there
are many other potential applications for cannabinoid agonist
and antagonist molecules under development. Perhaps the most
exciting area of research regarding cannabinoids is the identification of ways to manipulate the endocannabinoid system.
Unlike endogenous opioids, endocannabinoids are synthesized
by what appear to be relatively selective enzymes. Furthermore,
there is also intense focus on the mechanism of reuptake and
inactivation of the endocannabinoids. In the future, it may be
possible to manipulate the endocannabinoid system for the
treatment of pain in much the same way as the monoaminergic
system is targeted for the treatment of depression.
CONCLUSION
The potent antinociceptive and antihyperalgesic effects of
cannabinoid agonists, the presence of cannabinoid receptors in
pain-processing areas of the brain, spinal cord and periphery,
and the endogenous modulation of pain systems by cannabinoids support that cannabinoids exhibit significant potential
as analgesics.
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REVIEW
Pharmacokinetics of cannabinoids
Iain J McGilveray PhD
IJ McGilveray. Pharmacokinetics of cannabinoids. Pain Res
Manage 2005;10(Suppl A):15A-22A.
Delta-9-tetrahydrocannabinol (∆-9-THC) is the main psychoactive
ingredient of cannabis (marijuana). The present review focuses on
the pharmacokinetics of THC, but also includes known information
for cannabinol and cannabidiol, as well as the synthetic marketed
cannabinoids, dronabinol (synthetic THC) and nabilone. The variability of THC in plant material (0.3% to 30%) leads to variability in
tissue THC levels from smoking, which is, in itself, a highly individual
process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately
10 min after inhalation. Oral THC, on the other hand, is only 4% to
12% bioavailable and absorption is highly variable. THC is eliminated
from plasma in a multiphasic manner, with low amounts detectable
for over one week after dosing. A major active 11-hydroxy metabolite
is formed after both inhalation and oral dosing (20% and 100% of
parent, respectively). THC is widely distributed, particularly to fatty
tissues, but less than 1% of an administered dose reaches the brain,
while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes) occurs via
the feces and urine. Metabolites persist in the urine and feces for several weeks. Nabilone is well absorbed and the pharmacokinetics,
although variable, appear to be linear from oral doses of 1 mg to 4 mg
(these doses show a plasma elimination half-life of approximately 2 h).
As with THC, there is a high first-pass effect, and the feces to urine
ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and
psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials
have found that nabilone produces less tachycardia and less euphoria
than THC for a similar antiemetic response.
Key Words: Cannabinoids; Inhalation; Nabilone; Pharmacodynamics;
Pharmacokinetics
CHEMISTRY
Marijuana is the common name for Cannabis, a hemp plant
that grows throughout temperate and tropical climates in
almost any soil condition. The plant yields cannabinoids such
as delta-9-tetrahydrocannabinol (∆-9-THC; referred to as
THC), which is the main psychoactive ingredient of cannabis.
The flowering tops and leaves of this plant are used to produce
cannabis for smoking. Marijuana is most commonly smoked in
hand-rolled cigarettes (‘joints’) containing the plant material.
Recent work (1) has suggested that the restrictive phytochemical
definition of cannabinoids be changed to a broader definition
to include “all ligands of the cannabinoid receptor(s) and
related compounds, including endogenous ligands of the receptors and a large number of synthetic analogues”. The present
review, however, will be restricted to the pharmacokinetics of
Pharmacocinétique des cannabinoïdes
Le delta-9-tétrahydrocannabinol (∆-9-THC) est le principal ingrédient
psychoactif du cannabis (marijuana). Le présent article de synthèse s’attarde
à la pharmacocinétique du THC, mais inclut également des données sur
le cannabinol et le cannabidiol, de même que sur les cannabinoïdes de
synthèse sur le marché, soit le dronabinol (THC synthétique) et le
nabilone. La variabilité des taux de THC dans la substance végétale (0,3 %
à 30 %) donne lieu à des taux tissulaires variables de THC après l’inhalation, qui en soi, est déjà un processus hautement individuel. La biodisponibilité du THC est en moyenne de 30 %. Avec une cigarette dont la teneur
en THC est de 3,55 % un pic plasmatique de 152 ± 86,3 ng/mL s’obtient
environ 10 minutes après l’inhalation. D’autre part, le THC oral n’est
biodisponible que dans une proportion de 4 à 12 % et son absorption est
très variable. Le THC est éliminé du plasma de façon multiphasique, de
faibles quantités étant décelables encore dans les sept jours suivant la
consommation. Un important métabolite 11-hydroxy actif est formé
après l’inhalation ou la prise orale (20 % et 100 % de la molécule-mère,
respectivement). Le THC est très largement distribué, particulièrement
dans les tissus gras, mais moins de 1 % d’une dose administrée atteint le
cerveau, alors que la rate et les graisses corporelles en sont les sites de
réserve à long terme. L’élimination du THC et ses nombreux métabolites
(peu importe la voie d’administration) se fait par les selles et l’urine. Les
métabolites persistent dans l’urine et les selles pendant plusieurs semaines.
Le nabilone est bien absorbé et sa pharmacocinétique, bien que variable,
semble être linéaire avec des doses orales de 1 à 4 mg (qui ont une demi-vie
d’élimination plasmatique d’environ deux heures). Comme avec le THC,
on note un effet de premier passage important et le ratio selles-urine de
l’excrétion est semblable à celui d’autres cannabinoïdes. Par rapport à
ses effets cardiaques et psychotropiques, le modèle pharmacocinétiquepharmacodynamique plasmatique du THC révèle qu’après l’atteinte de
l’état d’équilibre, l’intensité de l’effet est proportionnelle à son profil plasmatique. Les essais cliniques ont montré que le nabilone entraîne moins
de tachycardie et moins d’euphorie que le THC, pour une réponse
antiémétique semblable.
the cannabinoids, including two synthetic compounds that
have been subjected to extensive clinical studies.
Although the leaves and flowering tops of Cannabis plants
yield more than 60 different cannabinoids, the major active
components are THC (Figure 1), cannabinol (CBN) and
cannabidiol (CBD) (Figure 2) (2).
Some reports mention the presence of ∆-8-THC, although
this may be formed by the isomerization (2) of ∆-9-THC during
isolation. ∆-9-THC is the principal psychoactive ingredient of
cannabis, and the other components, such as CBN, CBD and
∆-8-THC, are present in smaller quantities and are not
believed to make a significant contribution to the total effect
of marijuana on behaviour or perception; however, CBD may
have other pharmacological effects (3). THC is enantiomeric,
with only the (–) enantiomers occuring in nature and the
McGilveray Pharmacon Inc, and University of Ottawa, Ottawa, Ontario
Correspondence and reprints: Dr McGilveray, 1 Stonehedge Park, Nepean, Ontario K2H 8Z1. Telephone 613-829-8551, fax 613-829-5175,
e-mail mcgilver@magma.ca
Pain Res Manage Vol 10 Suppl A Autumn 2005
©2005 Pulsus Group Inc. All rights reserved
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Figure 1) The structure of delta-9-tetrahydrocannabinol (∆-9-THC)
using the common dibenzopyran numbering system. The ∆-9-THC
analogue ∆-8-THC is also shown
Figure 3) The structure of nabilone
ABSORPTION
Figure 2) The structure of cannabinol and cannabidiol
synthetic (+) enantiomers being inactive. ∆-9-THC is sparingly
soluble in water but has high lipid solubility (4). An oral form
of synthetic ∆-9-THC ([–] enantiomer), dronabinol (2.5 mg, 5 mg
or 10 mg capsules; dissolved in sesame oil), is marketed in the
United States and Canada as Marinol (Solvay Pharma,
Canada) (5).
Structure-activity relationships, comprising the effects of
alteration in the cannabinoid molecule, were studied extensively in the 1960s and 1970s. This led to one synthetic drug,
nabilone (6), being marketed as Cesamet capsules (Valeant
Canada limitée/Limited) (7) (Figure 3). Nabilone is a sparingly water-soluble, racemic (±) mixture that is crystalline,
unlike the resinous cannabinoid oils from the Cannabis plant.
Since the endogenous cannabinoid receptors were identified,
there has been a resurgence in the study of the structure-activity
relationship (8,9) of cannabinoids; however, while this research is
promising, new receptor agonists are not yet in clinical use (10).
Cannabis also contains variable amounts of the carboxylic
acid analogues of ∆-9-THC (tetrahydrocannabinolic acid
[THCA]), in which the carboxyl groups can be positioned on
carbon 2 or 4 of the molecule (according to the numbering in
the structure shown in Figure 1). These substances are not pharmacologically active, although they may be released by gastric
acid (1) and readily degrade on heating (eg, smoking) to yield
THC (11,12). The decarboxylation is said to occur within 5 min
at a temperature of 200°C to 210°C and within seconds in
smoked marijuana cigarettes. This is important because
according to Agurell et al (13), the total amount of THC and its
corresponding acids is almost always considered in potency content. This is crucial information relating to activity because the
ratio of inactive ∆-9-THCA to active ∆-9-THC is reported to
range from 2:1 in areas where cannabis is grown in warmer climates to 17:1 in plants grown in cooler climates (14).
PHARMACOKINETICS
The present section will be restricted to human pharmacokinetics, mainly of smoked cannabis and with some comparisons of oral THC, including dronabinol (Marinol).
16A
Smoked cannabis
The estimation of the dose administered by the smoking route
is a major variable in assessing the absorption of cannabinoids
(mainly THC) in humans. The source of the plant material and
the composition of the cigarette, together with the efficiency of
smoking by the subject, are additional uncontrolled factors. It is
reasonable to consider approximately 10% to 13% as the average
THC content in Canadian marijuana (Health Canada information) (15).
Regarding smoking techniques, one research group (16)
remarked, “it is incredible to see the variety of techniques marijuana users employ to smoke their cigarette”. It appears that
habitual heavy marijuana smokers can increase the amount
absorbed and this is attributed to more efficient smoking techniques (12,13).
Table 1 indicates some of the variation found by various
researchers (12,16-20) who investigated the amount of THC
lost during smoking, with 69% regarded as the maximum
available for absorption via mainstream smoke from a smoking
machine (16). However, as much as 50% of the active drug in
cigarettes can be lost due to pyrolysis. In one experiment, in
which cigarettes containing approximately 19 mg of THC
were smoked, it was reported that an average of 82% of the
THC in the marijuana cigarette did not appear in the systemic circulation; an average of 6 mg (31%) was retained in
the cigarette butts, with other losses due to pyrolysis and sidestream smoke during smoking (16,20). However, when the
butt was smoked, it was estimated that 50% of the total THC
dose was delivered. In experiments using a smoking machine,
16% to 19% of the THC was found in mainstream smoke, but
when the cigarette was smoked in a single puff, avoiding sidestream smoke, 69% of the THC was in mainstream smoke
(21); thus, approximately 30% of THC appears to be
destroyed by pyrolysis (16). The United States National
Institute of Drug Abuse (NIDA) group (16,20) reports that
20% to 37% of the THC is delivered in mainstream smoke,
with pyrolytic destruction of 23% to 30% and sidestream losses of 40% to 50%. Less is known about the fate of smoked
CBD and CBN, but it appears that the results are similar to
THC, except that CBN plasma levels appear to be approximately twice as variable as other cannabinoids (13).
In a very recent abstract (22), it was reported that from
plant material containing up to 18% of THC and its corresponding acid (THCA), approximately 50% was pyrolyzed
and, of the recovered amount, 50% of the THCA was converted to THC. It also appeared that some of the acid (or
THC) pyrolyzed was converted to CBD, CBN and smaller
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Pharmacokinetics of cannabinoids
TABLE 1
Estimates of the percentage of delta-9-tetrahydrocannabinol
flow during smoking
TABLE 2
Relationship between cannabis potency and peak delta-9tetrahydrocannabinol (THC) plasma concentrations
Plasma THC
(ng/mL) ± SD
THC range
(ng/mL)
6
90.4±20.2
45.6–187.8
6
100.0±10.1
62.8–125.3
1.97
6
119.8±10.6
44.5–180.9
2.40
18
63.0±8.6
2.54
6
162.6±18.7
107.4–204.7
Leander (12),
4.84
12
124.2±16.2
44.8–218.0
Ohlsson et al (19)
*Data adapted from reference 20
Delta-9-tetrahydrocannabinol flow (%)
Reference
Undifferentiated
stream
Sidestream Pyrolyzed Mainstream Butt
Fehr and
50–60
40–50
Kalant (17),
Truitt (18)
Agurell and
Huestis (16)
Perez-Reyes (20)
20
6–53
31–50
16–69* 10–21
40–50
23–30
20–37
*‘High’ from single-puff smoking machine (20)
amounts of cannabichromene. Unexpectedly, for every sample
analyzed, 50% of the THC was recovered compared with the
original THCA content.
THC absorption by inhalation (with a bioavailability of
18% to 50% from cigarettes [16]) is extremely rapid, and is
the main reason why this is the route of dosing preferred by
many people (23). From experiments with deuteriumlabelled THC given intravenously (5 mg) or smoked in cigarettes (10 mg), heavy smokers (n=14) were found to obtain
higher overall bioavailability (23% to 27%) of THC (24)
than light (n=13) marijuana smokers (10% to 14%) (25). In
the two experiments, there was high intersubject variability
(coefficient of variation 40% to 70%) with overlap between
groups. A mean bioavailability of 20%, with a range of 10%
to 30%, for THC is given by Iversen (23).
Standardized cigarettes have been developed by NIDA, and
the relationships among cannabis (THC) content, dose
administered and resultant plasma levels have been investigated.
The inhalation from smoking cannabis, containing 1.64%
THC (mean dose 13.0 mg THC), resulted in a mean peak
THC plasma level of 77 ng/mL (19). In another experiment,
controlled puffing of a 3.55% THC cigarette provided a maximum plasma level of 268.4 ng/mL (20). A comparison
between cannabis ‘joint’ potency and resulting plasma THC
concentrations from carefully controlled smoking experiments
is shown in Table 2.
Even in these controlled experiments, there is clearly great
variation in the amount absorbed among individuals and a poor
relationship between the amount of THC in cigarettes (1% to
4.8%) and peak plasma THC concentrations. It is possibe that
individuals control their own levels by limiting inhalation
according to effect. It is noted that the total THC level of Health
Canada medical marijuana is approximately 10%, although that
estimate likely includes THCA. There does not appear to be any
new pharmacokinetic information on this dose level.
Arguably, the most reliable information on absorption of
marijuana is from work by Huestis et al (26), where a strict
smoking protocol and an extremely rapid blood sampling technique were applied to six volunteers with cigarettes at two
THC dose levels (1.75% and 3.55%). Concentrations of THC
were detected in 2 min, just after the first puff, and peak concentrations occurred at 9 min, just before the last puff (which
began at 9.8 min). Average peak plasma concentrations of
79±25.2 ng/mL and 152±86.3 ng/mL were obtained for the
Pain Res Manage Vol 10 Suppl A Autumn 2005
THC content
in cannabis (%)
n
1.00
1.32
11.7–137.0
cigarettes containing 1.75% and 3.55% THC, respectively.
Despite a rigorous smoking protocol, the variation displayed
from the higher dose ranged from approximately 80 ng/mL to
260 ng/mL. Although the reported average maximum concentration occurred at 9 min, just before the final puff, the investigators noted that the time to peak concentration was
influenced by the number of puffs, time between puffs, and the
volume and length of inhalations; this was clear from other
detailed studies (27,28). However, the effectiveness of breathholding with 3.55% THC potency cigarettes appears to be limited. After puffing the cigarette, a 20 s hold did not increase
plasma concentrations significantly over a 10 s hold (27).
There is little information for THC and other cannabinoids
comparing pharmacokinetics in men and women. In a study with
tritiated THC administered intravenously and orally to six
young men and women, no differences in pharmacokinetics,
including disposition and metabolism were noted (28). In
another small study (29), three men and three women who were
experienced marijuana smokers smoked two 1% THC cigarettes,
with a 2 h interval between doses. They were asked to smoke at
their usual rate. There was a difference between men and women
in smoking rate, with men smoking more rapidly with more puffs
(28 puffs versus 11 puffs for the women). There was a tendency
for peak concentrations to be lower for the women, but there was
no significant difference in the area under the concentrationtime curve (AUC) (28,29). THC plasma levels decreased rapidly
after cessation of smoking and, at 2 h after smoking, were below
5 ng/mL; 15 min after reaching the maximum, mean concentrations declined by approximately 50% (26,30).
Using modern sensitive analytical techniques, THC can be
detected in the plasma for at least one day after a single dose,
and for 13 days in chronic users (31). The decline of THC in
plasma is multiphasic and, as Harvey (32) notes, estimates of
the terminal half-life of THC in humans have increased as
analytical methods have become more sensitive. Although
there is still no consensus, it is probably safe to say that the terminal half-life of THC averages at least one week, but could be
considerably longer. The half-life in plasma does not appear to
be different between heavy and light users (33,34).
Oral THC
Information on oral THC was obtained mainly with dronabinol. THC is almost completely absorbed (90% to 95%) after
single oral doses according to the recovery of 14C-labelled
dose (35), although these data include both THC and its
degradation products. From an oral dose of 20 mg THC in a
chocolate cookie, compared with an intravenous infusion of
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5 mg, the systemic availability was only 4% to 12% (19), and is
described as being slowly and unreliably absorbed (13). While
most subjects had peak plasma THC concentrations between
1 h and 2 h, some of the 11 subjects only peaked at 6 h and many
had more than one peak. When tritiated THC was administered
in oil enclosed in capsules (total doses of 15 mg in women and
20 mg in men) 10% to 20% of the administered dose reached
the systemic circulation. The peak THC concentrations
observed ranged from 10 ng/mL to 15 ng/mL, approximately
10% of the levels attained by efficient smoking (28). Only 10%
to 20% of synthetic THC (dronabinol) administered in capsules
with sesame oil enters the systemic circulation, indicating
extensive first-pass metabolism (5). The psychomotor effect or
‘high’ has been observed to occur more quickly by the smoking
than by the oral route (13,19); Iversen (36) remarks this as the
reason “smoking is the preferred route of cannabis for many people”. As with the administration by smoking, the elimination
phase from oral THC in plasma can be described using a twocompartment model with an initial (alpha) half-life of approximately 4 h and a beta half-life of 25 h to 36 h (37). However, as
noted previously, the terminal half-life of THC can be much
longer with considerable individual variability (31,32).
