Assessment of Cyclobenzaprine in the Treatment of Spasticity
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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.599 on 1 October 1972. Downloaded from Journal ofNeurology, Neurosurgery, and Psychiatry, 1972, 35, 599-605 Assessment of cyclobenzaprine in the treatment of spasticity PETER ASHBY, DAVID BURKE, SUDHAKAR RAO, AND RICHARD F. JONES From the Division of Neurology and the Department of Rehabilitation Medicine, Prince Henry Hospital, Sydney, Australia SUMMARY The efficacy of cyclobenzaprine 60 mg/day in the treatment of spasticity was assessed in a double-blind crossover trial of two weeks' duration in 15 patients suffering from cerebral or spinal spasticity. Independent clinical and electromyographic methods were used. The effects of cyclobenzaprine did not differ significantly from those of placebo. The administration of a higher dosage, 150 mg/day, to one patient revealed a dose-related response, but the degree of improvement was clinically small. Apart from a skin rash there were no significant untoward effects of therapy. Pharmacological agents play a small but signifi- no untoward side-effects in oral dosage of up to cant role in the management of the spastic 600 mg/day and intravenous dosage of 15 mg Protected by copyright. patient. Effective spasmolytic agents are valuable (Merck, Sharp and Dohme Research Labora- in the early stages following spinal cord trauma tories, personal communication). where spasticity makes nursing management Assessment of the efficacy of medication for difficult, when independent use of a wheelchair the relief of hypertonia must rely on clinical is threatened by deforming postures, and, most evaluation, despite potential observer incon- importantly, in the maintenance of a degree of sistency. The additional value of an objective muscle tone which allows effective use of residual assessment lies in its objectivity and in its poten- power. To fulfil these needs the development and tially greater discriminative power. In this trial testing of new drugs for the control of spasticity an objective assessment based on the electro- find their rationale. myographic method used by Jones, Burke, After encouraging preclinical reports and Marosszeky, and Gillies (1970) has been carried apparent success in an initial pilot study in man out to complement and amplify the clinical find- (Merck, Sharp and Dohme Research Labora- ings. Although the results of this study are essen- a double-blind tially are tories, personal communication), negative, they reported as a guide for http://jnnp.bmj.com/ trial was carried out to assess the efficacy of possible future trials of this drug. In addition, a cyclobenzaprine hydrochloride (MK130) in the simple and reliable objective method of assess- treatment of human spasticity. Cyclobenzaprine ment of spastic hypertonia is further elaborated. is a tricyclic amine related to amitriptyline. In animal experiments intravenous administration METHODS has been found to abolish the rigidity of both intercollicular decerebration ('gamma rigidity') Fifteen inpatients were studied. In five, aged 16 to 38 and anaemic decerebration ('alpha rigidity'), and years, spasticity was due to cervical or thoracic spinal on September 26, 2021 by guest. also to lessen the which follows cord damage of at least nine months' duration. In rigidity spinal two of these the lesion was clinically complete, and in cord ischaemia. Unpublished clinical trials of all five the clinical condition was stable. In the re- cyclobenzaprine in the treatment of psychiatric maining 10 patients, aged 8 to 69 years, brain damage disturbances (294 patients) and as a preanaes- was the aetiological factor, the causative lesion hav- thetic medication (450 patients) have demon- ing taken place two to 18 months previously. Six of strated that it is well tolerated by man, producing the 10 were hemiparetic, following cerebral throm- 594 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.599 on 1 October 1972. Downloaded from 600) Peter Ashby, David Burke, Sudhakar Rao, and Richard F. Jones bosis (three patients), cerebral embolus (two patients), benzaprine on the stretch reflex. The quadriceps and and subarachnoid haemorrhage (one patient). Four hamstrings muscles were stretched passively by man- patients had suffered diffuse brain-stem disease in ual movements of the leg at the knee. Knee joint motor vehicle accidents, resulting in hemiparesis in position was measured by a goniometer, the output two and quadriparesis in the remaining two patients. of which was differentiated (time constant 5 msec) to A double-blind crossover study was carried out to produce a voltage proportional to angular velocity. compare the efficacy of cyclobenzaprine 60 mg/day The electromyogram (EMG) of quadriceps