Baclofen for spasticity in multiple sclerosis. Double-blind crossover and three-year study. Baclofen, a new antispastic drug. A controlled, multicenter trial in patients with multiple sclerosis. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Treatment of spasticity with tizanidine in multiple sclerosis. Letter: Treatment of spasticity in multiple sclerosis with dantrolene. Effects of a GABA--derivative (BA-34647) on spasticity. Preliminary report of a double-blind cross-over study. Lioresal (baclofen) treatment of spasticity in multiple sclerosis. [Double-blind study of progabide in spasticity]. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. [Comparative double-blind study of the effectiveness and tolerance of baclofen, tetrazepam and tizanidine in spastic movement disorders of the lower extremities]. Comparison of dantrolene sodium and diazepam in the treatment of spasticity. Tizanidine versus baclofen in the treatment of spasticity in patients with multiple sclerosis. An antispasticity effect of threonine in multiple sclerosis. The effect of dantrolene sodium on spasticity in multiple sclerosis. Spasmolytic properties of dantrolene sodium: clinical evaluation. Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial. US Tizanidine Study Group. Multi-centre, double-blind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis. A double-blind comparative trial of new muscle relaxant, tizanidine (DS 103-282), and baclofen in the treatment of chronic spasticity in multiple sclerosis. A double-blind trial with baclofen (Lioresal) and diazepam in spasticity due to multiple sclerosis. Botulinum toxin A for spasticity, muscle spasms, and rigidity. Ketazolam once daily for spasticity: double-blind cross-over study. Prazepam in the treatment of spasticity. A quantitative double-blind evaluation. Evaluation of treatment protocols on minimal to moderate spasticity in multiple sclerosis. The treatment of spasticity in multiple sclerosis: a double-blind clinical trial of a new anti-spastic drug tizanidine compared with baclofen. Dantrolene sodium in chronic spasticity of varying etiology. A double-blind study. Treatment of spasticity with botulinum toxin: a double-blind study. The use of baclofen in treatment of spasticity in multiple sclerosis. Ketazolam treatment for spasticity: double-blind study of a new drug.
Baclofen is a safe and effective means for treating spasticity associated with multiple sclerosis. We found no toxic effects on hepatologic, hematopoietic, or renal function, acutely or for over 3 years of follow-up. A statistically significant reduction was noted in frequency of spasms, and clonus, and there was improved range of joint movement, which enabled patients to maintain functional status for prolonged periods. For the more disabled patients, treatment with baclofen gave symptomatic relief of painful spasms and made immobility more tolerable. Optimum effect was achieved when baclofen was administered in the early stages of disease, before major disabilities became permanent. A double-blind, five-week, multicenter trial was conducted to compare the effect of baclofen, a unique amino acid derivative, with that of placebo in the treatment of 106 patients with spasticity secondary to multiple sclerosis. A spasticity assessment method that included a neurological examination, physicians' clinical impressions of changes during treatment, and a patient's self-evaluation was used to determine efficacy. This method showed baclofen (70 to 80 mg daily maximum, titrated) is effective relative to placebo in relieving symptoms of spasticity, such as flexor spasms, pain and stiffness, resistance to passive joint movements, and tendon stretch reflexes. Patient self-evaluation results also showed a significant reduction in clonus. Side effects were generally mild and transient. The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression. Spasticity is a frequent and often disabling symptom in MS patients. Current drugs used as antispastic agents include Dantrolene Sodium, Baclofen and Diazepam. Tizanidine (5-chloro-4-(2imidazolin-2 yl amino)-2,1,3-benzothialdiazole) is a new antispasticity agent that has purported central action. A double blind placebo controlled trial was performed to study the efficacy of this drug in MS patients. Sixty-six patients entered an eight week therapeutic trial and fifty-nine completed the trial. Patients were assessed at 0, 2, 3 and 8 weeks of therapy for clinical effects. Electrophysiologic tests were performed at 0 and 8 weeks. A statistically significant benefit was noted in spastic muscle groups in the legs with concomitant significant reduction in hyperactive stretch reflexes and ankle clonus. Side effects most frequently cited included dry mouth and drowsiness. Two patients developed elevated liver function test that decreased with cessation of therapy. Other clinical details, side effects and electrophysiologic data will be presented. Tizanidine appears to reduce clinical spasticity and hyperreflexia in MS patients although no change in functional status was detected. Tizanidine may well serve as an alternate antispastic agent, alone or in combination with other agents. nan nan nan nan To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects.
                A consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials with two-week treatment periods.
                Patients attended as outpatients, but took the CME at home.
                Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1).
                Whole-plant extracts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5-120 mg/24 hours. Measures used: Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales. At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales, administered standard measures of disability (Barthel Index), mood and cognition, and recorded adverse events.
                Pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were improved by CME in some patients with these symptoms. Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME.
                Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings. In a double-blind comparative study, the therapeutic efficacy and safety of three centrally effective antispasmodics (Tetrazepam, Baclofen and Tizanidine) in patients suffering from multiple sclerosis with spastic motor disturbances of the lower extremities was to be examined. 47 patients of either sex at the age of 23 until 63 were allocated to one of the three therapies by means of minimization. The duration of treatment was limited to 35 days at a maximum. The dosage was optimized corresponding to the clinical symptoms. The antispasmodic efficacy and safety of the above-mentioned substances was investigated with well-established parameters and methods. The typical laboratory parameters were determined at the beginning and at the end of the study. -With reference to cloni, spasms and the muscular tonus, no systematic differences were found between the treatment groups. A previously existing clonus could not be altered decisively by the administration of the three antispasmodics, whereas the muscular tonus could comparably be decreased with all therapeutic measures. Statistically significant differences between the treatment groups were not observed. The patients of all three groups recorded a subjective sensation of relief with reference to the symptoms of spasms by the medication. As to the residual urinary volume, no relevant differences and alterations were determinated in the course of the treatment as well. With reference to undesired side effects quantitative and qualitative differences could be established, in which Tetrazepam showed the most favourable benefit/risk ratio. The effects of dantrolene sodium and diazepam were compared in a double crossover study of 42 patients with spasticity due to stable multiple sclerosis. Both drugs reduced the findings of spasticity, clonus, and hyperreflexia, and the complaints of muscle stiffness and cramping. Each drug had different side effects which suggest indications and contraindications for its use in spastic patients. Tizanidine (Sirdalud) was compared to baclofen (Lioresal) in a randomized, double-blind, cross-over trial. Each medication was introduced over a three week titration period and then maintained at the highest tolerated dose for five weeks. The two treatment phases were separated by a one week drug withdrawal and a two week washout period. Sixty-six patients entered the trial and forty-eight completed both treatment phases. At the end of the trial, neurologists and physiotherapists thought that baclofen was superior on the basis of perceived efficacy and tolerance (p less than or equal to 0.05). Although the efficacy of tizanidine or baclofen was judged as good to excellent by 24 and 39% of patients respectively, this difference was not statistically significant. Muscle weakness was the most common adverse effect. This was significantly more troublesome in patients treated with baclofen. Somnolence and xerostomia were more common in patients treated with tizanidine. Both baclofen and tizanidine appear to be useful adjuncts in the treatment of spasticity in patients with multiple sclerosis. Preference of either drug is tempered principally by side-effects. To determine whether the naturally occurring amino acid threonine, a potential precursor for glycine biosynthesis in the spinal cord, has an effect on spasticity in multiple sclerosis, 26 ambulatory patients were entered into a randomized crossover trial. Threonine administered at a total daily dose of 7.5 g reduced signs of spasticity on clinical examination, although no symptomatic improvement could be detected by the examining physician or the patient. In contrast to the side effects of sedation and increased motor weakness associated with antispasticity drugs commonly used for the treatment of multiple sclerosis, no side effects or toxic effects of threonine were identified. Levels of threonine were elevated in serum and cerebrospinal fluid during treatment, but glycine levels did not change. Enhancement by threonine of glycinergic postsynaptic inhibition of the motor reflex arc in the spinal cord may represent a non-sedating, nontoxic approach to the management of spasticity in multiple sclerosis. nan nan This multicenter, stratified, randomized, placebo-controlled, double-blind trial evaluated tizanidine for use in the United States for spasticity secondary to MS. The 15-week trial was divided into baseline (weeks 0 and 1), titration (2 mg to a maximum of 36 mg/d; weeks 2 to 4), and plateau (weeks 5 to 13) phases, followed by dose tapering (week 14) and a final visit (week 15). Primary efficacy parameters were scores on muscle tone (Ashworth Scale) and type and frequency of muscle spasms (patient diaries). All efficacy parameters were evaluated by the physician/assessor, and the physician/prescriber was responsible for all dosage adjustments. The patient, physician/assessor, and physician/prescriber made global evaluations of antispastic efficacy. Tizanidine