Rectal THC
In a pilot study (38), a suppository containing 11.8 mg of the
THC hemisuccinate ester (equivalent to 9 mg THC) was
administered to three women (two of whom had previously
exhibited low plasma THC levels with a 10 mg dose of the oral
THC dronabinol [Marinol]) and it provided comparatively
high plasma THC concentrations. The AUC for plasma THC
was more than 30-fold higher than after oral dosing. In
another pilot study (39), in two patients with spasticity, multiple 10 mg to 15 mg doses of oral THC (dronabinol [Marinol])
were compared with rectal THC hemisuccinate suppositories
(2.5 mg to 5 mg) over 24 h. After oral doses, peak plasma
levels from 2.1 ng/mL to 16.9 ng/mL THC and 74.5 ng/mL to
244.0 ng/mL metabolite were found and, after rectal doses,
peak plasma levels from 1.1 ng/mL to 4.1 ng/mL THC and
6.1 ng/mL to 42.0 ng/mL metabolite were measured over 8 h.
Corrected for dose, rectal THC was approximately twice as
bioavailable as the oral form, and this is attributed both to
lower absorption and higher first-pass metabolism from the
oral versus rectal route.
DISTRIBUTION
Distribution of THC begins immediately and rapidly after
absorption. The plasma protein binding of THC and its metabolites is approximately 97% (40,41). THC is mainly bound to low
density lipoproteins, with up to 10% present in red blood cells
(42), while the metabolite, 11-hydroxy-THC, is even more
strongly bound, with only 1% found in the free fraction (43).
Because of its lipid solubility, THC has a large apparent
volume of distribution, approximately 10 L/kg (13). Moreover,
animal studies show that it is sequestered to the fat tissues,
including the brain (32); however, considerably less than 1% of
an administered dose reaches the brain (44).The highest concentrations are found in the heart and adipose tissue, with levels
reaching 10- to 1000-fold that of plasma, respectively (18). THC
readily crosses the blood-brain barrier and the slight delay in correlating peak plasma concentration to effects is assumed to reflect
this distribution (19). In animal studies, while immediate distribution is high in the liver, the spleen and body fat are the major
18A
sites of distribution after 72 h and are the long-term THC storage
sites (45).
There has been concern about the possible consequences of
the long persistence of THC in fatty tissues. However, there is
no evidence that the THC residues persist in the brain, and
release from the fatty storage sites into blood is slow enough that
the levels attained are not high enough to cause psychological
effects. However, with regular use, THC will accumulate (32).
METABOLISM
The majority of the metabolism of cannabinoids occurs in the
liver, and different metabolites predominate when different
routes of administration are used. The complex metabolism of
THC involves allylic oxidation, epoxidation, decarboxylation
and conjugation (13). Cannabinoids are good substrates for
cytochrome P450 (CYP) mixed-function oxidases and, in
humans, the major site of hydroxylation is carbon 11, catalyzed
by CYP 2CP (32). This is considered to be the enzyme that may
influence potential drug interactions; however, the Marinol
monograph (37) states, “in studies involving patients with
AIDS and/or cancer, (dronabinol) capsules have been coadministered with a variety of medications (eg, cytotoxic agents, antiinfective agents, sedatives or opioid analgesics) without
resulting in any clinically significant drug to drug interactions.”
The major initial metabolites of THC are 11-hydroxy-THC
and 11-nor-9-carboxy-THC. Over 80 other metabolites of
THC, most of which are polar and acidic, have been identified
and isolated by conducting in vivo experiments in humans or
in vitro studies with human tissue (13). 11-hydroxy-THC is
rapidly formed by the action of hepatic microsomal oxidases,
and plasma levels parallel the duration of observable drug
action. 11-hydroxy-THC has been found to have psychotomimetic properties equal to THC (46-48). After smoking
1.75% and 3.55% THC cigarettes, this metabolite appears rapidly and peaks shortly after THC, approximately 15 min after
the start of smoking (16). 11-hydroxy-THC also exhibits peak
plasma concentrations of approximately 7.5 ng/mL (approximately 5% of parent THC) and the AUC profile of this
metabolite averages 20% of the parent. Similar results were
obtained with intravenous administration (13).
The psychoinactive 11-nor-9-carboxy-THC is the primary
acid metabolite of THC excreted in the urine (49), and it is
the cannabinoid most often monitored in forensic analysis of
body fluids (50). Peak plasma values of this metabolite occur 1.5 h
to 2.5 h after smoking and are approximately one-third the
concentration of parent THC. There are numerous oxidative
products from the side chain and further oxidation of the alcohols yield carboxylic acid products (13). Following oxidation,
the phase II metabolites of the free drug or hydroxy-THC
appear to be glucuronide conjugates (13) that appear in the
urine; however, they are not major or appreciably active.
There is limited information on the metabolism of CBD
and CBN in humans. As with THC, the 11-hydroxy metabolites appear to be the major phase I products (51). For CBD,
hydroxylation was found in all positions of the side chain, with
several minor dihydroxylated metabolites being identified
(52). For CBD, the amount of polar metabolites formed seems
greater than for THC (13). For CBN, as well as the 11-hydroxy
metabolite, dihydroxy-CBN, CBN-7-oic acid and more polar
metabolites are formed after intravenous administration (53).
It is known that polyaromatic hydrocarbons found in tobacco
and cannabis smoke induce the action of CYP 1A2. If it can be
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Pharmacokinetics of cannabinoids
shown that the metabolism of THC also involves this CYP, then
repeated exposure to cannabis could cause the more rapid disappearance of THC via this specific enzyme. However, animal
studies (54) suggest that there may be functional interactions
between THC and nicotine, which might have addiction
implications. Various other CYP enzymes are of interest for
potential drug interactions. In human liver microsome preparations, CBD has been shown to inhibit formation of THC
metabolites catalyzed by CYP 3A, with less effect on CYP 2C9
(32). However, others suggest that CBD decreases formation of
11-hydroxy-THC by inhibition of CYP 2C9 (55), but it does
not appear to present as a clinical interaction (56).
After oral doses of THC, parent THC and its active
metabolite, 11-hydroxy-THC, are present in approximately
equal concentrations in the plasma (54,57). Concentrations
of both parent drug and metabolite peak approximately 2 h to
4 h after oral dosing and decline over several days. Clearance
averages approximately 0.2 L/kg⋅h, but is highly variable due
to the complexity of cannabinoid distribution (37). The
larger amount of 11-hydroxy-THC metabolite from first-pass
metabolism by this route, which is similar in potency to THC,
complicates the interpretation of potential effects. With oral
THC dosing, absorption is slow and variable, and peak concentrations of THC may be only 10% of that from an efficiently smoked administration; however, the plasma levels of
active 11-hydroxy metabolite are approximately threefold
higher than that observed in the plasma from smoking
(28,56).
EXCRETION
Elimination of inhaled THC and its metabolites occurs via the
feces (65%) and urine (20%). After five days, 80% to 90% of
the total dose is excreted (28,34). Metabolites in the urine (of
which there are 20) are mainly acidic, such as 11-nor-9-carboxyTHC. Those in the feces are both acidic and neutral, the
most abundant metabolites being 9-carboxy-THC (29%) and
11-hydroxy-THC (21%) (28,32).
Similarly, following oral doses, THC and its biotransformation products are excreted in both feces and urine (37). Biliary
excretion (complicated with enterohepatic recycling) is the
major route of elimination, with approximately one-half of a
radiolabelled oral dose being recovered from the feces within
72 h, compared with 10% to 15% recovered from urine (58).
Less than 5% of an oral dose is recovered unchanged in the
feces (37). Following administration of a single oral dose, low
levels of THC metabolites have been detected for more than
five weeks in the urine and feces (37,59).
In forensic or employment situations when such testing
may be applied, it is important for patients (or recreational
users) to be aware that traces of marijuana can be detected in
urine even weeks after dosing (50).
NABILONE
As previously stated, dronabinol is identical to THC from the
marijuana plant. However, nabilone was developed from
structure-action evaluation by industry (7) and has been marketed in Europe and Canada for over 20 years for the management of severe nausea and vomiting associated with cancer
chemotherapy (8). It has also been studied for the treatment of
chronic pain of various etiologies, with some patients experiencing useful benefits; however, there remains a need for more
clinical trials on this aspect (60).
Pain Res Manage Vol 10 Suppl A Autumn 2005
Absorption
In radiotracer studies with 14C-nabilone administered intravenously and orally, 95.8% was absorbed (61) from oral administration (the disappearance from plasma was rapid due to
extensive distribution and rapid metabolism). Additionally, for
both the intravenous and the oral routes, the total radioactivity exhibited half-lives of 20.6 h and 35 h, respectively, and the
parent nabilone had a plasma elimination half-life of approximately 2 h (62). As with THC, there is a high first-pass effect,
but it is well absorbed and the pharmacokinetics appear to be
linear (but variable) from oral doses of 1 mg to 4 mg (62).
Distribution
Information on the protein binding of nabilone is lacking.
However, after intravenous tracer administration, the disappearance of total radioactivity, parent nabilone and the alcohol
metabolite was biphasic, with the first phase (half-life approximately 10 min) attributed to distribution into tissue and the
slower phase to elimination (61,63).
Metabolism
The metabolism of nabilone has not yet been fully elucidated.
The major metabolites of nabilone in plasma are a mixture of
isomeric alcohols yielded from the reduction of the ketone group
on carbon 9 (61,62). These metabolites are excreted in feces,
but not urine. The metabolites in urine are uncharacterized, and
are highly polar and acidic, although there is no evidence of sulfate or glucuronide conjugates (62). It is speculated that, like
THC, there is hydroxylation of various sites on the dimethylheptyl side chain (61) and one nabilone diol has been recovered
from feces with one alcohol on the carbon 9 and the other on
the side chain (64). There is virtually no information on drug
interactions for this agent.
Excretion
From both oral and intravenous tracer doses, over 90% of the dose
was recovered over seven days, with approximately 67% in feces
and 23% in urine (61,62). These values are similar to the feces to
urine ratio of excretion found with other cannabinoids (62).
PHARMACOKINETIC-PHARMACODYNAMIC
RELATIONSHIPS
Most studies (65) of plasma concentration and effect relationships for marijuana have been directed at the psychotropic effect
(‘high’) and the temporal relationship between this effect and
plasma levels, as well as at intoxication; impairment of cognitive
or motor function is not yet clear but is of major forensic interest
(66). The acute effect on heart rate has also been used for such
modelling (30). Dose and plasma concentration versus response
for possible therapeutic applications are ill-defined, except for
some information obtained for oral dosing with dronabinol for its
limited indications (19). Such correlations of THC pharmacokinetics are complicated by the emergence of active metabolites,
particularly 11-hydroxy-THC (47,49), which attains higher
plasma concentrations after oral than inhalation doses.
In one study (30), six volunteers smoked 1% by weight cigarettes with an average weight of 894 mg (total THC dose 8.9 mg),
and then smoked a second cigarette after 2 h. Plasma THC concentrations, heart rate and self-reported ‘high’ profiles were
documented. Similar psychological ‘highs’ occurred after both
cigarettes, but less heart rate acceleration was found for the second
cigarette. The heart rate for the first cigarette peaked at an
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average of 11 min after the start of smoking and was maintained
until approximately 30 min after smoking. Thus, the effect was
observed to begin at approximately 5 min after peak plasma concentration (mean 45 ng/mL) was reached – it exhibited a lag
time – and it returned to baseline at approximately 30 min,
when the plasma concentration was approximately 7 ng/mL.
Although the heart rate increase was much smaller with the
second cigarette, the lag time was similar. For the psychotropic
effect, there was a different pattern with a gradual emergence of
effect at 10 min (concentration of 30 ng/mL, post-peak), peaking at 30 min after smoking (concentration of approximately
7 ng/mL) and diminishing rapidly 45 min after smoking (concentration of 4.5 ng/mL). The second dose showed very similar
pharmacokinetic and response profiles to the first cigarette. The
data were fitted with a lag time model because the effect
emerged approximately 20 min after the peak plasma concentration. In another experiment (67), the relationship between
THC plasma concentrations and self-reported ‘highs’ with single
cigarettes of three different potencies were examined. The cigarettes were 1.3%, 2.0% and 2.5% in THC potency. Because
NIDA cigarettes average 900 mg, the total dose available ranged
from 11.7 mg to 22.5 mg. The results indicated a proportional
dose response, with the intensity and duration greatest for the
2.5% cigarette. As with the experiment above, there was a lag
time from the peak plasma concentration until the ‘high’ and, for
the highest dose, the feeling commenced at 5 min after smoking,
when the plasma concentration was approximately 140 ng/mL.
However, with the lowest dose, a similar intensity was noted at
5 min at a concentration of 90 ng/mL (which appears near the
peak concentration for this dose). For the low dose, the intensity
of the ‘high’ reached 50% of its maximum at 30 min and then
gradually declined over 2 h, whereas, for the high dose, the ‘high’
almost plateaued at 20 min for 60 min to 75 min at 70% intensity, before declining. Modelling this data suggests that the steadystate plasma concentration at 50% of the maximum high-effect
(Css[50]) would be 25 ng/mL to 29 ng/mL (67).
Other reports (16,66) showed similar results using a 3.55%
THC cigarette (which can yield an available dose of 32 mg of
THC). In this case, the effect was perceptible within 2 min to
3 min and exhibited a plateau that commenced at 9 min and
continued for 1.5 h before diminishing over 3 h to 4 h. A simultaneous average plasma concentration profile showed that
at 1.5 h, the THC level is approximately 10 ng/mL and the
11-hydroxy-THC level is somewhat less. It was noted that the
lack of correspondence between the plasma profile and the subjective ‘high’ response can be fitted with a more complex pharmacodynamic mode. This includes an ‘effect compartment’,
which, after a lag time, reaches equilibrium with an effect curve.
After equilibrium is reached, the intensity of the effect is proportional to the plasma THC profile. This concentration-effect
response demonstrates a counterclockwise hysteresis.
This type of modelling (66) supports a 10 ng/mL cutoff as
evidence of functional impairment, which agrees with the above
Css(50) estimate (67). In addition, the model was used to simulate
multiple dosing with a 1% cigarette containing 9 mg THC (68).
The duration of the maximal ‘high’ for this dose was estimated at
approximately 45 min after dosing and declined to 50% of this
peak effect at approximately 100 min after smoking. At this dose,
a dosing interval of 1 h gave a ‘continuous high’ and the recovery
after the last dose occurred at 150 min. The peak plasma concentration during this dosage was estimated at approximately
70 ng/mL and the Css(50) at approximately 30 ng/mL THC.
20A
The data relating concentration and response were limited
to the cardiac and subjective ‘high’ responses, and these show
dissimilarities in profile. The information obtained from oral
dosing with dronabinol was complicated because there is a
greater amount of psychoactive 11-hydroxy-THC metabolite
formed by this route of administration (49). Thus, the target
THC plasma concentrations derived actually depend on the
subjective ‘high’ response that may or may not be related to
the potential therapeutic applications. However, it is likely
that the psychoactivity that elicits this response from the central nervous system is receptor-derived and the concentrations
are useful for suggesting doses from smoking.
There are no formal pharmacokinetic-pharmacodynamic
correlations with nabilone; however, there have only been a
limited number of dose-response studies performed using doses
between 1 mg and 5 mg (69). The responses examined were
heart rate, blood pressure and subjective signs and symptoms,
particularly euphoria. There was a decrease in pulse rate with the
1 mg dose and a slight increase of 7 beats/min to 8 beats/min
with the 2.5 mg and 5 mg doses. There was no change in blood
pressure when the subjects were recumbent but, with the 5 mg
dose, blood pressure dropped significantly on standing and this
was associated with dizziness (68). Subjective signs and symptoms, including euphoria and relaxation, were also more
marked after the 5 mg dose. In experiments examining tolerance
to these effects, a 2 mg dose was administered twice daily for
seven days, and subjects were challenged with a 5 mg dose on
the eighth day and again after a week of washout. After six
days on the 2 mg dose, postural hypotension and euphoria were
absent and did not recur with an immediate higher dose.
However, after the washout, there was a change in blood pressure and subjective responses, although this was not as marked
as in naïve subjects. It is important to note that tolerance did
not develop to the relaxant and antiemetic effects of nabilone,
as has been confirmed by clinical trials (6,7,61). These trials
have also found that compared with THC, nabilone produces
less tachycardia and less euphoria for a similar antiemetic
response (70).
CONCLUSIONS
The chemistry of cannabinoids is complex (for a more detailed
description, see Grotenhermen [1], Mechoulam et al [2] and
Mechoulam [70]) and the information on pharmacokinetics is
limited, except for the THC component. Absorption from
smoked cannabis is rapid and highly variable, with fast effects on
heart rate and a quick attainment of the marijuana ‘high’; these
effects may be somewhat controlled by the smoker’s uptake.
Absorption from oral dosing is also variable; however, it is much
slower and the production of active THC metabolites (first-pass
metabolism) leads to some prolonged activity. The synthetic
derivative nabilone is rapidly well absorbed from the oral route
and also appears to have active metabolites, being more than 90%
eliminated in seven days. Less is known about the pharmacokinetics of other cannabis components, and the absorption and
fate by other routes, such as rectal or dermal. There is very recent
information on dermal uptake of ∆-8-THC (71) indicating that a
constant plasma concentration can be maintained for 48 h. While
there have been concerns about possible drug interactions of marijuana or THC (particularly with other central nervous system
drugs), and concerns in the treatment of frail patients on many
other treatments (eg, AIDS), there is no substantive literature to
indicate that these are clinically significant (72).
