Oral antispastic drugs in nonprogressive neurologic diseases
A systematic review
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Abstract
Objective: To assess the efficacy of oral drugs in the treatment of spasticity in patients with nonprogressive neurologic disease (NPND).
Methods: Systematic review of double-blind randomized controlled trials of antispastic oral drugs in the treatment of spasticity in NPND. Data sources: Electronic MEDLINE, PubMed, Cochrane Library, and hand searches.
Results: Twelve studies (469 patients) were included (6 on stroke, 3 on spinal cord diseases, and 3 on cerebral palsy). Tizanidine was assessed in four trials (276 patients, 142 exposed), dantrolene in four (103, 93), baclofen in three (70, 55), diazepam in two (127, 76), and gabapentin in one (28, all exposed). Most trials were of small size, of short duration, and their methodologic quality was inadequate. Ten trials were controlled with placebo and only two were direct comparisons between drugs. Efficacy outcome variables were heterogeneous. Only four reports described the magnitude of the antispastic effect. The incidence of adverse drug effects (drowsiness, sedation, and muscle weakness) was high.
Conclusion: Evidence on the efficacy of oral antispastic drugs in NPND is weak and does not include evaluation of patients’ quality of life. If any, efficacy is marginal. Adverse drug reactions were common. Better methodologic instruments are needed for the evaluation of antispastic treatment.
Spasticity is a complication of cerebrovascular disease, spinal cord injury, head trauma, cerebral palsy, and progressive neurologic disease such as multiple sclerosis (MS) or ALS. It is common and can severely impair normal daily functions such as walking, eating, and dressing and contributes to patient disability.1
The therapeutic objective is to reduce the excessive muscle tone in the affected limbs, with the aim of increasing patient’s functional capacity and reducing discomfort. Various therapeutic options are available, including physiotherapy, drugs, and surgery.2 Treatment should be considered when patients’ functionality is affected or when pain causes discomfort.
Several drugs with antispastic effect are available with various mechanisms of action.3 Baclofen, tizanidine, benzodiazepines, gabapentin, clonidine, and cannabinoids are centrally acting drugs. Dantrolene and botulinum toxin type A have peripheral action. Botulinum toxin A has local action and a long lasting effect. It is used to treat focal spasticity or localized spasms.
Several meta-analyses and systematic reviews on antispastic drugs have been performed, but they have either focused on the treatment of spasticity in a particular condition such as MS4,5⇓ or on the efficacy of individual antispastic agents.6–8⇓⇓ However, the efficacy of the various available oral agents in the treatment of spasticity in nonprogressive neurologic diseases has not been evaluated in a systematic review. The aim of our study was to review the efficacy of the various available oral drugs for the treatment of spasticity.
Methods.
Search strategy.
Studies were identified by various search strategies in MEDLINE, PubMed, and Cochrane Library. The search included combinations of the following MeSH terms: baclofen, tizanidine, dantrolene, benzodiazepines, diazepam, clonidine, muscle spasticity, and free text words as gabapentin. The last search was carried out in January 2004. Additional studies were identified from the reference list of retrieved reports. No contacts were made with pharmaceutical manufacturers and authors of articles for unpublished reports or additional information from published reports.
Selection criteria.
Randomized clinical trials (RCTs) of antispastic drugs in nonprogressive neurologic disease were sought. In order to limit clinical heterogeneity, the review focused on patients with nonprogressive neurologic disease. Language was restricted to English, French, German, and Spanish. Reports of clinical trials were considered if patients’ allocation was randomized, spasticity was due to nonprogressive neurologic diseases (spinal cord injury, cerebral palsy, and cerebrovascular disease), and the experimental drug was given by oral route. Only full publications were considered. Data from case reports, abstracts, and letters were excluded. Reports were also excluded if the study was not double-blind, when sample size was less than 10 patients, when patients with spasticity had MS, and when the experimental agent was administered by intrathecal or other parenteral routes (mainly baclofen and botulinum toxin A) (figure).
Figure. Selection of randomized clinical trials (RCTs) for the systematic review.
Data extraction and study characteristics.
The following information was extracted from each report meeting the inclusion criteria:
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Study characteristics: study design, sample size, duration of the observation period, outcome measures for spasticity, and efficacy and safety outcomes.
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Methodologic quality: methodologic quality was assessed based on the items of the Jadad scale: randomization, double blinding, and reporting of withdrawals and dropouts.9 The scoring range is 0 to 5.
