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An analgesic role for cannabinoids
Christopher W Vaughan and Macdonald J Christie
Cannabinoids have significant analgesic properties in animal
models, particularly for chronic pain states, but there are few human
studies. An endogenous cannabinoid system, with specific receptors
and transmitters, has recently been discovered. This discovery has
led pharmacologists to explore the potential of synthetic
cannabinoids to selectively target chronic pain disorders without
producing the side effects associated with cannabis.
Well-controlled clinical trials on cannabinoids, and cannabinoid
delivery systems, are now required.
MJA 2000; 173: 270-272
The endogenous cannabinoid system and pain -
Evidence for analgesic efficacy -
Adverse effects -
The place for analgesia -
Conclusion -
References -
Authors' details
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Natural and synthetic cannabinoids produce a range of
pharmacological effects with a number of potential therapeutic
applications, including the treatment of pain.1-3 However, the
political climate prevailing for much of the latter half of the 20th
century has censored investigation of its potential therapeutic
properties. Recently, expert groups convened by the British Medical
Association, the House of Lords, and the United States National
Institutes of Health have concluded that cannabinoids may have
therapeutic efficacy under some conditions.1,4,5 These groups have
recommended further study into the therapeutic benefits of cannabis
and cannabinoids, particularly in relation to the relief of chronic
pain.
Several developments provide compelling arguments to re-examine the medical use of cannabis and cannabinoids.
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The endogenous cannabinoid system and pain | |||
The actions of  -9-tetrahydrocannabinol (THC), the principal
active component in cannabis, can be understood in terms of the
natural functions of the endogenous cannabinoid system, which has
only recently been identified. Functional, cellular and molecular
studies suggest that cannabinoids might have important
applications in specific pain conditions (more detailed reviews are
available elsewhere2,3). There are at least two
distinct human cannabinoid receptors: CB1 and CB2 receptors (more
types may yet be found).6 CB1 receptors are located in
brain regions involved in mood, motor control, memory formation,
regulation of food intake, autonomic control and processing of
noxious or painful information, and in peripheral autonomic and
reproductive systems. CB2 receptors are found within immune and
reproductive tissues. The distinct localisation of CB1 and CB2
receptors is consistent with many of the therapeutic and adverse
effects of cannabinoids, and raises the possibility that synthetic
agents (unlike THC, which acts on both CB1 and CB2 receptors) can be
developed to selectively target different physiological systems.
THC mimics a group of natural substances produced within the body, including anandamide.7 These endogenous cannabinoids are partly similar to other neuromodulators in that they are synthesised within the brain, are released from neurones after stimulation, activate specific receptors, and undergo rapid uptake and degradation. However, there is still a great deal to be learned about this novel class of neuromodulators. There is now an intensive research effort to design drugs that will modify the metabolism of endogenous cannabinoids to influence these physiological functions in novel ways.8 Animal studies have clearly demonstrated that THC, synthetic cannabinoids, and endogenous cannabinoids produce analgesia and potentiate opioid analgesia.2,3 In many respects, the analgesic actions of cannabinoids and opioids are similar, although the two classes of drugs act on different receptors and act via partially distinct cellular mechanisms in pain control systems.2 Recent studies predict that cannabinoids might be effective in specific chronic pain states. The efficacy of cannabinoids is increased in nociceptive and inflammatory pain.9 In addition, cannabinoids (unlike opioids) maintain their analgesic activity in neuropathic or nerve injury induced pain and reduce the associated allodynia and hyperalgesia.10,11 | |||
Evidence for the analgesic efficacy of cannabinoids in humans | |||
| Although opioids are the most important drugs used to treat moderate to severe pain, some clinically important pain states, particularly neuropathic pain, are relatively insensitive to opioid treatment.12 Anecdotal evidence suggests that cannabinoids produce relief from pain in humans, but there are few well controlled clinical trials.1,4,5,13 Some studies have reported that THC and related analogues have acute analgesic activity, and relieve postoperative pain and chronic pain associated with cancer, multiple sclerosis and familial Mediterranean fever;14-17 others have reported that these compounds have no analgesic effect, or even produce hyperalgesia.18,19 It is difficult to reconcile the results of these studies given the different doses or purity of cannabinoid extracts, routes of administration (smoked, oral, intramuscular, intravenous), subject numbers and selection (naive or habitual users, patients with chronic pain), and the methods of analgesia testing.5 | |||