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REVIEW
Toxic effects of cannabis and cannabinoids: Animal data
Pierre Beaulieu MD PhD FRCA
P Beaulieu. Toxic effects of cannabis and cannabinoids:
Animal data. Pain Res Manage 2005;10(Suppl A):23A-26A.
Effets toxiques du cannabis et des cannabinoïdes : données d’études sur animal
The present article reviews the main toxic effects of cannabis and
cannabinoids in animals. Toxic effects can be separated into acute
and chronic classifications. Acute toxicity studies show that it is virtually impossible to die from acute administration of marijuana or
tetrahydrocannabinol, the main psychoactive component of
cannabis. Chronic toxicity involves lesions of airway and lung tissues,
as well as problems of neurotoxicity, tolerance and dependence, and
dysregulations in the immune and hormonal systems. Animal toxicity
data, however, are difficult to extrapolate to humans.
Le présent article passe en revue les principaux effets toxiques du cannabis
et des cannabinoïdes chez les animaux. On peut classer les effets toxiques
en deux catégories : aigus et chroniques. Selon les études de toxicité
aiguë, il est presque impossible de mourir d’une surdose de marijuana ou
de tétrahydrocannabinol, principal composant psychoactif du cannabis.
La toxicité chronique, de son côté, est associée à des lésions des voies
aériennes et des poumons, ainsi qu’à la neurotoxicité, tolérance et dépendance, et à la dysrégulation des systèmes immunitaire et hormonal. Il est
cependant difficile d’appliquer aux humains les données sur la toxicité
animale.
Key Words: Animal; Cannabinoids; Cannabis; Toxicity
ince its use in ancient times for therapeutic purposes,
cannabis has been known to produce deleterious effects.
The adverse effects of cannabis in humans are reviewed in the
present supplement to Pain Research & Management (1). Acute
effects of cannabis and cannabinoids are well established, while
some uncertainties exist with regard to its long-term effects (2).
However, as is often the case with cannabis, results of various
studies can be interpreted differently depending on the author;
for example, some authors may concentrate on the existence of
toxic effects, while others may insist that these effects are minor
(2). Overall, the most appropriate opinion on the use of medical marijuana may come from the United States Institute of
Medicine when they stated that “except for the harms associated
with smoking, the adverse effects of marijuana use are within
the range of effects tolerated with other medications” (3).
It has been suggested that there are 426 chemical entities in
the marijuana plant, of which more than 60 are cannabinoids
(4). Therefore, it is not surprising that some of these substances can exert adverse effects. Hundreds of studies, starting
in the 1970s, have been published on the toxicity of cannabinoids in animals, and it is well beyond the scope of the present
article to review them all. We will only concentrate on key
animal data regarding the acute and chronic toxic effects of
cannabis and cannabinoids. One must keep in mind that most
of the animal studies performed have used delta-9-tetrahydrocannabinol (THC) injections of 10 mg/kg to 20 mg/kg, whereas,
for an average adult of 70 kg smoking a cigarette containing
15 mg of THC, this corresponds to an administration of 40 µg/kg
of THC (5).
S
ACUTE TOXICITY
In animals, the administration of high doses of THC, other
cannabinoids or endogenous cannabinoids (endocannabinoids)
such as anandamide, produces a typical response characterized
by hypothermia, hypolocomotion, catalepsia and antinociception. From studies in knockout animals, it has been shown
that the cannabinoid receptor CB1 is responsible for these
effects (6).
The overall acute toxicity of THC is low. The mean lethal
dose (that which kills 50% of animals) of oral THC in rats is
800 mg/kg to 1900 mg/kg depending on sex and strain (7).
Animal studies have shown a very large separation (by a factor
of more than 10,000) between pharmacologically effective and
lethal doses (8). Furthermore, no cases of death were reported
following maximum THC oral doses of up to 3 g/kg and 9 g/kg
in dogs and monkeys, respectively (8). However, monkeys
treated acutely with 128 mg/kg or more intravenously, died
from respiratory arrest and cardiac failure, whereas all monkeys
survived with doses of 92 mg/kg or less (9).
Phillips et al (10) investigated the acute toxicity of pure
THC in rats and mice (Table 1). Both rats and mice became
ataxic 1 min to 2 min after having received an intravenous
injection of THC. If stimulated, they became hyperactive for
1 s to 2 s. The righting reflex was lost and dyspnea progressed
to death by respiratory depression. Postmortem examination
revealed that all organs (except the lungs, which were congested and edematous) were unremarkable. Survivors were free of
toxic signs after 24 h to 72 h.
In rodents, low doses of cannabinoids decrease locomotor
activities, while higher doses stimulate movements and even
higher doses lead to catalepsy (11). Similarly, in mice, Adams
and Martin (12) describe a ‘popcorn effect’ in animals treated
with THC (sedation associated with a jump in response to a
stimulus wthat, in turn, triggers another stimulation and the
jump of another mouse, etc). Furthermore, cannabinoids
cause an increase in gait width (13) and show rotarod
Department of Anesthesiology, CHUM – Hôtel-Dieu, Montréal, Québec
Correspondence: Dr Pierre Beaulieu, Department of Anesthesiology, CHUM – Hôtel-Dieu, 3840 rue St-Urbain, Montréal, Québec H2W 1T8.
Telephone 514-890-8000 ext 14570, fax 514-412-7222, e-mail pierre.beaulieu@umontreal.ca
Pain Res Manage Vol 10 Suppl A Autumn 2005
©2005 Pulsus Group Inc. All rights reserved
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TABLE 1
Dose range of delta-9-tetrahydrocannabinol administered by different routes in animals to produce various effects
Spontaneous Decreased
activity rectal temperature Antinociception Catalepsy
Mouse
1.0 mg/kg (iv) 1.4 mg/kg (iv)
1.4 mg/kg (iv)
LD50
1.5 mg/kg (iv)
Drug
Static
discrimination ataxia
42.5 mg/kg (iv)
Operant
suppression
Mortality
–
–
–
–
0.6 mg/kg (ip)
–
–
–
482 mg/kg (orally)
Rat
–
–
–
6.0 mg/kg (ip)
28.6 mg/kg (iv)
800–1900 mg/kg (orally)
Dog
–
–
–
–
–
–
0.2 mg/kg (iv)
Monkey
–
–
–
–
–
–
–
No deaths after doses
up to 3 g/kg (orally)
0.2 mg/kg (iv) No deaths after doses
up to 9 g/kg (orally).
Death after doses of
128 mg/kg or more (iv)
Data from Forney (18), Thompson et al (9), and Phillips et al (10). ip Intraperitoneally; iv Intravenously; LD50 Lethal dose (that which kills 50% of animals)
impairments in mice after direct injection of synthetic cannabinoids into the cerebellum (14).
Low doses of THC or other psychotropic cannabinoids produce a combination of sedative and stimulant effects, whereas
higher doses are mainly sedative (15). Animal studies have
also found that THC and anandamide cause deficits in shortterm memory in spatial learning tasks (16). These effects are
reversed by a cannabinoid CB1 antagonist. In addition,
cannabinoids and endocannabinoids reduce motor activity,
reduce body temperature, decrease reflex responses and muscle
tone, impair the ability to carry out complex behaviour and
decrease overt aggressive behaviour, especially in primates for
the latter.
In isolated heart, THC produces a biphasic effect on heart
rate with an initial increase followed by a decrease. THC also
decreases coronary blood flow and cardiac contractile force
(17). In the whole animal (dogs, cats and rats), THC produces
a decrease in blood pressure associated with bradycardia, but
these effects may vary with other species. Milzoff et al (cited by
Forney [18]) have studied the effects of THC on heart rate, respiratory rate and body temperature in anesthetized rats after
doses of 0.625 mg/kg to 10 mg/kg. They have reported decreases
in all the parameters measured.
Finally, in rodents, THC and, to a lesser degree, other
cannabinoids, such as nabilone and cannabinol, reduce intestinal motility by a CB1 receptor-mediated mechanism (19).
CHRONIC TOXICITY
A great number of chronic and potentially toxic effects of
cannabis on various systems have been described.
Lung toxicity
Animals exposed to varying doses of marijuana smoke for 12 to
30 months show extensive damage to the smaller airways as
well as acute and chronic pneumonia. However, rats exposed
to marijuana smoke for one year failed to demonstrate any
anatomical or functional evidence of emphysema (20).
exposure to THC or marijuana extracts persistently alters
the structure and function of the rat hippocampus, a paleocortical brain region involved with learning and memory
processes (21). It is suggested that both age during exposure
and duration of exposure may be critical determinants of neurotoxicity.
Periods of cannabis or THC exposure shorter than three
months have not yet been demonstrated to produce neurotoxic
effects in rats (21). Studies of monkeys with up to 12 months
of daily exposure have not consistently reported neurotoxicity,
although one must keep in mind that it represents less time of
exposure for these animals compared with rats (lifespan of
approximately 40 years for monkeys compared with two to
three years for rats).
Studies of the effects of cannabinoids on neurons in vitro
have yielded inconsistent results. Indeed, the mixed reports of
neurotoxic and neuroprotective effects of cannabinoids are
confusing (22) (Figure 1).
TOLERANCE AND DEPENDENCE
Phillips et al (10) administered THC to rats intraperitoneally
for 30 days at five dose levels ranging from 0 mg/kg to 30 mg/kg.
Animals displayed signs of increasing ataxia, lacrimation, diarrhea and depression. There was no evidence of developing tolerance, although Carlini (23) has reported that rats can
develop tolerance to the behavioural effects of THC when low
doses are administered over a short period of time.
Tolerance to the biological effects of THC has been demonstrated in cultured cells and animal species. Using the CB1
receptor antagonist SR141716A, a withdrawal syndrome can
be produced in rats, mice and dogs that have been maintained
on THC (24). The syndrome includes scratching, licking,
arched back and ptosis. However, there is no animal model of
cannabis dependence because animals do not typically selfadminister cannabis in the same way as they do with opioids,
cocaine or alcohol (24).
IMMUNE SYSTEM
Neurotoxicity
Although the presumed neurotoxic effects of marijuana enter
into the legalization argument, surprisingly few experimental
studies of marijuana toxicity have been published, at least
until recently. Several laboratories have reported that chronic
24A
Cell and animal experiments have shown that THC exerts
complex effects on humoral and cellular immunity (25).
Cannabinoids and endocannabinoids can be considered
immunomodulators that have an influence on almost every
component of the immune response machinery. Generally,
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Toxic effects of cannabinoids in animals
endocannabinoids exert a negative action on the onset of a
variety of parameters of the immune response, although their
role in normal immune homeostasis and the development of
immune system disorder is still far from being resolved (25).
Guinea pigs and mice have been used extensively as experimental models for documenting the effects of cannabinoids
(THC doses in the range of 0.2 mg/kg to 100 mg/kg) on host
resistance in the intact animal. It was established that THC
has the potential to compromise host resistance to both viruses
and bacteria (26). Furthermore, Mishkin and Cabral (27) have
demonstrated that the decreased antiviral responsiveness is
paralleled by decreased cellular and humoral immunity, suggesting that THC targets specific elements of the immune
system involved in antivirus responses.
In vitro studies have also demonstrated that cannabinoids
alter the functional activities of a variety of immune cell types
(28). However, at present, there are no definitive data that
demonstrate that these in vitro cellular effects are operative in
humans (26).
CANCER
The antineoplastic activities of THC and its analogue were
first observed in the early 1970s (29). Based on the immunosuppressive effects of cannabis, animal studies were originally
performed to investigate the possibility that marijuana smoking,
or long-term THC treatment, might favour tumour growth.
These studies, however, initially produced contradictory
results. The data of one study suggested that the growth of a
lung carcinoma was enhanced due to CB2 receptor-mediated
immune suppression (30). However, in a two-year administration of high oral doses (50 mg/kg) of THC to rats and
mice, Chan et al (31) showed that THC treatment tended to
increase survival (70% in the treated animals compared with
45% in the untreated controls) and lower the incidence of
primary tumours with no marked histopathological alterations in the brain or other organs. Indeed, it is now a fact
that cannabinoids inhibit tumour growth in laboratory animals by modulating key cell signalling pathways, thereby
inducing direct growth arrest and the death of tumour cells,
as well as by inhibiting tumour angiogenesis and metastasis
(32). Thus, cannabinoids are selective antitumour compounds that kill tumour cells without affecting their nontransformed counterparts.
Therefore, cannabinoids are potential anticancer agents,
which appear to be well tolerated in animal studies and which
do not produce the generalized toxic effects in normal tissues
that limit most conventional agents used in chemotherapy (33).
HORMONAL SYSTEM AND FERTILITY
Cannabis and THC act on the hypothalamic-pituitary adrenal
axis. In animal studies, a multitude of endocrine processes are
influenced by these drugs, including adrenocorticotropic hormone, thyroid-stimulating hormone and growth hormone.
Indeed, the administration of cannabinoids decreases plasma
growth hormone levels, reduces serum thyroid-stimulating
hormone levels (by 90% within 60 min of treatment in rats)
and stimulates the release of adrenocorticotropic hormone and
glucocorticoids (34). Thus, the regulation of blood glucose
levels may be affected.
THC has been reported to account for the majority of the
reproductive hazards of marijuana use. Animal studies in
males largely confirm the ability of cannabinoids to suppress
Pain Res Manage Vol 10 Suppl A Autumn 2005
Figure 1) Dual effect of cannabinoids on neurons. Cannabinoids may
lead to opposite effects on neuron survival/death. Stimulation of
cannabinoid receptors located on brain neurons (CB1) provides protection against excitotoxicity (through inhibition of glutamate release
and activation of intracellular signalling cascades) or augmentation of
excitotoxicity (by decreasing gamma aminobutyric acid [GABA] release
from GABAergic inhibitory interneurons). Finally, cannabinoids may
exert their neuroprotective effects via a third mechanism which does not
involve CB1 receptors. CNS Central nervous system; NMDA N-methylD-aspartate; THC Delta-9-tetrahydrocannabinol. Reproduced with permission from Mechoulam and Lichtman (22)
spermatogenesis, to induce aberrations in sperm morphology
(35), to reduce the weight of reproductive organs and to
decrease the plasma concentration of hormones such as testosterone (an acute dose of THC produces a 65% reduction in
plasma testosterone levels by 60 min in the rhesus monkey)
(36). These studies suggest that THC inhibits luteinizing hormone and follicle-stimulating hormone secretion, consequently
decreasing testosterone production and altering spermatogenesis
(34). High THC doses cause a modest increase in abnormally
formed sperm (5.3% in mice treated with 10 mg/kg of THC per
day for five days compared with 1.5% in controls) (35). In
females, THC prolongs the estrous cycle and decreases the
proestrous surge of luteinizing hormone inhibiting ovulation
(37). Acute cannabinoid exposure inhibits basal prolactin
release in monkeys and rats, and blocks the prolactin surge that
occurs on the day of proestrus or in response to suckling (34).
In addition, exposure to natural cannabis extracts during
pregnancy has been correlated with embryotoxicity and specific
teratological malformations in rats, hamsters and rabbits (37).
Finally, anandamide has been shown to impair pregnancy and
embryonic development in mice. However, anandamide has
been suggested to have a dual role, with low anandamide levels
being associated with implantation and high levels with uterine
changes during gestation (37).
EXTRAPOLATION OF ANIMAL DATA TO
HUMANS
Animal studies are important in determining the overall toxicity of compounds such as cannabis and cannabinoids. They allow
the use of various animal species, the choice of the route of
administration and doses, as well as the duration of the treatment to obtain acute or chronic conditions. Furthermore, it is
possible for animal studies to control for confounding factors,
and also to allow direct pathological studies of all the organs.
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When it comes to extrapolation of the data to humans, the
picture is more complex. Three main approaches based on
body weight, body surface area and pharmacokinetic data have
been used to extrapolate animal data to humans (2). However,
none of these approaches is ideal, and sometimes quite puzzling
results are obtained. For example, the lethal dose of THC in
nonhuman primates turned out to be five- to 10-fold higher
than that found in rats and dogs (6).
CONCLUSIONS
More data are needed on the adverse effects of cannabinoids in
animals, especially on controversial issues such as their effects on
the brain and immune system. However, one should be very
careful when interpreting the results and appying them to
humans. The best approach to human toxicology rests on the
study of human data.
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Cannabinoids for the treatment of pain:
An update on recent clinical trials
Mark Ware MBBS MRCP MSc1, Pierre Beaulieu MD PhD2
M Ware, P Beaulieu. Cannabinoids for the treatment of pain:
An update on recent clinical trials. Pain Res Manage
2005;10(Suppl A):27A-30A.
Over the past five years, there has been a considerable increase in
clinical research on cannabinoid use for a range of pain syndromes.
Cannabinoid products are becoming available for research and clinical use, and pharmaceutical industry interest in the potential for
cannabinoids in therapeutics is also gaining momentum. The present
article summarizes recent clinical trial data in the field of pain management and suggests that the potential for cannabinoid therapy for
chronic pain states is encouraging. Clinicians working in pain management should be aware of the options becoming available from the
cannabinoid class of medications.
Les cannabinoïdes pour le traitement de la
douleur : Le point sur les essais cliniques
récents
Au cours des cinq dernières années, on a effectué beaucoup de recherches
cliniques sur l’utilisation des cannabinoïdes dans divers syndromes
douloureux. Les dérivés des cannabinoïdes deviennent plus accessibles
pour la recherche, leur utilisation clinique se répand et l’industrie pharmaceutique manifeste un intérêt croissant pour leur potentiel thérapeutique. Le présent article fait le point sur les essais cliniques récents dans le
domaine du traitement de la douleur et confirme le potentiel des cannabinoïdes dans le traitement de la douleur chronique. Les médecins qui travaillent dans le domaine du contrôle de la douleur doivent être au courant
des options qu’offrent les cannabinoïdes en tant que classe pharmacologique.