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Patients’ characteristics: age, sex, and underlying neurologic disease.
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Pharmacologic treatments: drug, time of administration, doses and titration, treatment period, number of treatment arms, control with placebo, and washout period.
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Efficacy outcomes: scales for muscle tone (Ashworth scale),10 spasticity grade or accompanying symptoms, functional movements, scales assessing activities of daily living, and clinical evaluation by patients, their family, or health staff.
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Tolerability outcomes: rates and types of adverse events.
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Dropouts and withdrawals: rates and reasons.
Statistical analyses.
Descriptive statistical analyses (rates, means, and standard deviations) were carried out using the SPSS version 9.0 software package.
Results.
Trial flow.
A total of 325 articles were identified, of which 101 reported clinical trials. Eighty-nine reports were excluded because they described studies in patients with MS (38), the route of administration was not oral (31), the antispastic effect was not an outcome variable (8), less than 10 patients had been included in the trial (6), language other than those included (2), or they were not randomized or double-blind clinical trials (4), thus leaving 12 reports meeting the inclusion criteria (see the figure).11–22⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ The included reports were published between 1972 and 2001.
Clinical trials included.
A total of 469 patients were included in the 12 selected RCTs. Most of the trials (7, 58.3%) were crossover with a washout period of 7 to 11 days, except one where there was no washout.11 As shown in table 1, six RCTs (50%, 228 patients) assessed spasticity in patients with cerebrovascular disease or head trauma, three (25%, 174 patients) in patients with spinal cord injury, and three (25%, 67 patients) in children with cerebral palsy. Experimental drugs were tizanidine (four trials, 276 patients, 142 exposed to the drug), dantrolene (four trials, 103 patients, 93 exposed), baclofen (three trials, 70 patients, 55 exposed), diazepam (two trials, 127 patients, 76 exposed), and gabapentin (one trial, 28 patients, all exposed).
Table 1 Number of patients exposed to antispastic drugs in randomized controlled trials according to underlying condition
Ten RCTs compared an antispastic drug to placebo, and two trials compared tizanidine to other antispastic drugs (diazepam or baclofen). No trials with clonidine were found.
Sample size calculations were not reported in any trial (table 2). The randomization method was described in only one report.16 The method of blinding was described in eight reports, and the number of dropouts or withdrawals was specified in all of them. The overall Jadad score of the 12 trials was between 3 and 4.
Table 2 Methodologic characteristics of clinical trials
Patients’ age and sex varied according to the underlying condition. Patients with cerebral palsy (67) were children (44.3% male), those with spinal cord injury (174) were middle aged (mean of 40 years old) and predominantly men (88%), and those with cerebrovascular lesions or stroke (228 patients) were older (mean of 55 years old) and also predominantly men (64.7%). The mean weighed duration of follow-up was 97.5 days (range, 17 days to 12 months). Treatment duration was between 2 and 6 weeks, except in one trial (30 patients) in which treatment was maintained during 30 weeks18 and another (28 patients) where the treatment period was only 48 hours.16 The mean treatment period (not including titration phase, tapering period, or washout period) for each drug was 84 days for baclofen, 80 days for tizanidine, 37 days for dantrolene, 25 days for diazepam, and 2 days for gabapentin. Most of the trials included a 2- to 3-week dose titration phase depending on the individual response.
Results on efficacy.
Details of the studies are included in tables 3 through 6⇓⇓⇓. The efficacy outcomes were heterogeneous. The mean number of efficacy outcome variables was 4.3 per trial (range 1 to 8). The Ashworth scale was used and reported in only six trials (50%, 154 patients in parallel group studies and 85 patients in crossover studies). Other common spasticity outcomes measured and scored were muscle tone, spasms, clonus, stretch reflexes, and muscle strength. In six studies (50%, 126 patients in parallel group studies and 101 in crossover studies) functional movement was assessed (mainly walking capacity). In seven studies (58.3%, 163 patients in parallel group studies and 38 in a crossover study) scales of daily living activities were used. In seven studies (58.3%, 259 patients in parallel group studies and 126 in crossover studies) the clinical outcome measure was overall evaluation by the patient, a relative, or a health professional (physician, physiotherapist, or nurse). Only in two trials was the analysis by intention to treat (see table 2).
