Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial
http://www.100md.com
《英国医生杂志》
1 Danish Pain Research Center and Department of Neurology, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus C, Denmark
Correspondence to: F W Bach fbach@akh.aaa.dk
Abstract
Pain is an important symptom accompanying multiple sclerosis; acute or chronic pain syndromes occur in 30-80% of patients.1-6 The many different types of pain seen in multiple sclerosis include musculoskeletal pain, pain associated with spasms, and central pain from sclerotic plaque lesions affecting pain pathways in the central nervous system. The reported prevalence of central pain in multiple sclerosis patients is around 33%.7
In recent years the efficacy of cannabinoids in the treatment of multiple sclerosis symptoms, including pain and spasticity, has been discussed. Cannabinoids have been shown to decrease allodynia or hyperalgesia in various animal pain models, including inflammatory pain,8 9 neuropathic pain,10 11 capsaicin-induced pain,12-14 and cancer pain.15
The analgesic effects may be produced by both central and peripheral mechanisms.8 10-14 16-18 One theory is that cannabinoids inhibit release of transmitter from primary afferents19; another is that they activate descending modulatory pathways.20
Clinical studies evaluating the analgesic action of cannabinoids in humans are sparse. Clinical reports indicate that cannabinoids may alleviate pain in different pain conditions, including multiple sclerosis related pain.21-23 Only a few randomised clinical trials are available.24-27 Three randomised studies that evaluated the efficacy of cannabinoids on different neurogenic symptoms, including pain, have recently been published.27-29 Two of these studies included patients with multiple sclerosis.28 29 A large multicentre randomised placebo controlled study including 630 multiple sclerosis patients found an improvement in pain after 15 weeks of treatment with cannabinoids (oral -9-tetrahydrocannabinol or cannabis extract).29 The primary outcome measure of this study, however, was spasticity, and no information was given about subtypes of pain. Another randomised placebo controlled single patient crossover study including 24 patients with neurogenic symptoms (18 multiple sclerosis patients) found that extract of whole plant cannabis (-9-tetrahydrocannabinol and cannabidiol) administered by sublingual spray improved pain.28 Twelve of the 20 patients completing the study had neuropathic pain. The third study included a group of patients (n = 21) with many different neuropathic pain conditions (mainly peripheral neuropathic pain).27 In this randomised placebo controlled crossover study, one week of treatment with the synthetic cannabinoid CT-3 reduced neuropathic pain.
None of the previous studies has specifically explored the effect of cannabinoids on pain caused by central lesions in multiple sclerosis. We aimed to evaluate the efficacy of the synthetic -9-tetrahydrocannabinol dronabinol on central pain in multiple sclerosis patients in a randomised placebo controlled study. The objective was to provide better treatment options for central pain in multiple sclerosis, and we hypothesised that dronabinol would reduce central pain in multiple sclerosis.
Methods
Participants
Patients were recruited to the study in the period 27 February to 21 May 2002. The last telephone follow up took place on 26 July 2002. We screened 25 patients for the study (fig 1). One patient had an abnormal electrocardiogram and was not included. All enrolled participants (n = 24) completed the study protocol. Table 1 gives the characteristics of the participants.
Fig 1 Flow diagram of patients enrolled in study. ECG=electrocardiogram
Table 1 Characteristics of participants
One participant claimed that the container of study medication was empty after 15 days of treatment in both periods. We did not include the results of the SF-36 and quantitative sensory testing from this patient in analysis, because the patient ran out of treatment a week before the measurements were made.
One patient had a muscle sprain (provoked by a sudden movement) on day 14 in the second treatment period (active medication). The pain due to the sprain was different from the patient's normal pain, but she assessed the intensity of this new pain in the diary. On visit 4 (on day 18) the patient was asked to assess retrospectively the intensity of her normal pain from day 14 to day 18. We used the patient's retrospective assessment of spontaneous pain in the calculation of the median pain intensity of the last week of the second treatment period.