Key Words: Cannbinoid; Cannabis; Clinical trial; Pain; Review
he use of cannabinoids for the treatment of acute and
chronic pain has a long and well-documented history. As
reviewed elsewhere in this supplement, the mechanisms of
cannabinoid action, which have recently been identified, provide evidence for a pain pathway mediated by cannabinoids
(1). It is now recognized that 10% to 15% of patients with
chronic pain use herbal cannabis as part of their treatment (2)
and that this may result in reductions in opioid requirements
(3-5). The use of cannabis or cannabinoids in the treatment of
acute pain has not been as widely reported. Recent advances in
cannabinoid pharmacology have resulted in increasing attention on the therapeutic potential of cannabinoids, and a number of preparations have been or are being developed and
investigated in randomized controlled trials. The difficulties
with conducting clinical trials on pain include the fact that pain
is a subjective experience, and pain patients comprise a heterogenous group consisting of many different syndromes with a
variety of physical, psychological and social problems. In addition to this, cannabinoids are associated with considerable social
stigma, and cannabis for medical purposes has become a major
politicolegal issue for many Western governments.
Historically, clinical data for the efficacy of cannabinoids in
pain relief have been equivocal; a qualitative systematic review
published in 2001 (6) concluded “cannabinoids are no more
effective than codeine in controlling pain and have depressant
effects on the central nervous system that limit their use. Their
widespread introduction into clinical practice for pain management is therefore undesirable”. The study was criticized for
T
reaching conclusions that were not supported by the existing
literature (7). Reports of the use of cannabis for pain continue
to suggest a role for cannabinoids in pain management;
nabilone has been used with reported benefit for chronic pain
in clinical practice (8), and case reports (9) and case series
(10) suggest that cannabinoids deserve further enquiry. In the
past two years, a number of clinical trials have been reported
investigating the efficacy of number of therapeutic cannabinoid compounds. The purpose of the present paper is to summarize these recent reports, to consolidate our current
understanding of the effects of cannabinoids in pain management and to provide a stimulus for further research efforts.
METHODS
A review of publications relating to the use of cannabinoids in the
treatment of pain in humans was conducted. The search was based
on the authors’ libraries of material and communications with
other investigators. In addition, MEDLINE was searched for clinical trials of cannabinoids for acute and chronic pain; these were
summarized and categorized according to the compound used,
including naturally occurring and synthetic cannabinoids.
RESULTS
Acute pain
Since 1990, only three clinical studies of cannabinoids have
been performed in acute pain, two in human volunteers
(11,12) and one on postoperative pain patients (13).
1McGill
University; 2Université de Montréal, Montreal, Quebec
Correspondence: Dr Mark Ware, E19.145 Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4.
Telephone 514-934-8222 ext 4386, fax 514-934-8096, e-mail mark.ware@muhc.mcgill.ca
Pain Res Manage Vol 10 Suppl A Autumn 2005
©2005 Pulsus Group Inc. All rights reserved
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In 2000, Greenwald and Stitzer (11) reported a study of the
antinociceptive properties of smoked cannabis in recreational
drug users. The volunteers were healthy regular marijuana
users. Of the 13 participants enrolled, only five male volunteers completed the entire study, which consisted of three test
sessions, during which they smoked cigarettes containing 0%
(placebo) and 3.55% delta-9-tetrahydrocannabinol (THC)
(active). Cannabis smoking was divided in four bouts, during
which participants inhaled nine puffs (zero, three, six or nine
active puffs separated by 40 min each). Patients were also given
naltrexone (an opioid antagonist) – 0 mg, 50 mg or 200 mg
orally – 1 h before the first smoking session, to assess whether
endogenous opioids influence cannabis effects in humans. Test
sessions consisted mainly of antinociceptive measures using
finger withdrawal from radiant heat stimulation, a procedure
in humans that is comparable with a tail-flick assay. Overall,
cannabis produced significant dose-dependent antinociception
that was not antagonized by naltrexone. The effect was weak
and only significantly present at the highest dose. Despite
these positive results, the authors argued that because all participants were relatively frequent cannabis users, a greater tolerance to the antinociceptive effects of cannabis smoking may
have developed.
The analgesic effect of oral THC, morphine or their combination was reported in healthy subjects under experimental pain conditions (12). This was a randomized,
placebo-controlled, double-blind, crossover study involving
12 healthy cannabis-naïve volunteers (six female and six
male). Each subject orally received either 20 mg THC (dronabinol), 30 mg morphine, a mixture of 20 mg THC and 30 mg
morphine, or placebo as a single dose. The between-session
washout phases were at least seven days. Pain tests consisting
of pressure pain tolerance, heat pain (thermode), ice-cold
immersion, and single and repeated transcutaneous electrical
stimulation were performed every hour up to 8 h post-drug
administration. Furthermore, side effects and vital functions
were monitored, as well as plasma concentrations of THC and
its metabolites. In the heat test, neither morphine nor THC
produced any analgesic effect. In the cold test, morphine alone
and the combination morphine/THC were analgesic, but not
THC alone, whereas in the pressure test, only morphine alone
was analgesic. Finally, in the electrical stimulation test, morphine increased the pain detection threshold during single
mode stimulation, while morphine alone and in combination
with THC was analgesic during the repeated mode of stimulation. Drug administration was usually associated with mild side
effects, with most patients feeling sleepy and confused after
THC or THC/morphine administration. Interestingly, side
effects of THC (in particular, euphoria, hallucinations and
confusion) were lowered in the presence of morphine, and in
the reverse, THC decreased nausea and vomiting associated
with morphine when the two were given together. Taken
together, these results illustrate that THC provides poor pain
control in this battery of acute pain tests, which are characteristic of superficial pain (heat test and electrical stimulation)
and more deep pain (pressure and cold test). However, opioids
and non-steroidal anti-inflammatory drugs are known to provide
no analgesia in the heat and cold tests, respectively.
Furthermore, none of the experimental pain tests produced
inflammation or tissue damage. Therefore, as the authors mentioned in their discussion, it is not possible to rule out the fact
that THC would have an analgesic effect after induction of
28A
inflammation, or tissue or nerve damage. Finally, the plasma levels of THC in this study were very low; therefore, THC given
with a better bioavailability could increase its analgesic effect
and should be tested further.
A randomized clinical study (13) looking at postoperative
pain showed a lack of efficacy of oral THC in women undergoing elective total abdominal hysterectomy. After surgery, all
patients used a patient-controlled analgesia (PCA) device
with morphine for 24 h. After this time, the PCA was discontinued, and any patient requesting further analgesia was randomly assigned to receive either 5 mg THC capsules or
placebo. The primary outcome measure was the sum of the
pain intensity differences over a 6 h period, while the second
outcome measure was time to request for rescue analgesia in
the form of oral codeine (30 mg). Twenty patients were
recruited in each group. No differences in mean sum of the
pain intensity differences scores were found between the THC
and placebo groups. The only side effect reported to be different between the groups was an increased awareness of surroundings in the THC group. The lack of efficacy of THC
should be put into context of a study with a small number of
patients using a small dose of THC as a single dose at day 2
after surgery. This study needs to be repeated using larger doses
of THC (see below) or a combination of cannabinoids for a
longer period of time before cannabinoids can be excluded
from being effective in postoperative pain management.
Chronic pain
Ajulemic acid: Karst et al (14) conducted a small randomized
controlled trial of 1’,1’-dimethylheptyl-delta-8-THC-11-oic
acid in 21 patients with chronic neuropathic pain. In this
crossover study, 20 mg of 1’,1’-dimethylheptyl-delta-8-THC11-oic acid twice daily for four days followed by 40 mg twice
daily for three days was associated with reduced pain measured
3 h after intake of the study drug compared with placebo. Eight
hours after intake of the drug, the pain scale differences
between groups were not significant. Adverse effects were
transient dry mouth and tiredness, with no serious adverse
event reported.
Cannabis extracts (sublingual): Berman et al (15) conducted
a randomized controlled trial of two cannabis-based medicinal
extracts for neuropathic pain resulting from brachial plexus
avulsion. In this crossover trial, 48 patients received THC, a
mixture of THC/cannabidiol (CBD) or placebo in a sublingual
spray over a six-week period. Both THC and THC/CBD
improved sleep quality, pain and quality of life.
Wade et al (16) conducted a series of double-blind, randomized, placebo-controlled, single-patient, crossover trials
with two-week treatment periods in patients with intractable
neurogenic symptoms. Patients had a range of disorders,
including multiple sclerosis, spinal cord injury, brachial plexus
avulsion and amputation. The patients were administered
whole-plant extracts of THC, CBD, a combination of the two
or a matched placebo by sublingual spray at doses determined
by titration against symptom relief or unwanted effects within
the range of 2.5 mg/24 h to 120 mg/24 h. Pain relief from THC
and CBD was superior to placebo, while impaired bladder control, muscle spasms and spasticity were improved in some
patients. Three patients had transient hypotension and intoxication with rapid initial dosing of THC.
Notcutt et al (17) conducted a series of ‘n-of-1’ studies
using a sublingual cannabis extract in 34 patients with chronic
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Cannabinoids for the treatment of pain: Update
pain. Three cannabis-based medicine extracts (THC, CBD
and a 1:1 mixture of both) were given over a 12-week period.
After an initial open-label period, the cannabis-based medicine extracts were used in a randomized, double-blind, placebocontrolled, crossover trial. The extracts that contained THC
proved most effective in symptom control. Regimens for the
use of the sublingual spray emerged and a wide range of dosing
requirements was observed. Side effects were common and
were generally acceptable and similar to other psychoactive
agents that are used for chronic pain.
As the present paper went to press, Health Canada granted
conditional approval for the use of a buccal cannabis extract
for chronic neuropathic pain associated with multiple sclerosis.
Some of the data to support this have been cited above; other
data are currently only available in abstract form or are awaiting publication. Prescribing information has been added to the
recommendations section of this issue.
Cannabis extracts (oral): Zajicek et al (18) reported the
results of a large-scale, multicentre, randomized, controlled trial
of oral cannabinoids in the treatment of muscle spasticity associated with multiple sclerosis. Six hundred thirty participants
were treated at 33 United Kingdom centres with oral cannabis
extract (n=211), THC (n=206) or placebo (n=213). The trial
duration was 15 weeks. No treatment effect of cannabinoids
was observed on the primary outcome of muscle spasticity
measured by the Ashworth scale. There was evidence of a
treatment effect on patient-reported spasticity and pain. Side
effects were principally expected.
Svendsen et al (19) reported the results of a small, randomized controlled trial of oral THC (dronabinol) versus placebo in
24 patients with central pain associated with multiple sclerosis.
Treatment duration was three weeks with up to 10 mg of THC.
Median pain intensity during the last week of treatment was significantly reduced compared with placebo (visual analogue scale
4.0 versus 5.0, P=0.02). Dizziness was the most frequent adverse
event associated with THC, especially during the first week of
treatment (19).
Ongoing studies
Two studies with different designs are underway in the same
setting of postoperative pain and may shed light into the role
of cannabinoids in postoperative pain. The first study, funded
by the Medical Research Council (United Kingdom), is a multicentre study called CANPOP (Trial of Cannabis for Acute
Post-Operative Pain). Preliminary results of a dose-finding
study were presented in September 2003 at a European congress (European Federation of IASP Chapters) in Prague,
Czech Republic. Patients undergoing major orthopedic surgery
or hysterectomy were recruited and received a capsule from
one of the four following groups: cannabis extracts containing
mainly THC and CBD (Cannador, Society for Oncological
and Immunological Research, Germany), a synthetic delta-9THC (dronabinol), a standard analgesic (acetaminophen) or a
placebo. The primary objective of the study was to evaluate
pain scores using a visual analogue scale for 6 h following the
end of surgery. The dose-finding study showed that a dose of 10
mg of THC (Cannador) was effective (30 patients completed
the study and 15 required rescue analgesia), whereas a dose of
5 mg was not (the first 11 patients requested rescue analgesia,
so the dose was stopped). At the 10 mg dose, 29 patients were
without nausea and one patient had moderate nausea for 2 h.
Based on these results, a full-scale study has begun using THC
Pain Res Manage Vol 10 Suppl A Autumn 2005
10 mg, and definitive results should be available in a few
months.
Another study, funded by the Canadian Institute of Health
Research, has recently started and is testing the role of a synthetic analogue of THC, nabilone, in postoperative pain, nausea and vomiting (Pierre Beaulieu, Université de Montréal –
Centre hospitalier de l’Université de Montréal, Québec).
Patients undergoing major (orthopedic, gynecological, plastic
or urological) surgery receive capsules of either 1 mg or 2 mg of
nabilone, ketoprofen or placebo every 8 h for 24 h while simultaneously receiving morphine PCA. The primary objectives
are total quantity of morphine used in 24 h and pain scores at
rest and on movement. Finally, the incidence of nausea and
vomiting, tolerance of the study medications and quality of
sleep are also recorded. This prospective, randomized, doubleblind study will recruit a total of 160 patients.
For chronic pain, one pilot, randomized, placebo-controlled
study of smoked cannabis is underway at the McGill
University Health Centre, Montreal, Quebec. Thirty-two subjects are to be randomly assigned to receive four different
cannabis preparations ranging in THC content from 0% to
9.5%. Subjects will be allocated to receive all four preparations
in a crossover design trial. In each cycle, they will use 25 mg
three times daily for five days, on an outpatient basis, with
nine-day washout periods between cycles. The primary outcome is average pain intensity measured during the smoking
phase. The study is expected to be completed in late 2005.
An additional study is underway in patients with HIVassociated neuropathic pain in San Francisco, California,
USA. Preliminary findings of an open-label phase suggest that
patients using smoked cannabis obtain some pain relief, but
the data have not yet been published.
DISCUSSION
The present review was not conducted systematically and only
refers to studies available through the MEDLINE database.
Important trial results or other data that may exist elsewhere
may have been missed. However, the publications cited in the
present paper are not uniformly positive, and the possibility of
publication bias, while always a concern with controversial
drugs like cannabis, is assumed to be minimal because the therapeutic potential is of great interest to physicians and regulators, and the direction of any potential bias is not obviously
apparent.
These reports suggest that there is some therapeutic potential
for cannabinoids in acute and chronic pain, but that significant
hurdles exist in achieving clinically relevant outcomes with
minimal side effects. Much more work is needed to evaluate
appropriate outcomes, to develop alternative means of administration and to develop dosing strategies. Further work is needed
using new and existing cannabinoids to continue to explore the
therapeutic potential of cannabinoids in chronic pain.
As with morphine and nonsteroidal anti-inflammatory
drugs, cannabinoids may not be very effective in experimental
acute pain. Their role in postoperative pain may be more
attractive in the presence of tissue injury and inflammation.
Cannabinoids may act as adjuvants to opioids to control pain,
and also nausea and vomiting (20), which are not trivial symptoms in the postoperative period. From the current evidence,
when given in combination, opioids and cannabinoids may
reduce each other’s side effects and produce an adequate combination in the treatment of acute pain.
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For chronic pain, the evidence is mounting that cannabinoids may constitute a new class of agents to add to the pharmaceutical toolbox in the management of chronic pain. The effects
of cannabinoids on pain, including peripheral and central neuropathic pain states, and spasticity are measurable and meaningful to patients, and suggest that with appropriate prescribing and
monitoring, additional benefit to some patients may be expected
with cannabinoid therapy. Short-term side effects are well
described, and often are the main drawbacks to patient compliance with therapy. More specific information is required on the
long-term side effects of cannabinoid therapy, including drugdrug interactions, tolerance, cognitive impairment and risks of
addiction, but these issues are not unique to cannabinoids and
indeed point to the need for physicians to exercise diligence in
following patients on psychoactive medications.
SUMMARY
The past two years have seen the publication of several
important clinical trials that point to the potential role for
cannabinoids in pain management, and ongoing work promises to further explore and define these effects. Cannabinoids
are worthy of consideration for refractory pain conditions,
but it is important to fully inform patients who may embark
on this line of therapy of the side effect profile, and to monitor doses used and adverse events carefully. Not surprisingly,
the short-term risks are easier to evaluate than the long-term
ones. The former do not appear to be excessive. Definite
long-term risks exist, particularly for respiratory ailments,
cognitive functions and psychosis. While long-term use may
be quite sound, it requires active attention to an evolving
topic.
FINANCIAL SUPPORT: MW is supported by the fonds de la
recherche en santé (FRSQ) (Boursier-clinicien junior 1) and
holds grants from the Canadian Institutes of Health Research
(CIHR). MW has received honoraria from Valeant and
AstraZeneca, has sat on advisory boards for Bayer and Valeant, has
acted as a consultant to Cannasat, and has conducted research
with grants from GW Pharmaceuticals and Valeant. PB is supported
by the FRSQ (Boursier-clinicien junior 1), the Research Center of
the Centre hospitalier de l’Université de Montréal and holds a
grant from the CIHR.
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1. Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia
circuit activated by cannabinoids. Nature 1998;395:381-3.
2. Ware MA, Doyle CR, Woods R, Lynch ME, Clark AJ. Cannabis
use for chronic non-cancer pain: Results of a prospective survey.
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3. Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral
cannabinoids in familial Mediterranean fever. Anaesthesia
1997;52:483-6.
4. Chatterjee A, Almahrezi A, Ware M, Fitzcharles MA.
A dramatic response to inhaled cannabis in a woman with
central thalamic pain and dystonia. J Pain Symptom Manage
2002;24:4-6.
5. Lynch ME, Clark AJ. Cannabis reduces opioid dose in the
treatment of chronic non-cancer pain. J Pain Symptom Manage
2003;25:496-8.
