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J'ournal of Neurology, Neurosurgery, and Psychiatry 1994;57:1355-1359 1355

Correlations between dose, plasma
concentrations, and antispastic action of
tizanidine (SirdaludO)
M Emre, G C Leslie, C Muir, N J Part, R Pokorny, R C Roberts

Abstract tions of tizanidine. ' We report data on the
In a double blind, placebo controlled, correlations between single doses, plasma
cross over study the correlations between concentrations, and antispastic action of
single doses (2, 4, and 8 mg), plasma con- tizanidine in patients with spasticity due to
centrations, and antispastic action of multiple sclerosis, by means of an objective
tizanidine were investigated in 16 quantitative method and a clinical scale for
patients with extensor spasticity of the the assessment of spasticity.
legs due to multiple sclerosis. An electro-
goniometer was used to assess muscle
tone at knee extensors, applying Methods
Wartenberg's pendulum test. Blood sam- PATIENT SELECTION
ples, a clinical assessment of muscle tone Seventeen patients were entered into the
by the Ashworth scale, and muscle study, but one patient was excluded from fur-
strength by the British Medical Research ther analysis because the baseline severity of
Council scale were obtained concomi- spasticity decreased during the study to below
tandy. Confirmatory analysis using the that stipulated in the protocol. There were 13
change in the relaxation index (R2 value) women and four men, mean age 43 (range
1.5 hours after each treatment, showed a 24-58) years. All patients had definite multi-
statistically significant (p = 0.0123) linear ple sclerosis, diagnosed by clinical criteria and
dose-response relation between single paraclinical investigations. Spasticity had
doses and antispastic action of tizanidine. been present for a mean of 70 (range 12-180)
Further statistical analysis showed a months and had been stable for a mean of 17
strong within patient linear correlation (range 2-48) months. Extensor spasticity
between plasma concentrations and anti- reaching a minimum score of 2 on the
spastic action at 4 and 8 mg doses (p = Ashworth scale in at least one leg and remain-
0-014 and 0'004 respectively), but only ing stable for at least one month was required
weak between patient correlations. The as an entry criterion. All patients had a base-
analysis of the dose-plasma concentra- line score of either 2 or 3 on knee extensors,
tion relation showed results consistent none had a score of 4, and none of them
with linear pharmacokinetics. The com- were bedridden. Patients receiving any drugs
parison of changes in the R2 ratio with with antispastic action, those with significant
concomitant Ashworth scores showed a systemic diseases, local complications, an
significant correlation between the two. It exacerbation of the disease, or abnormalities
is concluded that there are linear corre- in laboratory tests were excluded from the
Clinical Research, lations between single doses, plasma con- study.
CNS Department centrations, and antispastic action of
M Emre tizanidine. Because of the strong within EXPERIMENTAL PROCEDURE
Clinical Research, patient but weak between patient cor- The protocol was approved by the committee
Human Pharmacology relation between plasma concentrations on medical ethics of Dundee General
Departnent, Sandoz
Pharma Ltd, 4002 and antispastic action of tizanidine the Hospitals, and informed consent was
Basle, Switzerland effective doses should be determined obtained from each patient before they
R Pokorny individually. entered the trial. Patients were allocated a
Department of treatment sequence according to a randomisa-
Anatomy and
Physiology (9 Neurol Neurosurg Psychiatry 1994;57: 1355-1359) tion schedule based on a latin square design.
G C Leslie Each patient received in a double blind, ran-
C Muir domised, cross over design single doses of 2
N J Part
Tizanidine (SirdaludO) is a centrally active a, mg, 4 mg and 8 mg of tizanidine and one dose
Department of adrenergic receptor agonist with potent of placebo on four separate days, allowing a
Medicine, The
University, Dundee myotonolytic action.l The substance was wash out period of at least 72 hours between
DD1 4HN, UK shown to suppress selectively polysynaptic the different doses. Tizanidine and placebo
R C Roberts spinal reflexes while sparing the monosynaptic tablets had the same appearance, and each
Correspondence to: reflexes.5 Clinical investigations have consis- dose contained the same number of tablets
Dr M Emre, Sandoz
Pharma Ltd, Clinical tently shown an antispastic effect of tizanidine with the same appearance to maintain blind-
Research, CNS that was associated with little undue muscle ness.
