Cannabinoids for pain and nausea
BMJ 2001; 323 doi: https://doi.org/10.1136/bmj.323.7303.2 (Published 07 July 2001) Cite this as: BMJ 2001;323:2All rapid responses
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Never once did your research mention the testing of the potent
cannabinoid painkiller known as WIN55212. WIN55212 has far greater
painkilling capability than codeine. Back to the drawing board mates, you
didn't do your homework.
Competing interests: No competing interests
The conclusion reached by Fiona A. Campbell et.al, that "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 nonsteroidal antiinflammatory drugs or simple
analgesics" (1) is premature. The authors acknowledged that
all of the studies reviewed involved single cannabinoids.
Findings from single cannabinoid studies do not demonstrate
the therapeutic potential of whole cannabis.
Cannabis contains over 60 cannabinoids which may have
therapeutic potential either by themselves or in some
combination. Cannabinoids have been shown to act
synergistically to provide increased therapeutic value. For
instance, when the CB1 receptor agonist, anadamide, and CB2
receptor agonist, palmitoylethanolamide, are administered
together, the two compounds reduce pain responses 100-fold
more potently than either compound alone (2). A study
conducted by the New Mexico Department of Health found that
smoked cannabis was more effective at alleviating vomiting
than THC (3)
The authors also claim that "adverse effects associated with
the cannabinoids were common and sometimes severe."
However, synthetic cannabinoids were associated with the
most problematic side effects in the studies they reviewed.
Cannabidiol, which is found in whole cannabis, has been
shown to alleviate many of the problematic side effects
associated with THC (4). The New Mexico study found that
THC was far more likely to cause problematic side effects
than smoked cannabis (3).
Cannabis is an incredibly safe drug. In over 5,000 years of
use, there has never been a recorded fatal overdose. The
low density of receptors in medullary nuclei is consistent
with the lack of lethal effects in humans (5). The studies
on chronic marijuana use that have been conducted suggest
that tolerance rapidly develops to many of the effects of
cannabis use and field studies have failed to find any major
consequences from chronic heavy use of cannabis (6). No
clinical evidence has been discovered suggesting increased
prevalence of opportunistic infection or malignancy among
cannabis users (7). Marijuana use appears to have little
effect on human mortality (8).
The authors were correct in pointing out the serious lack of
human studies into the therapeutic potential of whole
cannabis as an analgesic. However, there are thousands of
anecdotal reports from humans and hundreds of animal studies
demonstrating the potential for cannabis to alleviate many
types of pain. Given the safety of cannabis, those who are
suffering should be allowed access to this medication, while
studies are conducted to determine what types of
cannabinoids are most effective as analgesics.
References:
1. Campbell FA, Tramr MR, Carroll D, Reynolds DJM, Moore
RA, McQuay HJ. BMJ 2001;323:13-16
2. Calignano A, La Rana G, Giuffrida A and Piomelli D.
Control of pain initiation by endogenous cannabinoids.
Nature 1998;394:277-281.
3. State of New Mexico, Health and Environment Dept. Report
of the Lynn Pierson Therapeutic Research Program : oral vs.
inhaled cannabinoids for nausea/vomiting from cancer
chemotherapy. Santa Fe: N.M. Health and Environment Dept.,
Behavioral Health Services Division, 1984
4. 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,.
5. Mechoulam R, Hanus L, Martin BR. Search for endogenous
ligands of the cannabinoid receptor. Biochemical
Pharmacology 1994;48:1537-1544.
6. Hollister LE. Health aspects of cannabis.
Pharmacological Reviews 1986;38:1-20.
7. Hollister LE. Cannabis-1988. Acta Psychiatr Scand Suppl
1988;345:108-118.
8. Sidney S, Beck JE, Tekawa IS, Quesenberry CP Jr, Friedman
GD. Marijuana use and mortality. Am J Pub Health
1997;87:585-590.
Competing interests: No competing interests
This interesting review of literature and opinion remains squarely in
the vanity of it's rut. For the genuine medicinal herbalist cannabis lives
purposefully as a functional anodyne, nervine, sudorific, anti-spasmodic.
The patentable fractions for the profit-driven perspectives sway with
commercial and political winds and proport to report and respect fact.
While it is quite interesting yes, important even, for these voices of
pharmaceutical exploitation, to examine this issue it is laughable and
regretable they are heard as prime or sole experts of the subject.
Competing interests: No competing interests
What becomes clear on reading the papers on cannabinoid therapy in
emesis and pain management is that in many cases the studies were doomed
from the start in light of the huge advances in cannabinoid biology over
the past few years.
In particular the identification of an endogenous cannabinoid signalling
system makes it possible to predict that in instances where this system is
perturbed (such as spasticity associated with neronal degeneration in MS)
then cannabinoid therapy is highly likely to be effective.
