Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review
BMJ 2001; 323 doi: https://doi.org/10.1136/bmj.323.7303.13 (Published 07 July 2001) Cite this as: BMJ 2001;323:13
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Sir,
The reviews conducted by Campbell1 and Tramer2 help to summarise the
limited information available on the use of cannabinoid therapies in pain
and nausea. What is clear is that these compounds do not offer the
miraculous symptom relief that the media feel keen to proselytise with a
predictability that is becoming wearisome. Animal work strongly supports
the notion that agonists at the CB1 receptor are analgesic and that this
analgesia is maintained in situations such as neuropathic pain when opioid
sensitivity is often lost. It is this possible application to the unique
circumstances of neuropathic pain that should be of interest to
clinicians.
In this setting, the answer to Kalso's3 question "..is there
any need?" has to be an unqualified "yes". Neuropathic pain is often
desperately difficult to treat. The current mainstay of treatment, namely
antidepressants, anticonvulsants and opioids seem to help little over half
of all patients with neuropathic pain. There remains a substantial
minority with unrelieved pain for whom new classes of analgesics are most
certainly required. When we examined the use of the synthetic cannabinoid
nabilone in such a group of "treatment failures", we found the drug to be
tolerated as well as other drugs used in the patients' previous management
and effective analgesia was achieved in approximately 30%4.
These results
must be taken in the context of an open study but we, in conjunction with
colleagues elsewhere in Northern England and the West of Scotland are
currently recruiting patients to a double blind, randomised cross over
study examining the use of nabilone in neuropathic pain.
Kalso makes the important point that there are many synthetic
cannabinoids and these may offer a further advantage over existing
compounds although their application in the human setting is likely to
take time. Regrettably, a vociferous campaign supporting the availability
of recreational cannabis has hijacked the debate and unwittingly, doctors
appear to have been duped along with many others. Meek's 1994 survey
suggesting that 74% of U.K. doctors wished to be able to prescribe
cannabis for their patients is illustrative of the point.
It would have
been revealing to ask those same doctors to name another cannabinoid
agonist, or even to name the major active ingredient of cannabis
preparations - we would suggest that the percentage capable of doing
either would have been far less than 74%. Would those same doctors also
advocate their right to prescribe dried opium poppy extract to patients
with cancer pain or would they prefer to use sustained release purified
morphine?
Strang5 called for "a more considered examination of eight
conceptually separate issues". It is to be hoped that these excellent
reviews will at least allow doctors to concentrate on therapeutic issues.
Dil Kapur
Consultant
Bernhard Frank
Research Fellow
Pain Management Unit,
Royal Victoria Infirmary,
Queen Victoria Road,
Newcastle upon Tyne
NE1 4LP
dilkapur@nbpa.org.uk
Reference List
1. Campbell F, Tramer M, Carroll D, Reynolds D, Moore R, McQuay H.
Are cannabinoids an effective and safe treatment in the management of
pain? A qualitiative systematic review. BMJ 2001;323:13-16.
2. Tramer M, Carroll D, Campbell F, Reynolds D, Moore R, McQuay H.
Cannabinoids for the control of chemotherapy induced nausea and voniting:
quantitative systematic review. BMJ 2001;323:16-21.
3. Kalso E. Cannabinoids for pain and nausea. BMJ 2001;323:2-
3.(Abstract)
4. Frank B, Kapur D. Further experience with nabilone. Presented at
the annual scientific meeting of the Pain Society of Great Britain, April
2001 2001;(Abstract)
5. Strang J, Witton J, Hall W. Improving the quality of the cannabis
debate: defining the different domains. BMJ 2000;320:108-110.(Abstract)
Competing interests: No competing interests
The apparent objectivity of a systematic review by Campbell et al1
obscures the dearth of high quality randomised controlled trials and is
ignored in the subjectively derived conclusions. We assert that the
statements made by Campbell et al1 are not justified and an independent
randomised placebo-controlled, active control study of cannabis for the
management of acute pain is timely.