Department, 94/504A, 4002
Basle, Switzerland. weakness,69 sometimes associated with an The examination schedule and content as
Received 7 February 1994 improvement in paresis.10 There is, however, well as timing of meals were standardised for
and in revised form little information on the correlation between each patient and across the patients. The
24 May 1994.
Accepted 30 May 1994 the antispastic effect and plasma concentra- medication was taken with a glass of water

. 14 This sured by means of an electrogoniometer and is the ratio of the amplitude of the first swing of applying the Wartenberg pendulum test. 2017 . which was used as the analyse and interpret the data. R2. 4) %11 m Confirmatory data analysis -a 01) This analysis was performed to assess the lin- 0) earity of the dose-effect relation at the R2 = 1-359 expected time of maximum effects (1 5 hours CD 0 after medication). Leslie. The individual effects of the four treatment regimens (placebo. and 8 mg of tizanidine) were split into a linear. transformed c 4) 4) c value of the R2 ratio. 30 minutes before via a CED 1401 intelligent interface breakfast and after the baseline evaluations (Cambridge Electronic Design). on October 26."3 The lower leg was lifted as on the rebound swing. and a cubic component. and 8 the mean value of each variable from the next hours after dosing. 1. Pokomny. The was placed in the cubital vein 30 minutes first swing was for practice and it was not before the daily baseline evaluations. where di was 0 for do (placebo). and 30 assessment data were obtained by calculating minutes and 1. Muscle tone was also assessed clinically ing the upper leg off the couch. patient before (upper trace) and one hour after (lower trace) a 4 mg dose DATA ANALYSIS of tizanidine.Published by group. The relaxation index R2 was calcu- action of gravity. The additional measurements were used for taking a measurement: The patients the ratio Rl (the ratio of the amplitude of the lay on a couch with the lower legs hanging first swing to the amplitude of first rebound over the end. 4. and 8 for d. The angle data were sampled measurements. were distracted by music played through immunoassay method with a sensitivity of headphones to maximise muscle relaxation 250 ng/l. Three types of quantitative measure of spasticity. The examined leg was indirectly swing). Having with the Ashworth scale. Seven tests had been performed. 6. These were tested for statistical significance including also the sequence effect (one way analysis of variance (ANOVA). Thereafter all measure. between the start and final resting position tern of the lower leg. 2 for d. 15. the less In the spasticity. A quantified version of R2 was used for the confirmatory data analysis. The log of the ratio quadriceps muscle. (8 mg of Time (s) tizanidine). Goniometric assessments were performed at MEASUREMENT OF SKELETAL MUSCLE TONE baseline immediately before drug intake and Each patient was given an initial screening 30 minutes. this has been confirmed by Brown et al. An indwelling catheter were taken at each assessment session. depends on the tone in the lated with PC software. 1-5. the maximum velocity on the first Giles. Plasma tizanidine concen. The systolic and diastolic blood pressures and pulse rate were measured Figure I R2 = a/b = 0-966 after each goniometric assessment in each Electrogoniometer traces 0 session. 6. the lower leg knee extensors and flexors was assessed was then released and allowed to swing freely immediately after each series of goniometric under gravity. the maximum acceleration on at the knee by the method described by Bajd the first 1356 Emre. after the drug intake. Downloaded from http://jnnp.'4 The following procedure was analysis. the maximum velocity on the first attached to an electrogoniometer (Penny and swing. Bajd and Vodovnik"3 have proposed that ments were performed on the leg that had the the best quantitative assessment of spasticity higher spasticity score at the knee extensors. 4 for d2 (4 mg). Statistics of the samples were taken at baseline. is defined in the statistical analysis were performed. and 8 hours assessment at which muscle tone was evalu. near to the horizontal as possible without tak. as it swings under the (fig 1). 1-5. Roberts between 8 00 and 9 00 am. is made from the relaxation index. 4. The greater were predetermined in the study protocol. the value of R2. and the maximum acceleration and Vodovnik. 2 mg. ated for both legs. which upper trace. . 2. Any adverse event occurring after obtainedfrom the same drug intake was recorded. a quadratic. and The tone of the quadriceps muscle was mea. During the examination patients trations were analysed by a specific radio. Blood included in the analysis. Type PGS) so as to measure the angle rebound swing. (2 0 mg). Muir.'5 Tone of both the ensured that the leg was relaxed. with the log. The strength of knee flexor for 10 seconds by a 286 PC microcomputer and extensor muscles was also assessed with the British Medical Research Council (BMRC) scale. 2. The dose was transformed as log (1 + didl).bmj. Part.'2 the leg on release to the difference in angle The principle of this test is that the swing pat. six tests. 4 mg. The ratio a The concept described by Abt'6 was used to R2. 3.bmj. the test was reintroduced by Bajd and Further data were derived from the pendulum Vodovnik"3 and is able to distinguish spasticity swing traces for descriptive and exploratory and rigidity. and to standardise experimental conditions. 3. p = 0 05).

