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Title:
National Institutes of Health -- Workshop on the Medical Utility of Marijuana
Author:
Ad Hoc Group of Experts
Date:
Feb. 19-20, 1997
Summary:
Over the past 18 months there has been wide-ranging public discussion on the potential medical uses of marijuana, particularly smoked marijuana. To contribute to the resolution of the debate
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Part 3 of 5

TOC | Part 1 | Part 2 | Part 2a | Part 3 | Part 4 | Part 5


Analgesia

Use of Marijuana in Neurological and Movement Disorders


ANALGESIA

1. What research has been done and what is known about the possible medical uses of marijuana?

A number of studies have been conducted on the antinociceptive or analgesic effect of tetrahydrocannabinol (THC) or marijuana in both animals and human subjects; the results have been conflicting. Of interest is the recent identification of cannabinoid receptors as well as an endogenous ligand, anandamide. There is some evidence that they are part of a natural pain control system distinct from the endogenous opioid system. Recognizing that some studies have demonstrated an antinociceptive (analgesic) effect of THC and related compounds in rodents, it may be useful to identify what specific kinds of pain may be relieved by marijuana or THC.

Animal studies on the analgesic effect of marijuana have produced inconsistent results. Whereas one study shows that delta-9-tetrahydrocannibinol (Delta9-THC) is equipotent to morphine in rats (tailflick test), and more potent than morphine in mice (hotplate test), other studies showed that Delta9-THC was less potent than morphine in both mice and rats. Cannabinoids have been shown to be possibly analgesic in animal models of neuropathic pain.

There have been a few studies of marijuana/Delta9-THC employing different models of experimentally induced pain in volunteer subjects, and these studies have also yielded conflicting results. Raft and colleagues (1977) found that, in oral surgery patients, premedication with intravenous Delta9-THC was less effective than diazepam or placebo in reducing two kinds of experimentally induced pain. Another study showed that smoked marijuana increased pain tolerance, while others showed either no effect or a lowering of pain threshold after oral or intravenous dosing with Delta9-THC or smoking marijuana. The current "FDA Guideline for the Clinical Evaluation of Analgesic Drugs" (FDA 1992) notes that "Evidence is still inadequate to establish that any experimental pain model will consistently and accurately predict the clinical efficacy of new analgesics, . . . [and] they cannot substitute for controlled trials in patients with pathologic pain [naturally occurring pain caused by disease or tissue injury] in producing substantial evidence of analgesia . . ." This is also the overwhelming consensus of investigators who conduct controlled clinical trials of analgesic efficacy. Therefore, the above studies contribute little information about the analgesic efficacy of marijuana/Delta9-THC in patients with pain.

There appear to be no controlled analgesic studies of smoked marijuana in patients with naturally occurring pain. However, Noyes and his colleagues conducted two studies of oral Delta9-THC in inpatients with cancer pain. Both of these studies used the same standard single-dose analgesic study methodology and met the criteria for well-controlled clinical trials of analgesic efficacy, but with small sample sizes. Both were randomized, double-blind, crossover comparisons employing a full-time nurse-observer, who collected hourly subjective ratings of pain intensity and pain relief. Observed and reported side effects were recorded, as were the responses to an 11-item subjective effects questionnaire.

The first study in 10 cancer patients compared a placebo and 5, 10, 15, and 20 mg doses of Delta9-THC over a 6-hour observation period (Noyes et al. 1975a). The slope of the dose-response curve for pain relief was significant, as was a pairwise comparison of pain relief after the two lower doses combined versus the two higher doses combined. There was also a clear dose-response relationship for sedation, mental clouding, and other central nervous system (CNS) related side effects. Because of sedation, the 20-mg dose was judged to be "of limited value for most patients."

The second study in 36 cancer patients compared placebo, 10, and 20 mg of Delta9-THC and 60 and 120 mg of codeine over a 7-hour observation period (Noyes et al. 1975b). Codeine 120 mg and Delta9-THC 20 mg were similar to each other and significantly superior to placebo for the sum of the pain intensity differences and total pain relief, while other pairwise contrasts were not significant. Relative potency analysis was not performed.

The time-effect curves for both doses of codeine and for Delta9-THC, 10 mg, peaked at the third hour. As in the first study, the 20 mg dose of Delta9-THC peaked at the fifth hour, which probably reflects the delayed absorption of oral THC. "Patients receiving 20 mg of THC were heavily sedated and even at 10 mg reported considerable drowsiness. Other dose limiting side effects included dizziness, ataxia and blurred vision" (Noyes et al. 1975b). Mental clouding, thinking impairment, disconnected thought, disorientation, slurred speech, and impaired memory were much more prominent after both doses of Delta9-THC than after codeine administration, and patients expressed particular concern over their "loss of control" over thought and action. Five patients experienced very unpleasant psychic effects after Delta9-THC; three patients said they felt as if they were dying, one patient experienced depressed mood, and one patient suffered paranoid ideation. In two patients, the adverse mood effects persisted 3 or 4 days.

These studies indicate that Delta9-THC has some analgesic activity in humans. They also indicate that there is, at best, a very narrow therapeutic window between doses that produce useful analgesia and those that produce unacceptable adverse CNS effects.

2. What are the major unanswered scientific questions?

Since oral Delta9-THC has some analgesic activity, it is highly likely that smoked marijuana has some analgesic activity in some kinds of clinical pain. Because Delta9-THC from smoked marijuana is absorbed directly into the pulmonary circulation, this route of administration results in a Delta9-THC blood level curve much more like that produced by an intravenous injection than that after oral administration. It is therefore likely that smoked marijuana potentially allows a more precise titration to effect than oral administration of Delta9-THC with its delayed, poor, and erratic bioavailability. Theoretically, smoked marijuana or inhaled THC potentially has some of the characteristics of a patient-controlled analgesia (PCA) pump. It is therefore possible that some pain patients could use smoked marijuana to titrate themselves into the therapeutic window of adequate pain relief while avoiding unacceptable adverse effects. Although the above scenario is pharmacologically reasonable, only properly designed controlled clinical analgesic studies can determine if it actually works and is practically useful. For example, it is also possible that the minimum blood level of Delta9-THC that produces useful analgesia also usually produces a level of sedation, mental clouding, and thinking impairment that is unacceptable to most patients.

There are currently available a great variety of both opioid and nonsteroidal anti-inflammatory drug (NSAID) analgesics in various dosage formulations suitable for many routes of administration. Adroit use of these can manage most acute pain and even chronic cancer pain satisfactorily. If marijuana is to be a useful analgesic, healthcare providers need to know how it compares in efficacy and safety to at least a few of the standard analgesics that would be used in managing a particular kind of pain.

3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study?

Neuropathic pain represents a treatment problem for which currently available analgesics are, at best, marginally effective. Since Delta9-THC is not acting by the same mechanism as either opioids or NSAIDs, it may be useful in this inadequately treated type of pain. Evaluation of cannabinoids in the management of neuropathic pain, including HIV-associated neuropathy, should be undertaken. A few animal studies support this idea. Another potentially useful role for marijuana/Delta9-THC might be as an adjuvant when added to a regimen of standard analgesics.

    References
    FDA Guideline for the Clinical Evaluation of Analgesic Drugs. DHHS Pub. No. 93-3093. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, 1992.

    Noyes, R., Jr.; Brunk, S.F.; Baram, D.A.; and Canter, A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15(2-3):139-143, February-March, 1975a.

    Noyes, R., Jr.; Brunk, S.F.; Avery, D.A.H.; and Canter, A.C. The analgesic properties of delta-9-tetrahydrocannabinol. Clin Pharmacol Ther 18(1):84-89, July, 1975b.

    Raft, D.; Gregg, J.; Ghia, J.; and Harris, L. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Clin Pharmacol Ther 21(1):26-33, 1977.

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USE OF MARIJUANA IN NEUROLOGICAL AND
MOVEMENT DISORDERS

1. What research has been done and what is known about the possible medical uses of marijuana?

There have been numerous studies both in animals and in various clinical states on the use of cannabinoids on neurological and various movement disorders. These results range from anecdotal reports to surveys and clinical trials. Marijuana or tetrahydrocannabinol (THC) is reported to have some antispasticity, analgesic, antitremor, and antiataxia actions, as well as some activity in multiple sclerosis (MS) and in spinal cord injury patients.

The spasticity and nocturnal spasms produced by MS and partial spinal cord injury have been reported to be relieved by smoked marijuana and to some extent by oral THC in numerous anecdotal reports. The effect seems to appear rapidly with smoked marijuana; patients are able to titrate the dose by the amount they smoke. No large-scale controlled studies or studies to compare either smoked or oral THC with other available therapies have been reported. Several relatively good therapeutic alternatives exist. There is no published evidence that the cannabinoid drugs are superior or even equivalent.

Substantial experimental animal literature exists showing that various cannabinoids, given primarily by parenteral routes, have a substantial anticonvulsant effect in the control of various models of epilepsy, especially generalized and partial tonic-clonic seizures. Scant information is available about the human experience with the use of marijuana or cannabinoids for the treatment of epilepsy. This is an area of potential value, especially for cannabis therapies by other than the smoked route.

Several single case histories have been reported indicating some benefit of smoked marijuana for dystonic states. It must be remembered that dystonia is a clinical syndrome with numerous potential causes, and the information available now does not differentiate which causes are most likely to be improved. Smoked marijuana and oral THC have been tested in the treatment of Parkinson's disease and Huntington's chorea without success.

The cannabinoids also have been used as experimental immunologic modifiers to treat such conditions as the animal models of experimental allergic encephalomyelitis (EAE) and neuritis. Parenteral cannabinoids have been successful in modifying EAE in animals, suggesting that cannabinoids may be of value in a more fundamental way by altering the root cause of a disease such as MS rather than simply treating its symptoms. Smoked marijuana would not be acceptable for such a role because of the variability of dose with the smoked route.

2. What are the major unanswered scientific questions?

The discovery of dedicated systems of central nervous system (CNS) neurons approximately 8 years ago, which express receptors specific for the cannabinoids, is of major scientific interest and importance. The distribution of these cannabinoid receptor-bearing neurons corresponds well with the clinical effects of smoked marijuana; for instance, their presence in the forebrain may relate to adverse changes in short-term memory, but perhaps positively in the control of epilepsy. Cannabinoid receptors in the brainstem and cerebellum may relate to the recognized incoordination that accompanies smoked marijuana use. The discovery of intrinsic ligands for these receptors in the mammalian brain is also of great importance. This system of cannabinoid receptors and ligands may be analogous to the discovery of opiate receptors and endorphins, which linked various opium derivatives (heroin and morphine) to an intrinsic system of neurons in the CNS. That discovery was of major importance for pain research.

The major unanswered scientific questions are:

  • How useful is smoked marijuana of known specific potency in controlling various neurologic conditions?

  • In comparative studies, how useful is smoked marijuana in altering objective abnormalities such as spasticity versus current standard therapies that have already been approved for human use?

  • Can alternative delivery systems (other than the oral route) be developed to provide rapidity of action with more safety than smoked marijuana?
  • Can available or newly developed synthetic cannabinoids be used more effectively to stimulate or block receptor activity in the cannabinoid system of the CNS?
  • What are the immune-modulating characteristics of the cannabinoids and can they be used for therapeutic human benefit?
  • Can the long-term risks of daily smoked marijuana be quantified so that useful risk versus benefit ratios can be determined, especially when considering treatment of long-term conditions such as spasticity or epilepsy?

3. What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study?

Marijuana or the use of other cannabinoids as human therapies might be considered for treating spasticity and nocturnal spasms complicating MS and spinal cord injury, for various active epilepsy states, for some forms of dystonia, and perhaps most interestingly, for treating neuropathic pain (Zeltser et al. 1991). (Also see the chapter titled Analgesia.) Neuropathic pain complicates many CNS diseases. Few available therapies provide even partial relief.

    Reference
    Zeltser, R.; Seltzer, Z.; Eisen, A.; Feigenbaum, J.J.; and Mechoulam, R. Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties. Pain 47(1):95-103, October 1991.

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TOC | Part 1 | Part 2 | Part 2a | Part 3 | Part 4 | Part 5