6. Campbell FA, Tramer MR, Carroll D, Reynolds DJ, Moore RA,
McQuay HJ. Are cannabinoids an effective and safe treatment
option in the management of pain? A qualitative systematic review.
BMJ 2001;323:13-6.
7. Iversen L. Cannabinoids in pain management. Few well controlled
trials of cannabis exist for systemic review. BMJ 2001;323:1250.
8. Price MAP, Notcutt WG. Cannabis and cannabinoids in pain
relief. In: Brown DT, ed. Cannabis: The Genus Cannabis, 1st edn.
Amsterdam: Harwood Academic Publishers, 1998:223-46.
9. Hays H. Marijuana for the management of proximal mytonic
myopathy. J Pain Symptom Manage 2001;21:267-9.
10. Ware MA, Gamsa A, Persson J, Fitzcharles MA. Cannabis for
chronic pain: Case series and implications for clinicians. Pain Res
Manage 2002;7:95-9.
11. Greenwald MK, Stitzer ML. Antinociceptive, subjective and
behavioral effects of smoked marijuana in humans. Drug Alcohol
Depend 2000;59:261-75.
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combination in healthy subjects under experimental pain
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Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG,
Rowbotham DJ. Lack of analgesic efficacy of oral delta-9tetrahydrocannabinol in postoperative pain. Pain 2003;106:169-72.
Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U.
Analgesic effect of the synthetic cannabinoid CT-3 on chronic
neuropathic pain: A randomized controlled trial. JAMA
2003;290:1757-62.
Berman JS, Symonds C, Birch R. Efficacy of two cannabis based
medicinal extracts for relief of central neuropathic pain from
brachial plexus avulsion: Results of a randomised controlled trial.
Pain 2004 Dec;112:299-306.
Wade DT, Robson P, House H, Makela P, Aram J. A preliminary
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Safety issues concerning the medical use of
cannabis and cannabinoids
Mark A Ware MBBS MRCP MSc1,2, Vivianne L Tawfik BSc2
MA Ware, VL Tawfik. Safety issues concerning the medical
use of cannabis and cannabinoids. Pain Res Manage
2005;10(Suppl A):31A-37A.
Safety issues are a major barrier to the use of cannabis and cannabinoid medications for clinical purposes. Information on the safety of
herbal cannabis may be derived from studies of recreational
cannabis use, but cannabis exposure and effects may differ widely
between medical and recreational cannabis users. Standardized,
quality-controlled cannabinoid products are available in Canada,
and safety profiles of approved medications are available through the
Canadian formulary. In the present article, the evidence behind
major safety issues related to cannabis use is summarized, with the
aim of promoting informed dialogue between physicians and patients
in whom cannabinoid therapy is being considered. Caution is advised
in interpreting these data, because clinical experience with cannabinoid use is in the early stages. There is a need for long-term safety
monitoring of patients using cannabinoids for a wide variety of conditions, to further guide therapeutic decisions and public policy.
Key Words: Adverse events; Cannabis/cannabinoid; Safety;
Therapy
hysicians’ concerns about the use of cannabis for medical
purposes, particularly in its widely used and unregulated
herbal form, are often focused on safety issues. Because herbal
cannabis has been used recreationally for many years and has
been extensively studied, information on the safety concerns
may be obtained by extrapolating results from epidemiological
studies. Safety information about medicinal cannabinoid use
may also be obtained from preparations of single cannabinoid
compounds, which have been approved by regulatory agencies
and have been prescribed for more than 20 years. The use of
cannabis by patients with diseases such as HIV/AIDS, epilepsy,
chronic noncancer pain, glaucoma and multiple sclerosis gives
rise to potential safety concerns that are not addressed in
observational research on recreational users. Examples of such
concerns are potential drug-drug interactions, alterations in
the immune functions of immunocompromised patients, and
the risk of developing dependency disorders when cannabis is
used in a medical context.
The present paper is an overview of safety issues regarding
medicinal cannabis use. The aim is to promote a meaningful and
informed dialogue between patients and health care providers
regarding cannabis use.
P
Innocuité du cannabis et des cannabinoïdes
utilisés à des fins médicales
Les problèmes d’innocuité représentent un obstacle de taille à l’utilisation
du cannabis et des médicaments dérivés des cannabinoïdes à des fins cliniques. Les données d’innocuité relatives à l’utilisation de la plante peuvent en effet provenir d’études sur l’utilisation du cannabis à des fins
récréatives. Or, l’exposition au cannabis et ses effets peuvent différer considérablement selon que les utilisateurs le consomment à des fins médicales ou récréatives. Au Canada, on trouve des produits dérivés des
cannabinoïdes standardisés et soumis à un contrôle de la qualité et les profils d’innocuité des médicaments approuvés peuvent être consultés par
l’entremise du Formulaire canadien. Dans le présent article, l’auteur offre
un résumé des principaux enjeux liés à l’innocuité du cannabis dans le but
de favoriser un dialogue éclairé entre médecins et patients chez qui on
envisage un traitement par cannabinoïdes. La prudence s’impose lorsque
l’on interprète les données de la recherche clinique, puisque l’expérience
pratique avec les cannabinoïdes en est à ses débuts. Il faudra exercer une
surveillance à long terme de l’innocuité des cannabinoïdes chez les
patients atteints de divers problèmes de santé pour mieux orienter les
décisions thérapeutiques et les politiques en matière de réglementation.
METHODS
Search strategy
The published literature on MEDLINE from 1966 to December
2004 was searched using the medical subject headings “marijuana
smoking” and “adverse effects”, and with the limitations of
human studies, studies published in English and studies available
with abstracts. Papers on the effects of prenatal cannabis exposure on offspring were not reviewed in detail. Abstracts were
reviewed by the lead author (MAW), and relevant papers were
obtained and reviewed. The quality of the studies was not formally evaluated. Further safety information was obtained from
safety summaries previously prepared by both authors in preparation for clinical trials, and further sources were identified from
antecedent references. Where multiple studies were found to
report on the same safety concerns, the most recent or representative reports were reviewed.
Data on the adverse events of cannabinoid drugs that are available on the Canadian market were taken from the 2004
Compendium of Pharmaceuticals and Specialties (1). Data on investigational cannabinoid drugs in development were not considered.
Major safety issues were categorized and explored in more
detail.
1Montreal
General Hospital; 2McGill University, Montreal, Quebec
Correspondence: Dr Mark Ware, E19.145 Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4.
Telephone 514-934-8222 ext 4386, fax 514-934-8096, e-mail mark.ware@muhc.mcgill.ca
Pain Res Manage Vol 10 Suppl A Autumn 2005
©2005 Pulsus Group Inc. All rights reserved
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TABLE 1
Incidence of adverse events of regulated cannabinoids:
Probable causal relationships with incidences of greater
than 1%
Adverse event
Dronabinol (%)
Nabilone (%)
‘High’
8–24
38.8
Somnolence
3–10
66
Dizziness
3–10
58.8
Dry mouth
21.6
Euphoria
3–10
Paranoid reaction
3–10
Nausea
3–10
Abdominal pain
3–10
Thinking abnormalities/confusion
3–10
Ataxia
4.0
>1
12.8
Asthenia
>1
7.6
Amnesia
>1
Anxiety/nervousness
>1
Depersonalization
>1
Vomiting
>1
Palpitations
>1
Tachycardia
>1
Vasodilation/facial flush
>1
Blurred vision
12.8
Sensation disturbance
12.4
Anorexia
7.6
Headache
7.2
Orthostatic hypertension
5.2
Hallucinations
2.0
Data from reference 1
RESULTS
One hundred fifty-seven papers were identified from the literature search for adverse effects, of which 79 were felt to be of
relevance. The product monographs for nabilone and dronabinol were obtained.
Cannabinoid-based drugs
A summary of the adverse event profiles obtained from the 2004
Compendium of Pharmaceuticals and Specialties (1) for dronabinol
and nabilone are provided in Table 1. The most commonly
reported adverse events are a ‘high’, drowsiness, dizziness and dry
mouth. For further information, refer to the product monographs of these drugs (2,3).
Herbal cannabis
Herbal cannabis is most often smoked. Survey data suggest that
patients with chronic pain smoke between one and four puffs
from a cannabis joint two to three times a day (4) (although
larger doses are also known to be used by some patients). The
exposures reported in recreational epidemiological and
experimental studies range widely, from single exposures to
over 20 years of daily heavy cannabis use.
The major safety concerns may be divided into those about
the quality of the product and those about the administration
of the drug itself. Drug administration effects are further divided
into effects related to the delivery system and effects directly
related to the cannabinoid compounds.
32A
Quality concerns
Adverse events due to the use of contaminated cannabis were
reported only in cannabis smokers. Contamination with
Aspergillus has given rise to concerns of lung infections in
immunocompromised patients (5-7). Contamination with
paraquat (a potent pesticide) has not been associated with
adverse effects (8). Contamination with formaldehyde has
been reported to impair memory (9) and may be life threatening (10). Cannabis soaked in embalming fluid has been reported
to cause phencyclidine-like responses (11).
The sharing of cannabis with contaminated smoking paraphernalia has been associated with small outbreaks of tuberculosis (12) and meningococcal disease (13,14).
Safety concerns related to cannabis smoking: Respiratory
function
Cannabis smoking poses a potential health risk. Cannabis
smoke has been shown to have qualitatively the same constitution as tobacco smoke but with quantitatively higher concentrations of polyaromatic hydrocarbons, which are known
carcinogens (15). Cannabis smoke, like tobacco smoke, contains carbon monoxide, which preferentially binds hemoglobin
at the expense of oxygen binding.
A higher prevalence of chronic bronchitis symptoms, such
as cough, phlegm and wheeze, has also been noted in cannabis
smokers (16-19). All symptoms were most evident in heavy,
chronic users, defined as those who had smoked more than
three joints per day for 25 years or more. There is a published
report (20) of four cases of emphysema in adults with a history
of cannabis smoking. However, observational surveys of heavy,
chronic cannabis use have failed to find any lung damage in
long-term smokers (21). Pneumomediastinum and pneumothorax have been reported following the prolonged Valsalva
manoeuvre that may accompany cannabis smoking (possibly
through rupturing emphysematous bullae) (22-25).
Several case studies of young patients with carcinoma of the
upper respiratory tract have been published (26). There is concern that heavy cannabis smoking is a causative factor of this
type of cancer, which is rare in adults under the age of 60 years,
even in those who smoke tobacco and drink alcohol (27,28).
One case-control study (29) reported an increased risk of upper
respiratory tract cancer due to cannabis smoking; however, two
recent case-control studies (30,31) have failed to find any
increased risk of oral squamous cell cancers due to cannabis
smoking. No association between cannabis smoking and
tobacco smoking-related cancers was found in a large retrospective cohort study (32).
The effects of exposure to cannabis smoke in low doses in
patients using cannabis therapeutically have not been determined. The doses used by patients for symptom relief may be
low, and risks increase with heavy, chronic use of cannabis.
Acute effects
Mood effects: Acute reactions, such as nausea, anxiety, paranoia and disorientation often occur in new cannabis users but
are uncommon in regular cannabis users (33). Many patients
were considered to be asymptomatic after abstinence from
cannabis for four months (34). For patients seeking symptom
relief, the psychological high associated with cannabis smoke
inhalation may be another unwanted effect, but this moodaltering effect may be an important part of the overall therapeutic response. Euphoria, altered time perception and
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Safety issues with the medical use of cannabis/cannabinoids
relaxation are acute reactions that disappear within 3 h to 4 h
and are considered part of the high (35).
Acute toxicity: Unlike opioids, cannabis does not cause central respiratory depression (36). Acute hyperthermia has been
reported following cannabis use and jogging on a warm day
(37). Overdosing is extremely rare and is usually accompanied
by the use of other drugs, such as alcohol. A lethal tetrahydrocannabinol (THC) dose has not been reported. From a purely
pharmacological perspective, cannabinoids appear to be very
safe. For a more detailed review of toxicity, please see the article by Beaulieu (pages 23A-26A). Doctors at the HaightAshbury clinic in the San Francisco Bay area who work
primarily with drug addicts have stated that it is virtually impossible to die of a cannabis overdose (33).
Anxiety and panic: Acute anxiety and panic are recognized as
possible complications of cannabis use, usually in the new user
(35,38). Patients usually respond to reassurance. Cannabis use
in a relaxed and supportive atmosphere may help reduce anxiety. In addition, patients appreciate being made aware of likely
psychoactive effects on first doses, and gradual titration to an
effective dose may promote tolerance to adverse psychoactive
effects. Some subjects may find the anxiety unpleasant enough
to stop using cannabis. Feelings of paranoia have been
observed among recreational users with bipolar and panic disorders (39). The illegal status of the drug may be an important
confounder in this regard.
Cardiac and other vascular effects: The cardiovascular effects
of cannabis were recently reviewed (40). An increased relative
risk of nonfatal myocardial infarction in the first hour following cannabis smoking has been described (41). Myocardial
infarction following cannabis use and Viagra (Pfizer Canada
Inc) consumption has been reported (42). The increase in heart
rate following cannabis use may play a role by increasing
myocardial oxygen demand, but other factors, such as plaque
rupture and arrhythmias, may also have an effect (43-45).
Cannabis smoking-induced tachycardia may be problematic
for patients with comorbid ischemic heart disease or arrhythmias. It has been found that inhalation of cannabis smoke
reduces the amount of exercise required to cause an attack of
angina by 50% (46). Cannabis-induced tachycardia is reduced
by clonidine, an alpha-2 agonist, which suggests that THC
may play a role in sympathetic nervous system stimulation
(47), although a reduction in parasympathetic tone has also
been suggested (48).
Cannabis is known to cause postural hypotension immediately after smoking (49). It also causes peripheral vasodilation,
resulting in characteristic conjunctival reddening. It is plausible that the increased heart rate and drop in blood pressure
may be secondary to a drop in peripheral vascular resistance. In
addition, antiretroviral therapy (ie, highly active antiretroviral
therapy) has been shown to cause lipid abnormalities in
patients with HIV/AIDS. These lipid abnormalities may result
in an increased risk for ischemic heart disease, which could be
exacerbated by cannabis (50).
Transient ischemic attacks (51) and cerebrovascular stroke,
usually following acute cannabis use, have also been reported
in several case reports (52-56). Renal infarction following
cannabis smoking has also been reported (57).
Cognitive function: Impaired performance has been observed
using the circular lights test after subjects smoked two cannabis
cigarettes containing 2.8% THC (58). A slight slowing of reaction was found by using digit symbol substitution and automated
Pain Res Manage Vol 10 Suppl A Autumn 2005
tracking tests after three doses of 0%, 1.3% and 2.7% THC.
Inhalation of cannabis smoke had no effect on performance in
the divided attention task (59). Performance measures have
shown no dose-related effects on reaction times, but a doseresponse effect on accuracy has been observed (60). Acute
cannabis exposure has been associated with a hangover or
residual effect on psychomotor performance (61,62).
Effects on driving: The literature concerning the risks of
cannabis and driving is controversial, and no studies have
been published on the effects of medicinal cannabis use on
driving. The results are often influenced by the confounding
effects of alcohol. Cannabis is known to cause mild euphoria,
altered time perception and decreased motor coordination,
which affect driving skills. Studies (63) have found that perceptual motor speed and accuracy are impaired after smoking
a cannabis joint. However, it has been suggested that, unlike
users of alcohol, cannabis users are aware of their level of
intoxication and compensate for the effects by becoming very
cautious, resulting in a decrease in the speed and the frequency of overtaking, as well as an increase in the following
distance (64). It is recognized that cannabis may have significant effects on driving ability, with exaggerated effects in the
presence of alcohol (65).
Seizures: Data on the risk of epileptic seizures following
cannabis use were nonconclusive (66).
Long-term effects
Dependency: The risk of cannabis dependency is an important
consideration when contemplating its medical use. In the present supplement, this is discussed further by Gourlay (pages 38A43A). Although dependence on cannabis has been described, it
is difficult to quantify the extent of this risk. Cannabis has a
lower rate of conditional dependence (the risk of developing
dependence among those who have used the drug) than alcohol, cocaine, heroin or tobacco, although the rate increases
with the amount used (67). Substance abuse rarely begins with
therapeutic use alone, as the experience with opioid analgesics
has shown (68). Withdrawal symptoms such as cravings, irritability, anxiety, depression, reduced appetite and poor sleep
after withdrawal from oral THC and smoked cannabis have
been described (69-71), but the symptoms are limited to
heavy, chronic users and are relatively short lived (72).
The abuse potential of nabilone (73) and dronabinol (74)
have been examined and there is no published evidence that
these drugs are prone to abuse or diversion (however, see the
article by Gourlay). Long-term monitoring data on addictive
behaviours are needed.
Cognitive function: The effects of long-term cannabis use on
cognitive function remain controversial (75,76). In chronic
users (10 to 15 years), cognitive impairments, such as deficits
in memory of word lists, compared with nonusers are observed,
but these resolve after 30 days of abstinence and may be related to acute effects (77). A meta-analysis (78) of the residual
neurocognitive effects of cannabis use reported decreases in
the performance of memory tasks. A recent study (79) suggested
that patients with advanced HIV/AIDS may be at risk for aggravated memory impairment due to cannabis use. The long-term
effects of cannabis use on neurocognitive function may be due
to a direct effect of cannabis use or may be due to confounding
effects (80); further research is required to draw conclusions.
Drug interactions: THC and other cannabinoids are metabolized by enzymes that are also responsible for the metabolism of
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commonly prescribed medicines. This may potentially result in
important drug-drug interactions. At least two cytochrome
(CY) P450 enzyme systems, CYP2C and CYP3A, have been
shown to be involved in the metabolism of cannabinoids (81).
Recently, it was found that although delta-9-THC and antiretroviral drugs are metabolized by CYP3A, administration of
THC (smoked or orally) does not significantly reduce plasma
concentrations of antiretroviral drugs in patients with
HIV/AIDS (82). Potential interactions with tricyclic antidepressants have been reported (83-85), but a conclusive link has
not been established.