as the quadratic and cubic (differences from baseline (on the day of components of the dose-response curve were experiment) by means of tw o way ANOVA not statistically significant (p = 0-413 and for goniometric variables ancd the Wilcoxon 0x708 respectively). or both) with regard to time 0 30 0 30 after drug treatment or dose dependency of Plasma tizanidine (ng/l) significant locations was found.04 ' Placebo (0) 2 4 8 transformation of the dose was examined by regression analysis (F test). Overall within patient 1. In addition. In the 0. .000 r= 0. They axis represents log R2 pared with the Ashworth score (difference value 1 5 hours after each 0. Within patient ernpirical correla- tion coefficients were tested for difference PLASMA CONCENTRATION-RESPONSE RELATION from zero for each dose.969. the dose- placebo.923. suggesting that "nominal" significances occurred by Figure 3 Ratio R2 (see fig 1) v plasma concentrations of tizinadine Jforfour patients. trations and the goniometric variables. p = 0. seen under placebo occurred up to three hours after taking the drug. as iwell as between In each patient.014) for the r= 0. 1-5 hours after medica- obtained after each dose of sttudy medication tion. No p pattern r = 0. linear correlations were calcu- patient empirical correlation coefficients for lated for each dose between plasma concen- each time point and each do se.bmj. ence in R2 ratios between placebo v active treatment were also calculated. Downloaded from http://jnnp. given. As a log transformation was used for were compared with those obtained after both the dose and the R2 ratio. For nine of the 16 patients the slope of the regression line was significantly different from zero.8 H correlation analysis between plasma concen- tration and the difference in the R2 ratios of placebo and active treatment gave a mean correlation coefficient of 0005 (p = 0967) for the 2 mg dose. and 0-536 (p = 0-004) for the 0 8 mgdose. 2017 . p = 0. p= 0.12 F.Published by group. For chance. Figure dose normalised area und er the plasma 3 gives examples of regression lines between concentration-time curve (AlUC 0-8 hours) the plasma concentration of tizanidine and and maximum plasma concentrations (Cma. from placebo) by a within patient rank correla- dose of tizanidine and tion analysis. and antispastic action of tizanidine (Sirdalude) 1 357 Figure 2 Dose efficacy 0-14 r were compared by means of a two way relation in the 2-8 mg dose ANOVA (p = 0 05).648.) concomitant R2 ratios at the 8 mg dose for four patients. On each graph the value of the correlation coefficient (r) is give? as is the level of significance (p) of the difference in slope of the line from zero. confirmatory analysis the logl0 of the differ- ence between the R2 ratio at 1-5 hours and the R2 ratio at baseline for that day and a log 0.bmj. The slope of the r Co4 AJ Results linear trend component has 0.059 4 mg dose. placebo. 0 347 (p = 0. across subjects between the antispastic effects of tizanidine and plasma concentrations.4 relations. at each time point a:fter medication.06 .972. investigated.0.000 (clustering of significant correlations at a o dose. The x axis represents the dose 0 expressed as log (1 + 4. p = 0. time point. Figure 1 gives examples of goniometric recordings before and after tizanidine. This analysis gave Dose (Log(1 + dc oseI2)mg) p = 0-0123 for the linear component of the dose-response curve.08 0 0123). In the descriptive data matched pair signed rank testt for the clinical analysis antispastic effects different from that scores (p = 0 05). plasma Correlations between dose. This indicated a rather weak relation each subject the data were obtained on the day on which the 8 mg dose of tizinadine was of.000 r= 0.8 between plasma concentrations and the differ- __.10 dosel2).lations between interactions showed no evidence for carry plasma concentrations of tizanidine and over effects between the two sequences of goniometric variables (di fference from placebo followed by 8 mg v 8 mg followed by placebo in the baseline correcited