Primary outcome measure
We observed no significant carryover effect for the primary outcome measure (P = 0.24). The median spontaneous pain intensity during the last week of treatment was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02) (fig 2). The estimated difference in pain scores between dronabinol and placebo treatments was -0.6 (95% confidence interval -1.8 to 0) (Hodges-Lehmann estimator). In the group of patients randomised to active medication in the first period the change in spontaneous pain intensity from baseline was -1.0 (25th to 75th centiles -1.9 to -0.1) during dronabinol treatment and 0 (-2.0 to 0) during placebo treatment. In the group of patients randomised to placebo in first period the change in pain from baseline was -1.5 (-2.8 to -0.3) during dronabinol treatment and 0 (0 to 0.9) during placebo treatment. The estimated relative difference in pain reduction from baseline between dronabinol and placebo treatments was -20.5% (95% confidence interval -37.5 to -4.5) (Hodges-Lehmann estimator).
Fig 2 Spontaneous pain intensity during one week baseline, last week of active treatment, and last week of placebo treatment. Each line represents one patient. Active-placebo group=patients randomised to active medication in first treatment period (n=12); placebo-active group=patients randomised to placebo in first treatment period (n=12); NRS=numerical rating scale
Secondary outcome measures
Table 2 shows the secondary outcome measures. Median radiating pain intensity during the last week of treatment was lower during dronabinol treatment than during placebo treatment, and a higher pain relief score was obtained during dronabinol treatment than during placebo treatment. On the basis of pain relief scores, the number of patients that needed to be treated for one additional case of 50% pain relief was 3.45 (95% confidence interval 1.9 to 24.8). No differences between treatments occurred in period preference, escape medication, or expanded disability status scale score.
Table 2 Primary and secondary outcome measures. Values are medians (25th to 75th centiles) unless stated otherwise
The pressure pain threshold was higher after dronabinol treatment than after placebo treatment. No differences between treatments occurred in cold sensibility, warm sensibility, tactile detection, tactile pain detection, vibration sense, temporal summation, or mechanical and cold allodynia. On the SF-36, the patients scored slightly higher (better) in the bodily pain and mental health domains during dronabinol treatment than during placebo treatment.
Adverse events
Adverse events were more common during dronabinol treatment than during placebo treatment. During dronabinol treatment 23 (96%) patients had adverse events compared with 11 (46%) patients during placebo treatment (P = 0.001, Mainland-Gart test) (table 3). Eleven of the patients had adverse events in both treatment periods; none had adverse events during placebo treatment only. The number of patients with adverse events was higher during the first week of dronabinol treatment than during the last week of treatment.
Table 3 Adverse events during treatment with dronabinol and placebo. Values are numbers (percentages) of patients with adverse event, number of adverse events
During active treatment four (17%) patients had their doses reduced (three patients to 7.5 mg daily and one patient to 5 mg daily) because of intolerable adverse events. The reduction of dose decreased the side effects for all four patients. The rest of the patients had no need for dose reduction during active treatment and were all treated with 10 mg daily. No patients had their dose reduced during placebo treatment.
The most common adverse events during dronabinol treatment were related to the central nervous system (dizziness, headache, tiredness) and the muskuloskeletal system (myalgia, muscle weakness) (table 3). Four patients had an aggravation of multiple sclerosis during the trial—one during dronabinol treatment, two during placebo treatment, and one during the washout period. The last patient was admitted to the hospital. The washout period of this patient was extended (57 days) because of the adverse event. The head of the multiple sclerosis clinic confirmed that the patient's neurological condition was stable before the second treatment period (placebo) was started.
Assessment of blinding
Sixteen (67%) of the patients correctly identified the period in which they received active medication. Six (25%) patients identified the wrong period, and two (8%) patients were unable to choose one of the treatments (P = 0.19, Fisher's exact test).
Length of treatment periods and number of capsules taken
The median treatment period was 20 (range 15-21) days for both active treatment and placebo. The median washout period was 21 (19-57) days. The average number of capsules taken was 62 (54-72) during active treatment and 66 (56-72) during placebo treatment.
Discussion
Archibald CJ, McGrath PJ, Ritvo PG, Fisk JD, Bhan V, Maxner CE, et al. Pain prevalence, severity and impact in a clinic sample of multiple sclerosis patients. Pain 1994;58: 89-93.
Clifford DB, Trotter JL. Pain in multiple sclerosis. Arch Neurol 1984;41: 1270-2.
Moulin DE, Foley KM, Ebers GC. Pain syndromes in multiple sclerosis. Neurology 1988;38: 1830-4.