The need for such trials has been endorsed by the international
scientific community2,3 and thus the CANPOP trial has been funded by the
MRC, using Cannador, a cannabis extract (European Society for Oncological
and Immunological Research, Berlin, Germany), in addition to Marinol, a
synthetic cannabinoid (tetrahydrocannabinol, Unimed Pharmaceuticals, USA).
The trial is designed to provide the evidence to confirm or refute the
medicinal role of cannabis in acute pain.
Errors abound in Campbell et al’s1 review: enumeration, contextual,
typographical and conceptual. For example, the authors have obfuscated
the issue by failing to distinguish between studies performed with
cannabis and its extracts versus synthetic cannabinoids. There is evidence
that cannabis plant extract has a more favourable side effect profile than
synthetic cannabinoids as summarised in the House of Lord’s Select
Committee Report2 and from pharmacological studies of cannabidiol, one of
the other predominant cannabinoids in cannabis4,5. The only study reviewed
by Campbell et al1that used cannabis plant extract was that of Holdcroft
et al6, in a single patient.
The only paper purportedly supporting Campbell et al’s1 conclusions
on cannabis in postoperative pain management was a clinical trial of a
synthetic cannabinoid, levonantradol7. The two trials reported in this
paper did not include codeine as an active comparator yet the key message
was ‘cannabinoids give about the same level of pain relief as codeine in
postoperative pain’ and in the discussion ‘in the two postoperative pain
trials levonantradol was superior to placebo but no more effective than
codeine’. There is simply no evidence to support these statements based on
Jain et al’s study7.
1. Campbell FA, Tramer MR, Carroll D, Reynolds JM, Moore RA, McQuay
HJ. Are cannabinoids an effective and safe treatment option in the
management of pain? A qualitative systematic review. BMJ 2001;323:13-16 (7
July).
2. House of Lords. Cannabis: the Scientific and Medical Evidence.
Ninth Report from the Select Committee on Science and Technology. London:
The Stationery Office, 1998.
3. Joy JE, Watson SJ Jr, Benson JA. Marijuana and Medicine: Assessing
the Science Base. Washington DC: National Academy Press 1999.
4. Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R. Antipsychotic
effect of cannabidiol. J Clin Psych 1995;56:485-6.
5. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of
cannabidiol on the anxiety and other effects produced by delta 9-THC in
normal subjects. Psychopharmacology 1982;76:245-250.
6. Holdcroft A, Smith M, Jaklin A, Hodgson H, Smith B, Newton M.Evans
F. Oral cannabinoids in familial Mediterranean Fever: a case report.
Anaesthesia 1997;52:483-488.
7. Jain AK, Ryan JR, McMahon FG, Smith G. Evaluation of intramuscular
levonantradol and placebo in acute postoperative pain. J Clin Pharmacol
1981;21:320S-326S.
Trial Steering Committee of the CANPOP MRC Multicentre Clinical Trial
(ISRCTN 25994117)
Magdi Hanna, Chairman
Consultant Anaesthetist and Specialist in Pain Management, The Pain
Research Unit, King’s College Hospital, Denmark Hill, London SE5 9RS
magdi.hanna@kcl.ac.uk
Anita Holdcroft,
Reader in Anaesthesia and Honorary Consultant Anaesthetist, Chelsea and
Westminster Hospital, 369, Fulham Road, London SW10 9NH
aholdcro@ic.ac.uk
Mervyn Maze,
Professor of Anaesthesia, Chelsea and Westminster Hospital, 369, Fulham
Road, London SW10 9NH m.maze@ic.ac.uk
Simon Thompson,
Professor of Medical Statistics and Director MRC Biostatistics Unit,
Institute of Public Health, Robinson Way, Cambridge CB2 2SR
simon.thompson@mrc-bsu.cam.ac.uk
Tony Moffat,
Chief Scientist Royal Pharmaceutical Society, 1, Lambeth High Street,
London SE1 7JN
tmoffat@rpsgb.org.uk
Andrew Nunn,
Head, Division Without Portfolio, MRC Clinical Trials Unit, 222, Euston
Road, London NW1 2DA a.nunn@ctu.mrc.ac.uk
David Bowsher,
Pain Specialist, Pain Research Institute, Clinical Sciences centre,
University Hospital Aintree, Lower lane, Liverpool L9 7AL
bowsher@liv.ac.uk
Kay Glendinning,
Patient Representative, Dunhill Medical Trust, 1, Fairholt Street, London
SW7 1EQ
dmt@dunhillmedical.demon.co.uk
1.