values) were placebo. between patient linear correlations on October 26. The analysis showed that 14 out of 288 (4 9%) calculated correlations were significant. DOSE-RESPONSE RELATION a value of 0 0314 (p = 00. Exploratory data analysis Analysis of variance for treatment/period In this analysis the linear corre. There were no non-linear components actual values and baseline c:orrected values to this relation. o As well as the analysis of within patient cor- C.. indicating a statistically significant relation between the dose and anti- Descriptive data analysis spastic action of tizanidine in the single dose All goniometric variables anc1 clinical scores range of 2 to 8 mg. and R2 values were com- range of tizanidine. response relation was considered to be linear The evaluations were performed with both (fig 2).

Roberts DOSE-PLASMA CONCENTRATION RELAIrION ratio and Ashworth score were negatively Plasma concentrations of tizanidi ne were correlated in both between and within patient obtained at 11 standard times in eac]h investi. 'Similarly. These results suggest that at a given plasma concentration the antispastic action of tizanidine may vary from patient to patient.. however. followed placebo. to achieve sufficient antispastic efficacy in a given patient. 229% at 4 beats/min). and there were no severe must be interpreted with caution fpiven the adverse events. and score two hours after medication was.327 (p = tions.bmj. however. quantitative assessment of showed that the changes in these two variables knee extensor muscle tone. Adverse events appeared in a dose dependent manner. doses. four patients The mean change from baseline in ikshworth in the 4 mg.Published by group. was found in the between patient ECl analysis of the relation between plasma con- Co centrations and antispastic effects of tizani- dine. Pokorny. In the exploratory data ana: lysis. 1. Part. Therefore. and antispastic effects of tizanidine.5 hours after drug intake. and by dry mouth. Figure 4 shows the m(ean drug ratio. this was Figure 4 Mean 20 roughly at the time at which the peak plasma tizanidine plasma concentrations of the drug occurred. correlation analysis-that is. CORRELATION BETWEEN ASHWORTH S5 CORE Drowsiness was the most frequent adverse AND R2 RATIO event (one patient in the 2 mg. 29% for 2 mg. pharmacokinetics in the dose range u sed.bmj. the higher the R2 gation day. Muir. o 4mg relation between plasma concentrations of 15 A 2mg tizanidine and its antispastic effect showed a strong linear relation at the two higher doses. Leslie. as measured by the statistical evaluation of dose-normalLised area BMRC scale did not show any detectable under the curve (AUC) and the nnaximum decrease in either extensor or flexor muscle concentration (Cm. Thus at the single 01) doses examined there were strong within c patient correlations between dose. There was also a linear relation between dose and plasma concentration. the lower the extensor tone on the plasma concentration curves at t]he three Ashworth scale. plasma 10 concentrations. patient rank correlation analysis shc)wed sig- nificant correlations between the two variables at all doses. Downloaded from http://jnnp."1 17 different doses of the drug were given on different a 8mg Within patient correlation analysis of the days. Spasticity was assessed by an electrogoniome- and 0-629 (p = 0-0001) for 8 mg). Total number of adverse non-linear nature of the Ashworth secale. These mean 1358 Emre. indicating a strong withiin patient Discussion linear correlation between the R2 Iratio and The purpose of this study was to assess the Ashworth score for extensor tone (S)pearman relations between dose. As suggested by the weak > between patient correlations. plasma concentra- rank order correlation coefficients 0. 001) for 2 mg. ter using Wartenberg's pendulum test. No clearcut linear correlation. 