Rae-Grant AD, Eckert NJ, Bartz S, Reed JF. Sensory symptoms of multiple sclerosis: a hidden reservoir of morbidity. Mult Scler 1999;5: 179-83.
Stenager E, Knudsen L, Jensen K. Acute and chronic pain syndromes in multiple sclerosis. Acta Neurol Scand 1991;84: 197-200.
Svendsen KB, Jensen TS, Overvad K, Hansen HJ, Koch-Henriksen N, Bach FW. Pain in patients with multiple sclerosis: a population-based study. Arch Neurol 2003;60: 1089-94.
Boivie J. Central pain. In: Wall PD, Melzack R, eds. Textbook of pain. New York: Churchill Livingstone, 1999: 879-914.
Jaggar SI, Hasnie FS, Sellaturay S, Rice AS. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain 1998;76: 189-99.
Martin WJ, Loo CM, Basbaum AI. Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain 1999;82: 199-205.
Bridges D, Ahmad K, Rice AS. The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol 2001;133: 586-94.
Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, et al. The role of central and peripheral cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 2001;92: 91-100.
Johanek LM, Heitmiller DR, Turner M, Nader N, Hodges J, Simone DA. Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms. Pain 2001;93: 303-15.
Rukwied R, Watkinson A, McGlone F, Dvorak M. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain 2003;102: 283-8.
Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998;75: 111-9.
Kehl LJ, Hamamoto DT, Wacnik PW, Croft DL, Norsted BD, Wilcox GL, et al. A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain. Pain 2003;103: 175-86.
Martin WJ, Coffin PO, Attias E, Balinsky M, Tsou K, Walker JM. Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res 1999;822: 237-42.
Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 1998;345: 145-53.
Nackley AG, Suplita RL, Hohmann AG. A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 2003;117: 659-70.
Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG, et al. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology 2001;40: 221-32.
Walker JM, Hohmann AG, Martin WJ, Strangman NM, Huang SM, Tsou K. The neurobiology of cannabinoid analgesia. Life Sci 1999;65: 665-73.
Holdcroft A, Smith M, Jacklin A, Hodgson H, Smith B, Newton M, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997;52: 483-6.
Notcutt W, Price M, Chapman G. Clinical experience with nabilone for chronic pain. Pharm Sci 1997;3: 551-5.
Hamann W, di Vadi PP. Analgesic effect of the cannabinoid analogue nabilone is not mediated by opioid receptors. Lancet 1999;353: 560.
Noyes RJ, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975;15: 139-43.
Jain AK, Ryan JR, McMahon FG, Smith G. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 1981;21: 320-6S.
Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain 2003;106: 169-72.
Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003;290: 1757-62.
Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 2003;17: 21-9.
Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362: 1517-26.
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: 227-31.
Merskey H, Bogduk N, eds. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms prepared by the International Association for the Study of Pain, Task Force of Taxonomy. Seattle: IASP Press, 1994.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: 1444-52.
Goldberg JM, Lindblom U. Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J Neurol Neurosurg Psychiatry 1979;42: 793-803.
Jensen TS, Bach FW, Kastrup J, Dejgaard A, Brennum J. Vibratory and thermal thresholds in diabetics with and without clinical neuropathy. Acta Neurol Scand 1991;84: 326-33.
Brennum J, Kjeldsen M, Jensen K, Jensen TS. Measurements of human pressure-pain thresholds on fingers and toes. Pain 1989;38: 211-7.
Gottrup H, Kristensen AD, Bach FW, Jensen TS. Aftersensations in experimental and clinical hypersensitivity. Pain 2003;103: 57-64.
Bjorner JB, Damsgaard MT, Watt T, Bech P, Rasmussen NK, Kristensen TS, et al. Copenhagen: Lif, 1997. (In Danish.)
Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ 1995;310: 452-4.
Senn S. Cross-over trials in clinical research. Chichester: John Wiley, 2002.
Vestergaard K, Andersen G, Gottrup H, Kristensen BT, Jensen TS. Lamotrigine for central poststroke pain: a randomized controlled trial. Neurology 2001;56: 184-90.
Lachin JM. Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials 1981;2: 93-113.
