J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.4.334 on 1 April 1981. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry, 1981, 44, 334-339 The effect of dantrolene sodium in relation to blood levels in spastic patients after prolonged administration W J MEYLER,* H BAKKER,t J J KOK,+ S AGOSTON,* AND H WESSELING* From the Institute of Clinical Pharmacology, State University Groningen, Groningen,* the Rehabilitation Hospital "De Hoogstraat," Leersum,t and the Rehabilitation Hospital, "Heliomare," Wijk aan Zee,+ The Netherlands SUMMARY In 25 patients with spasticity, pharmacokinetics and effects of dantrolene sodium were investigated after prolonged administration. A beneficial effect occurred in seven patients. The results were better on 100 mg daily than on a higher daily dose. An increase of the daily dose from 200 to 400 mg was not associated with higher blood levels. Many side effects were noted such as: anorexia, nausea, drowsiness, depression and muscle weakness. From this study we conclude that dantrolene sodium is a muscle relaxant with a weak to moderate effect in patients with spasticity; the effect at doses higher than 200 mg daily is probably poor. Protected by copyright. Dantrolene sodium is a muscle relaxant used in the mg), was supplied according to the following dosage treatment of spasticity. 1-9 Though effective in various schedule: 25 mg twice daily, 25 mg four times daily, 50 mg spastic conditions, reports on its therapeutic useful- four times daily, 100 mg four times daily, until the "opti- ness are conflicting and overshadowed by possible mal" dose of the drug was achieved, provided the maximum daily dose of 400 mg was not exceeded. The drug-related side effects and toxic reactions,.8 '0 1 "optimal" daily dose was defined as the dose with which It is not, however, known if such effects are cor- the therapeutic goal was obtained without unacceptable related with blood levels and whether failures may side effects. The speed of dosage titration depended on be due to insufficient blood levels. The purpose of the the individual patient's tolerance of the drug. Patients present study was not primarily to quantify thera- were kept on a particular dose level for two weeks before peutic drug effects. Of the patients available for this the next higher dose was given. Each patient maintained study most had been treated with various drugs and his "optimal" dose till the end of the study. Patients who other therapies. Dantrolene sodium was given in displayed drug intolerance were dropped from the study. increasing doses to these patients and effects were In patients with intercurrent illness, during which dantro- lene sodium therapy seemed to be inappropriate, the drug noted; the main purpose of this study was to collect and toxicity data. was temporarily discontinued, but it was resumed after pharmacokinetic recovery. http://jnnp.bmj.com/ Base line and follow-up measurements Data were Patients and methods collected before the start ofthe study, and control measure- ments were made before and at 14 days intervals during Twentyseven patients (23 males and four females) with the study. They consisted of: (1) Complete neurologic spasticity of various origin entered to study. Their ages examination during which resistance against passive ranged from 19 to 68 years (mean of 40 5 years). The spasticity, which was supposed to be stable, was in 22 Table 1 Diagnosis in 25 patients. Two patients with spinal cases of spinal origin and in five cases of cerebral origin cordpathology were omittedfront the study, because of (table 1). Patients with cardiovascular, metabolic and slight impairment ofliverfunctioni on October 1, 2021 by guest. present or past liver diseases were excluded from the study. Spasticity was prominent in 16 patients, disturbance Number ofpatients of activity of daily living (ADL) in five patients, nursing SPINAL CORD PATHOLOGY difficulties in disturbance of motor in Quadriplegia 9 two, performance Paraplegia 10 four, pain in four patients and clonus in one patient. MULTIPLE SCLEROSIS 1 Dosage Dantrolene sodium (in capsules of 25 and 100 SUPRASPINAL PATHOLOGY Hemiplegia 2 Address for reprint requests: Dr WJ Meyler, Institute of Clinical Cerebral palsy I Pharmacology, 9713 BZ Groningen, The Netherlands Contusio cerebri 2 Accepted 30 November 1980 334 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.4.334 on 1 April 1981. Downloaded from The effect ofdantrolene sodium in relation to blood levels in spastic patients 335 Run in Trial Weeks 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Neurological examination x x x x x x x x x ADL x x x x x x x x x Urine analysis x x x x x x x x x Blood x x x Blood chemistry x x x x x _ xx x x x xX Fig 1 Summary ofproceedings Blood sample before and during the study. dant rolene x x x x x x x x x x estimation Previous muscle , relaxant therapy' 