Adverse effects of cannabinoids | |||
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There is a risk of serious adverse effects of cannabis, but these have
often been overstated.20 The adverse effects,
although sufficiently serious to restrict legitimate medical use,
should be considered in the context of potential benefits and the
severity of disorders for which its use is contemplated. Many drugs
(including opioids) currently used for similar indications,
particularly intractable pain, are associated with much more
serious risks, such as respiratory depression. More extensive
comparisons of the therapeutic benefits and adverse effects of
cannabinoids are available elsewhere.1,2,5,13,21-23
Cannabis is sufficiently intoxicating to impair ability to carry out critical tasks safely for several hours after consumption.23 Although intoxication is sought by recreational users, it is often cited as a reason to discontinue therapeutic use. Cannabis can produce temporary distress and panic, transient psychosis, exacerbation of pre-existing mental illness, particularly schizophrenia,23 and has been linked to an increased risk of suicide.24 Medical use of cannabis would be contraindicated in individuals with a history of these responses or predispositions. Regular recreational use of cannabis can lead to dependence, as defined by standard criteria for substance-misuse disorders.23 While the incidence of serious cannabis dependence is difficult to estimate, regular heavy use, producing a state of near-continuous intoxication, occurs in 5%-10% of regular recreational users. The potential for dependency disorders among medical cannabis users is uncertain, but, by analogy with other addictive drugs such as opioids, prevalence of addiction would be expected to be relatively low with appropriate therapeutic use. In this regard, the US Drug Enforcement Administration has recently transferred oral THC (dronabinol) from a Schedule II to a Schedule III non-narcotic drug.25 Cannabis produces acute tachycardia, and long term exposure produces postural hypotension and bradycardia.2,5,13,23 The severity of this risk has not been established, but is of sufficient concern to exclude individuals with a history of cardiovascular disorders from clinical trials. Smoked cannabis carries similar risks of respiratory disorders as smoked tobacco, which restricts the circumstances for which this route of administration can be considered. | |||
The place of smoked cannabis for analgesia | |||
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Some disorders seem to respond better to smoked cannabis, whereas
others are relieved just as well by oral THC, which is legally
available for clinical use (as dronabinol) in many parts of the
world.5,13 The reasons for these
differences are still unknown. Subjective reports indicate that
smoked cannabis produces a more rapid and reliable effect than oral
THC, permitting the patient to titrate desired actions while
minimising side effects.2,22 Cannabis smoke contains
carcinogens and airway irritants which increase the risk of cancers
of the mouth, throat and lung, but the severity of this risk has not been
established. However, smoked cannabis might prove more beneficial
to some patients if the risks of smoking are outweighed by benefits
such as relief from intractable pain. Limited availability of smoked
marijuana was recommended by both the House of Lords
committee4 and the Institute of
Medicine21 as an interim solution.
In the long term, delivery systems such as inhalation devices are needed to provide patients with non-smoked, rapid-onset cannabinoid delivery systems for rapid, precise control over both beneficial and adverse effects.5,13,21 Such developments and licensing are expected to take at least five years. | |||
| Conclusion | There is some experimental evidence to suggest that cannabinoids may have therapeutic efficacy in various pain states, but there is an urgent need for well controlled clinical trials to establish the utility of both natural and synthetic cannabinoids, and cannabinoid delivery systems. Pharmacologists have only just begun to explore the therapeutic potential of synthetic cannabinoids that might avoid the undesirable side-effects of psychomotor impairment, cognitive disruption and intoxication. Smoked cannabis does not have long term prospects as a therapeutic agent, but there is some evidence and sufficient pharmacokinetic grounds to expect this mode of administration to have benefits in terms of patient control over desired and adverse effects. Major international expert groups have therefore recommended on compassionate grounds that smoked cannabis be made available to patients with severe debilitating diseases while superior cannabis delivery systems are being developed. | ||
| References |
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Authors' details | |||
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Department of Pharmacology, University of Sydney, Sydney, NSW.
Christopher W Vaughan, PhD, MBiomedE, R D Wright Research Fellow; Macdonald J Christie, PhD, BSc(Hons), Head of Department and Medical Foundation Fellow.
Reprints: Dr C W Vaughan, Department of Pharmacology, The
University of Sydney, Sydney, NSW 2006.
©MJA 2000
Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> © 2000 Medical Journal of Australia. We appreciate your comments. | |||