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Page 137 4 THE MEDICAL VALUE OF MARIJUANA AND RELATED SUBSTANCES During the course of drug development, a typical compound is found to have some medical benefit and then extensive tests are undertaken to determine its safety and proper dosage for medical use. In contrast, marijuana has been widely used in the United States for decades.162 In 1996, 68.6 million people 32% of the U.S. population over 12 years oldhad tried marijuana or hashish at least once; 5% were current users.162 The data on the adverse effects of marijuana are more extensive than the data on its effectiveness. Clinical studies of marijuana are difficult to conduct: researchers interested in clinical studies of marijuana face a series of barriers, research funds are limited, and there is a daunting thicket of regulations to be negotiated at the federal level (those of the Food and Drug Administration, FDA, and the Drug Enforcement Agency, DEA) and state levels (see chapter 5). Consequently, the rapid growth in basic research on cannabinoids contrasts with the paucity of substantial clinical studies on medical uses. This chapter is devoted to an analysis of the therapeutic value of marijuana and cannabinoids for specific symptoms associated with various conditions. The risks associated with the medical use of marijuana are discussed in chapter 3. It should be noted that THC, the primary active ingredient in marijuana, is an FDA-approved drug referred to as dronabinol and marketed as Marinol. Marijuana is advocated primarily for relief from the symptoms of disease rather than as a cure. For the most part, the logical categories for the medical use of mari-
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Page 138 juana are not based on particular diseases but on symptomssuch as nausea, appetite loss, or chronic paineach of which can be caused by various diseases or even by treatments for diseases. This chapter is therefore organized by symptoms rather than by diseases. There are eight sections. The first section explains clinical trials, the following five deal with specific symptoms and conditions, and the last two summarize the medical benefits of marijuana and cannabinoids. The five sections on symptoms and conditions are as follows: pain, nausea and vomiting, wasting syndrome and appetite stimulation, neurological symptoms (including muscle spasticity), and glaucoma. The Institute of Medicine (IOM) study team received reports of more than 30 different medical uses of marijuana, more than could be carefully reviewed in a report of this length; even more uses are reported elsewhere.62,63 For most of the infrequently mentioned medical uses of marijuana there are only a few anecdotal reports. This report reviews only the most prominent symptoms that are reportedly relieved by marijuana. However, many of those diseases not reviewed here share common symptoms, such as pain, nausea and vomiting, and muscle spasms, which might be relieved by cannabinoid drugs. Standards For Evaluating Clinical Trials Before evaluating individual clinical trials concerning the efficacy and safety of medical uses of marijuana and cannabinoids, it is useful to review the general qualities of clinical trials. Clinical trials involve groups of individuals in which different treatments are compared among different groups. Such trials measure the efficacy of a medication and are required by the FDA for approval of any new drug or new use of a drug (discussed further in chapter 5). The degree of assurance that the outcome of a clinical trial is due to the treatment being tested depends on how well the trial is designed. Three important factors to consider in evaluating the design of a clinical trial are sample selection, subjective effects, and effects that are independent of the treatment. For sample selection it is important to ensure that patients are allocated to different treatment groups in such a way that the groups are not biased toward a particular treatment outcome. For example, the health status, gender, and ages of different treatment groups should be equivalent. Subjective effects must be controlled because they influence experimental results in two important ways. First, a patient's expectation that a treatment will be effective can influence the degree of its effect (for example, in the control of nausea). Second, the investigator's expectation can influence his or her interpretation of the treatment effect (for example, when assessing the level of pain experienced by a patient).