Immunity: It is apparent that delta-9-THC has immunomodulating effects, but the related health risks are not well defined.
The dose required to obtain such effects is greater than that
required for psychoactive or therapeutic effects (86). In a randomized, double-blind study of the effects of smoked cannabis
(3.95% THC, 1 g three times daily) and oral THC (2.5 mg
three times daily) administered over 21 days in patients with
HIV/AIDS, neither the smoked nor the oral THC had a significant effect on CD4 cell counts or viral loads compared with
placebo (82).
Nausea and vomiting: A recent case series (87) described a
cyclical vomiting syndrome associated with chronic, heavy
cannabis use (‘cannabinoid hyperemesis’), which was linked to
an abnormal washing behaviour.
Psychological effects: While cannabis use is associated with
depression (88) and anxiety (89), a causative link has not been
established. A recent systematic review (90) did not find a
strong association between chronic cannabis use in young people and psychosocial harm.
Long-term cognitive effects: The presence of long-term cognitive effects following chronic, heavy use has been shown
(75,78), particularly in the domains of memory and learning,
and there is debate over whether these effects are reversible
(91,92). Under medical use conditions, the relevance of these
effects has been questioned (78).
Psychosis and schizophrenia: An association between
cannabis use and an increased risk of psychosis and schizophrenia has been reported (93). In a study by Zammit et al (93),
cannabis use was found to be a risk factor for developing schizophrenia (in a dose-dependent manner). Cannabis has also
been shown to be associated with a schizotypal personality disorder (94), but the direction of this association is unclear.
Cannabis has been shown to be a risk factor in the development of psychotic symptoms in young people, particularly
among those with a predisposition for psychosis (95). Recent
modelling studies (96) have suggested that daily cannabis use
is causally associated with the development of psychosis.
‘Cannabis psychosis’ (97) has been shown to be clinically distinct from acute schizophrenia, with a shorter duration and
high rates of remission (98); however, one report (99) has
questioned the existence of cannabis psychosis disorder. A
recent retrospective study (100) and a review (101) have confirmed the association between cannabis use and precipitation
of schizophrenia in predisposed people and in people without a
history of schizophrenia.
Effects on pregnancy: The effects of cannabis on the reproductive system in humans are uncertain because the published evidence is limited and inconsistent (35). Results from human
epidemiological studies are difficult to interpret because
cannabis users are more likely than nonusers to smoke tobacco,
drink alcohol and use other illicit drugs during pregnancy.
34A
Cannabis use during pregnancy has been correlated with low
birth weight (102,103), prematurity (104) and intrauterine
growth retardation (105), although contradictory findings have
also been reported (106). Frequent maternal cannabis use may
be a weak risk factor for sudden infant death syndrome (107).
Risk of death: In one large retrospective cohort study of
patients with HIV/AIDS (108), current cannabis use was not
associated with an increased risk of non-AIDS death in men
(RR=1.72, 95% CI 0.89 to 1.39); however, it was associated
with an increased risk of AIDS-related death (RR=1.90,
95% CI 1.33 to 2.73) when compared with nonusers and
experimental users of cannabis. For women, current cannabis
use was not associated with total mortality (RR=1.09, 95% CI
0.80 to 1.49) (107). It is not clear whether the use of cannabis
was causally related to AIDS-related mortality or whether
cannabis smoking was used to treat worsening symptoms and
was a confounder in this analysis.
Vascular effects: Peripheral arteritis, which is analogous to
Buerger’s disease in tobacco smokers, has been reported in several case reports (109,110).
DISCUSSION
The use of cannabis in any form poses potential health risks
that are well described (although some remain controversial).
Cannabis smoking clearly poses unique risks, both from the
smoke and from potential contamination. The use of standardized and quality-controlled cannabis preparations with accurate monitoring and follow-up may identify and reduce these
risks. The use of pharmaceutical cannabis preparations has
risks that are well documented on product labels, but further
research is required on the long-term effects of these products.
The safety of cannabinoids in children, the elderly and
patients with comorbid disorders (eg, diabetes, hypertension,
ischemic heart disease, renal and hepatic impairment, and diseases that damage the immune system), as well as the effects of
cannabinoid use on concurrent psychiatric illness (eg, depression, anxiety, psychosis and drug abuse) are all subjects for further research.
Some broad clinical recommendations based on existing
safety information may be put forward, but these must be continuously revised as new data are published. Patients with a history of a psychotic disorder such as schizophrenia should not use
cannabis. The use of cannabis during pregnancy should be
avoided. Patients with uncontrolled hypertension and active
ischemic heart disease should avoid cannabis. Patients using
cannabis therapeutically should not drive or operate heavy
machinery while experiencing the psychoactive effects of
cannabis (consistent with advice concerning the therapeutic
use of other psychoactive agents such as benzodiazepines and
opioids). Patients with comorbid depression and other psychiatric disorders should be carefully monitored. Cannabinoids
should be administered initially at low doses and titrated slowly
to balance the positive and negative acute effects. Patients
should be advised of the nature and likelihood of acute effects,
and close monitoring is advised during the initial dose titration.
Most of our current knowledge about the risks of herbal
cannabis is derived from studies of recreational users, and these
risks may or may not be relevant in a medical use paradigm.
The doses used may be different, the psychoactive effects at
therapeutic doses may have a different impact, and the total
lifetime exposure may be different. A considerable cumulative
dose response to cannabinoids has been observed in many
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Safety issues with the medical use of cannabis/cannabinoids
areas and, therefore, some risks apply only to those who use
cannabis over a long period of time.
CONCLUSIONS
Cannabis is used by many patients with a wide range of chronic
disorders. Canadian physicians are being asked to support patient
applications for authorizations to cultivate and possess cannabis
for medical purposes. Physicians need to be able to provide a concise summary of known or suspected risks to their patients. It is
hoped that this review will be a useful tool in this regard.
SUGGESTED FURTHER READING
• Zimmer L, Morgan JP. Marijuana Myths, Marijuana
Facts: A Review of the Scientific Evidence. New York:
Lindesmith Centre, 1997.
• Joy JE, Watson SJ, Benson JA, eds. Marijuana and Medicine:
Assessing the Science Base. Institute of Medicine report.
Washington: National Academy Press, 1999.
• Iversen LL. The Science of Marijuana. Oxford: Oxford
University Press, 2000.
• Castle D, Murray R, eds. Marijuana and Madness.
Cambridge: Cambridge University Press, 2004.
• Grinspoon L, Bakalar JB. Marijuana: The Forbidden
Medicine. New Haven: Yale University Press, 1997.
SUPPORT: Dr Mark Ware is supported by the fonds de la
recherche en santé (Boursier-clinicien junior 1) and holds grants
from the Canadian Institutes of Health Research. He has received
honoraria from Valeant and AstraZeneca, has sat on advisory boards
for Bayer and Valeant, has acted as a consultant to Cannasat, and
has conducted research with grants from GW Pharmaceuticals and
Valeant.
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REVIEW
Addiction and pain medicine
Douglas Gourlay MD FRCPC FASAM
D Gourlay. Addiction and pain medicine. Pain Res Manage
2005;10(Suppl A):38A-43A.
The adequate cotreatment of chronic pain and addiction disorders is
a complex and challenging problem for health care professionals.
There is great potential for cannabinoids in the treatment of pain;
however, the increasing prevalence of recreational cannabis use has
led to a considerable increase in the number of people seeking treatment for cannabis use disorders. Evidence that cannabis abuse liability
is higher than previously thought suggests that individuals with a history of substance abuse may be at an increased risk after taking
cannabinoids, even for medicinal purposes. Smoked cannabis is significantly more reinforcing than other cannabinoid administration
methods. In addition, it is clear that the smoked route of cannabis
delivery is associated with a number of adverse health consequences.
Thus, there is a need for pharmaceutical-grade products of known
purity and concentration using delivery systems optimized for safety.
Another factor that needs to be considered when assessing the practicality of prescribing medicinal cannabinoids is the difficulty in differentiating illicit from prescribed cannabinoids in urine drug testing.
Overall, a thorough assessment of the risk/benefit profile of cannabinoids as they relate to a patient’s substance abuse history is suggested.
La dépendance et les analgésiques
Le cotraitement pertinent de la douleur chronique et des troubles de
dépendance est un problème complexe et ambitieux pour les professionnels de la santé. Les cannabinoïdes ont un grand potentiel dans le traitement de la douleur, mais la prévalence croissante d’utilisation récréative
du cannabis s’associe à une augmentation considérable du nombre de personnes qui cherchent à se faire traiter pour des troubles reliés à l’utilisation du cannabis. Des données démontrant que les dommages reliés à
l’usage de cannabis sont plus élevés qu’on le pensait auparavant laissent
supposer que les personnes ayant des antécédents d’abus de drogues
seraient plus vulnérables après avoir pris des cannabinoïdes, même pour
des besoins médicinaux. Le cannabis fumé est un agent considérablement
plus renforçant que les cannabinoïdes administrés autrement. En outre, il
est clair que la voie d’administration du cannabis fumé entraîne diverses
conséquences nocives pour la santé. Ainsi, il est nécessaire de mettre au
point des produits de qualité pharmaceutique dont la pureté et la concentration sont connues, au moyen de systèmes de perfusion à l’innocuité
optimisée. Un autre facteur dont il faut tenir compte lorsqu’on évalue la
possibilité de prescrire des cannabinoïdes médicinaux demeure la difficulté de distinguer les cannabinoïdes prescrits des cannabinoïdes illicites
dans les tests de dopage. Dans l’ensemble, une analyse approfondie du profil risque-avantage des cannabinoïdes par rapport aux antécédents d’abus
de drogues du patient est suggérée.
Key Words: Addiction; Cannabis; Risk management; Substance abuse;
Urine drug testing
epending on the prevailing attitudes of the time, certain
pharmacotherapies have been perceived as either villains
or heros. At the crux of this debate has been the risk of substance misuse and addiction in the management of chronic
pain. As cannabis enters the field of pain medicine, it must
also be examined in this light.
D
THE PAIN AND ADDICTION CONTINUUM
The notion that pain and addiction can coexist is a relatively
recent concept. Previously, the literature suggested that the
prevalence of addictive disorders in the pain population was so
uncommon that it did not merit investigation (1,2). This belief
still persists today (albeit much less so) despite the fact that the
prevalence of addictive disorders within the general population
is typically quoted as 10% (3). The reasons for this are complex.
A dichotomous approach to pain and addiction is simple,
even if it is potentially incorrect. The only requirement for this
approach is to establish a ‘legitimate’ pain diagnosis and, thus,
obviate the need to enquire into issues related to substance
misuse and addiction. In some circles, asking questions related
to drug and alcohol use is seen as tantamount to dismissing the
patients’ complaints of pain. In no other area of medicine
would such a conclusion be drawn. It is becoming clear that
pain and addiction can, and do, coexist (4-7).
In understanding the relationship between pain and addiction, part of the problem seems to be nomenclature. Pain specialists and addiction practitioners alike have used common
terms that, depending on the individual’s point of view and
training, have come to mean entirely different things. To this
end, in 1999, the American Pain Society, the American
Academy of Pain Medicine and the American Society of
Addiction Medicine formed a group called the Liaison
Committee for Pain and Addiction. The first task for this group
was the creation of a set of definitions for addiction, dependence and tolerance that could be embraced by all three organizations. These definitions were published in 2003 (8).
Addiction
“Addiction is a primary, chronic, neurobiologic disease,
with genetic, psychosocial and environmental factors
influencing its development and manifestations. It is
characterized by behaviours that include one or more of
the following: impaired control over drug use, compulsive use, continued use despite harm and craving.” (8)
Unlike the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV) (9) definition for addiction,
Centre for Addiction and Mental Health, Toronto, Ontario
Correspondence: Dr Douglas Gourlay, Addiction Medicine Clinic, Centre for Addiction and Mental Health, 33 Russell Street, Toronto,
Ontario M5S 2S1. Telephone 416-535-8501 ext 6754, fax 416-595-6821, e-mail doug-gourlay@camh.net
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physical dependency (withdrawal) and tolerance are not considered in making the diagnosis.
The usefulness of the DSM-IV definition is severely
reduced when the identified drug of misuse is also a drug which
could ultimately be an appropriate part of the patients’ pharmacological management. Although validated tools to assess
risk in the context of pain and addiction are being developed
(10), at the present time there are no tools that can differentiate between appropriate and problematic use (either misuse or
addiction) of a medication where the identified drug of choice
may also play a useful role in the management of chronic pain.
This is currently the case with opioids used in chronic noncancer pain management (11) and will undoubtedly present a
diagnostic challenge when cannabis becomes more widely used
to treat chronic pain.
Physical dependence
“Physical dependence is a state of adaptation that is
manifested by a drug class specific withdrawal syndrome
that can be produced by abrupt cessation, rapid dose
reduction, decreasing blood level of the drug, and/or
administration of an antagonist.” (8)
The phenomenon of physical dependence is an expected,
neuroadaptive change that occurs in response to chronic exposure to certain drugs. It is not, in itself, suggestive of anything
beyond this.
Tolerance
“Tolerance is a state of adaptation in which exposure to
a drug induces changes that result in a diminution of one
or more of the drug’s effects over time.” (8)
In the case of tolerance, it is important to remember that it is
neither good nor bad; it simply is. In some cases, such as the cognitive blunting effects of opioids, tolerance occurs relatively
quickly and is considered positive. On the other hand, tolerance
to the constipating effects of opioids virtually never occurs.
What is particularly important about these definitions is
that the boards of representative organizations from both the
pain management and addiction medicine communities have
endorsed them. While these definitions represent a compromise, they are an important step forward in reducing the risk of
the continued use of imprecise terms in both the pain management and addiction medicine literature.
Although the true prevalence of addiction within the
chronic pain management population is unknown, the enormous problem that chronic pain represents in the substance
abuse treatment population is beginning to be appreciated
(12,13). A study by Rosenblum et al (14) found that 37% of
patients surveyed within methadone maintenance treatment
programs suffered from chronic severe pain. They also concluded that self-medication with psychoactive drugs for pain
was especially problematic for substance abusers enrolled in
drug-free (abstinence-based) treatment programs.
THE DISEASE OF ADDICTION
Drug abuse and addiction represent challenges to society at
several levels. While it is tempting to focus on the impact of
Pain Res Manage Vol 10 Suppl A Autumn 2005
addiction on individualistic health, there is also an adverse
impact on public health.
In 1998, the Substance Abuse and Mental Health Services
Administration estimated that 13.6 million Americans aged
12 years and older had used an illicit drug in the previous
month (15). The harm done by this use occurs not only at the
level of the brain, but is also seen in increased rates of HIV transmission, hepatitis B and C, and tuberculosis. The societal cost of
associated criminality and social dysfunction is difficult to
accurately ascertain but has been estimated at US$109 billion
annually (16).
There are many different factors that lead to drug use
including genetic, physiological and even social factors (17). In
addition, there are both risk and protective factors that modify
the expression of a substance use disorder. Risk factors include
weak family structure, peer group pressures and growing up in
high-crime neighbourhoods. On the other hand, strong family
bonds and academic achievement may be protective (18).
By stepping beyond the question of why some people choose
to use drugs recreationally and by focusing only on those who do,
it is realized that in the at-risk individual, the chronic exposure to
certain psychotropic substances causes changes in brain structure and function. Addiction is not only a ‘disease of the brain’
(19) but also a disease with both behavioural and social expression. Treatment of addiction requires changes to be made both
within the patient and in the surrounding environment.
PREVALENCE OF DRUG USE AND
DEPENDENCE
There is considerable variation in the prevalence of drug use
depending on the drug being considered and the population
under study. Alcohol, tobacco and caffeine are the most commonly used psychotropics (20). Drugs like heroin and cocaine
are much less commonly used.
In general, the use of cannabis has remained relatively constant over recent years; however, it is on the rise among young
adults in certain ethnic and racial groups (21). In fact,
cannabis has been shown to be the most widely used illicit substance in communities around the world (22-24).
In the United States, according to the 2000 United States
National Household Survey on Drug Abuse (22), 2.8 million
Americans met the criteria in the previous year for either
cannabis dependence (1.6 million) or abuse (1.2 million).
Furthermore, this survey reported that 25% (713,000) of those
with cannabis use disorder actually seek treatment. That is more
than those seeking treatment for cocaine, hallucinogens, stimulants, pain relievers, inhalants, tranquilizers, heroin or sedatives
(25).
In the United States, it is estimated that of those who have
ever used cannabis, 10% will develop dependence (26). Of those
who try cannabis more than once, approximately one-third will
become regular users even though most will have stopped using
it by their late 20s or 30s (27). In fact, the relative potential for
dependence on cannabis, expressed in terms of conditional
dependence (the risk of developing dependence among those
who have ever used that substance) (26), is approximately 9%,
which is lower than other substances such as alcohol (15%),
cocaine (17%), heroin (23%) or tobacco (32%) (26,28).
In Canada, the number of Canadians aged 15 years and older
who admit to using cannabis nearly doubled between 1989 and
2002, with the highest rate among teenagers (29). In fact,
6.5% of Canadians reported using cannabis in 1989, 7.4% in
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1994 and 12.2% in 2002. Of those who reported use in the
previous year, approximately 47% had used cannabis less than
once per month. However, 20% reported regular use, with onehalf of these using it weekly and the other one-half using it daily
(29). In the Ontario Student Drug Use Survey of grades 7, 9
and 11 students, 21.8% had used cannabis in the past year in
1977, 9.9% in 1991 and 27.8% in 2003 (30).
A recent study (31) in Nova Scotia examining cannabis use
in patients suffering from chronic pain showed that 36% had previously used cannabis, 15% had tried it for pain relief and 10%
were currently using it for the treatment of their chronic pain.
CANNABIS USE
Cannabis as a drug with abuse liability
For some time, cannabinoids were considered unimportant in
brain reward systems, despite the fact that they are clearly
euphorigenic in humans and do have abuse liability (32,33).