Many scientists in light of the current biological evidence would not now
sanction the use of cannabinoids in many of the areas previously
investigated where clinical outcome was disappointing such as acute post-
operative pain, wheras chronic neropathic pain is likely to respond well
to cannabinoid therapy.
In the future further understanding of this exciting area of neurobiology
will enable us to develop vastly improved therapeutic agents to not only
treat symptoms effectively but also greatly reduce contraindications such
as central psychoactive effects.
Yours faithfully
Gareth Pryce
Competing interests: No competing interests
Pooled data of elder studies miss relevant information
Dear Sirs:
The articles by Campbell et al. (2001) and by Tramer et al. (2001)
are indeed high quality reviews, but I am less sure whether the methods
applied are able to answer the questions of today's interest. If you pool
the data on elder pain studies you will miss most of the interesting
information, particularly differences in efficacy for different painful
conditions and differences between the cannabinoids and interindividual
differences with regard to side effects.
It is well-known that cannabinoids are weak analgesics compared to
the opiates (Grotenhermen 1999). The question of interest is not so much
whether cannabinoids are potent analgesics compared to codeine but in
which painful conditions cannabinoids are effective. By stating that
cannabinoids may have potential in neuropathic pains particularly with
spastic components even Kalso (2001) hints to a need for such a
differentiated assessment. The same is true for side effects.
Levonantradol has not been brought on the market because of a higher rate
of side effects compared to THC. Today an interesting question might be by
which strategies psychotropic side effects could be reduced (Pertwee
2001). There is a high interindividual variation with regard to side
effects and the ratio of side effects and benefits. Some patients may
profit more since they tolerate relative high doses without perceiving
unpleasant effects (Brenneisen 1996). Will we learn to find out which
patients have a favourable ratio of risks and benefits?
With regard to the antiemetic efficacy I agree that modern serotonin
receptor antagonists are very effective to treat nausea and vomiting in
cancer chemotherapy, but sometimes they fail and sometimes cannabinoids
seem to be superior (Gonzalez-Rosales and Walsh 1997).
The study by Maurer et al. (1990) cited by Campbell and colleagues
refers to another important aspect, the synergistic use of several
pharmacological effects of cannabinoids, in this case the analgesic and
antispastic effects in a patient with a spinal cord injury. Research that
cannabinoids reduce opioid-induced emesis (Simoneau et al. 2001) and act
synergistically with opioids against pain point to a possible combination
of analgesic and antiemetic effects of cannabinoids. In my opinion
cannabinoid receptor agonists will find their place in modern medicine
within the next few years. It will be interesting to see for which
indications they will be approved and used and whether they will be
limited to synthetic derivatives from Bayer (Siegling et al. 2001),
Novartis (Fox et al. 2001) and other companies engaged in cannabinoid
research.
Sincerely,
Franjo Grotenhermen, M.D.
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. 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.
3. Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y. The effect of
orally and rectally administered delta 9-tetrahydrocannabinol on
spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther
1996;34(10):446-452.
4. Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, James I. The
role of central and peripheral Cannabinoid(1) receptors in the
antihyperalgesic activity of cannabinoids in a model of neuropathic pain.
Pain 2001;92(1-2):91-100.
5. Gonzalez-Rosales F, Walsh D. Intractable nausea and vomiting due to
gastrointestinal mucosal metastases relieved by tetrahydrocannabinol
(dronabinol). J Pain Symptom Manage 1997;14(5):311-314.
6. Grotenhermen F. Cannabis in der Schmerztherapie - ein neues Adjuvans
[Cannabis in pain therapy – a new adjuvans]? Forschung und Praxis,
Wissenschaftsjournal der Ärztezeitung 1999;276:22-26.
Kalso E. Cannabinoids for pain and nausea. Some evidence but is there any
need? [Editorial] BMJ 2001;323:2-3.
7. Maurer M, Henn V, Dittrich A, Hofmann A. Delta-9-tetrahydrocannabinol
shows antispastic and analgesic effects in a single case double-blind
trial. Eur Arch Psychiatry Neurol Sci 1990;240(1):1-4.
8. Pertwee R. Sites and Mechanisms of Action. In: Grotenhermen F, Russo E,
eds. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic
potential. Haworth Press, Binghamton/New York 2001, in press.
9. Siegling A, Hofmann HA, Denzer D, Mauler F, De Vry J. Cannabinoid CB(1)
receptor upregulation in a rat model of chronic neuropathic pain. Eur J
Pharmacol. 2001 Mar 9;415(1):R5-R7.
10. Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F,
Makriyannis A, Malan TP Jr. The cannabinoid agonist WIN55,212-2 suppresses
opioid-induced emesis in ferrets. Anesthesiology 2001 May;94(5):882-887.
Competing interests: No competing interests