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Page 139 For these reasons, double blinding, in which neither the subject nor the person who assesses the drug's effect is aware of the subject's treatment group, is particularly important in cannabinoid drug studies. Another important control for subjective effects includes the use of placebo drugs, which are inert substances, or the use of comparison drugs that have effects similar to the experimental drug. Finally, the quality of the experimental design depends on controlling for factors that are unrelated to the test drug but that might nonetheless influence the treatment outcome. Sequencing effects are one example of such factors. For example, patients might react differently to the same medication depending on whether the medication was administered after an effective or an ineffective treatment. Likewise, a patient whose symptoms are initially mild might react differently to a drug than would a patient whose symptoms are initially severe. Because psychological effects are associated with cannabinoid drugs, it is important to consider how such side effects might influence the therapeutic value of the treatment. Conditions such as pain and nausea are especially susceptible to subjective influences. For example, depending on the person, THC can reduce or increase anxiety; it is important to determine to what extent this ''side effect'' contributes to the therapeutic effect. While double-blind, randomized, controlled clinical trials offer the highest degree of assurance of drug efficacy, such trials are not always feasible. Vulnerable populations, such as children, older patients, and women of child-bearing age, are often excluded from experimental drug trials for safety reasons. Nonetheless, such patients are part of everyday clinical practice. The challenge of integrating the ideal of standardized and rigorous processes for treatment evaluation with everyday clinical practice has encouraged interest in single-patient trials.67 Methods for such trials have been established and tested in a variety of clinical settings, usually under everyday conditions.66,105,159 They are particularly valuable when physicians or patients are uncertain about the efficacy of treatment for symptomatic diseases. Controls can be incorporated even in this kind of trial. Such trials can be double blinded and can involve crossover designs in which the patient is treated with alternating treatments, such as placebo-drug-placebo or one drug followed by another drug. As with any other clinical trial, a single-patient trial should be designed to permit objective comparison between treatments. Analgesia Pain is the most common symptom for which patients seek medical assistance.5 Pain associated with structural or psychophysiological disorders can arise from somatic, visceral, or neural structures. Somatic pain results from activation of receptors outside the brain and is transmitted to
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Page 140 the brain via peripheral nerves. Visceral pain results from activation of specific pain receptors in the intestine (visceral nociceptive receptors); it is characterized as a deep aching or cramping sensation, but its source is often experienced at sites remote from the site of receptor activation, a phenomenon known as referred pain. Neuropathic pain results from injury to peripheral receptors, nerves, or the central nervous system; it is typically burning, the skin feels abnormally unpleasant when gently touched (dysesthesia), and it often occurs in an area of sensory loss, as in the case of postherpetic neuralgia (shingles). All of the currently available analgesic (pain-relieving) drugs have limited efficacy for some types of pain. Some are limited by dose-related side effects and some by the development of tolerance or dependence. A cannabinoid, or other analgesic, could potentially be useful under any of the following circumstances: · There is a medical condition for which it is more effective than any currently available medication. · It has a broad clinical spectrum of efficacy and a unique side effect profile. · It has synergistic interactions with other analgesics. · It exhibits "side effects" that are considered useful in some clinical situations. · Its efficacy is enhanced in patients who have developed tolerance to opioids. There have not been extensive clinical studies of the analgesic potency of cannabinoids, but the available data from animal studies indicate that cannabinoids could be useful analgesics. In general, cannabinoids seem to be mild to moderate analgesics. Opiates, such as morphine and codeine, are the most widely used drugs for the treatment of acute pain, but they are not consistently effective in chronic pain; they often induce nausea and sedation, and tolerance occurs in some patients. Recent research has made it clear that CB1 receptor agonists act on pathways that partially overlap with those activated by opioids but through pharmacologically distinct mechanisms (see chapter 2). Therefore, they would probably have a different side effect profile and perhaps additive or synergistic analgesic efficacy. In light of the evidence that cannabinoids can reduce pain in animals, it is important to re-evaluate the evidence of analgesic efficacy in humans and to ask what clinical evidence is needed to decide whether cannabinoids have any use in the treatment of pain.
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Page 141 Clinical Studies of Cannabinoids There have been three kinds of studies of the effects of cannabinoids on pain in human volunteers: studies of experimentally induced acute pain, studies of postsurgical acute pain, and studies of chronic pain. Overall, there have been very few studiesonly one since 1981and they have been inconclusive. Experimentally Induced Acute Pain Early studies of cannabinoids on volunteers did not demonstrate consistent analgesia when experimental pain models were used. In fact, three early volunteer studies of THC and experimental pain caused by a variety of pain modalitieselectrical stimulation, tourniquet pain, and thermal painresulted in an increase in pain sensitivity (hyperalgesia).22,84,108 Other studies also failed to show an analgesic effect of THC, but they were not well designed. Raft and co-workers found no evidence of THC effect on pain thresholds and pain tolerance following electrical stimulation and noxious pressure.150 But their study suffers from two major methodological problems. First, they measured only the extremes of pain sensationthreshold (the lowest intensity at which a particular stimulus is perceived as painful) and tolerance (the maximum intensity of pain that a subject can withstand). However, most pain is experienced in an intermediate range, where effects on pain suppression are most detectable. Modern methods of pain assessment in humans typically use ratings of the intensity of the sensation of pain; those methods are superior to assessing the effects of a drug on the extremes of pain.192 Second, Raft and coworkers did not include a positive control; that is, they did not demonstrate the adequacy of their method by showing that an established analgesic, such as an opiate or narcotic, was effective under their study conditions. Clark and co-workers22 tested the effect of smoked marijuana on thermal pain in volunteers and failed to observe an analgesic effect. However, because of the study design, the results are inconclusive. First, there was no positive control to demonstrate the adequacy of their methods; second, the study subjects were habitual marijuana users. During the study, they were hospitalized and allowed free access to marijuana cigarettes for a period of four weeks, consuming an average of four to 17 marijuana cigarettes per day. Pain was tested "approximately every one to two weeks." Thus, it is quite likely that the subjects were tolerant to THC at the time of testing.
