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Nabilone in the treatment of multiple sclerosis
recorded and the safety committee advises that recruitment within this interval should continue. The fact that there may be a difference in adverse outcomes between those treated up to 3 h compared with those treated beyond this time suggests that the time of administration of thrombolytic agents is critical.
*Geoffrey A Donnan, Stephen M Davis, Brian R Chambers, Peter C Gates, Graeme J Hankey, John J McNeil, David Rosen, Edward G Stew art-Wynne, Roger R Tuck Department of Neurology, Austin Hospital, Heidelberg, Victoria 3084, Australia
1 Benes V, Zabramski JM, Boston M, et al. Effect on intra-arterial antifibrinolytic agents on autologous arterial emboli in the cerebral circulation of rabbits. Stroke 1990; 21: 1594-99. 2 Mori E. Safety and efficacy of fibrinolytic agents in acute ischaemic stroke. Cerebrovasc Dis 1993; 3: 264-68. 3 Wardlow JM, Warlow CP. Thrombolysis in acute ischemic stroke: does it work? Stroke 1992; 23: 1826-39. 4 Gruppo Italiano per lo Studio Della Sopravvivenza Nell’Infarto Miocardico: GISSI-2. A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet 1990; 336: 65-71. 5 Donnan GA, Davis SM, Chambers BR, et al. Australian Streptokinase Trial (ASK). In: del Zoppo GJ, Mori E, Hacke W, eds. Thrombolytic therapy in acute ischaemic stroke II. Berlin, Heidelberg: Springer-
Verlag,
1993: 80-85.
Type
Figure: Symptoms in relation
Nabilone in the treatment of multiple sclerosis
containing nabilone were indistinguishable from those containing placebo and neither he nor his doctors were aware which treatment periods had been allocated to the active drug. He evaluated the effectiveness of treatment at the end of each week by noting frequency of nocturia on the previous night and by use of visual analogue scales to quantify pain and discomfort from muscle spasm and record how he felt generally. are
summarised in the
to treatment
reports show a striking reduction in frequency of nocturia and severity of muscle spasm and an improvement in mood and wellbeing that correspond with the periods of treatment with nabilone. Transient feelings of euphoria are experienced by some patients taking nabilone. Our patient did not report such an effect, although he noticed a brief period of mild sedation after taking the active drug. This may have helped him distinguish between active drug and placebo but it seems unlikely that the benefits he experienced derived from nabilone’s mood-elevating effects. High-affinity cannabinoid binding sites are present in the neocortex, hippocampus, striatum, amygdala, and hypothalamus of the human brain and there are anecdotal reports that smoking marijuana is of benefit in patients with multiple sclerosis.3 The results of small clinical trials of 9-delta-tetrahydrocannabinol suggest that it can reduce tremor and spasticity in some patients with multiple sclerosis and to reduce spasticity in experimental animals perhaps through an inhibitory effect on reflexes.’°’ Use of 9-deltapolysynaptic tetrahydrocannabinol is likely to be limited by its prominent psychoactive properties, but our experience with this patient suggests that synthetic cannabinoids might be of value in the treatment of spasticity and that a randomised controlled trial that included objective measurement of muscle tone would be worthwhile.
patient’s
SIR-After reading accounts in the press that smoking cannabis had improved the symptoms of other patients with multiple sclerosis, a 45-year-old man with multiple sclerosis persuaded his general practitioner to prescribe nabilone. Nabilone is a synthetic cannabinoid with powerful antiemetic effects licensed for short-term use in patients undergoing chemotherapy. He obtained immediate benefit from a small dose of the drug, reporting decreased pain from muscle spasm, cessation of nocturia, and an improvement in how he felt generally. Because nabilone is only available by hospital prescription, his general practitioner was unable to continue the drug and he was referred to the Wessex Neurological Centre. The patient had previously been seen by one of us (LSI) in 1974. At that time, symptoms and signs of right-sided sensory disturbance together with a history of uniocular central visual loss and, on fundoscopy, pallor of both optic discs suggested a diagnosis of multiple sclerosis. Over the next 20 years, his disease had pursued a relapsing and remitting course but his disability had gradually increased. He now has a severe spastic paraparesis and is no longer independently mobile. We were unsure whether the improvement in symptoms that this patient reported was due to a pharmacological effect of nabilone or a placebo response and suggested to him that we evaluate the treatment in an n-of-1 trial.’ He readily agreed. Nabilone 1 mg every second day or placebo was given for four successive periods each lasting 4 weeks. The starting treatment was randomly allocated and thereafter treatments alternated (see figure). The patient knew about the design of the study but the capsules
The results of the trial
m treatment
figure. The
*C N Wessex
Martyn, L S Illis, J Thom
Neurological Centre, Southampton Southampton SO16 6YD, UK
1 2
3 4
5
General
Hospital,
Campbell MJ. Commentary: n of 1 trials may be useful for informed decision making. BMJ 1994, 309: 1045-46. Westlake TM, Howlett AC, Bonner TI, Matsuda LA, Herkenham M. Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer’s brains. Neuroscience 1994; 63: 637-52. Going to pot. The Guardian 1994; Sept 23, part 2:1-2. Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 1983; 13: 669-71. Petro DJ, Ellenberger C Jr. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J Clin Pharmacol 1981; 21 (suppl 8-9): 413S-16S.