and ham- with that of placebo. All sedatives, tranquillizers, and strings muscles was recorded by surface electrodes in muscle relaxants in use before the trial were sus- standardized positions 15 cm apart over the relevant pended for the duration of the study. Each treatment muscle. Such surface electrodes have been shown to period was of two weeks' duration. Patients were provide the most reliable measurements of EMG in randomly assigned to one treatment group, crossing day to day testing (Buskirk and Komi, 1970). The over to the other after two weeks. Cyclobenzaprine EMG records were monitored on an oscilloscope to was administered in 10 mg tablets, 30 mg/day in detect artefact and to assess field spread of activity three divided doses for the first three days, and from the antagonistic muscle. The EMG potentials 60 mg/day for the remainder of the treatment period. were integrated (time constant 0-2 sec), and recorded Placebo tablets were administered in an identical in both the raw and integrated forms, together with manner. the records ofjoint position and angular velocity, on Clinical assessment was carried out daily by two of a four-channel Offner Dynograph (for quadriceps) the authors (S.R. and R.F.J.), and trained physio- or a four-channel Grass polygraph (for hamstrings). therapists made additional daily observations. The The velocity of the stretching movement was clinical assessment evaluated functional changes, plotted against the amplitude of the resulting inte- muscle power, muscle tone, tendon hyperreflexia, grated EMG and linear regression analysis was per- and clonus. Voluntary power was graded using the formed for those movements which produced EMG. Medical Research Council scale. Muscle tone was The EMG:velocity relationship could then be ex-Protected by copyright. graded from no resistance (0), through slight (1), pressed in terms of the intercept of the regression moderate (2), and marked resistance (3) to complete line on the velocity axis (the 'threshold velocity') and rigidity of the limb (4). Tendon reflexes were re- the slope of the regression line. Changes in the corded as 0 (absent), + (reduced), + + (normal), relationship produced by cyclobenzaprine were + + + (increased), and + + + + (markedly in- taken to represent alterations in the sensitivity of the creased). The duration of muscle clonus was record- stretch reflex, and could be readily expressed as a ed in seconds, longer than 30 sec being regarded as change in the threshold velocity or in the slope of the maximal. Disability scores were calculated by averag- regression line. The EMG produced at 200°/sec was ing the ratings of each examiner over the last five determined from the regression line and was used as days of the treatment period. The significance a point of comparison for statistical purposes. The of changes in these indices was assessed using velocity 200°/sec was chosen because it has been Student's t test. noted empirically that if the threshold velocity ex- The objective assessment was performed by two ceeds 200°/sec it is usually difficult to detect in- authors (P.A. and D.B.) on the last day of each treat- creased muscle tone clinically. ment period, and was carried out completely inde- Patients were specifically questioned each day to pendently of the clinical evaluation. There was no determine side-effects of the medication, with par- http://jnnp.bmj.com/ collaboration between authors until the completion ticular attention to anticholinergic effects. Other of the study. The maximum force that could be de- side-effects were looked for on physical examination, veloped by voluntary isometric contraction of the and in addition at the end of each trial period an paretic quadriceps muscle was estimated with the electroencephalogram was performed and full blood knee joint at 90° flexion, using a force transducer count, serum electrolytes, serum creatinine, blood strapped to the limb above the ankle. The size of the urea, and liver function tests were determined. quadriceps tendon jerk was measured under the same conditions, the mean of the largest 10 readings being on September 26, 2021 by guest. documented. The significance ofchanges in voluntary RESULTS power and of changes in the tendon jerk was assessed using Student's t test. There was a general tendency for all patients A comparison of the relationship between the with cerebral spasticity to improve slowly both velocity of stretch and the resulting reflex response physically and mentally throughout the month of when on cyclobenzaprine with that when on placebo the trial. This improvement may have resulted was used as an indication of the effect of cyclo- from more frequent passive movements and more J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.35.5.599 on 1 October 1972. Downloaded from