Table 3 Clinical trials on antispastic drugs in cerebral palsy
Table 4 Clinical trials on antispastic drugs in spinal cord injury
Table 5 Clinical trials on antispastic drugs in cerebrovascular disease or head trauma
Table 6 Clinical trials on antispastic drugs in stroke
Placebo-controlled RCTs.
Ten trials were placebo-controlled, four with dantrolene12,13,19,22⇓⇓⇓ (98 patients), two with tizanidine14,21⇓ (141 patients), two with baclofen11,20⇓ (40 patients), one with diazepam15 (22 patients), and one with gabapentin16 (28 patients). Seven (171 patients) were crossover,11,12,15,16,20–22⇓⇓⇓⇓⇓⇓ and three (163 patients) were of parallel groups.13,14,19⇓⇓ Only five reports (including 124 patients in parallel group studies and 85 in crossover studies) described the effects on muscle tone by means of the Ashworth scale. In all studies the experimental drug was significantly better than placebo, but the magnitude of the therapeutic effect was only described in four trials, and it was modest (see tables 3 through 6⇑⇑⇑). Only in two of seven trials assessing daily living activities or the overall clinical status (with 20 and 22 patients) was the experimental drug better than placebo.
Direct comparisons between antispastic drugs.
Two parallel-group RCTs with direct comparisons between two drugs were included, one comparing tizanidine to diazepam17 and another comparing tizanidine to baclofen.18 Both were of parallel groups and assessed spasticity in patients with cerebrovascular disease (135 patients). In only one of them was the Ashworth scale used. No significant differences in efficacy outcomes between the drugs under comparison were found.
Adverse effects, dropouts, and withdrawals.
All reports gave information on adverse events in the different treatment arms, and their rates, except two12,21⇓ (see tables 3 through 6⇑⇑⇑). Adverse effects were generally more frequent in the active treatment groups (range 25 to 91%) than in the placebo groups (range 0 to 53%). Adverse events associated with tizanidine (range 60 to 88% of patients treated) were mainly drowsiness and dry mouth, and less frequently increases in liver enzymes. Dantrolene was associated with a high incidence of adverse events (range 64 to 91%), mainly weakness, drowsiness, and malaise. Diazepam (range 27 to 72% of patients) was associated with drowsiness, fatigue, and muscle weakness. Baclofen (range of adverse events of 25 to 27% of patients) was associated with sedation, dizziness, and muscle weakness. Neurologic events seemed to be dose-related, and they tended to disappear when doses were reduced.
The mean rate of dropouts and withdrawals was 21.2% (range 11 to 38%), and in two trials no dropouts were reported. Of 106 withdrawals and dropouts, 56 (53%) were due to adverse events. No association was found between treatment duration and the rate of withdrawals due to adverse events.
Discussion.
Our results indicate that the evidence on the efficacy of orally administered antispastic agents is scarce and weak. Only 12 double-blind RCTs on five drugs were found in a total of 469 patients. Between 28 and 142 patients had been exposed to each of the drugs of interest. There were few patients with each of the underlying conditions of interest. Exposure to the experimental drugs was of the order of a few weeks, a too short period for a lifelong condition. Only two trials (135 patients) were of direct comparisons of two antispastic drugs (tizanidine vs diazepam or vs baclofen), and no significant differences were found. The outcome variables were heterogeneous. A high proportion of studies used several outcome variables and we did not find sample size calculation in any of them, thus increasing the likelihood of type I error. Most trials were small, which implies reduced power and consequently increasing the chance of a type II error. Only two reports described outcome analysis by intention to treat. In most of the trials, withdrawals and dropouts were not included in the efficacy analyses. The general methodologic quality was poor, which impedes performing a meta-analysis and reaching a firm conclusion23 regarding the clinical management of spasticity.
The magnitude of the therapeutic effect was described in only four trials and it was modest. In clinical trials on the management of spasticity, an improvement has been considered clinically significant when muscle tone score (measured by the Ashworth scale) decreases at least by 25%.6 This effect magnitude was only described in two trials comparing tizanidine to placebo, where muscle tone reductions of 34% and between 20 and 26% were seen.14,21⇓ In addition, the outcome measures used in each trial were heterogeneous. Poor efficacy of antispastic drugs on muscle tone is not surprising, because most antispastic drugs reduce reflex activity.24 In contrast, recent pathophysiologic evidence has suggested that exaggerated reflexes contribute little to spastic muscle hypertonia.25 This adds difficulty to the interpretation of the whole data. On the other hand, in the majority of mobile patients, impairment of functional movements is clinically more relevant than impairment of muscle tone. Functional movements were only assessed in half of the trials. Daily living activities and the overall patients’ status were also rarely assessed, which contrasts with the therapeutic objective in routine clinical practice.