579
*Geoffrey A Donnan, Stephen M Davis, Brian R Chambers, Peter C Gates, Graeme J Hankey, John J McNeil, David Rosen, Edward G Stew art-Wynne, Roger R Tuck Department of Neurology, Austin Hospital, Heidelberg, Victoria 3084, Australia
1 Benes V, Zabramski JM, Boston M, et al. Effect on intra-arterial antifibrinolytic agents on autologous arterial emboli in the cerebral circulation of rabbits. Stroke 1990; 21: 1594-99. 2 Mori E. Safety and efficacy of fibrinolytic agents in acute ischaemic stroke. Cerebrovasc Dis 1993; 3: 264-68. 3 Wardlow JM, Warlow CP. Thrombolysis in acute ischemic stroke: does it work? Stroke 1992; 23: 1826-39. 4 Gruppo Italiano per lo Studio Della Sopravvivenza Nell’Infarto Miocardico: GISSI-2. A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet 1990; 336: 65-71. 5 Donnan GA, Davis SM, Chambers BR, et al. Australian Streptokinase Trial (ASK). In: del Zoppo GJ, Mori E, Hacke W, eds. Thrombolytic therapy in acute ischaemic stroke II. Berlin, Heidelberg: Springer-
Verlag,
1993: 80-85.
Type
Figure: Symptoms in relation
Nabilone in the treatment of multiple sclerosis
containing nabilone were indistinguishable from those containing placebo and neither he nor his doctors were aware which treatment periods had been allocated to the active drug. He evaluated the effectiveness of treatment at the end of each week by noting frequency of nocturia on the previous night and by use of visual analogue scales to quantify pain and discomfort from muscle spasm and record how he felt generally. are
summarised in the
to treatment
reports show a striking reduction in frequency of nocturia and severity of muscle spasm and an improvement in mood and wellbeing that correspond with the periods of treatment with nabilone. Transient feelings of euphoria are experienced by some patients taking nabilone. Our patient did not report such an effect, although he noticed a brief period of mild sedation after taking the active drug. This may have helped him distinguish between active drug and placebo but it seems unlikely that the benefits he experienced derived from nabilone’s mood-elevating effects. High-affinity cannabinoid binding sites are present in the neocortex, hippocampus, striatum, amygdala, and hypothalamus of the human brain and there are anecdotal reports that smoking marijuana is of benefit in patients with multiple sclerosis.3 The results of small clinical trials of 9-delta-tetrahydrocannabinol suggest that it can reduce tremor and spasticity in some patients with multiple sclerosis and to reduce spasticity in experimental animals perhaps through an inhibitory effect on reflexes.’°’ Use of 9-deltapolysynaptic tetrahydrocannabinol is likely to be limited by its prominent psychoactive properties, but our experience with this patient suggests that synthetic cannabinoids might be of value in the treatment of spasticity and that a randomised controlled trial that included objective measurement of muscle tone would be worthwhile.
patient’s
SIR-After reading accounts in the press that smoking cannabis had improved the symptoms of other patients with multiple sclerosis, a 45-year-old man with multiple sclerosis persuaded his general practitioner to prescribe nabilone. Nabilone is a synthetic cannabinoid with powerful antiemetic effects licensed for short-term use in patients undergoing chemotherapy. He obtained immediate benefit from a small dose of the drug, reporting decreased pain from muscle spasm, cessation of nocturia, and an improvement in how he felt generally. Because nabilone is only available by hospital prescription, his general practitioner was unable to continue the drug and he was referred to the Wessex Neurological Centre. The patient had previously been seen by one of us (LSI) in 1974. At that time, symptoms and signs of right-sided sensory disturbance together with a history of uniocular central visual loss and, on fundoscopy, pallor of both optic discs suggested a diagnosis of multiple sclerosis. Over the next 20 years, his disease had pursued a relapsing and remitting course but his disability had gradually increased. He now has a severe spastic paraparesis and is no longer independently mobile. We were unsure whether the improvement in symptoms that this patient reported was due to a pharmacological effect of nabilone or a placebo response and suggested to him that we evaluate the treatment in an n-of-1 trial.’ He readily agreed. Nabilone 1 mg every second day or placebo was given for four successive periods each lasting 4 weeks. The starting treatment was randomly allocated and thereafter treatments alternated (see figure). The patient knew about the design of the study but the capsules
The results of the trial
m treatment
figure. The
*C N Wessex
Martyn, L S Illis, J Thom
Neurological Centre, Southampton Southampton SO16 6YD, UK
1 2
3 4
5
General
Hospital,
Campbell MJ. Commentary: n of 1 trials may be useful for informed decision making. BMJ 1994, 309: 1045-46. Westlake TM, Howlett AC, Bonner TI, Matsuda LA, Herkenham M. Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer’s brains. Neuroscience 1994; 63: 637-52. Going to pot. The Guardian 1994; Sept 23, part 2:1-2. Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 1983; 13: 669-71. Petro DJ, Ellenberger C Jr. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J Clin Pharmacol 1981; 21 (suppl 8-9): 413S-16S.
579