Finnerup NB, Gottrup H, Jensen TS. Anticonvulsants in central pain. Expert Opin Pharmacother 2002;3: 1411-20.
Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999;83: 389-400.
Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60: 927-34.
Farrar JT, Portenoy RK, Berlin JA, Kinman JL, Strom BL. Defining the clinically important difference in pain outcome measures. Pain 2000;88: 287-94.
Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC, Staats PG, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002;58: 1404-7.
Clermont-Gnamien S, Atlani S, Attal N, Le MF, Guirimand F, Brasseur L. Presse Med 2002;31: 1840-5. (In French.)
Noyes RJ, Brunk SF, Avery DA, Canter AC. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975;18: 84-9.
Campbell FA, Tramer MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001;323: 13-6.(Kristina B Svendsen, rese)
Correspondence to: F W Bach fbach@akh.aaa.dk
Abstract
Pain is an important symptom accompanying multiple sclerosis; acute or chronic pain syndromes occur in 30-80% of patients.1-6 The many different types of pain seen in multiple sclerosis include musculoskeletal pain, pain associated with spasms, and central pain from sclerotic plaque lesions affecting pain pathways in the central nervous system. The reported prevalence of central pain in multiple sclerosis patients is around 33%.7
In recent years the efficacy of cannabinoids in the treatment of multiple sclerosis symptoms, including pain and spasticity, has been discussed. Cannabinoids have been shown to decrease allodynia or hyperalgesia in various animal pain models, including inflammatory pain,8 9 neuropathic pain,10 11 capsaicin-induced pain,12-14 and cancer pain.15
The analgesic effects may be produced by both central and peripheral mechanisms.8 10-14 16-18 One theory is that cannabinoids inhibit release of transmitter from primary afferents19; another is that they activate descending modulatory pathways.20
Clinical studies evaluating the analgesic action of cannabinoids in humans are sparse. Clinical reports indicate that cannabinoids may alleviate pain in different pain conditions, including multiple sclerosis related pain.21-23 Only a few randomised clinical trials are available.24-27 Three randomised studies that evaluated the efficacy of cannabinoids on different neurogenic symptoms, including pain, have recently been published.27-29 Two of these studies included patients with multiple sclerosis.28 29 A large multicentre randomised placebo controlled study including 630 multiple sclerosis patients found an improvement in pain after 15 weeks of treatment with cannabinoids (oral -9-tetrahydrocannabinol or cannabis extract).29 The primary outcome measure of this study, however, was spasticity, and no information was given about subtypes of pain. Another randomised placebo controlled single patient crossover study including 24 patients with neurogenic symptoms (18 multiple sclerosis patients) found that extract of whole plant cannabis (-9-tetrahydrocannabinol and cannabidiol) administered by sublingual spray improved pain.28 Twelve of the 20 patients completing the study had neuropathic pain. The third study included a group of patients (n = 21) with many different neuropathic pain conditions (mainly peripheral neuropathic pain).27 In this randomised placebo controlled crossover study, one week of treatment with the synthetic cannabinoid CT-3 reduced neuropathic pain.
None of the previous studies has specifically explored the effect of cannabinoids on pain caused by central lesions in multiple sclerosis. We aimed to evaluate the efficacy of the synthetic -9-tetrahydrocannabinol dronabinol on central pain in multiple sclerosis patients in a randomised placebo controlled study. The objective was to provide better treatment options for central pain in multiple sclerosis, and we hypothesised that dronabinol would reduce central pain in multiple sclerosis.
Methods
Participants
Patients were recruited to the study in the period 27 February to 21 May 2002. The last telephone follow up took place on 26 July 2002. We screened 25 patients for the study (fig 1). One patient had an abnormal electrocardiogram and was not included. All enrolled participants (n = 24) completed the study protocol. Table 1 gives the characteristics of the participants.
Fig 1 Flow diagram of patients enrolled in study. ECG=electrocardiogram
Table 1 Characteristics of participants
One participant claimed that the container of study medication was empty after 15 days of treatment in both periods. We did not include the results of the SF-36 and quantitative sensory testing from this patient in analysis, because the patient ran out of treatment a week before the measurements were made.