produced a significantly greater reduction than placebo in spasms and clonus (patient diaries) but no significant differences in Ashworth scores. Patients and physician/prescribers, but not physician/assessors, gave significantly better scores in the overall assessment of efficacy and tolerability. No significant differences in other secondary efficacy parameters were noted. Adverse events were reported for 66 (61%) of the 109 placebo-treated patients and 101 (91%) of the 111 tizanidine-treated patients; 6 (6%) and 14 (13%) discontinued treatment, respectively. Patient and physician perception of improvement demonstrated more consistent differences between groups than did the Ashworth Scale, perhaps because of inexperience with this measure or failure to consider time between drug administration and assessment. A multi-centre, double-blind study was carried out in 100 patients suffering from chronic spasticity due to multiple sclerosis to compare the effectiveness of tizanidine hydrochloride with that of baclofen. Patients were allocated at random to receive treatment initially with daily doses of either 6 mg tizanidine or 15 mg baclofen and the dose was increased during the first 2 weeks up to a maximum of 24 mg tizanidine or 60 mg baclofen per day. Patients were then treated with the optimum dose for 6 weeks. Efficacy and tolerability parameters were evaluated after 2 and 8 weeks. Tizanidine and baclofen improved the functional status of patients in 80% and 76% of cases, respectively, but there were no significant differences between the two drugs. The antispastic efficacy of tizanidine was greater after 8 weeks than after 2 weeks, whereas the efficacy of baclofen decreased slightly with time. Both drugs showed good overall tolerability in more than 60% of patients. Thus, tizanidine is a well tolerated and effective muscle relaxant, the antispastic efficacy of which is well maintained over time, and it promises to be particularly useful in the treatment of spasticity due to multiple sclerosis. A double-blind trial with two parallel groups was carried out to compare the antispastic effect and tolerability of a new muscle relaxant, tizanidine (DS 103-282), with those of baclofen in the treatment of spasticity due to multiple sclerosis. Twenty-one hospitalized patients with stable spasticity participated in the 6-week trial. Eleven received tizanidine and 10 baclofen in gradually increasing daily doses. The optimal daily dose of tizanidine was between 8 and 36 mg and that of baclofen between 10 and 80 mg. Overall spastic state, spasms and clonus were similarly improved with both medications. In contrast, muscle strength, bladder function and the activities of daily living were more improved on tizanidine than on baclofen. Tiredness was the most frequent side-effect on tizanidine and muscle weakness on baclofen. The laboratory tests did not show any pathological changes with either medication. According to these results, tizanidine provides a new therapeutic alternative in the treatment of spasticity. In 17 in-patients suffering from spasticity due to multiple sclerosis, the effect and tolerability periods were 4 weeks each. As to efficacy, the variables: spasticity, clonus, flexor spasms, gait and bladder function were evaluated clinically. No significant difference was found between the two drugs. As far as side-effects are concerned, sedation was specifically inquired about. Apart from that, spontaneoulsy reported side-effects were recorded. Sedation was more often seen during treatment with diazepam, while the side-effects during baclofen treatment were more varied. The total number and severity of side-effects were equal in the two treatment groups. A preference for one of the two treatment periods was stated by the investigator before the code was broken. A significant difference (p less than 0.001) in favor of Lioresal was found. This is discussed in the light of the fact that no significant difference was found for the individual symptoms or side-effects. We studied the effects of botulinum toxin A in 12 patients with spasticity and in eight patients with rigidity. The study design was a double-blind, placebo-controlled crossover trial with botulinum toxin A versus saline. Using the Ashworth Scale for spasticity and the Unified Parkinson's Disease Rating Scale for rigidity, we gave the patients a tone grade before and 2 weeks after treatment. Improvement in tone by two grades or more was considered clinically significant. In the spasticity group, botulinum toxin A reduced the tone of all patients significantly, improved functionality and nursing care in eight of 12 patients, and alleviated painful spasms in five of five patients. In the rigidity group, muscle tone was decreased in seven of eight patients, functionality improved in four of seven, and joint and muscle pain decreased in four of five. We conclude that botulinum toxin A is effective against the disabling effects of spasticity and rigidity. The treatment was well tolerated. This double-blind cross-over study of 14 severely spastic inpatients with chronic multiple sclerosis reveals that once-daily doses of ketazolam, a new drug, are effective in reducing spasticity in a significant proportion of patients without significant side-effects. Added to the similar findings of an earlier double-blind controlled study of divided doses, the results suggest that this special feature of ketazolam provides a unique flexibility that may be exploited in individual cases. nan Thirty men and women diagnosed with definite multiple sclerosis (MS) were treated for ten weeks in a