More recent work over the past 15 years has shown cannabinoids to interact with the brain reward systems in a similar
fashion to other drugs with addiction liability (34,35).
Drugs with addiction liability often share certain qualities,
which can be demonstrated in the animal laboratory setting.
One of these is the involvement of the endogenous opioid
system even for nonopioid addictive drugs.
In this case, the rewarding effect of cannabinoids can be
attenuated by opioid antagonists, which is characteristic of
drugs with addiction liability (32). More recently, Justinova et al
(36) demonstrated this attenuating effect of the opioid antagonist naltrexone on the reinforcing effects of delta-9-tetrahydrocannabinol (THC) in squirrel monkeys.
Finally, in previously dependent but now abstinent animals,
drugs with addiction liability are often able to reinstate drugseeking and self-administration behaviour in response to a
‘priming’ dose of the drug. Although there is a paucity of data
in this area, there is evidence that the intravenous priming of
former heroin-dependent rats with cannabinoid agonists can
lead to reinstatement of drug-seeking behaviour (32,37).
Recently, it has been demonstrated with cannabis-naïve
squirrel monkeys that THC can act as an effective reinforcer of
drug-taking behaviour in monkeys with no history of exposure
to other drugs. This suggests that self-administration of THC
by monkeys may provide a reliable animal model of human
cannabis abuse (38).
Thus, it would be reasonable to conclude that cannabinoids
share many of the qualities demonstrated in other drugs, which
are clearly seen as having a high addiction liability (33). This
becomes important when assessing risk in the use of this class of
drug for the management of pain, especially in those individuals
with a history or an increased risk of a substance use disorder.
Cannabis dependence, tolerance and withdrawal
The existence of a definable withdrawal syndrome with cannabis
has long been questioned. Before the publishing of the DSM-IV,
cannabis dependence did not exist as a specific diagnostic category (34). More recently, research has begun to characterize this
phenomenon more clearly. Tolerance to cannabis can develop
after periods of daily use as short as one to three weeks. The
resultant withdrawal symptoms that occur on abrupt discontinuation of cannabis typically begin after 24 h, peak at 72 h and are
usually over within seven to 10 days (39). The symptoms are
nonspecific and include irritability, anxiety, physical tension,
and decreases in mood and appetite. In some cases, there is
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restlessness, tremors, sweating, insomnia and even vivid
dreams. The time frame is highly variable and appears to be similar to that seen with other drugs of abuse (40).
Cannabis use disorders
Recent studies in the United States have shown that more
people are self-identifying themselves as having cannabis use
disorders (as indicated by a tremendous increase in admissions
to publicly funded treatment programs). The demand for treatment from health professionals, however, remains low relative
to the apparent problem. In 1999, the United States
Treatment Episode Data Set (41) recorded more than 220,000
admissions for cannabis use disorder treatment, which represents 14% of all admissions to these facilities – a doubling in
rate compared with 1993 (42). By 2000, cannabis admissions
accounted for 61% of all adolescent admissions. These trends are
also observed in Australia, where they have seen a doubling in
the national rates of cannabis treatment-seeking individuals
from 2000/2001 to 2001/2002, with an overall rate of 21% and
a specific rate of 45% in those younger than 20 years of age
(43). There has also been a concomitant increase in cannabisrelated emergency room visits in the United States. Adjusting
for population changes, this represents a 139% increase in
reported visits for the period of 1995 to 2002 (44).
In a recent article (21) examining the prevalence of
cannabis use disorders in the United States duing 1991/1992
and 2001/2002, the authors indicate that despite an overall stable
prevalence of cannabis use, more adults in the United States
had a cannabis use disorder in 2001/2002 compared with
1991/1992. While these rates did not increase for young, white
men and women, their rates of use remained high (34.4% for
2001/2002). In contrast, the rates of cannabis abuse or dependence increased by 18% from 30.2% in 1991/1992 to 35.6% in
2001/2002 across the general population surveyed (21).
Two important factors were identified that might help to
explain the increase in cannabis use disorders. The first is the
significant increase in the potency of cannabis from police
seizures over the time period of 1992 to 2002 (45). In the
absence of any systematic increase in frequency or quantity of
cannabis used over the time frame studied, the increasing rates
of cannabis use disorders may reflect an increased potency of
the cannabis used (21).
Although research clearly indicates that concentrations of
seized cannabis have been rising, the actual percentage increase
has been difficult to assess (45,46). The cannabinoid concentration of cannabis seized in Canada does appear to have been
increasing over the years. Although the concentrations quoted
vary widely, depending on the sample and method of analysis,
the average cannabinoid concentration of cannabis seized in the
1980s was less than 1%, while the average over the period of
1996 to 2000 was 6.7% (47). The use of selective breeding and
hydroponic cultivation has dramatically increased the potency
of today’s cannabis (48). Information from ‘street seizures’ in
Canada from April 2000 to April 2002 indicates a mean THC
content of 10% with a range of 3% to 30% (49). According to
the World Health Organization, the average joint contains 0.5 g
to 1.0 g of cannabis plant matter (50). This makes the estimation of ‘average dose’ exceedingly difficult.
The second possible factor to explain increased cannabis
use disorders relates to the increase in use observed in the
younger age groups. Because an early onset of drug use has been
consistently associated with an increased risk of developing a
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substance use disorder (51-53), the increase in duration of use
associated with this younger using population may help to
account for the increased prevalence in rates of cannabis abuse
and dependence (21).
Methods of cannabis use
Cannabis is used in a wide variety of ways. Most commonly, it is
smoked either alone as a cannabis cigarette or mixed with
tobacco (27). It can also be refined into a smokable resinous
mass (hashish) or further refined into a potent oil (‘hash oil’ or
‘honey oil’) that is either smoked with tobacco-containing products or vaporized with a constant-temperature device (54). In
some cultures, cannabis is taken orally as either an ingredient in
foods (55) (eg, ‘hash brownies’) or as a tea (‘ganja tea’). The
mode of delivery directly affects the speed of onset and duration
of action of the desired (and sometimes undesired) effects of this
drug and, therefore, affects the abuse liability.
The speed of drug delivery also affects the reinforcing
nature of a drug and, hence, its abuse liability. The inhaled
route is a fast and effective method of delivering precise quantities of drug at the instant the individual desires it (56). With
inhalation (ie, smoked), the drug is delivered into the cerebral
vascular circulation very rapidly. Coupled with the fact that
the user can titrate the quantity of drug delivered by the degree
of force used during inhalation and the time that the breath is
held, the inhaled route is a fast and very reinforcing means of
delivering substances to the human brain (57).
Smoking as a delivery system
It is important to separate the drug from the delivery system in
the assessment of risk. As presented in other articles in this
symposium, there is significant potential for cannabinoids in
the treatment of pain. In addition, it is clear that the smoked
route of delivery is potentially associated with a number of
adverse health consequences (58). Thus, it is a priority to minimize the risks of smoking. Appreciating this point, both natural
plant extract (59,60) and synthetic oral cannabinoids have
been developed (61).
SYNTHETIC CANNABINOIDS
At the present time, two synthetic cannabinoids are available
for medical use in Canada. The first is a true synthetic THC,
dronabinol (Marinol, Solvay Pharma Inc, Canada) (62), and
the other is a synthetic cannabinoid called nabilone (Cesamet,
Valeant Canada limitée/Limited) (63).
Marinol
Marinol was first approved for use in the United States in 1985
and it is currently available for two specific indications: the
treatment of anorexia associated with weight loss in patients
with AIDS, and the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to
respond adequately to conventional antiemetic treatments
(62). Marinol is a synthetic THC dissolved in sesame seed oil
and, when taken orally, the drug is unpredictably absorbed
from the gastrointestinal tract. In contrast to the inhaled route
of administration, there is very little opportunity for the
patient to titrate the dose to effect. Adverse side effects are
common (64).
In the past, it has been reported that the abuse liability of
Marinol is low (65); the authors support this by stating that the
drug lacks the desirable qualities of rapid onset and titratability
Pain Res Manage Vol 10 Suppl A Autumn 2005
commonly seen in drugs of abuse (65). At the present time,
Marinol is available in 2.5 mg, 5 mg and 10 mg capsules.
Cesamet
Cesamet is a synthetic cannabinoid that has been developed for
use as an antiemetic agent, notably for chemotherapy-induced
nausea. It is available as a pulvule (powder-containing capsule) in
0.5 mg and 1 mg strengths. This form of delivery does not appear
to lend itself to volatilization or combustion and, thereby, limits
misuse via the pulmonary route of administration.
Nabilone has been studied in comparison with the reinforcing
properties of oral THC and smoked cannabis in subjects with
previous cannabis experience. These data indicate that smoked
cannabis was significantly more reinforcing than all other
cannabis compounds studied, regardless of drug use history (66).
DRUG MONITORING
Whenever a drug or member of a class of drugs is legitimately
present in a test sample, as is the case with any prescribed medication, it becomes very difficult to monitor misuse of that drug or
class of drug. An example of this would be the problems associated with monitoring an abstinent heroin user who has been
prescribed codeine-containing analgesics for the management of
pain. In this case, morphine that results from the metabolism of
heroin (diacetyl morphine) will be impossible to distinguish from
the morphine that would be expected to be present due to the
metabolism of the prescribed codeine (67,68).
From a monitoring perspective, it is relatively difficult to
distinguish smoked cannabis from orally administered or
smoked Marinol. Both routes of administration produce
immunoassay-positive screen results for THC and, because they
are identical molecules, they cannot even be distinguished by
gas chromatography/mass spectroscopy. Naturally occurring
THC-containing products are a mix of cannabinoids. One
specific cannabinoid that can be identified by sophisticated
testing, delta-9-tetrahydrocannabivarin (THCV), has been proposed as a way to specifically identify the naturally occurring
product from the synthetic agent (69,70).
In 2001, ElSohly et al (69) reported results from a cleverly
designed study using a small number of cannabis users as test
subjects. The study used a three-session, within-subject,
crossover design. Each subject randomly received on separate
sessions either an oral dose of Marinol (15 mg), a smoked dose of
pure THC (16.98 mg dronabinol) in a placebo cannabis cigarette or an equivalent smoked dose of cannabis (2.11% THC
and 0.12 mg THCV/800 mg cigarette = 16.98 mg THC and
0.96 mg THCV). They found that use of cannabis with or without Marinol could be distinguished from the use of Marinol
alone (69). Previously, they had found that the confirmatory
analytes, THC carboxylic acid and THCV carboxylic acid,
found in urine drug specimens supported these findings (70).
Cesamet, however, does not trigger a positive immunoassay
screen or a confirmatory gas chromatography/mass spectroscopy test for THC (71). In this context, a positive screen
for THC in a patient being prescribed Cesamet is consistent
only with the use of a THC-containing product such as
cannabis or Marinol.
PRACTICAL CONSIDERATIONS
IN DRUG TESTING
Urine drug testing can and should play an important role in
chronic pain management. There are, however, some limitations
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Gourlay
to its use. Apart from therapeutic drug level monitoring, the
application of drug toxicology in clinical medicine has been
largely limited to the emergency room setting. Its use is well
known within forensic settings, such as the Department of
Transportation testing, and in workplace testing. In this context, testing is often adversarial and certainly often not in the
patient’s best clinical interests. Drug testing may, however,
be patient-centred if used properly (68,72). Motivating
behavioural change, encouraging maintenance of healthy
changes already made, advocacy with third parties and early
identification of undiagnosed substance use disorders, where
they exist, make the rational use of urine drug testing a welcome addition to clinical medicine. No medical test should be
used to limit treatment or deny appropriate care. Urine drug
testing should be no exception.
Testing techniques can be divided into initial ‘screening’ and
the more definitive ‘confirmatory’ tests. Screening tests are commonly immunoassay-based and usually identify classes of drugs
rather than specific agents. Screen tests are typically very sensitive because they often react to all members of the test class
rather than to simply one specific drug. However, there are
exceptions to this, as in the case of methadone. In contrast, confirmatory testing is often less sensitive but able to accurately identify specific drugs. For example, a patient taking codeine would
be expected to have an initial positive screen for ‘opiates’, but
only on confirmatory testing do the specific agents responsible for
this positive screen (codeine and its active metabolite morphine)
become identified (67,68).
It is important to remember that neither screening nor confirmatory testing can detect all substances that may, in fact, be
present in a sample. A number of factors, including both concentration effects (dilute urine) and limitations in the testing
methodology can account for the failure to detect drugs that
may be present in a sample, including prescription drugs that
the patient is known to be taking (67,68).
A detailed description of the patient-centred approach to
urine drug testing is beyond the scope of this paper; however,
useful recommendations for the use of drug testing in the
primary care setting can be found on the Internet at
<http://www.alaskaafp.org/udt.pdf> (67), and in a report by
Heit and Gourlay (68).
CONCLUSIONS
The abuse liability and reinforcing nature of cannabis are well
established. In trying to assess the role of cannabinoids in the
management of chronic pain, one must consider the risk/benefit
profile of this class of drugs and the population in which the
agent will be used. Similarly, when determining the most effective route of administration, the patient’s history must be
examined.
If future research suggests that the smoked route of administration of cannabinoids is the ‘gold standard’ in pain management, it will be important to know the test populations’
previous experience with cannabinoids. If this is the perspective of cannabis-naïve subjects, inhaled cannabis may indeed
be the preferred route of administration. On the other hand, if
this preference seems to be largely associated with those subjects who have extensive histories with smoked cannabis, this
gold standard may become severely tarnished.
This should not diminish the potential role for cannabinoids in medicine, but rather emphasize the need for pharmaceutical grade products of known purity and concentration
using delivery systems optimized for safety, and for further
research on the safety of smoked cannabis when used for therapeutic purposes. In particular, in this case, the risks of the
delivery system must be separated from the risks of the drug.
Given that pain and addictive disorders coexist, and that
cannabinoids appear to have similar abuse liability to other
drugs that activate the brain reward systems, these drugs must
be approached with an appropriate level of caution. As is often
the case, risk lies not solely with the drug, but with the drug
used in the context of an at-risk individual.
Taking into account the prevalence of recreational cannabis
use in modern society, coupled with the increased potency of
the available street product, cannabis use disorder should be
seen as a progressive entity. Failure to rationally approach this
issue will put both the patient and the practitioner at an unacceptable and potentially reducible risk.
Those who have previously met the DSM-IV criteria for a
substance use disorder with any licit or illicit substance will
likely be at an increased risk when using cannabinoids, even
for medical purposes. Whether this elevated risk will rise to the
level of an absolute contraindication remains to be seen.
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REVIEW
Guidelines for the use of cannabinoid
compounds in chronic pain
AJ Clark MD FRCPC1, ME Lynch MD FRCPC2, M Ware MBBS MRCP MSc3, P Beaulieu MD PhD FRCA4,
IJ McGilveray PhD5, D Gourlay MD FRCPC FASAM6
AJ Clark, ME Lynch, M Ware, P Beaulieu, IJ McGilveray,
D Gourlay. Guidelines for the use of cannabinoid compounds in
chronic pain. Pain Res Manage 2005;10(Suppl A):44A-46A.
OBJECTIVE: To provide clinicians with guidelines for the use of
cannabinoid compounds in the treatment of chronic pain.
METHODS: Publications indexed from 1990 to 2005 in the
National Library of Medicine Index Medicus were searched through
PubMed. A consensus concerning these guidelines was achieved by
the authors through review and discussion.
RESULTS: There are few clinical trials, case reports or case series
concerning the use of cannabinoid compounds in the treatment of
chronic pain. There are no randomized clinical trials examining the
use of herbal cannabis in the treatment of chronic pain.
CONCLUSIONS: A practical approach to the treatment of chronic
pain with cannabinoid compounds is presented. Specific suggestions
about the off-label dosing of nabilone (Cesamet, Valeant Canada
limitée/Limited) and dronabinol (Marinol, Solvay Pharma Inc,
Canada) in the treatment of chronic pain are provided.
Key Words: Cannabinoid; Chronic pain; Dronabinol; Guideline;
Nabilone; Treatment
n Canada, there are presently two synthetic cannabinoids
and one cannabis-based medicine available by prescription.
The synthetic agents include nabilone (Cesamet, Valeant
Canada limitée/Limited) and the synthetic delta-9-tetrahydrocannabinol dronabinol (Marinol, Solvay Pharma Inc,
Canada), both of which are available in oral preparations. The
cannabis-based medicine (Sativex, GW Pharma Ltd, United
Kingdom) is available as a buccal spray and consists of an extract
containing delta-9-tetrahydrocannabinol and cannabidiol.
Sativex has only recently been approved by Health Canada (as
of April 2005) under a conditional notice of compliance.
The approved indication for nabilone and dronabinol is for
antiemesis in chemotherapy-induced nausea and vomiting,
while the indication listed for the buccal extract is adjunctive
treatment for the symptomatic relief of neuropathic pain in
multiple sclerosis. Any of these agents prescribed for pain
would be considered an ‘off-label’ use.
In addition, since July 30, 2001, Canadians have had the
opportunity to apply for a license to possess herbal cannabis
under the Medical Marijuana Access Regulations. Patients
may also apply for a license to grow marijuana or may purchase
marijuana supplied by Health Canada by completing appropriate forms.
I
Lignes directrices à l’égard de l’utilisation des
substances cannabinoïdes en cas de douleur
chronique
OBJECTIF : Fournir aux cliniciens des lignes directrices à l’égard de l’utilisation des substances cannabinoïdes dans le traitement de la douleur
chronique.
MÉTHODOLOGIE : Une recherche a été effectuée dans les publications indexées entre 1990 et 2005 dans la National Library of Medicine
Index Medicus par l’entremise de PubMed. Les auteurs sont parvenus à un
consensus à l’égard des présentes lignes directrices par suite d’une analyse
et de discussions.