34% for 4 mg. which a between patient rank correlation analysis gives an objective. the Muscle strength. All adverse events were rated 38% for 8 mg. The events as well as the sum of intensity scores comparison of changes in the R2 vEalue with peaked around two hours after drug adminis- concomitant changes in the Ashwoirth score on October 26. In two concentration-time curves other studies. lations increased dose dependently.28% for three patients in the placebo group). mild to moderate. the effective o 2 4 6 8 10 unit doses can vary from patient to patient. roughly corresponding to the time of for extensor muscles by means of a within maximum plasma concentration. nine patients in the 8 mg. Time (h) The effects of the 2 mg dose of tizanidine on . The There was a mild decrease in blood pres- variability in the peak plasma conce ntrations sure (mean 18 mm Hg systolic and 10 mm Hg between patients given the same dose of diastolic pressure) and heart rate (5 tizanidine was low (36% at 2 mg. The R2 Confirmatory analysis showed a linear rela- tion between dose and antispastic efficacy of tizanidine in the single dose range of 2 mg to 8 mg.) at the three dc)se levels strength at any time after any of the doses of examined gave results consistent wiith linear tizanidine. the antispastic action of tizani- for 16 patients. On the basis of significantly correlated with each ot]her at all previous experience14 the ratio R2 was chosen dose levels. as the primary outcome measure of efficacy. The three Dose tizaniidine dine was maximum also at 60-90 minutes. one to two hours after the 8 mg and 8 mg). 2017 . single dose of tizanidine. The number of significa nt corre. individual effective plasma concentrations should be reached and E0 maintained. and antispastic efficacy of N tizanidine. 0-431 (p = 0-009) for 4 mg.

Descriptive data analysis: a concept between con- strong in within patient comparisons-that is. J7 Neurol Sci 1982. Gendron D. Tizanidine (DS 103-282). Quinlan JE. Selective muscle relaxant properties of detectable decrease in muscle strength was tizanidine and an examination of its mode of action. Leah JD. Pendulousness of the legs as a diagnostic test. WJ. 13 Bajd T. quantitative measurement of mus. This suggests that adverse events may Biomed Eng 1984. selec- At doses at which there was a clinically tively depresses excitation of feline dorsal horn neurons measurable decrease in spastic muscle tone to noxious peripheral stimuli by an action at alpha-2- adrenoceptors.'0 It must be borne in mind. Can J Neurol Sci 1987.79:9-1 1. ciated with any undue muscle weakness. was mild drowsiness. Antiparetic and not differ from that known from previous antispastic effects induced by tizanidine in patients with spastic paresis. The frequency and Frankel H. Spinal intemeuron depres- reliably used to provide quantitative assess. sion by DS 103-282 BrJ Pharmacol 1983. DS 103-282. Acta Neurol Scand 1988. Selective depression of synaptic transmission of spinal intemeurons in the cat by a new centrally acting detected by the Ashworth scale. plasma concentrations. Desai P. Lawson DA. Single doses of tizanidine up to 8 mg were eds. Pendulum testing of spasticity. Multi-centre.10:699-708.192:540-2. van Marle S. with the Ashworth scale. Minderhoud JM. in some patients an antiparetic effect was D. Review of clinical trials with tizanidine strength.1:18-24. however. 153-184. The pharmacology ments. Pharmacodynamics and pharmacokinetics of the oral antispastic agent tizanidine in patients with severity of adverse events increased in a spinal cord injury. 3-benzo- thiadiazole (DS 103-282). and antispastic action of tizanidine (Sirdalude) 1 359 spastic muscle tone did not differ from between plasma concentrations and antispas- placebo. no clinically 5 Coward DM. McLellan DL. however.26:77-8. In: Emre M and Benecke R. 8 Hoogstraten MC. Burki HR. a novel myotonolytic agent. so that unit doses higher than 2 mg tic effects seem to be less pronounced.76: also suggest that the electrogoniometer can be 473-81.6:9-16. 1 Sayers AC. Vodovnik L. Methods of Information in Medicine 1987. The adverse event profile did 10 Knutsson E. 1. Electrogoniometric measure. roughly dose dependent manner and peaked 12 Wartenberg R. 1988. Carnforth: Parthenon Publishing. Hill DR. Practioner 1964. muscle tone.bmj. tizanidine. double-blind trial of a novel antispastic agent. around the time of maximum plasma concen. found on the BMRC scale. 9 Emre M. sclerosis. Rohmer F. Does the be related to peak plasma concentrations. Tizanidine that the BMRC scale may not be sensitive versus baclofen in the treatment of spasticity in multiple enough to measure slight changes in muscle sclerosis patients. Gransberg L. dine. Downloaded from http://jnnp. Jf Neurol Neurosurg Psychiatry between single doses. 2017 . Boisson fact.Published by group. experience. Barkas the antispastic action of tizanidine is not asso. (SirdaludO) in spasticity. for each patient. Eichenberger E. Neurology 1951. Johnston SE. This suggests that 6 Lapierre Y. In 7 Eyssette on October 26. van der Ploeg RJO.bmj. J tration. Double-blind comparison of closely related to plasma concentrations of single doses of DS 103-282. than the clinical assessment to the changes in Arzneimittelforschung 1980. plasma concentration. 4 Davies J.77:224-30.14:513-7. The unit doses and dose dard way (by the same investigator). Triangle 1981. in a given patient the antispastic effect is 17 Hassan N. 1989.51:1178-86. Tansey C. 14 Brown RA.30:793-803. The results muscle relaxant. Bouchard S. This finding tizanidine should be determined individually is important as it suggests that used in a stan. Preliminary trial of carisoprodol on multiple sclerosis. baclofen and placebo for suppression of spasticity. seemed to be more sensitive of 5-chloro-4-(2-imidazolin-2-yl-amino)-2. the effective doses of cle tone by an electrogoniometer. firmatory and exploratory data analysis.26:9-16. Francis GS. certain plasma concentration does not always This study also showed a good correlation lead to the same amount of muscle relaxation between the clinical scale (Ashworth scale) in all patients. J Neurol Neurosurg Psychiatry tizanidine. and antispastic effects of tizanidine in the 2-8 15 Ashworth B. objective. the intervals should be chosen so as to maintain Ashworth scale can be reliably used to assess an effective plasma concentration. a centrally acting muscle relaxant. Preet MJ.53: 187-204. ment of muscle tone in spasticity. Neurosci Len 1984. This relation is especially 16 Abt Correlations between dose. so that small changes may not be 2 Davies J.43:1132-6. Vreeling A. Martensson A.48:197-202. plasma concentrations. El Masri W. well tolerated.9 The most frequent adverse event 11 Mathias CJ. Leslie GC. van der Burg W. spasticity in large scale clinical studies in which the use of an electrogoniometer may not be possible. Wartenberg pendulum test differentiate quantitatively It is concluded that there is a linear relation between spasticity and rigidity? A study in elderly stroke and Parkinsonian patients. Serratrice G. J Rehabil Res Dev 1989. Treatment of spasticity with tizanidine in multiple sclerosis. 3 Curtis DR. thus a are likely to be necessary in most patients. Spasticity. The current status of research and treatment.20:151-8. Br J7 Pharmacol 1982. Curr Med Res Opin 1988. The between patient correlations 1980. in spasticity associated with multiple associated with the antispastic effect of tizani. . Warter JM. Baker H. mg dose range. and efficacy was found. et al. Luckitt J. Because a close within patient most often used to assess spasticity and the relation between dose.

11. N J Correlations between dose. 2017 .bmj. Sign up in the service box at the top right corner of the online article. R Pokorny and R C Roberts J Neurol Neurosurg Psychiatry 1994 57: 1355-1359 doi: To subscribe to BMJ go to: These include: Email alerting Receive free email alerts when new articles cite this article.Published by group. M Emre.1136/jnnp. and antispastic action of tizanidine (Sirdalud).bmj.bmj. C Muir.bmj.1355 Updated information and services can be found at: http://jnnp. Downloaded from http://jnnp. Notes To request permissions go to: http://group. plasma To order reprints go to: http://journals. G C .com/ on October 26.bmj.