Competing interests: No competing interests
Campbell et al's systematic review (1) of the best available evidence
for cannabinoids used as analgesics, and the wide publicity this
generated, illustrate the complex and unique nature of the medicinal
cannabis debate. Complex because of the variability of results obtained
from studying pain of differing pathophysiologies and from employing
various types of cannabinoid. Unique because of its high profile status,
which means that emphasis on a particular aspect can be misinterpreted and
generate myths.
The review has contributed to the impression that cannabinoids are
unlikely to replace the existing effective treatments for post-operative
pain. It has also acknowledged that there are therapeutic areas which are
more intruiging than nociceptive pain, such as neuropathic pain and
spasticity. Indeed, this potential has been illustrated by the one study
reviewed which looked at a single patient with these symptoms, and
demonstrated a beneficial effect on both from delta-9-tetrahydrocannabinol
5mg orally which was well tolerated (2). These contrasting aspects are
contained within the body of the review, yet in the conclusions much more
generalised statements about the potential role of cannabinoids in pain
management are made. The authors also seem to use the terms "cannabinoid"
and "cannabis" interchangeably in the paper, when in fact none of the
reviewed studies used whole cannabis.
The reports of Campbell et al's paper which subsequently appeared in
the lay media further exaggerated these conclusions. Such bias may
undermine the efforts of groups like our own to carry out clinical
research into therapeutic applications for cannabis derivatives which
could have genuine merit.
Medical scientists have an obligation to evaluate reports from the
many patients who find relief from intractable symptoms by using cannabis
illegally. Adequately powered randomised controlled trials are the only
reliable way of achieving this. Fortunately, these are now underway.
1. Campbell FA, Tramer MR, Carroll D, Reynolds DJM, Moore RA, McQuay
H. Are cannabinoids an effective and safe treatment option in the
management of pain? A qualitative systematic review. BMJ 2001; 323:13-16
2. Maurer M, Henn V, Dittrich A, Hoffmann A. Delta-9-
tetrahydrocannabinol shows antispastic and analgesic effects in a single
case double-blind trial. Eur Arch Psychiatry Clin Neurosci 1990; 240(1):1-
4
Petra Makela
Research Registrar
Rivermead Rehabilitation Centre, Oxford
Derick Wade
Consultant and Professor in Neurological Disability
Rivermead Rehabilitation Centre, Oxford
Philip Robson
Senior Research Fellow
University Department of Psychiatry,
Warneford Hospital,
Oxford
Possible competing interests:
We are currently conducting clinical research into the use of
cannabis extracts supplied by GW Pharmaceuticals plc for the treatment of
pain, spasticity and other symptoms in neurological conditions. Dr Robson
also holds the post of Medical Director for GW Pharmaceuticals.
Competing interests: No competing interests
The distinguished authors of this review gave themselves an
impossible task. Anyone who has reviewed the scientific literature on the
medical uses of cannabis rapidly discovers that there is a dearth of well
controlled clinical trials (1). A meta-analysis of the use of cannabis in
treating pain is therefore likely to find little of substance to comment
on.
Unfortunately this did not deter the authors from coming to a series
of emphatic but ill-founded conclusions. One hopes that these will not be
taken as the last word on the topic, since there are now large and well
controlled clinical trials about to start in this country (2), and a
wealth of animal data supports a role for cannabinoids in pain modulation
(3)
References
1 Iversen,L.L. (2000) The Science of Marijuana, Oxford University Press
2 House of Lords Select Committtee on Science & Technology,(2001),2nd
Report on Therapeutic Uses of Cannabis, HM Stationery Office
3. Pertwee, R.G.(2001) Cannabinoid receptors and pain, Prog Neurobiol.63,
569-611
Competing interests: No competing interests
17 July 2001
The Editor
British Medical Journal
Dear Editor
We would like to make the following comment on the paper published by
Campbell et al., BMJ 2001-323: 13-16.