All agents were associated with varying rates and incidences of muscle weakness, sedation, and drowsiness. We could not confirm that the incidence of debilitating muscle weakness was lower with tizanidine than with other drugs, as has been reported.6,26⇓
We limited our review to oral treatment because this should be the preferred therapy for ambulatory patients. Spasticity is usually a long-term or even lifelong condition, in need of good quality evidence-based alternative treatments. These treatments should be easy to take, their effects should be easily familiar to patients in order to facilitate self dose-adjustment, they should be well tolerated and safe on the long term, and they should not interfere with other symptoms and treatments.27 In order to reduce clinical heterogeneity, we also limited our study to spasticity in nonprogressive diseases. Although a comprehensive search of the literature was performed, publication bias cannot be completely excluded. However, we believe that our main findings would not be materially different had hypothetically unpublished small trials been included in the study: first, because unpublished or difficult to locate RCTs tend to be of low methodologic quality and have negative results,28 and second, because actually published reports depict an already gloomy panorama on the treatment of chronic spasticity by oral route.
Our results are similar to those of other systematic reviews on the management of progressive and nonprogressive spasticity,4,5,29⇓⇓ and on the effect of individual antispastic drugs,6–8,30⇓⇓⇓ in that no recommendation can be made to guide prescribing due to low methodologic quality, small sample sizes, short duration of treatment and follow-up, and the scarce patient functioning outcomes assessed. Our review focused on drugs that are marketed in the United States and in the majority of European Union countries.31 Baclofen was the first antispastic agent marketed and remains the most commonly used antispastic agent in several countries.27 On the other hand, the results of a recent review of the use of cannabinoids in MS have been equivocal,32 partly because the clinical relevance of the outcomes assessed in trials has been questioned.
As with any symptomatic therapy, the management of spasticity should be individualized and adjusted to the activities of daily living of the patient.33 Antispastic drugs should be used with caution in the mobile spastic patient, because the decrease in muscle tone may seriously impair movement performance.25 Only when the patient is totally dependent because of severe spasticity may it be advisable to improve spasticity even at the cost of undesirable weakness or drowsiness.
Therefore, there is a clear need for well-designed large RCTs in patients with spasticity associated with nonprogressive neurologic diseases. The outcomes should not only focus on spasticity, but also on other frequently associated symptoms, functional movements, and general quality of life. Scales measuring spasticity in relation to the patient’s general quality of life should be developed, agreed, and validated. This would enable a better appraisal of the relative efficacy of potential antispastic treatments. The assessed interventions should be flexible enough to enable patients’ involvement in adjusting dosage regimens. A clinically based and patient-oriented approach should be developed, and consensus should be sought between patients’ organizations, medical specialists, physiotherapists, nurses, and regulatory authorities on the methods of therapeutic research in this area. Baclofen, tizanidine, diazepam, and dantrolene have different modes of action; efficacy, if any, is marginal; and they are associated with frequent side effects that can limit their usefulness. These results are not surprising in view of our present knowledge about pathophysiologic mechanisms underlying spasticity.
The evidence on the efficacy of oral antispastic treatment of nonprogressive neurologic diseases is poor. Further methodologic development and research are needed in order to improve the management of patients with spasticity.
Acknowledgments
Supported by Pfizer Spain. The conception, methods, analysis, and publication of the present study have been independent from the funding source.
The authors thank Xavier Montalbán, MD, for his comments.
- Received March 23, 2004.
- Accepted May 28, 2004.
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Letters: Rapid online correspondence
- Oral antispastic drugs in nonprogressive neurologic diseases: A systematic review
- William M. Landau, Washington University in St. Louis, 660 S. Euclid Ave, Saint Louis, MO 63110landauw@neuro.wustl.edu
Submitted February 01, 2005 - Reply to Landau
- Eva Montané, Fundació Institut Català de Farmacologia, Hospitals Vall d'Hebron. Pg. Vall d'Hebron, nº119-129. 08035 Barcelona. Spain.eme@icf.uab.es
- Antoni Vallano, and Joan-Ramon Laporte
Submitted February 01, 2005
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