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Page 142 Surgical Acute Pain Raft and co-workers150 found no analgesic effect of THC on surgical pain induced by tooth extraction. However, that study suffered from several serious limitations: the tooth extraction included treatment with the local anesthetic lidocaine, the pain during the procedure was assessed 24 hours later, and there was no positive control. Levonantradol (a synthetic THC analogue) was tested in 56 patients who had moderate to severe postoperative or trauma pain.89 They were given intramuscular injections of levonantrodol or placebo 24 hours after surgery. To control for previous drug exposure, patients with a history of drug abuse or addiction and those who received an analgesic, antiinflammatory, tranquilizer, sedative, or anesthetic agent within 24 hours of the test drug were excluded from the study. On average, pain relief was significantly greater in the levonantradol-treated patients than in the placebo-treated patients. Because the authors did not report the number or percentage of people who responded, it is not clear whether the average represents consistent pain relief in all levonantradol-treated patients or whether some people experienced great relief and a few experienced none. Chronic Pain The most encouraging clinical data on the effects of cannabinoids on chronic pain are from three studies of cancer pain. Cancer pain can be due to inflammation, mechanical invasion of bone or other pain-sensitive structure, or nerve injury. It is severe, persistent, and often resistant to treatment with opioids. In one study, Noyes and co-workers found that oral doses of THC in the range of 5-20 mg produced analgesia in patients with cancer pain.139,140 The first experiment was a double-blind, placebo-controlled study of 10 subjects and measured both pain intensity and pain relief.140 Each subject received all drug treatments: placebo and 5, 10, 15, and 20 mg of THC in pill form; each pill was identical in appearance and given on successive days. The 15- and 20-mg doses of-THC produced significant analgesia. There were no reports of nausea or vomiting. In fact, at least half the patients reported increased appetite. With a 20-mg dose of THC, patients were heavily sedated and exhibited "depersonalization," characterized by a state of dreamy immobility, a sense of unreality, and disconnected thoughts. Five of 36 patients exhibited adverse reactions (extreme anxiety) and were eliminated from the study. Only one patient experienced this effect at the 10-mg dose of THC. The mean age of the patients was 51 years, and they were probably not experienced marijuana smokers. A limitation of this study is that there were no positive con-
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Page 143 trolsthat is, other analgesics that could provide a better measure of the degree of analgesia produced by THC. In a later larger single-dose study, the same investigators reported that the analgesic effect of 10 mg of THC was equivalent to that of 60 mg of codeine; the effect of 20 mg of THC was equivalent to that of 120 mg of codeine.139 (Note that codeine is a relatively weak analgesic.) The side effect profiles were similar, though THC was more sedating than codeine. In a separate publication the same authors published data indicating that patients had improved mood, a sense of well-being, and less anxiety.139 The results of the studies mentioned above on cancer pain are consistent with the results of using a nitrogen analogue of THC. Two trials were reported: one compared this analogue with codeine in 30 patients, and a second compared it with placebo or secobarbital, a short-acting barbiturate.175 For mild, moderate, and severe pain, the THC analogue was equivalent to 50 mg of codeine and superior to placebo and to 50 mg of secobarbital. Case Reports and Surveys The few case reports of clinical analgesia trials of cannabinoids are not convincing.85,120 There are, however, anecdotal surveys that raise the possibility of a role for cannabinoids in some patients who have chronic pain with prominent spasticity. A recent survey of over 100 patients with multiple sclerosis reported that a large number obtained relief from spasticity and limb pain (discussed further under the section on multiple sclerosis).28 Several said that it relieved their phantom pain and headache.41 Migraine Headaches There is clearly a need for improved migraine medications. Sumatriptan (Imitrex) is the best available medication for migraine headaches, but it fails to abolish migraine symptoms in about 30% of migraine patients.118,147 Marijuana has been proposed numerous times as a treatment for migraine headaches, but there are almost no clinical data on the use of marijuana or cannabinoids for migraine. Our search of the literature since 1975 yielded only one scientific publication on the subject. It presents three cases of cessation of daily marijuana smoking followed by migraine attacksnot convincing evidence that marijuana relieves migraine headaches.43 The same result could have been found if migraine headaches were a consequence of marijuana withdrawal. While there is no evidence that marijuana withdrawal is followed by migraines, when analyzing the strength of reports such as these it is important to consider