RÉSULTATS : Peu d’essais cliniques, de rapports de cas ou de séries de
cas portent sur le recours aux substances cannabinoïdes dans le traitement
de la douleur chronique. Aucun essai clinique aléatoire ne traite de
l’usage du cannabis végétal dans le traitement de la douleur chronique.
CONCLUSIONS : Une démarche pratique envers le traitement de la
douleur chronique à l’aide de substances cannabinoïdes est présentée. Des
suggestions précises sont fournies au sujet du dosage dans une indication
non autorisée du nabilone (Cesamet, Valeant Canada limitée/Limited) et
du dronabinol (Marinol, Solvay Pharma Inc., Canada) dans le traitement
de la douleur chronique.
The cannabinoid research field is growing rapidly and there
are research programs around the world working on the development of cannabinoids for clinical applications. This
includes extracts of naturally occurring agents and the development of novel synthetic cannabinoid agonists and agents
that may allow for the modulation of the endogenous cannabinoid system.
As reviewed in the present supplement by Ware and
Beaulieu (1) and previously by Campbell et al (2), there are
few clinical trials regarding synthetic cannabinoids and there
are no randomized clinical trials regarding herbal cannabis in
the treatment of chronic pain. In the past three years, several
reports have been published about the use of smoked herbal
cannabis for the treatment of chronic pain related to various
causes including HIV, multiple sclerosis, neuropathic pain and
general chronic pain (3-8). These reports have identified that
15% to 36% of patients with pain have used, and 10% to 14%
continue to use, herbal cannabis for symptom relief. Moreover,
these reports have provided information about how herbal
cannabis is used, including ‘doses’, route of administration and
side effects that were experienced with use. However, this
information remains inadequate for the development of guidelines for the use of herbal cannabis. This is also the case with
1University
of Calgary, Calgary, Alberta; 2Dalhousie University, Halifax, Nova Scotia; 3McGill University; 4Université de Montréal, Montréal,
Québec; 5University of Ottawa, Ottawa; 6Centre for Addiction and Mental Health, Toronto, Ontario
Correspondence: Dr AJ Clark, Chronic Pain Centre, Calgary Health Region, #160, 2210 – 2nd Street SW, Calgary, Alberta T2S 3C3.
Telephone 403-943-9900, fax 403-209-2955, e-mail john.clark@calgaryhealthregion.ca
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Guidelines: Cannabinoid compounds in chronic pain
the buccal cannabis-based extract and, thus, these guidelines
will focus on the two oral cannabinoids currently available by
prescription in Canada. For information regarding herbal
cannabis under the Medical Marijuana Access Regulations,
clinicians are referred to the Health Canada Web site
(http://www.hc-sc.gc.ca/hecs-sesc/ocma/).
In general, contraindications to the use of cannabinoids
include pregnancy, uncontrolled hypertension, active ischemic
heart disease, arrhythmias and schizophrenia. A history of psychosis is a relative contraindication, and because cannabinoids
can cause anxiety, they should be used with caution in patients
with a past or current anxiety or panic disorder. Moreover,
cannabinoids can cause sedation and cognitive effects. Thus, the
usual cautions given for opioids, benzodiazepines or any potentially sedating agent are applicable. Patients should be cautioned
not to drive or to operate heavy machinery, etc, if experiencing
any side effects that would impair their performance in these
activities. Patients with comorbid depression and other psychiatric disorders should be carefully monitored. Cannabinoids
should be administered initially at low doses and titrated slowly to
balance positive and negative acute effects. Patients should be
advised of the likelihood and nature of acute effects, and close
monitoring is advised during initial dose titration.
EVALUATING A PATIENT FOR A TRIAL OF A
CANNABINOID
Prudent medical practice incorporates a comprehensive evaluation of a patient when new therapies are considered. The following suggestions are similar to those endorsed by the Canadian
Pain Society in its consensus statement and guidelines for the use
of opioid analgesics in the treatment of noncancer pain (9):
•
•
•
Full assessment, establish diagnosis of pain
Assess psychosocial issues and risk of addiction
Determine history of previous use of illicit substances or
misuse of prescription drugs
• Develop a treatment plan assuring that pharmacotherapy
takes place within an overall active participatory approach
• Ensure that traditional approaches to chronic
pain management have been tried or considered
Pain is inadequately treated
•
•
•
•
Consider cautions and ensure no contraindications to use of cannabinoid
Discuss potential adverse effects
Consider discussing urine testing
Review and sign treatment agreement
•
Cannabinoid-naïve:
Start an oral cannabinoid
available by prescription*
*NCesamet® (synthetic
analogue of THC,
nabilone) or NMarinol®
(synthetic THC,
dronabinol)
Previous use of cannabinoids:
• Obtain a full history of previous
cannabinoid use
• Specific cannabinoid, dose, route
of administration
• Symptoms treated and outcome
• Adverse effects
• Encourage oral route of administration
and initiate trial of oral cannabinoid
available by prescription*
If oral nabilone or dronabinol trial fails or is not financially feasible, consider cannabis:
• Discuss the fact that there are not yet clear guidelines regarding efficacy,
• doses and toxicity
• Raise awareness of oral and vaporized routes of administration
• Refer patient to Health Canada Web site and documents regarding
cannabis product
• Follow the usual clinical guidelines to start low and titrate dose slowly
Figure 1) Algorithm for the treatment of chronic pain with cannabinoids
• perform a history and examination;
• assess the level of pain;
• assess psychological contributors and risk of addiction
or substance abuse;
• document any history or current use of illicit or
nonprescribed drugs, including cannabis and synthetic
cannabinoids;
• determine the effect of the previous use of
cannabinoids on pain;
• consider urine drug screening to assess the current use
of prescribed and nonprescribed medications;
• set goals of treatment with a cannabinoid – consider
reduction of pain, increased functional abilities,
improved sleep quality, increased quality of life and a
reduction in the use of other medications;
• develop a treatment plan incorporating these goals;
• discuss possible side effects that may be experienced
with use (eg, central nervous system, cardiovascular
and respiratory);
• discuss the risks of addiction;
• develop a follow-up schedule to periodically review the
patient (the five As – Analgesia, Activities, Adverse
events, Abuse behaviours and Adequate
documentation);
• determine whether the goals of treatment are being
achieved and the appropriateness of response; and
Pain Res Manage Vol 10 Suppl A Autumn 2005
• consider developing a treatment agreement with the
patient, particularly if he/she is at risk.
Documentation is essential to demonstrate the evaluation
of the patient, the rationale for the use of a cannabinoid in the
context of the overall management plan and the periodic
review of the patient’s status.
An algorithm for the treatment of chronic pain is provided
in Figure 1.
Common side effects associated with the use of the
cannabinoids are detailed in Table 1.
Risk of addiction to and abuse of Cesamet, Marinol and
Sativex
Marinol is available suspended in sesame oil in capsule form in
2.5 mg, 5 mg and 10 mg strengths. Cesamet is available as a
pulvule (powder-containing capsule) in 0.5 mg and 1 mg
strengths. Sativex is available as a buccal spray. As Gourlay
(10) notes in the present supplement, it has been previously
reported that the abuse liability of Marinol is low because the
drug lacks the desirable qualities of rapid onset and titratability
commonly seen in drugs of abuse. The same is true for Cesamet
due to its compounding as a pulvule; it too does not appear to
lead to misuse or abuse. Comparisons of the reinforcing properties of oral tetrahydrocannabinol, smoked cannabis and
nabilone in subjects with previous cannabis experience indicate that smoked cannabis was significantly more reinforcing
than all other cannabis compounds studied, regardless of
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Clark et al
TABLE 1
Common and important side effects of cannabinoids
Central nervous
system
Euphoria
Anxiety
Panic
Paranoia
When other therapies have failed to provide adequate pain
relief or have caused unacceptable side effects, it is reasonable
to consider a trial of an oral cannabinoid:
• initiate Marinol at 2.5 mg orally at night time; and
• increase dose by 2.5 mg every two to three days to a
maximum dose of 10 mg twice daily orally.
Psychosis
Sedation
Dizziness
Somnolence
Depression
Ataxia
Possible visual/hearing disturbances
Asthenia
Possible cognitive effects
Cardiovascular
Tachycardia
Postural hypotension
Palpitations
Vasodilation (flushing, red eyes)
Increased risk of myocardial infarction within
1 h of use
Respiratory (if smoked) Bronchitis/chronic obstructive pulmonary disease
Lung infection
Increased risk for upper airway cancer
Other
Dry mouth
Headache
Abdominal pain/bloating
drug-use history (10). We do not currently have adequate
information concerning Sativex and abuse liability.
Guidelines for the use of Cesamet
Cesamet has been available in Canada since 1981 and is indicated for use as an antiemetic and to treat anorexia associated
with AIDS. There have been no adequate randomized clinical
trials on the use of Cesamet in chronic pain, although there are
two clinical reports (11,12) showing a modest benefit in some
patients.
When other therapies have failed to provide adequate pain
relief or have caused unacceptable side effects, it is reasonable
to consider a trial of an oral cannabinoid:
• initiate Cesamet at 0.5 mg orally at night time; and
• increase dose by 0.5 mg every two to three days to a
maximum dose of 2 mg orally twice daily.
Guidelines for the use of Marinol
Marinol is indicated for use as an antiemetic. There is one randomized clinical trial (13) of Marinol (with a dose up to 10 mg)
showing a modest effect in the treatment of central pain in
patients with multiple sclerosis. An ‘N-of-1’ trial in noncancer
pain subjects has demonstrated improvement in pain similar to
that with codeine at doses of 10 mg or higher (14).
46A
Sativex
Sativex is only approved for use as an adjunctive treatment for
the symptomatic relief of neuropathic pain in multiple sclerosis.
The product monograph for Sativex recommends a “gradual
increase in dose as needed and tolerated until satisfactory pain
relief is achieved” (15). There is insufficient published information on the dosing of Sativex to make recommendations
about its use at this time.
REFERENCES
1. Ware M, Beaulieu P. Cannabinoids for the treatment of pain:
An update on recent clinical trials. Pain Res Manage
2005;10(Suppl A):27A-30A.
2. Campbell FA, Tramer MR, Carroll D, Reynolds DJ, Moore RA,
McQuay HJ. Are cannabinoids an effective and safe treatment
option in the management of pain? A qualitative systematic review.
BMJ 2001;323:13-6.
3. Lynch ME, Clark AJ. Cannabis reduces opioid dose in the
treatment of chronic non-cancer pain. J Pain Symptom Manage
2003;25:496-8.
4. Ware M, Gamsa A, Persson J, Fitzcharles M. Cannabis for chronic
pain: Case series and implications for clinicians. Pain Res Manag
2002;7:95-9.
5. Ware MA, Doyle CR, Woods R, Lynch ME, Clark AJ. Cannabis
use for chronic non-cancer pain: Results of a prospective survey.
Pain 2003;102:211-6.
6. Page SA, Verhoef MJ, Stebbins RA, Metz LM, Levy JC. Cannabis
use as described by people with multiple sclerosis. Can J Neurol Sci
2003;30:201-5.
7. Clark AJ, Ware MA, Yazer E, Murray TJ, Lynch ME. Patterns of
cannabis use among patients with multiple sclerosis. Neurology
2004;62:2098-100.
8. Prentiss D, Power R, Balmas G, Tzuang G, Israelski DM. Patterns
of marijuana use among patients with HIV/AIDS followed in a
public health care setting. J Acquir Immune Defic Syndr
2004;35:38-45.
9. Jovey RD, Ennis J, Gardner-Nix J, et al; Canadian Pain Society.
Use of opioid analgesics for the treatment of chronic noncancer pain –
consensus statement and guidelines from the Canadian Pain
Society, 2002. Pain Res Manage 2003;8(Suppl A):3A-28A.
10. Gourlay D. Addiction and pain medicine. Pain Res Manag
2005;10(Suppl A):38A-43A.
11. Notcutt WG, Price M, Chapman G. Clinical experience with
nabilone for chronic pain. Pharm Sci 1997;3:551-5.
12. Martyn CN, Illis LS, Thom J. Nabilone in the treatment of
multiple sclerosis. Lancet 1995;345:579.
13. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid
dronabinol reduce central pain in multiple sclerosis? Randomised
double blind placebo controlled crossover trial. BMJ 2004;329:253.
14. Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A,
Brenneisen R. The analgesic effect of oral delta-9tetrahydrocannabinol (THC), morphine, and a THC-morphine
combination in healthy subjects under experimental pain
conditions. Pain 2003;105:79-88.
15. Sativex product monograph. GW Pharmaceuticals. Salisbury:
United Kingdom, 2005.
Pain Res Manage Vol 10 Suppl A Autumn 2005
Instructions to Authors_pain.qxd
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Pain Research & Management
PAIN RESEARCH & MANAGEMENT will consider for publication original papers on any scientific aspect of pain, namely basic
science and animal studies, and clinical topics, including epidemiological, social, psychological and psychiatric aspects, as well as
reviews and case reports. Management topics, the economic aspects of pain and historical studies are also welcome. Papers may
deal with specific Canadian aspects of pain, but there is no restriction in this respect and international submissions will be readily
received. The Journal is pleased to accept articles in either English or French. Manuscripts are received with the understanding
that they are submitted solely to Pain Research & Management, and that none of the material contained in the manuscript has been
published previously or is under consideration for publication elsewhere, with the exception of abstracts.
INSTRUCTIONS TO AUTHORS
Hardcopy manuscripts can be sent (in triplicate, including three copies of all illustrations) accompanied by an electronic
version saved on floppy disk or CD-ROM to:
Dr Harold Merskey, Editor-in-Chief, Pain Research & Management,
71 Logan Avenue, London, Ontario N5Y 2P9
Authors are encouraged to contact the editor by telephone at 519-679-1045, by fax at 519-679-6849 or
by e-mail at merskey@sympatico.ca
IMPORTANT
To ensure that the final, published version matches the electronic file, make sure that you use only the
following fonts: Arial, Courier, Symbol and Times. The use of nonstandard fonts may lead to missing
symbols. The font size should be no smaller than 7 point and no larger that 14 point.
There is no charge for black and white figures. However, authors will be charged for colour figures at the
rate of $300 for the first figure and $100 for each subsequent figure.
SUBMISSIONS
1)Save text and graphics on floppy disk or CD-ROM.
2)Label all submissions with your name and filenames. Please also include details of the platform (PC or Mac) used.
3)Ensure that electronic and hardcopy versions of your manuscript are identical. In cases of a discrepancy, the hardcopy
version will be used as the definitive version.
TEXT
Text files must be saved as .doc files.
TABLES: Type double-spaced, on a separate page from the rest of the text with the table number above the table and
explanatory notes below. Table numbers should appear in Arabic numerals and should correspond to the order of the tables
in the text. If abbreviations are used, an alphabetical listing must be included in the footnote. Written permission from the
publisher to reproduce any previously published tables must be included.
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which figures are presented in the text. Identify all abbreviations appearing on figures in alphabetical order at the end of each
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MANUSCRIPTS
All manuscripts must be accompanied by a covering letter detailing what is being submitted and indicating the author to whom we
should address correspondence and page proofs in the case of multiple authors (please include a contact address, telephone/fax
numbers and e-mail address).
Author must sign a publishing agreement supplied by Pulsus Group Inc upon acceptance for publication.
Abbreviations must be defined at first mention in the text. All measurements should be in SI units. Appropriate headings and
subheadings should be provided in the methods, results and discussion sections. References, figures and tables should be cited in
the text with numbers assigned according to the order of mention in the text.
Arrange the manuscript as follows: title page, summary, structured abstract and key words, introduction, methods, results,
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TITLE PAGE: In addition to the main title, a short running title of 45 characters or less and the authors’ names (including full,
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ABSTRACT: On a separate page, type a structured abstract of no more than 250 words for major articles (including review
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rather than purely descriptive. Abbreviate only standard units of measurement.
KEY
WORDS:
At the end of the abstract, include a list of 3 to 6 key words for indexing purposes.
ACKNOWLEDGEMENTS: Brief acknowledgements may appear at the end of the text, before the references.
REFERENCES: Identify references in the text by Arabic numerals in parentheses on the line. Type the reference list doublespaced, separate from the text, with each reference numbered consecutively in the order in that it is mentioned in the text.
References cited in figures and tables, but not in the text, should also be numbered following the text references. Personal
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mentioned in the text in parentheses. Identify abstracts with the abbreviation ‘Abst’ and letters to the editor by ‘Lett’ in
parentheses; abstracts should not be cited if they are more than 2 years old.
The style of references is that of Index Medicus. Journal references should contain inclusive page numbers; book references,
specific page numbers; and Web site references, the date of last update, if available, and date of access (references to other
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Internet. The style and punctuation of references are as follows:
Periodicals
List all authors if 6 or less; otherwise list first 3 and add ‘et al’. Do not use periods after authors’ initials.
1. Kohl P, Day K, Noble D, et al. Cellular mechanisms of cardiac mechano-electric feedback in a mathematical model. Can J Cardiol 1998;14:111-9.
Books
2. Svensson LG, Crawford ES. Cardiovascular and Vascular Disease of the Aorta. Toronto: WB Saunders Company, 1997:184-5.
Chapter in book
3. Trehan S, Anderson JL. Thrombolytic therapy. In: Yusuf S, Cairns JA, eds. Evidence Based Cardiology. London: BMJ Books, 1998:419-44.
Web sites
4. National Library of Medicine. Images from the History of Medicine. <http://www.ihm.nlm.nih.gov/> (Version current at January 5, 1999).
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Potential authors who have further questions about these issues should contact the editorial office at 519-679-1045.
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Volume 10 Supplement A • Autumn 2005
Pain Research
&Management
Cannabinoids for Pain Management
Guest Editor: Dr Alexander J Clark
Publication of this supplement sponsored by an
unrestricted educational grant from Valeant
The Journal of the Canadian Pain Society
Journal de la société canadienne pour
le traitement de la douleur
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