Can you make a good omelette out of rotten eggs?
The aim of systemic reviews with meta-analysis of pooled data from
chosen studies is an attempt to reach a balanced conclusion about a
specific intervention. Campbell et. al., in their systemic review of
cannabinoids for treating pain have followed this same line of research.
Unfortunately, they have encountered two additional disadvantages: there
is simply not enough published studies to analyse and whatever is
available was done many years ago. The issue here then changes from
whether cannabinoids are efficacious for treating pain to whether such a
review is allowed to be published in the first place.
Would a paper that examined a small number of patients with different
pain syndromes from diverse diagnoses be allowed as a proof of concept of
efficacy of a drug? If a phase 2 study was conducted with the same numbers
and pain syndromes as that analysed by Campbell et. al., it would never be
accepted by the regulatory authorities or by a proper scientific journal
for publication.
The quote above was the response of Professor Patrick Wall to the
recent trend in using systemic reviews to analyse Pain trial data. A
careful look at the data pooled by Campbell et. al., would conclude that
there is indeed a lot of “rotten eggs” that is employed. The medical
utility of cannabinoids is a controversial and emotive subject. There is
a risk that this publication with its flawed conclusion will mislead the
judicial and legislature powers as well as the wider public. What is
needed are large trials of cannabinoids to be undertaken and not as in
this case, an analysis too far!
Yours sincerely
Dr Magdi Hanna Dr Sam Chong
Competing interests: No competing interests
I read with interest the review article on cannabinoids
in treatment of pain. As a neurologist and researcher I was
pleased to see reference to a paper I co-authored on the
efficacy of a cannabinoid, Delta-9 THC, in treating
spasticity(1).
My confusion in reading the review was the
implication that my paper published over 20 years ago, had
anything to do with pain. Spasticity and pain are two
distinctively different entities. While pain may accompany
symptoms of spasticity such as flexor or tonic spasms, the
assessments of spasticity do not usually include the type of
measures seen with analgesics.I am gratified that over the
years, our results have been confirmed by other researchers
and antispasticity activity documented for marijuana (2),
THC(3) and nabilone(4).
More importantly, no study has been
published which did not show an antispasticity effect for
the cannabinoids. Currently, a significant research effort
is underway to evaluate cannabinoids in patients with
multiple sclerosis. This effort is undermined when review
articles are cited in the media as evidence that
cannabinoids are either ineffective or unsafe.
1. Petro DJ, Ellenberger Jr C. Treatment of human spasticity
with delta-9-tetrahydrocannabinol. J Clin Pharm
1981;21(suppl8-9):S413-S416.
2. Meinck HM,Schonle PW, Conrad B. Effect of cannabinoids on
spasticity and ataxia in multiple sclerosis. J Neurol
1989;236:120-122.
3. Ungerleider JT, Andyrsiak T, Fairbanks L, Ellison GW,
Myers LW. Delta-9-THC in the treatment of spasticity
associated with multiple sclerosis. Adv Alcohol Subst Abuse
1987;7(1):39-50.
4. Martyn CN, Illis LS, Thom J. Nabilone in the treatment of
multiple sclerosis
Competing interests: No competing interests
The only conclusion that can be drawn from this study is that there
is insufficient information on the beneficial effects and problems
associated with the clinical use of cannabinoids. For the authors to state
that they should not be used in acute postoperative pain, on the basis of
36 patients in a double study of levonantradol from 1981, is presumptive.
To make statements on 2 single patients with non-malignant chronic pain is
likewise. To consider that studying single doses of cannabinoids in
comparison to analgesics, with a very different mode of action, over a few
hours, in the complex pain of cancer, is anything more than a starting
point, is to prejudge the issue. There are much more appropriate methods
of studying such agents [for example (1)]. The understanding of pain and
its management has moved on a long way since the 1970’s.