blinded, cross-over study. Patients with minimal to moderate spasticity were randomized to one of three sequences to evaluate the effects on MS-related spasticity of baclofen alone, stretching regimen with placebo, placebo alone, and stretching regimen with baclofen. The Cybex II isokinetic unit, timed gait, Ashworth scale, and subject's assessment of function were objective and subjective measures used to evaluate changes in hypertonicity. There was significant correlation between the Cybex and Ashworth as methods of measuring spasticity. Overall, treatment with baclofen alone significantly improved moderate quadriceps spasticity as measured by Cybex flexion scores. A trend, indicative of enhancing the beneficial effects of baclofen, was noted when stretching exercises were added to the treatment. The anti-spastic effect of a new drug, tizanidine, was compared with that of baclofen in a double-blind clinical trial; 40 seriously handicapped patients with multiple sclerosis (MS) were randomly allocated treatment with one or the other drug for a 6-week period. The antispastic effect was evaluated by clinical criteria. The optimal daily dose of both drugs varied considerably from patient to patient, and was on the average 23 mg for Tizanidin and 59 mg for baclofen. To the extent an antispastic effect was observed, the 2 drugs appeared to be equally effective when given at a 1:2 ratio (mg tizanidine: mg baclofen). Side effects of both drugs were sleepiness, muscular weakness and dry mouth. Tizanidine had a mild depressive effect on blood pressure. Sudden withdrawal of both drugs was accompanied by a transient relative increase of spasticity in approximately half the patients. There were no other changes suggesting physical or psychological dependence. The present study underscores that neither baclofen nor tizanidine are ideal antispastic drugs, and emphasize the need for further research. Seventeen patients, 13 males and 4 females, with moderate to severe spasticity caused by varying neurological disorders attended a double-blind, placebo-controlled trial to determine the efficacy and safety of dantrolene sodium. Three patients discontinued, two because of side effects and one because of a laboratory abnormality. In the fourteen subjects who completed the trial there was a statistically significant decrease in resistance to passive stretch, clonus and hyperreflexia without significant reduction of muscle strength. A positive clinical effect was observed in ten patients while a very slight or no effect was seen in four cases. All patients reported adverse reactions during the dantrolene period, six patients during the placebo treatment. Six patients wanted to go on with dantrolene after the trial. On many occasions the urine of the patients turned bright yellow with high doses of dantrolene. It is concluded that dantrolene sodium is an effective antispastic drug in about one-third of patients who suffer from spasticity of varying etiology. We studied the effect of botulinum-A toxin on spasticity of the leg adductors in 9 patients who were either chair-bound or bed-bound with chronic stable multiple sclerosis. We injected botulinum toxin (400 mouse units) or placebo into the adductor muscles in a randomized, crossover, double-blind design. Two physicians, who were unaware of the treatment order, used an objective rating scale and independently assessed the patients; interobserver correlation was excellent (r = 0.93-0.81). We found that botulinum toxin produced a significant reduction in spasticity (p = 0.009) and a significant improvement in the ease of nursing care (p = 0.009). There were no adverse effects during this short-term trial. This is the first demonstration of the beneficial effect of botulinum toxin on focal spastic muscle contractions. Baclofen was used in a double-blind crossover placebo-controlled trial to treat spasticity in patients with multiple sclerosis (MS). While on Baclofen, patients obtained a significant (p less than 0.001) reduction in spasticity compared to controls. The drug was particularly effective in alleviating flexor and extensors spasms, as well as their associated pain. Side effects were common in this study, but were usually well tolerated by the patients. The commonest side effects were sedation, nausea and vomiting. There were no changes in hepatic, renal, or hematological function in any patients. Increase weakness due to loss of spasticity for support was also a fairly common complaint. The drug seems best indicated in patients in whom spasticity is not required for support or other activities of daily living. Careful monitoring of the patient is essential for effective use of this drug. A minor tranquilizer, ketazolam, was tested in a double-blind, randomized, crossover study of 50 patients for its effects in neurologic spasticity. The drug was compared with diazepam (widely accepted as an effective antispasticity agent) and a placebo. The patients with spasticity were almost all cases of multiple sclerosis (24) or stroke (24). Thirty-nine patients completed the study. There was not statistically significant superiority of either diazepam or ketazolam, but both relieved symptoms significantly better than the placebo, as measured clinically and by electromyographic recording of deep tendon reflexes. Ketazolam is a relatively safe and clinically effective antispasticity agent (especially for patients with multiple sclerosis). The well-known "big 3"--dantrolene sodium, baclofen, and diazepam--produce large and small problems in many individual cases; hence, ketazolam now offers a safe and clinically useful alternative.