25mg 50mg 100mg danttrolene.I 25LrngI'K. qid qid qid bid 1I immediately wash stopped out stretch (according to the Ashworth rating scale12), and Results strength, clonus and tendon jerk reflexes (according to predetermined rating scales) were measured (2) Activity Because of slightly impaired liver function, two of daily living (ADL) evaluation, (3) Laboratory observa- quadriplegic patients were excluded from participa- tions including checks of haemoglobin, haematocrit, tion. Seventeen of the 25 patients completed the 19 sedimentation rate, white cells, platelets, as well as Protected by copyright. determination in serum of urea, creatinine, direct and weeks study, while eight patients had to stop earlier. indirect bilirubin, glutamic oxaloacetic transaminase, Three patients stopped because of non-drug related glutamic pyruvic transaminase, lactic dehydrogenase, reasons (operation, removal or lack of motivation), and alkaline phosphatase. The urine was analysed for Five patients were withdrawn because of intolerable red and white blood cells, casts, protein and glucose. The side effects (incontinence 1, muscle weakness 2, same follow-up measurements were done before and pain 2). The minimum duration of participation for during the trial at two weeks intervals. The diagram shows all patients was five weeks. The daily dose of the the relevant proceedings (fig 1). patients with intolerable side effects never exceeded A 5 was ml blood sample collected every two weeks 100 mg per day. approximately three hours after the morning ingestion for the estimation of drug levels. The samples (cells The following data are based on the analysis of plasma) were deep-frozen until analysis. Dantrolene 25 patients. In table 2 the data of the neurological sodium, 5-hydroxy dantrolene and the acetylated meta- examinations are summarised. bolite were measured according to the method of Holli- In 12 of the 23 patients with increased passive field and Conklin.'3 At the end of the 19 weeks study the resistance dantrolene sodium gave an improvement "overall clinical result" was evaluated. Any change in (two other patients had muscle spasms not in their spasticity, as judged by the doctor was scored as improved, limbs, but in the abdominal muscles, which made equal and worse. The blood levels after prolonged proper evaluation impossible). Most patients ex- http://jnnp.bmj.com/ administration of dantrolene sodium were compared at hibited a decrease of reflex activity and clonus. In different daily doses. Changes (in a set of consistent contrast with other experiences more patients trends) in spasticity and in side effects were compared with dosage and blood levels of dantrolene sodium. If the complained of worsening of involuntary movements patient used other muscle relaxants (diazepam or and pain. baclofen), this medication was stopped if possible. In seven paretic patients muscle strength improved Depending on the condition of the patient, such medica- during the study, while 13 patients showed a more or tion was either withdrawn immediately or gradually less distinct improvement of ADL; deterioration of during the first three weeks (fig 1). ADL was observed in three patients. It should be on October 1, 2021 by guest. Table 2 Results ofdantrolene sodium treatment on various parameters ofspasticity in 25 patients Passive* Pcaresis Reflex Clonus* Involuntary* Pain * A DL resistance hyperactivity movements Improvement 12 7 20 16 3 5 13 No change 8 16 4 1 6 5 7 Deterioration 3 2 1 3 5 7 3 *These symptoms were not present in all patients J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.44.4.334 on 1 April 1981. Downloaded from 336 WJ Meyler, H Bakker, J J Kok, S Agoston, and H Wesseling noticed that the regular rehabilitation programme ,ug/ml was continued for each patient during the study. It is difficult, therefore, especially as far as muscle 1 5 strength and ADL functions are concerned, to discriminate between the drug effect and the effect of the other therapeutic measures. Before the start of the study, patients used a different muscle relaxant (baclofen 4, diazepam 4, 10- baclofen combined with diazepam 3). This medica- tion was eliminated during the first three weeks in 10 patients, while one patient remained on con- current diazepam medication during the whole study. 0*5- Table 3 lists the various dose levels that were obtained -1.................. and the number of corresponding patients. The mean blood levels of dantrolene sodium and 5- 1. hydroxydantrolene were determined at each dose 0 level after 14 days of administration. If in those 0 50 100 200 300 40( mg dos /day patients, who gradually increased their dose to 400 mg per day, the daily doses are plotted against Fig 2 Mean blood levels (± SEM) ofdantrolene the of sodium (-) and 5-hydroxy-dantrolene (-) at different blood levels of dantrolene sodium and those daily doses.