My colleagues and I now have over 13 patient-years of clinical
experience in treating chronic non-malignant pain with sublingual
standardised cannabis extract. Our experience in 19 patients is very
different to that outlined in this paper. 15 of our patients have
continued into a long-term study (some for over 1 year now) without any
significant problems with side effects. Unfortunately the studies are
particularly difficult and time-consuming to undertake if we are to
produce quality information to inform the scientific debate.
May I suggest that pain specialists and others spend the next 5-10
years exploring these agents. Afterwards, Campbell and her colleagues can
come back and look at the evidence that has been amassed from modern
clinical trials, using standardised preparations, delivered by a variety
of routes, in a large number of patients with different clinical
conditions, in acute and chronic pain and for other symptom and disease
control.
There is a lot of clinical work that needs to done in this field.
Recycling old research that has been pored over endlessly at conferences,
in review papers and in books contributes nothing.
Possible Competing Interests:
For the last 13 months I have been conducting a clinical study of
cannabis extracts in chronic non-malignant pain under a DDX licence. I
receive supplies of cannabinoid extract free from GW Pharmaceuticals. I
have received no payments from this company. They sponsored me as a
speaker at 2 University conferences in the USA in 2000.
1. McQuay HJ, Carroll D, Glynn CJ. Dose-response for analgesic effect
of amitriptyline in chronic pain. Anaesthesia. 48(4):281-5, 1993 Apr.
Competing interests: No competing interests
Editor,
Campbell et al. in the last edition of this Journal reported a
systematic review of randomised controlled trials to establish whether
cannabis is an effective and safe treatment in the management of pain (1).
The authors conclude that the widespread introduction of cannabinoids into
clinical practice is undesirable and that they should not be used in acute
postoperative pain.
The conclusions of this paper have been widely advertised by the media
with some newspapers headlines stating that, according to the results of a
new study, cannabis is not an effective painkiller in humans. In fact the
review by Campbell et al. is a new publication but not a new study: the
review incorporates publications mainly published in the 1970’s and 80’s;
the total number of patients reviewed is modest to allow definitive
conclusions considering that pain is not just one entity.
Indeed, Campbell
et al. have classified pain into cancer pain, postoperative pain and non-
malignant pain. One should realize that only two patients were included in
the two clinical trials looking at non-malignant pain. Furthermore, there
is a discrepancy in the number of patients studied in the two clinical
trials looking at postoperative pain. First Campbell et al. mentioned that
"two trials comprised six patients with postoperative pain" and further in
the text that "thirty six patients were studied in two trials" and finally
in the Table that 36 patients received 1.5 or 2.0 mg of levonantradol or
placebo and another 36 patients received 2.5 or 3.0 mg of levonantradol or
placebo. In fact Jain et al. stated in their paper that "a total of 56
hospitalized patients … participated in the study" (2).
Furthermore, the
authors mentioned that an early Phase II trial was completed but without
any mention of the number of patients enrolled and they also stated that
it was unpublished data. Furthermore, the two groups reported by Campbell
et al. were of 28 patients each (again for a total of 56 patients) and not
36. Jain et al. studied their patients for only 6 hours after a single
dose of levonantradol and although the authors mentioned that blood was
collected after dosing for plasma drug levels in patients who gave their
consent, the actual number of patients is not stated and in the results
section they only mentioned that "the drug was adequately absorbed".
Finally, pain assessment, although valid, was not reported as it would be
done today, 20 years later.
Thus, cannabinoids have been evaluated in the review paper of Campbell et
al. in only one patient with neuropathic pain, where THC was better than
placebo and equal to codeine but also where it relieved spasticity, and in
a total of 56 orthopaedic patients postoperatively, where again it was
better than placebo with mild adverse effects. Is that sufficient to
conclude that introduction of cannabinoids into clinical practice is
undesirable and that they should not be used in acute postoperative pain.
I doubt that such conclusions are valid in this context.
Cannabinoids in animal experiments have been shown to be most effective in
neuropathic pain (3-5), an area where few medications available today are
effective, including morphine or its derivative.