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Page 144 all logical possibilities. Various people have claimed that marijuana relieves their migraine headaches, but at this stage there are no conclusive clinical data or published surveys about the effect of cannabinoids on migraine. However, a possible link between cannabinoids and migraine is suggested by the abundance of cannabinoid receptors in the periaqueductal gray (PAG) region of the brain. The PAG region is part of the neural system that suppresses pain and is thought to be involved in the generation of migraine headaches.52 The link or lack thereof between cannabinoids and migraine might be elucidated by examining the effects of cannabinoids on the PAG region.110 Recent results indicating that both cannabinoid receptor subtypes are involved in controlling peripheral pain15 suggest that the link is possible. Further research is warranted. Conclusions: Analgesia A key question to address is whether there is any receptor selectivity for the analgesic efficacy of cannabinoids. Are the unwanted side effects (amnesia and sedation) caused by the same receptors in the same brain regions as those producing the analgesia? If the answer is yes, enhancing efficacy will not solve the problem of sedation. Similarly, are the pleasant side effects due to an action at the same receptor? Can the feelings of wellbeing and appetite stimulation be separated by molecular design? Recent results indicating that both cannabinoid receptor subtypes are independently involved in controlling peripheral pain15 (discussed in chapter 2) strongly suggest that this is possible and that further research is warranted. Further research into the basic circuitry underlying cannabinoid analgesia should be valuable. The variety of neural pathways that underlie the control of pain suggests that a synergistic analgesia "cocktail" would be effective. For example, Lichtman and Martin have shown the involvement of an a2 adrenoreceptor in cannabinoid analgesia.111 Perhaps a combination of a CB1 agonist and an a2 agonist (such as clonidine) would provide enhanced analgesia with less severe side effects. Clinical studies should be directed at pain patients for whom there is a demonstrated need for improved management and where the particular side effect profile of cannabinoids promises a clear benefit over current approaches. The following patient groups should be targeted for clinical studies of cannabinoids in the treatment of pain: · Chemotherapy patients, especially those being treated for the mucositis, nausea, and anorexia.
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Page 145 · Postoperative pain patients (using cannabinoids as an opioid adjunct to determine whether nausea and vomiting from opioids are reduced). · Patients with spinal cord injury, peripheral neuropathic pain, or central poststroke pain. · Patients with chronic pain and insomnia. · AIDS patients with cachexia, AIDS neuropathy, or any significant pain problem. In any patient group an essential question to be addressed is whether the analgesic efficacy of opioids can be augmented. The strategy would be to find the ceiling analgesic effect with an opioid (as determined by pain intensity and tolerability of side effects) and then add a cannabinoid to determine whether additional pain relief can be obtained. That would begin the investigation of potential drug combinations. As with any clinical study on analgesic drugs, it will be important to investigate the development of tolerance and physical dependence; these are not themselves reasons to exclude the use of cannabinoids as analgesics, but such information is essential to the management of many drugs that are associated with tolerance or physical dependence. A secondary question would be whether THC is the only or the best component of marijuana for analgesia. How does the analgesic effect of the plant extract compare with that of THC alone? If there is a difference, it will be important to identify the combinations of cannabinoids that are the most effective analgesics. In conclusion, the available evidence from animal and human studies indicates that cannabinoids can have a substantial analgesic effect. One exception is the lack of analgesic effect in studies on experimentally induced acute pain, but because of limitations in the design of those studies they were inconclusive. Further clinical work is warranted to establish the magnitude of the effect in different clinical conditions and to determine whether the effect is sustained. Although the usefulness of cannabinoids appears to be limited by side effects, notably sedation, other effects such as anxiolysis, appetite stimulation, and perhaps antinausea and antispasticity effects should be studied in randomized, controlled clinical trials. These very "special" effects might warrant development of cannabinoid drugs for particular clinical populations. Nausea and Vomiting Nausea and vomiting (emesis) occur under a variety of conditions, such as acute viral illness, cancer, radiation exposure, cancer chemotherapy, postoperative recovery, pregnancy, motion, and poisoning. Both
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Page 146 are produced by excitation of one or a combination of triggers in the gastrointestinal tract, brain stem, and higher brain centers (Figure 4.1, Emesis-stimulating pathways).127 There are numerous cannabinoid receptors in the nucleus of the solitary tract, a brain center that is important in the control of emesis.79,80 Although the same mechanisms appear to be involved in triggering both nausea and vomiting, either can occur without the other. Much more is known about the neural mechanisms that produce vomiting than about those that produce nausea, in large part because vomiting is a complex behavior involving coordinated changes in the gastrointestinal tract, respiratory muscles, and posture, whereas nausea is a sensation involving primarily higher brain centers and lacks a discrete observable action.104,128 Most reports on the antiemetic effects of marijuana or cannabinoids are based on chemotherapy-induced emesis; they are the subject of the following section. Chemotherapy-Induced Nausea and Vomiting The use of effective chemotherapeutic drugs has produced cures in some malignancies and retarded the growth of others, but nausea and Figure 4.1 Emesis-stimulating pathways. Source: Bruton, L.L. 1996. P. 929 in Hardman et al., eds., The Pharmacological Basis of Therapeutics, 9th edition. New York: McGraw-Hill. Reprinted with permission.