One patient had a muscle sprain (provoked by a sudden movement) on day 14 in the second treatment period (active medication). The pain due to the sprain was different from the patient's normal pain, but she assessed the intensity of this new pain in the diary. On visit 4 (on day 18) the patient was asked to assess retrospectively the intensity of her normal pain from day 14 to day 18. We used the patient's retrospective assessment of spontaneous pain in the calculation of the median pain intensity of the last week of the second treatment period.
Primary outcome measure
We observed no significant carryover effect for the primary outcome measure (P = 0.24). The median spontaneous pain intensity during the last week of treatment was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02) (fig 2). The estimated difference in pain scores between dronabinol and placebo treatments was -0.6 (95% confidence interval -1.8 to 0) (Hodges-Lehmann estimator). In the group of patients randomised to active medication in the first period the change in spontaneous pain intensity from baseline was -1.0 (25th to 75th centiles -1.9 to -0.1) during dronabinol treatment and 0 (-2.0 to 0) during placebo treatment. In the group of patients randomised to placebo in first period the change in pain from baseline was -1.5 (-2.8 to -0.3) during dronabinol treatment and 0 (0 to 0.9) during placebo treatment. The estimated relative difference in pain reduction from baseline between dronabinol and placebo treatments was -20.5% (95% confidence interval -37.5 to -4.5) (Hodges-Lehmann estimator).
Fig 2 Spontaneous pain intensity during one week baseline, last week of active treatment, and last week of placebo treatment. Each line represents one patient. Active-placebo group=patients randomised to active medication in first treatment period (n=12); placebo-active group=patients randomised to placebo in first treatment period (n=12); NRS=numerical rating scale
Secondary outcome measures
Table 2 shows the secondary outcome measures. Median radiating pain intensity during the last week of treatment was lower during dronabinol treatment than during placebo treatment, and a higher pain relief score was obtained during dronabinol treatment than during placebo treatment. On the basis of pain relief scores, the number of patients that needed to be treated for one additional case of 50% pain relief was 3.45 (95% confidence interval 1.9 to 24.8). No differences between treatments occurred in period preference, escape medication, or expanded disability status scale score.
Table 2 Primary and secondary outcome measures. Values are medians (25th to 75th centiles) unless stated otherwise
The pressure pain threshold was higher after dronabinol treatment than after placebo treatment. No differences between treatments occurred in cold sensibility, warm sensibility, tactile detection, tactile pain detection, vibration sense, temporal summation, or mechanical and cold allodynia. On the SF-36, the patients scored slightly higher (better) in the bodily pain and mental health domains during dronabinol treatment than during placebo treatment.
Adverse events
Adverse events were more common during dronabinol treatment than during placebo treatment. During dronabinol treatment 23 (96%) patients had adverse events compared with 11 (46%) patients during placebo treatment (P = 0.001, Mainland-Gart test) (table 3). Eleven of the patients had adverse events in both treatment periods; none had adverse events during placebo treatment only. The number of patients with adverse events was higher during the first week of dronabinol treatment than during the last week of treatment.
Table 3 Adverse events during treatment with dronabinol and placebo. Values are numbers (percentages) of patients with adverse event, number of adverse events
During active treatment four (17%) patients had their doses reduced (three patients to 7.5 mg daily and one patient to 5 mg daily) because of intolerable adverse events. The reduction of dose decreased the side effects for all four patients. The rest of the patients had no need for dose reduction during active treatment and were all treated with 10 mg daily. No patients had their dose reduced during placebo treatment.
The most common adverse events during dronabinol treatment were related to the central nervous system (dizziness, headache, tiredness) and the muskuloskeletal system (myalgia, muscle weakness) (table 3). Four patients had an aggravation of multiple sclerosis during the trial—one during dronabinol treatment, two during placebo treatment, and one during the washout period. The last patient was admitted to the hospital. The washout period of this patient was extended (57 days) because of the adverse event. The head of the multiple sclerosis clinic confirmed that the patient's neurological condition was stable before the second treatment period (placebo) was started.
Assessment of blinding
Sixteen (67%) of the patients correctly identified the period in which they received active medication. Six (25%) patients identified the wrong period, and two (8%) patients were unable to choose one of the treatments (P = 0.19, Fisher's exact test).