Furthermore, cannabinoids
act by a new mechanism of action. Cannabinoids have also antiemetic
properties and are superior to conventional antiemetics in chemotherapy
(6). Moreover, the opioid and cannabinoid systems are interrelated systems
with synergistic interactions (7). Cannabinoids are likely to decrease
opioids consumption when given simultaneously for pain relief. This is the
basis of multimodal analgesia as advocated nowadays. Thus, the use of
cannabinoids with opioids may reduce opioids associated adverse effects
such as nausea and vomiting, pruritus, urinary retention and in particular
respiratory depression which has been associated with death. Cannabinoids
are not associated with life-threatening complications even in overdose.
This is due to the relative weak concentration of cannabinoid receptors
(CB1 receptors) present in the brainstem. Pain and nausea and vomiting are
the two major complaints of patients in the postoperative period. Thus,
cannabinoids or cannabis in an adequate form of administration such as a
spray, are potentially beneficial to patients. Properly designed clinical
trials looking at these issues of postoperative pain, nausea and vomiting
and neuropathic pain will give true answers on the role of cannabinoids.
Cannabinoids in animal experiments have been shown to act centrally, in
the spinal cord and in the periphery to attenuate pain perception. These
last two sites of action are of potential value for divorcing the pain
relief properties of cannabis from its psychoactive effects. Intrathecal
or topical administration of cannabinoids may prove very effective in
treating pain without central side effects.
A report by Notcutt et al. (1997)(8) also published in 1999 as a book
chapter (9) was not included in the review by Campbell et al., although it
may have been excluded from it. Indeed, it was not a formal trial and no
placebos were used. However, they found in 60 patients with various severe
pain syndrome from a pain clinic in Great Yarmouth that nabilone was
useful in about 30% of the cases to relieve pain in a group of patients
who had no pain relief from other available medications.
In summary, it is not yet possible to give any conclusions, as Campbell et
al. did, on the role of cannabis or cannabinoids in the clinical treatment
of neuropathic and postoperative pain in view of the paucity of data
available and the absence of well-designed clinical trials. The
development of new forms of delivery of cannabis (spray) and cannabinoids
(a water soluble compound has been developed and used in animals)(10)
would also help greatly to perform such trials. Until then one should be
very cautious before drawing any conclusions on this very controversial
and highly "mediatised" topic.
References
1. Campbell FA, Tramèr MR, Carroll D, Reynolds DJM, 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.
2. Jain AK, Ryan JR, McMahon FG, Smith G. Evaluation of intramuscular
levonantradol and placebo in acute postoperative pain. J Clin Pharmacol
1981; 21: 320S-326S.
3. Herzberg U, Eliav E, Bennett GJ, Kopin IJ. The analgesic effects of
R(+)-WIN55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat
model of neuropathic pain. Neurosci Lett 1997; 221: 157-160.
4. Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, James IF.
The role of central and peripheral CB1 receptors in the antihyperalgesic
activity of cannabinoids in a model of neuropathic pain. Pain 2001; 92: 91
-100.
5. Bridges D, Ahmad K, Rice ASC. The synthetic cannabinoid WIN55,212-2
attenuates hyperalgesia and allodynia in a rat model of neuropathic pain.
Br J Pharmacol 2001; 133: 586-594.
6. Tramèr MR, Carroll D, Campbell FA, Reynolds DJM, Moore RA, McQuay HJ.
Cannabinoids for control of chemotherapy induced nausea and vomiting:
quantitative systematic review. BMJ 2001; 323: 16.
7. Welch SP, Eads M. Synergistic interactions of endogenous opioids and
cannabinoid systems. Brain Res 1999; 848: 183-190.
8. Notcutt WG, Price M, Chapman G. Clinical experience with nabilone for
chronic pain. Pharmaceutical Science 1997; 3: 551-555.
9. Notcutt W, Price M, Blossfeldt P, Chapman G. Clinical experience of the
synthetic cannabinoid nabilone for chronic pain. In: Nahas GG, Sutin KM,
Harvey DJ, Agurell S, éd. Marihuana and Medicine. Totowa: Humana Press;
1999. p. 567-572.