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Page 147 vomiting are frequent side effects of these drugs. Nausea ranks behind only hair loss as a concern of patients on chemotherapy, and many patients experience it as the worst side effect of chemotherapy. The side effects can be so devastating that patients abandon therapy or suffer diminished quality of life. As a result, the development of effective strategies to control the emesis induced by many chemotherapeutic agents is a major goal in the supportive care of patients with malignancies. The mechanism by which chemotherapy induces vomiting is not completely understood. Studies suggest that emesis is caused by stimulation of receptors in the central nervous system or the gastrointestinal tract. This stimulation appears to be caused by the drug itself, a metabolite of the drug, or a neurotransmitter.6,12,35 In contrast with an emetic like apomorphine, there is a delay between the administration of chemotherapy and the onset of emesis. This delay depends on the chemotherapeutic agent; emesis can begin anywhere from a few minutes after the administration of an agent like mustine to an hour for cisplatin.12 The most desirable effect of an antiemetic is to control emesis completely, which is currently the primary standard in testing new antiemetic agents (R. Gralla, IOM workshop). Patients recall the number of emetic episodes accurately, even if their antiemetics are sedating or affect memory;101 thus, the desired end point of complete control is also a highly reliable method of evaluation. The degree of nausea can be estimated through the use of established visual analogue scales.*21,55,101 Another consideration in using antiemetic drugs is that the frequency of emesis varies from one chemotherapeutic agent to another. For example, cisplatin causes vomiting in more than 99% of patients who are not taking an antiemetic (with about 10 vomiting episodes per dose), whereas methotrexate causes emesis in less than 10% of patients.55,82,83 Among chemotherapeutic agents, cisplatin is the most consistent emetic known and has become the benchmark for judging antiemetic efficacy. Antiemetics that are effective with cisplatin are at least as effective with other chemotherapeutic agents. Controlling for the influence of prior chemotherapy and balancing predisposing factors such as, sex, age, and prior heavy alcohol use among study groups are vital for reliability. Reliable randomization of patients and blinding techniques (easier when there are no psychoactive effects) are also necessary to evaluate the control of vomiting and nausea. *The visual analogue scale is a continuous line representing all possible levels of a particular sensation. It is an estimation of a patient's subjective evaluation and not a true measurement. Patients select a point anywhere on the line to demonstrate the level of sensation they are experiencing, with one end representing one extreme, such as no sensations, and the other end representing the opposite extreme, such as a maximum level of that sensation.
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No clear link has been established between symptoms of Tourette's and cannabinoid sites or mechanism of action. Pimozide and haloperidol, two widely used treatments for Tourette's, inhibit effects mediated by the neurotransmitter, dopamine, whereas cannabinoids can increase dopamine reiease.~56, I84 The physiological relevance, if any, of these two observations has not been established. The clinical reports consist of four case histories indicating that marijuana use can reduce tics in Tourette's patients.79 ~66 in three of the four cases, the investigators suggest that beneficial effects of marijuana might have been due to anxiety-reducing properties of marijuana rather than to a specific anti-tic effect. ~66 Therapy for Movement Disorders There are a variety of drugs available, listed in table 4.3, to treat the different movement disorders. Common side effects of many of these c rugs include sedation, lethargy, school and work avoidance, social phobia, and increased risk of parkinsonism and tardive dyskinesia.' With some of these medications, like those used for dystonia, efficacy is lacking in as much as 50 percent of the patients. [n addition to medications, surgical interventions such as pallidotomy and neuro surgical transplantation of embryonic substantia nigra tissue into the patient's striatum have been tried in Parkinson's patients. Surgery is generally palliative, and is still considered to be in the developmental phase. Dyskinesia is the development of irreversible, involuntary dyskinetic movements. 4.32
Representative terms from entire chapter: