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Goya
P et al. Cannabinoids and Neuropathic Pain.
Mini Reviews in Medicinal Chemistry 2003;
3 : 765-772 |
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A brief overview of the endocannabinoid system
(CB receptors, and endocannabinoids) and of
the cannabinergic ligands, some general issues
related to cannabinoids and pain are commented.
Finally, the most important findings regarding
cannabinoids and neuropathic pain are discussed
in detail.
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MacDonald
J.Christie and Christopher W.Vaughan, Cannabinoids
act backwards. Nature Vol 410, March 2000,
pp 527:530 |
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No abstract available
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Meng
ID, Manning BH et al. An analgesia circuit
activated by cannabinoids. Nature 1998:
395: 381-83 |
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Although many anecdotal reports indicate that
marihuana and its active constituent, delta-9-tetrahydrocannabinol
(delta-9-THC), may reduce pain sensation, studies
of humans have produced inconsistent results.
In animal studies, the apparent pain-suppressing
effects of delta-9-THC and other cannabinoid
drugs are confounded by motor deficits. Here
we show that a brainstem circuit that contributes
to the pain-suppressing effects of morphine
is also required for the analgesic effects of
cannabinoids. Inactivation of the rostral ventromedial
medulla (RVM) prevents the analgesia but not
the motor deficits produced by systemically
administered cannabinoids. Furthermore, cannabinoids
produce analgesia by modulating RVM neuronal
activity in a manner similar to, but pharmacologically
dissociable from, that of morphine. We also
show that endogenous cannabinoids tonically
regulate pain thresholds in part through the
modulation of RVM neuronal activity. These results
show that analgesia produced by cannabinoids
and opioids involves similar brainstem circuitry
and that cannabinoids are indeed centrally acting
analgesics with a new mechanism of action.
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Rice
A. Cannabinoids and pain. Current Opinion
in Investigational Drugs 2001;2(3): 399-414 |
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Recent advances have dramatically increased
our understanding of cannabinoid pharmacology:
the psychoactive constituents of Cannabis sativa
have been isolated, synthetic cannabinoids described
and an endocannabinoid system identified, together
with its component receptors, ligands and their
biochemistry. Strong laboratory evidence now
underwrites anecdotal claims of cannabinoid
analgesia in inflammatory and neuropathic pain.
Sites of analgesic action have been identified
in brain, spinal cord and the periphery, with
the latter two presenting attractive targets
for divorcing the analgesic and psychotrophic
effects of cannabinoids. Clinical trials are
now required, but are hindered by a paucity
of cannabinoids of suitable bioavailability
and therapeutic ratio.
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Beaulieu
P et Rice ASC.: Pharmacologie des dérivés
cannabinoïdes: applications au traitement
de la douleur. Ann Fr Anesth Réanim
2002; 21: 493-508 |
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OBJECTIVE: To present the cannabinoid
system together with recent findings on the
pharmacology of these compounds in the treatment
of pain.
DATA SOURCES: Search through
Medline database of articles published in French
and English since 1966. Also use of other publications
such as books on cannabis.
STUDY SELECTION: All the relevant
documents within the theme of this review were
used.
DATA EXTRACTION: All the data
linked to the present topic were searched.
DATA SYNTHESIS: Recent advances
have dramatically increased our understanding
of cannabinoid pharmacology. The psychoactive
constituents of Cannabis sativa have been isolated,
synthetic cannabinoids described and an endocannabinoid
system identified, together with its component
receptors and ligands. Strong laboratory evidence
now underwrites anecdotal claims of cannabinoid
analgesia in inflammatory and neuropathic pain.
Sites of analgesic action have been identified
in brain, spinal cord and the periphery, with
the latter two presenting attractive targets
for divorcing the analgesic and psychotrophic
effects of cannabinoids. Clinical trials are
now required, but are hindered by a paucity
of cannabinoids of suitable bioavailability
and therapeutic ratio.
CONCLUSION: The cannabinoid
system is a major target in the treatment of
pain and its therapeutic potential should be
assessed in the near future by the performance
of new clinical trials.
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Price
M. A.P. and Notcutt W. G., Cannabis and
Cannabinoids in Pain Relief. Cannabis: the
genus cannabis. Harcowt Acad. Public. 1998 |
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A complete overview of the endocannabinoid system
is discussed in detail. Clinical experiences
with sixty patients treated with nabilone in
the pain relief service of Janes Paget Hospital
is also presented.
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Rice
AS et al. Endocannabinoids and pain: spinal
and peripheral analgesia in inflammatory
and neuropathy. Prostaglandins Leukot Essent
Fatty Acids 2002 ; 66(2-3):243-56 |
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Analgesia is an important physiological function
of the endocannabinoid system and one of significant
clinical relevance. This review discusses the
analgesic effects of endocannabinoids at spinal
and peripheral levels, firstly by describing
the physiological framework for analgesia and
secondly by reviewing the evidence for analgesic
effects of endocannabinoids obtained using animal
models of clinical pain conditions.In the spinal
cord, CB(1) receptors have been demonstrated
in laminae of the dorsal horn intimately concerned
with the processing of nociceptive information
and the modulation thereof. Similarly, CB(1)
receptors have been demonstrated on the cell
bodies of primary afferent neurones; however,
the exact phenotype of cells which express this
receptor requires further elucidation. Local
administration, peptide release and electrophysiological
studies support the concept of spinally mediated
endocannabinoid-induced analgesia. Whilst a
proportion of the peripheral analgesic effect
of endocannabinoids can be attributed to a neuronal
mechanism acting through CB(1) receptors expressed
by primary afferent neurones, the antiinflammatory
actions of endocannabinoids, mediated through
CB(2) receptors, also appears to contribute
to local analgesic effects. Possible mechanisms
of this CB(2)-mediated effect include the attenuation
of NGF-induced mast cell degranulation and of
neutrophil accumulation, both of which are processes
known to contribute to the generation of inflammatory
hyperalgesia.The analgesic effects of cannabinoids
have been demonstrated in models of somatic
and visceral inflammatory pain and of neuropathic
pain, the latter being an important area of
therapeutic need.Analgesia is one of the principal
therapeutic targets of cannabinoids. This review
will discuss the analgesic effects of endocannabinoids
in relation to two areas of therapeutic need,
persistent inflammation and neuropathic pain.
The more general aspects of the role of cannabinoids,
endogenous and exogenous, in analgesia have
been recently reviewed elsewhere (Rice, Curr
Opi Invest Drugs 2001; 2: 399-414; Pertwee,
Prog Neurobil 2001; 63: 569-611; Rice, Mackie,
In: Evers A. S, ed. Anesthetic Pharmacology:
Physiologic Principles and Clinical Practice.
St. Louis: Harcourt Health Sciences, 2002).
Since a major goal in the development of cannabinoid-based
analgesics is to divorce the antinociceptive
effects from the psychotrophic effects, the
discussion will focus on the antinociceptive
effects produced at the spinal cord and/or peripheral
level as these areas are the most attractive
targets in this regard. A mechanistic discussion
of the "framework" for analgesia will
be followed by a description of studies examining
the role of endocannabinoids in relieving pain;
since the elucidation of these effects was undertaken
using synthetic cannabinoids, reference will
also be made to such studies, in the context
of endocannabinoids.
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Pertwee
RG. Cannabinoid receptors and pain. Prog
Neurobiol. 2001 Apr;63(5):569-611. |
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Mammalian tissues contain at least two types
of cannabinoid receptor, CB(1) and CB(2), both
coupled to G proteins. CB(1) receptors are expressed
mainly by neurones of the central and peripheral
nervous system whereas CB(2) receptors occur
centrally and peripherally in certain non-neuronal
tissues, particularly in immune cells. The existence
of endogenous ligands for cannabinoid receptors
has also been demonstrated. The discovery of
this 'endocannabinoid system' has prompted the
development of a range of novel cannabinoid
receptor agonists and antagonists, including
several that show marked selectivity for CB(1)
or CB(2) receptors. It has also been paralleled
by a renewed interest in cannabinoid-induced
antinociception. This review summarizes current
knowledge about the ability of cannabinoids
to produce antinociception in animal models
of acute pain as well as about the ability of
these drugs to suppress signs of tonic pain
induced in animals by nerve damage or by the
injection of an inflammatory agent. Particular
attention is paid to the types of pain against
which cannabinoids may be effective, the distribution
pattern of cannabinoid receptors in central
and peripheral pain pathways and the part that
these receptors play in cannabinoid-induced
antinociception. The possibility that antinociception
can be mediated by cannabinoid receptors other
than CB(1) and CB(2) receptors, for example
CB(2)-like receptors, is also discussed as is
the evidence firstly that one endogenous cannabinoid,
anandamide, produces antinociception through
mechanisms that differ from those of other types
of cannabinoid, for example by acting on vanilloid
receptors, and secondly that the endocannabinoid
system has physiological and/or pathophysiological
roles in the modulation of pain.
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Richardson
JD et al. Cannabinoids reduce hyperalgesia
and inflammation via interaction with peripheral
CB1 receptors. PAIN 1998, 75 : 111-119 |
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Central antinociceptive effects of cannabinoids
have been well documented. However, relatively
little is known about the peripheral effects
of the cannabinoids on inflammation. In the
present study, we evaluated the effects of peripherally
administered cannabinoids on three indices of
inflammation: carrageenan-induced thermal hyperalgesia,
carrageenan-induced edema, and capsaicin-induced
plasma extravasation. In addition, we determined
the effect of cannabinoids on capsaicin-evoked
neuropeptide release from isolated rat hindpaw
skin. Our results indicate that cannabinoids
produce antihyperalgesia via interaction with
a peripheral CB1 receptor. Peripheral, but not
systemic, administration of 0.01 ng anandamide
inhibited the induction of hyperalgesia. Peripheral
administration of anandamide also attenuated
hyperalgesia after its development via interaction
with the CB1 cannabinoid receptor subtype as
indicated by its reversal with the CB1 receptor
antagonist SR 141716A. Additionally, peripheral,
but not systemic, administration of 0.01 ng
anandamide inhibited edema. Peripherally administered
cannabinoids also interacted with CB1 receptors
to inhibit capsaicin-evoked plasma extravasation
into the hindpaw. One potential mechanism for
the anti-inflammatory actions of the cannabinoids
is the inhibition of neurosecretion from the
peripheral terminals of nociceptive primary
afferent fibers. This hypothesis is supported
by the finding that anandamide inhibited capsaicin-evoked
release of calcitonin gene-related peptide from
isolated hindpaw skin. Collectively, these results
indicate that cannabinoids reduce inflammation
via interaction with a peripheral CB1 receptor.
A potential mechanism for this effect is the
inhibition of neurosecretion from capsaicin-sensitive
primary afferent fibers.
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Fuentes
JA, Ruiz-Gayo M, et al : Cannabinoids as
potential new analgesics. Life Sciences
1999; Vol. 65, Nos 6/7: pp. 675-685 |
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Among other pharmacological properties analgesia
is one of the important features of cannabinoids
with therapeutical prospects. Cannabinoids have
been shown to produce antinociception in experimental
animals and humans. Recently a new system of
neuromodulation based upon the existence of
cannabinoid receptors and their endogenous agonists
has emerged. This has been proposed as another
of the endogenous pain control systems. Current
evidence indicate an interaction between cannabinoid
and opioid systems, the latter being of known
relevance in nociception. The fact that either
exogenous or endogenous opioids enhanced cannabinoid-induced
antinociception suggests simultaneous activation
of both opioid and cannabinoid receptors by
drugs as a new analgesic strategy.
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Calignano
A. et al, Control of pain initiation by
endogenous cannabinoids. Nature 1998; Vol
394 : 277-281 |
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The potent analgesic effects of cannabis-like
drugs and the presence of CB1-type cannabinoid
receptors in pain-processing areas of the brain
and spinal cord indicate that endogenous cannabinoids
such as anandamide may contribute to the control
of pain transmission within the central nervous
system (CNS). Here we show that anandamide attenuates
the pain behaviour produced by chemical damage
to cutaneous tissue by interacting with CB1-like
cannabinoid receptors located outside the CNS.
Palmitylethanolamide (PEA), which is released
together with anandamide from a common phospholipid
precursor, exerts a similar effect by activating
peripheral CB2-like receptors. When administered
together, the two compounds act synergistically,
reducing pain responses 100-fold more potently
than does each compound alone. Gas-chromatography/mass-spectrometry
measurements indicate that the levels of anandamide
and PEA in the skin are enough to cause a tonic
activation of local cannabinoid receptors. In
agreement with this possibility, the CB1 antagonist
SR141716A and the CB2 antagonist SR144528 prolong
and enhance the pain behaviour produced by tissue
damage. These results indicate that peripheral
CB1-like and CB2-like receptors participate
in the intrinsic control of pain initiation
and that locally generated anandamide and PEA
may mediate this effect.
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Russo
E.: Cannabis for migraine treatment: the
once and future prescription? An historical
and scientific review. Pain. 1998 May;76(1-2):3-8.
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Cannabis, or marihuana, has been used for centuries
for both symptomatic and prophylactic treatment
of migraine. It was highly esteemed as a headache
remedy by the most prominent physicians of the
age between 1874 and 1942, remaining part of
the Western pharmacopoeia for this indication
even into the mid-twentieth century. Current
ethnobotanical and anecdotal references continue
to refer to its efficacy for this malady, while
biochemical studies of THC and anandamide have
provided a scientific basis for such treatment.
The author believes that controlled clinical
trials of Cannabis in acute migraine treatment
are warranted.
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Noyes
R et al, The analgesic properties of de
Δ9-THC and codeine. Clinical Pharmacology
and Therapeutics 1975; Vol 18, No.1:84-89 |
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The administration of single oral doses of delta-9-tetrahydrocannabinol
(THC) to patients with cancer pain demonstrated
a mild analgesic effect. At a dose of 20 mg,
however, THC induced side effects that would
prohibit its therapeutic use including somnolence,
dizziness, ataxia, and blurred vision. Alarming
adverse reactions were also observed at this
dose. THC, 10 mg, was well tolerated and, despite
its sedative effect, may analgesic potential.
No abstract available
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| CLINICAL
STUDIES |
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Burstein
SH, Karst M, Schneider U, Zurier RB. Ajulemic
acid: A novel cannabinoid produces analgesia
without a "high". Life Sci. 2004
Aug 6;75(12):1513-22. |
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A long-standing goal in cannabinoid research
has been the discovery of potent synthetic analogs
of the natural substances that might be developed
as clinically useful drugs. This requires, among
other things, that they be free of the psychotropic
effects that characterize the recreational use
of Cannabis. An important driving force for
this goal is the long history of the use of
Cannabis as a medicinal agent especially in
the treatment of pain and inflammation. While
few compounds appear to have these properties,
ajulemic acid (AJA), also known as CT-3 and
IP-751, is a potential candidate that could
achieve this goal. Its chemical structure was
derived from that of the major metabolite of
Delta9-THC, the principal psychotropic constituent
of Cannabis. In preclinical studies it displayed
many of the properties of non-steroidal anti-inflammatory
drugs (NSAIDs); however, it seems to be free
of undesirable side effects. The initial short-term
trials in healthy human subjects, as well as
in patients with chronic neuropathic pain, demonstrated
a complete absence of psychotropic actions.
Moreover, it proved to be more effective than
placebo in reducing this type of pain as measured
by the visual analog scale. Unlike the narcotic
analgesics, signs of dependency were not observed
after withdrawal of the drug at the end of the
one-week treatment period. Data on its mechanism
of action are not yet complete; however, the
activation of PPAR-gamma, and regulation of
eicosanoid and cytokine production, appear to
be important for its potential therapeutic effects.
Copyright 2004 Elsevier Inc.
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Notcutt
W, Price M, Miller R, Newport S, Phillips
C, Simmons S, Sansom C. Initial experiences
with medicinal extracts of cannabis for
chronic pain: results from 34 'N of 1' studies.
Anaesthesia. 2004 May;59(5):440-52. |
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Three Cannabis Based Medicinal Extracts (CBMEs)
for sublingual use became available in 2000.
A total of 34 'N of 1' studies were undertaken
using this novel therapy for patients with chronic,
mainly neuropathic, pain and associated symptoms
to explore efficacy, tolerability, safety and
dosages. Three CBMEs (Delta9 Tetrahydrocannabinol
(THC), Cannabidiol (CBD) and a 1:1 mixture of
them both) were given over a 12-week period.
After an initial open-label period, the CBMEs
were used in a randomised, double-blind, placebo
controlled, crossover trial. Extracts which
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, reflecting
a learning curve for both patient and study
team. These were generally acceptable and little
different to those seen when other psycho-active
agents are used for chronic pain. These initial
experiences with CBME open the way to more detailed
and extensive studies.
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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 Oct 1;290(13):1757-62. |
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CONTEXT: 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic
acid (CT-3), a potent analog of THC-11-oic acid,
produces marked antiallodynic and analgesic
effects in animals without evoking the typical
effects described in models of cannabinoids.
Therefore, CT-3 may be an effective analgesic
for poorly controlled resistant neuropathic
pain.
OBJECTIVE: To examine the
analgesic efficacy and safety of CT-3 in chronic
neuropathic pain in humans.
DESIGN AND SETTING: Randomized,
placebo-controlled, double-blind crossover trial
conducted in Germany from May-September 2002.
PARTICIPANTS: Twenty-one patients
(8 women and 13 men) aged 29 to 65 years (mean,
51 years) who had a clinical presentation and
examination consistent with chronic neuropathic
pain (for at least 6 months) with hyperalgesia
(n = 21) and allodynia (n = 7).
INTERVENTIONS: Patients were
randomized to two 7-day treatment orders in
a crossover design. Two daily doses of CT-3
(four 10-mg capsules per day) or identical placebo
capsules were given during the first 4 days
and 8 capsules per day were given in 2 daily
doses in the following 3 days. After a washout
and baseline period of 1 week each, patients
crossed over to the second 7-day treatment period.
MAIN OUTCOME MEASURES: Visual
analog scale (VAS) and verbal rating scale scores
for pain; vital sign, hematologic and blood
chemistry, and electrocardiogram measurements;
scores on the Trail-Making Test and the Addiction
Research Center Inventory-marihuana scale; and
adverse effects.
RESULTS: The mean differences
over time for the VAS values in the CT-3-placebo
sequence measured 3 hours after intake of study
drug differed significantly from those in the
placebo-CT-3 sequence (mean [SD], -11.54 [14.16]
vs 9.86 [21.43]; P =.02). Eight hours after
intake of the drug, the pain scale differences
between groups were less marked. No dose response
was observed. Adverse effects, mainly transient
dry mouth and tiredness, were reported significantly
more often during CT-3 treatment (mean [SD]
difference, -0.67 [0.50] for CT-3-placebo sequence
vs 0.10 [0.74] for placebo-CT-3 sequence; P
=.02). There were no significant differences
with respect to vital signs, blood tests, electrocardiogram,
Trail-Making Test, and Addiction Research Center
Inventory-marihuana scale. No carryover or period
effects were observed except on the Trail-Making
Test.
CONCLUSIONS: In this preliminary
study, CT-3 was effective in reducing chronic
neuropathic pain compared with placebo. No major
adverse effects were observed.
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Notcutt
W et al. Clinical experience of the synthetic
cannabinoid nabilone for chronic pain. Marihuana
and Medicine 1999; 47 : 567-572 |
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Sixty patients were treated with nabilone while
in the pain relief service of Janes Paget Hospital.
Eighteen have obtained useful benefit, and 15
have been equivocal or have experienced significant
side-effects. Twenty-seven have obtained no
benefit. A 30% success rate would be considered
poor by many standards. However, these patients
suffered from the worst pain problems of our
service and do not respond to placebos.
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Hamann
W and di Vadi PP. Analgesic effect of the
cannabinoid analogue nabilone is not mediated
by opioid receptors. The Lancet 1999; 353
: p. 560 |
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The mechanism of action of cannabinoid compounds
is known to be mediated through activation of
the cannabinoid receptors type 1 and 2 (CB1
and CB2), with the former located throughout
the brain and the latter in peripheral tissues.
This hypothesis that cannabinoid analgesia is
mediated through a ? opiate receptor has been
tested. The finding demonstrated that pain relief
produced by nabilone was not reversed by the
opioid receptor antagonist naloxone. This clinical
observation is important, as it suggests that
cannabinoids exert their analgesic effects independently
of ? receptors and are therefore not merely
a substitute for opiates.
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Holdcroft
A. et al, Case Report: Pain relief with
oral cannabinoids in familial mediterranean
fever. Anaesthesia 1997; 52 : 483-488 |
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Cannabinoids have analgesic and, possibly, anti-inflammatory
properties but their clinical use has been restricted
by legislation. This is the first United Kingdom
report of the controlled use of a standardised
pharmaceutical preparation of cannabinoids in
capsular form. The therapy was assessed in a
patient with familial Mediterranean fever, who
presented with chronic relapsing pain and inflammation
of gastrointestinal origin. After determining
a suitable analgesic dosage, a double-blind
placebo-controlled cross-over trial was conducted
using 50 mg tetrahydrocannabinol daily in five
doses in the active weeks and measuring effects
on parameters of inflammation and pain. Although
no anti-inflammatory effects of tetrahydrocannabinol
were detected during the trial, a highly significant
reduction (p < 0.001) in additional analgesic
requirements was achieved. Future study designs
can now incorporate prescribable forms of cannabinoids
but the choice of previous cannabis users only
as patients has clinical limitations. Cannabis
naive patients would tolerate controlled investigations
but may generate medicolegal problems.
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Ware
M.A. et al: Cannabis for chronic pain: Case
series and implications for clinicians.
Pain Res Management Summer 2002; 7(2): 95-99 |
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Chronic pain is one of the most common reasons
for therapeutic cannabis use.
OBJECTIVES: To describe therapeutic
cannabis use among patients with chronic pain.
METHODS: Patients with chronic
pain who voluntarily indicated that they used
cannabis therapeutically completed a questionnaire
about the type of cannabis used, the mode of
administration, the amount used and the frequency
of use, and their perception of the effectiveness
of cannabis on a set of pain-associated symptoms
and side effects. The study was approved by
the McGill University Health Centre Research
Ethics Board.
RESULTS: Fifteen patients
(10 male) were interviewed (median age 49.5
years, range 24 to 68 years). All patients smoked
herbal cannabis for therapeutic reasons (median
duration of use six years, range two weeks to
37 years). Seven patients only smoked at night-time
(median dose eight puffs, range two to eight
puffs), and eight patients used cannabis mainly
during the day (median dose three puffs, range
two to eight puffs); the median frequency of
use was four times per day (range one to 16
times per day). Twelve patients reported improvement
in pain and mood, while 11 reported improvement
in sleep. Eight patients reported a 'high';
six denied a 'high'. Tolerance to cannabis was
not reported.
CONCLUSIONS: The results of
this self-selected case series must be interpreted
with caution. Small doses of smoked cannabis
may improve pain, mood and sleep in some patients
with chronic pain. Clinical trials are warranted
to test these effects. Further prospective studies
should examine the patterns and prevalence of
cannabis use among chronic pain populations.
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Rudich
Z, Stinson J, Jeavons M, Brown SC.Treatment
of chronic intractable neuropathic pain
with dronabinol: case report of two adolescents.
Pain Res Manag. 2003 Winter;8(4):221-4. |
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OBJECTIVE: To evaluate the
effectiveness of dronabinol for the treatment
of neuropathic pain refractory to previous treatment.
METHODS: We studied the response
(reduction of pain intensity and functional
improvement) to dronabinol (5 mg/day to 25 mg/day)
in two adolescents with neuropathic pain and
depression refractory to previous treatments
over two and five years, respectively.
RESULTS: Reduction in pain
intensity (45%) was achieved in patient 2 and
was unchanged in patient 1. Functional improvement
was markedly increased in terms of academic
performance, mood and sleep in both patients
over four to five months, without major adverse
effects. While these improvements dissipated
over time, the patients were more reconnected
with rehabilitation and focused less on the
intrusiveness of their pain problem in their
every day lives.
CONCLUSIONS: Dronabinol appeared
to be effective in improving pain affect and
psychosocial functioning in the treatment of
refractory neuropathic pain and may be considered
as an adjuvant medication in the rehabilitation
process. Well-controlled placebo studies are
required for further evaluation.
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Buggy
DJ, Toogood L, Maric S, Sharpe P, Lambert
DG, Rowbotham DJ. Lack of analgesic efficacy
of oral delta-9-tetrahydrocannabinol in
postoperative pain. Pain. 2003 Nov;106(1-2):169-72. |
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We have evaluated the efficacy of delta-9-tetrahydrocannabinol
(delta-9-THC), the main psychoactive constituent
of cannabis, in postoperative pain. In a randomized
double-blind, placebo-controlled, single-dose
trial, we investigated 40 women undergoing elective
abdominal hysterectomy. Randomization took place
when postoperative patient-controlled analgesia
was discontinued on the second postoperative
day. When patients requested further analgesia,
they received a single, identical capsule of
either oral delta-9-THC 5 mg (n=20) or placebo
(n=20) in a double-blind fashion. The primary
outcome measure was summed pain intensity difference
(SPID) at 6 h after administration of study
medication derived from visual analogue pain
scores on movement and at rest. Secondary outcome
measures were time to rescue medication and
adverse effects of study medication. Mean (SD)
VAS pain scores before medication in the placebo
and delta-9-THC groups were 6.3(2.6) and 6.4(1.3)cm
on movement, and 3.2(1.9) and 3.3(0.9) on rest,
respectively. There were no significant differences
in mean (95% confidence interval of the difference)
SPID at 6 h between the groups [placebo 7.9,
delta-9-THC 4.3(-1.8 to 9.0)cm h on movement;
placebo 8.8, delta-9-THC 4.9(-0.2 to 8.1)cm
h at rest] and time to rescue analgesia [placebo
217, delta-9-THC 163(-22 to 130)min]. Increased
awareness of surroundings was reported more
frequently in patients receiving delta-9-THC
(40 vs 5%, P=0.04). There were no other significant
differences with respect to adverse events.
This study demonstrates no evidence of an analgesic
effect of orally administered delta-9-THC 5
mg in postoperative pain in humans.
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Naef
M, Curatolo M, Petersen-Felix S, Arendt-Nielsen
L, Zbinden A, Brenneisen R. The analgesic
effect of oral delta-9-tetrahydrocannabinol
(THC), morphine, and a THC-morphine combination
in healthy subjects under experimental pain
conditions. Pain. 2003 Sep;105(1-2):79-88.
Related Articles, Links |
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From folk medicine and anecdotal reports it
is known that Cannabis may reduce pain. In animal
studies it has been shown that delta-9-tetrahydrocannabinol
(THC) has antinociceptive effects or potentiates
the antinociceptive effect of morphine. The
aim of this study was to measure the analgesic
effect of THC, morphine, and a THC-morphine
combination (THC-morphine) in humans using experimental
pain models. THC (20 mg), morphine (30 mg),
THC-morphine (20 mg THC+30 mg morphine), or
placebo were given orally and as single doses.