10. Pertwee RG, Gibson TM, Stevenson LA et al. O-1057, a potent water-
soluble cannabinoid receptor agonist with antinociceptive properties. Br J
Pharmacol 2000; 129: 1577-1584.
Competing interests: No competing interests
I'm grateful for this review. Clinical effects in the serious theater
of profound needs is indeed compelling but, as a previous replier reminds
us, the synthetic forms of cannabis but a limited form of this produce.
Herbalism uses cannabis amidst other elements to balance some of the
problematic side effects while the recreational user may well enjoy some
of those effects..amidst self medicating for their specific needs. It's
important to have these serious reviews but I believe social policy
determined or directed as if from them misses essential reality which
after all is what clinical trial science pretends to report and be
resposbile to.
Competing interests: No competing interests
Cannabinoids are not cannabis
Dear Sir,
The studies on the efficacy of certain oral cannabinoids described in the papers of Campbell et al. 1 and Tramèr et al.2 are very interesting. However, the authors of both articles came to conclusions that are too generalised.
The article of Campbell et al. only describes the oral administration of Delta-9-tetrahydrocannabinol (THC) and two synthetic cannabinoids in single dose. The authors conclude: “The best that can be achieved with single dose cannabis in nociceptive pain is analgesia equivalent to single dose codeine 60 mg, which rates poorly on relative efficacy compared with non-steroidal anti-inflammatory drugs or simple analgesics.“ This conclusion is not supported by the results of their analysis for several reasons:
Cannabis is not the same as cannabinoids. In the first place cannabis contains over 70 cannabinoids of which THC is considered the main component, but it is not the only active one. Patients using cannabis as a medicine report that there are differences between different breeds of cannabis. In some cases breeds of low THC content are said to be more active then other breeds with higher content. Also there are differences in activity depending on the indication the cannabis is used for. Since at least two cannabinoid receptors are identified, different cannabinoids can have different profiles of action and equally cannabis breeds with different cannabinoid profiles can have different profiles of action.
Secondly, in the studies included in the analysis the cannabinoids are administered orally. This gives a strong first pass effect and a much slower uptake compared to other routes of administration, like inhalation. Patients claim that there is a difference in efficacy between cannabis taken as a herbal tea, or smoked, or inhaled as a vapour. The latter are said to be more effective.
Thirdly, sometimes it is mentioned that the analgesic action of cannabis begins with an effect opposite to analgesia, and it becomes effective only after a few days. There are only unconfirmed data for this initial effect, but, if proven, it completely undermines the relevance of this study.
The other study is much more accurate in its conclusions, but also this one neglects that there are much more known cannabinoids then the three included in the analysis. Also might the efficacy of inhaled cannabis be better.
I agree that further studies should be designed to establish the usefulness of cannabinoids as adjuncts to modern antiemetics like 5-HT3 receptor antagonists, but the principle point here is to find the most promising cannabinoid or cannabis breed. This opens also the way to separate the psycho-active side effects from the therapeutic action.
One of the elements in the Dutch policy of stimulating the development of a registered cannabis-based medicine is to find a highly standardised cannabis preparation with an optimal profile. Our approach is to concentrate on the most promising indications, among which the anti-emetic and the analgesic effect. However, we do not focus on pain in general, but on chronic pain.3
Ministry of Health, Welfare and Sport
Willem K. Scholten MSc., Pharm., MPA.
head, Office of Medicinal Cannabis of the Directorate of Pharmaceutical Affairs and Medical Technology,
P.O.Box 20350,
NL - 2500 EJ The Hague,
The Netherlands
e-mail wk.scholten@minvws.nl
1 Campbell FA, Tramèr MR et al., Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review, BMJ 2001;323:13-6
2 Tramèr MR, Campbell FA et al., Cannabinoids for control of chemoterapy induced nausea and vomiting: quantitative systematic review, BMJ 2001:323:16-21
3 Scholten Willem K. Dutch measures to control medical grade marijuana: facilitating clinical trials. Drug Information Journal, Volume 35, Issue 2 (April-June) 2001: 481-484
Competing interests: No competing interests