Length of treatment periods and number of capsules taken
The median treatment period was 20 (range 15-21) days for both active treatment and placebo. The median washout period was 21 (19-57) days. The average number of capsules taken was 62 (54-72) during active treatment and 66 (56-72) during placebo treatment.
Discussion
Archibald CJ, McGrath PJ, Ritvo PG, Fisk JD, Bhan V, Maxner CE, et al. Pain prevalence, severity and impact in a clinic sample of multiple sclerosis patients. Pain 1994;58: 89-93.
Clifford DB, Trotter JL. Pain in multiple sclerosis. Arch Neurol 1984;41: 1270-2.
Moulin DE, Foley KM, Ebers GC. Pain syndromes in multiple sclerosis. Neurology 1988;38: 1830-4.
Rae-Grant AD, Eckert NJ, Bartz S, Reed JF. Sensory symptoms of multiple sclerosis: a hidden reservoir of morbidity. Mult Scler 1999;5: 179-83.
Stenager E, Knudsen L, Jensen K. Acute and chronic pain syndromes in multiple sclerosis. Acta Neurol Scand 1991;84: 197-200.
Svendsen KB, Jensen TS, Overvad K, Hansen HJ, Koch-Henriksen N, Bach FW. Pain in patients with multiple sclerosis: a population-based study. Arch Neurol 2003;60: 1089-94.
Boivie J. Central pain. In: Wall PD, Melzack R, eds. Textbook of pain. New York: Churchill Livingstone, 1999: 879-914.
Jaggar SI, Hasnie FS, Sellaturay S, Rice AS. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain 1998;76: 189-99.
Martin WJ, Loo CM, Basbaum AI. Spinal cannabinoids are anti-allodynic in rats with persistent inflammation. Pain 1999;82: 199-205.
Bridges D, Ahmad K, Rice AS. The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol 2001;133: 586-94.
Fox A, Kesingland A, Gentry C, McNair K, Patel S, Urban L, et al. The role of central and peripheral cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 2001;92: 91-100.
Johanek LM, Heitmiller DR, Turner M, Nader N, Hodges J, Simone DA. Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms. Pain 2001;93: 303-15.
Rukwied R, Watkinson A, McGlone F, Dvorak M. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain 2003;102: 283-8.
Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998;75: 111-9.
Kehl LJ, Hamamoto DT, Wacnik PW, Croft DL, Norsted BD, Wilcox GL, et al. A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain. Pain 2003;103: 175-86.
Martin WJ, Coffin PO, Attias E, Balinsky M, Tsou K, Walker JM. Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res 1999;822: 237-42.
Richardson JD, Aanonsen L, Hargreaves KM. Antihyperalgesic effects of spinal cannabinoids. Eur J Pharmacol 1998;345: 145-53.
Nackley AG, Suplita RL, Hohmann AG. A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 2003;117: 659-70.
Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG, et al. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology 2001;40: 221-32.
Walker JM, Hohmann AG, Martin WJ, Strangman NM, Huang SM, Tsou K. The neurobiology of cannabinoid analgesia. Life Sci 1999;65: 665-73.
Holdcroft A, Smith M, Jacklin A, Hodgson H, Smith B, Newton M, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997;52: 483-6.
Notcutt W, Price M, Chapman G. Clinical experience with nabilone for chronic pain. Pharm Sci 1997;3: 551-5.
Hamann W, di Vadi PP. Analgesic effect of the cannabinoid analogue nabilone is not mediated by opioid receptors. Lancet 1999;353: 560.
Noyes RJ, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975;15: 139-43.
Jain AK, Ryan JR, McMahon FG, Smith G. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 1981;21: 320-6S.
Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain 2003;106: 169-72.
Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003;290: 1757-62.
Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 2003;17: 21-9.
Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362: 1517-26.
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: 227-31.
Merskey H, Bogduk N, eds. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms prepared by the International Association for the Study of Pain, Task Force of Taxonomy. Seattle: IASP Press, 1994.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: 1444-52.
Goldberg JM, Lindblom U. Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation. J Neurol Neurosurg Psychiatry 1979;42: 793-803.
Jensen TS, Bach FW, Kastrup J, Dejgaard A, Brennum J. Vibratory and thermal thresholds in diabetics with and without clinical neuropathy. Acta Neurol Scand 1991;84: 326-33.
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