Twelve healthy volunteers were included in the
randomized, placebo-controlled, double-blinded,
crossover study. The experimental pain tests
(order randomized) were heat, cold, pressure,
single and repeated transcutaneous electrical
stimulation. Additionally, reaction time, side-effects
(visual analog scales), and vital functions
were monitored. For the pharmacokinetic profiling,
blood samples were collected. THC did not significantly
reduce pain. In the cold and heat tests it even
produced hyperalgesia, which was completely
neutralized by THC-morphine. A slight additive
analgesic effect could be observed for THC-morphine
in the electrical stimulation test. No analgesic
effect resulted in the pressure and heat test,
neither with THC nor THC-morphine. Psychotropic
and somatic side-effects (sleepiness, euphoria,
anxiety, confusion, nausea, dizziness, etc.)
were common, but usually mild.
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Jain
AK, Ryan JR, McMahon FG, Smith G. Evaluation
of intramuscular levonantradol and placebo
in acute postoperative pain. J Clin Pharmacol.
1981 Aug-Sep;21(8-9 Suppl):320S-326S. Related
Articles, Links |
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Double-blind administration of a single intramuscular
dose of 1.5, 2.0, 2.5, or 3.0 mg levonantradol
or placebo to 56 patients with moderate to severe
postoperative or trauma pain showed significant
analgesic effects of each dose of levonantradol
as compared to placebo (P less than 0.05). However,
no significant dose response was observed. Compared
to 2/16 patients on placebo, 23/40 patients
(57 per cent) on levonantradol reported one
or more side effect. Drowsiness was most frequent.
Dry mouth, dizziness, "weird dreams,"
mild hallucinations, nervousness, apprehension
and confusion occurred less frequently. Changes
in resting heart rate and blood pressure were
minor and general acceptability was good.
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Raft
D, Gregg J, Ghia J, Harris L. Effects of
intravenous tetrahydrocannabinol on experimental
and surgical pain. Psychological correlates
of the analgesic response. Clin Pharmacol
Ther. 1977 Jan;21(1):26-33. |
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Two intravenous doses of tetrahydrocannabinol
(THC) (0.022 mg/kg and 0.044 mg/kg) were compared
to intravenous diazepam (0.157 mg/kg) and to
placebo (Ringer's lactate) as premedication
for dental extraction in 10 healthy volunteers.
Pain detection and tolerance thresholds were
measured and psychiatric interviews were supplemented
by Minnesota Multiphasic Personality Inventories
(MMPI), the Zung Depression Scale (ZDS), Beck
Depression Inventories (BDI), and the State-Trait
Anxiety Inventory (STAI). Pain detection thresholds
were altered unpredictably with high THC doses,
but analgesia as indicated by pain tolerance
was less than that after diazepam and placebo.
In three subjects low-dose THC (0.022 mg/kg)
was a better analgesic than placebo but not
diazepam. Six subjects preferred placebo to
low-dose THC as an analgesic; this group experienced
increases in subjective surgical pain and were
submissive, rigid, and less introspective with
high State Anxiety and MMPI profiles that differed
from subjects whose pain was not increased.
STAI following THC presaged a poor analgesic
response in this group.
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Noyes
R Jr, Brunk SF, Avery DA, Canter AC.The
analgesic properties of delta-9-tetrahydrocannabinol
and codeine. Clin Pharmacol Ther. 1975 Jul;18(1):84-9. |
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The administration of single oral doses of delta-9-tetrahydrocannabinol
(THC) to patients with cancer pain demonstrated
a mild analgesic effect. At a dose of 20 mg,
however, THC induced side effects that would
prohibit its therapeutic use including somnolence,
dizziness, ataxia, and blurred vision. Alarming
adverse reactions were also observed at this
dose. THC, 10 mg, was well tolerated and, despite
its sedative effect, may analgesic potential.
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Noyes
R Jr, Brunk SF, Baram DA, Canter A. Analgesic
effect of delta-9-tetrahydrocannabinol.
J Clin Pharmacol. 1975 Feb-Mar;15(2-3):139-43. |
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A preliminary trial of oral delta-9-tetrahydrocannabinol
(THC) demonstrated an analgesic effect of the
drug in patients experiencing cancer pain. Placebo
and 5, 10, 15, and 20 mg THC were administered
double blind to ten patients. Pain relief significantly
superior to placebo was demonstrated at high
dose levels (15 and 20 mg). At these levels,
substantial sedation and mental clouding were
reported.
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