Quick viewing(Text Mode)

Effects of Two Different Doses of Eperisone in the Treatment of Acute

Effects of Two Different Doses of Eperisone in the Treatment of Acute

Effects of Two Different Doses of Eperisone in the Treatment of Acute Frandisco Colomer Rusinyol; Ramón Viladot Pericé°, Enrique Rodriguez Boronat°, Francisco Ferrer Bosch°°.

Traumatology and Orthopaedic Service, Hospital Municipal de Badalona; °Traumatology and Orthopaedic Service, Clinica Tres Torres, Barcelona; °°Traumatology Service, Clinica Metalùrgica, Barcelona (Spain).

Correspondence and reprint requests to: Dr. Ramón Viladot Pericé, Clinica Tres Torres, Doctor Roux Street 76, E-08017 Barcelona (Spain). Tel. 93 204 13 00; Fax 93.280 64 88; email: ctt@grup- trestorres.com

KEY WORDS: eperisone, , reducing muscle contracture and impair- muscle relaxants, contracture. ment of working capacity.

Conclusions: Eperisone represents a sig- ABSTRACT nificant advancement among the cen- Objectives: to evaluate efficacy and tol- trally active agents both erability of two different dosages of in terms of efficacy and safety. A daily eperisone (150 and 300 mg/day) in com- dosage of 300 mg appears to be effective parison with those of diazepam 15 for management of patients with acute mg/day, orally given for seven days. painful spinal muscle contracture.

Methods: Spontaneous and provoked INTRODUCTION pain, muscular contracture and its Acute low back pain (LBP) is a very impact on working capacity as well as common symptom affecting up to 90% “hand-to-floor” distance and degree of of all adults at least once in their life. lumbar tract flexion were assessed in a Most of cases are represented by an randomised double-blind trial on 90 LBP episode or a nonspecific lumbago, patients with acute muscle contractures. which is usually self-limited without any Adverse effects were also monitored. serious underlying pathology, but some- times the LBP may be the spy of an Results: Diazepam and eperisone 150 underlying severe , such as cauda mg/day had comparable efficacy, but the equina syndrome, cancer, infection or incidence of adverse effects and drowsi- fracture1. ness was significantly lower in Among patients with acute nonspe- eperisone— than in diazepam-treated cific mechanical LBP, the most frequent patients. Moreover, eperisone 300 pharmacological approach is the admin- mg/day was superior to diazepam in istration (or self-administration) of Vol. 9, No.1 & 2, 2009 • The Journal of Applied Research 23 paracetamol, nonsteroidal anti-inflam- of -type centrally acting mus- matory drugs (NSAID) and skeletal cle relaxant drugs; moreover, muscle relaxants. The rationale for using tolperisone, eperisone and silperisone8 muscle relaxants is that spine muscles had also a marked effect on voltage- contraction may produce clinical disabil- gated calcium channels. These data sug- ity by interfering with posture, motor gest that eperisone and its analogues capacity, nursing or daily living activities. exert their spinal reflex inhibitory action In these cases, the distribution of muscle predominantly via a presynaptic inhibi- over-activity can be limited by the use of tion of the transmitter release from the drugs that modulate neurotransmitters primary afferent endings via a combined acting at the cortico-spinal level, such as action on voltage-gated sodium and cal- Á-aminobutyric acid (GABA), glycine, cium channels9. glutamate, noradrenaline and serotonin2. In addition, it has been reported that Sometimes, centrally acting drugs the effects of eperisone in patients with such as , and chronic LBP could be mediated by an diazepam, could be preferred in the activity on the paraspinal muscle hemo- muscle contracture of spinal origin, dynamics with improved intramuscular whereas sodium, due to its oxygenation during lumbar extension primarily peripheral mechanism of and flexion10. action, may be preferable in of In spite of it’s large clinical use, pub- central origin (stroke and traumatic lished evidences of the efficacy of brain injury) where sensitivity to sedat- eperisone are limited to the treatment of ing effects is generally higher3. However, patients with myelopathy or tropical most of these treatments have recently spastic paraparesis11, neurogenic been recently questioned by the bladder12, increased muscular tone after Cochrane group4; thus, an interest exists stroke13, and muscle cramps from for new centrally active muscle relaxant diseases14; in addition, a double-blind, agents without detrimental effects on randomized, placebo-controlled trial has the central nervous system (CNS). shown a clear benefit of eperisone on Eperisone hydrochloride is a novel pain in the nuchal region, back pain, antispastic agent, which has been devel- pain in arms and shoulders, stiffness and oped in Japan and is now marketed in other symptoms in patients with cervical Japan, India and the Far East under the spondylosis15. brand name Myonal®. It works by relax- On the contrary, there areis no con- ing both skeletal muscles and vascular trolled comparative clinical trials in the smooth muscles, thus demonstrating a treatment of patients with LBP; thus, we variety of effects such as reduction of wanted to investigate the efficacy and myotonia, improvement of circulation, the tolerability of two escalating dosages and suppression of the pain reflex. The of eperisone (150 mg and 300 mg daily), drug inhibits the vicious cycle of myoto- in comparison with those of diazepam nia by decreasing pain, and 15 mg daily. in skeletal muscles, thus alle- viating stiffness and spasticity, and facili- MATERIALS AND METHODS tating muscle movement5-7. Ninety patients of both sexes aged over Results obtained with compounds more than 18, were selected among belonging to the same pharmacological those visiting the Orthopaedic and class, such as tolperisone, support the Traumatology Divisions of our hospitals view that blockade of sodium channels for medical advice because of LBP. may be a major component of the action Criteria for inclusion were a clinically

24 Vol. 9, No. 1 & 2, 2009 • The Journal of Applied Research Table 1. Effects of the different treatment on pain at rest and on palpation, muscular con- tracture, working capacity and “hand-to-floor” distance (see text for methods of assess- ment). Statistically significant difference: * p<0.01 vs. eperisone 50 mg t.i.d.; ° p<0.01 vs. diazepam 5 t.i.d.

Day diazepam 5 mg tid Eperisone 50 mg tid Eperisone 100 mg tid Pain at rest 0 1.57 ± 0.73 1.73 ± 0.74 1.65 ± 0.63 3 1.10 ± 0.72 1.25 ± 0.65 0.91 ± 0.59* 7 0.52 ± 0.63 0.77 ± 0.71 0.36 ± 0.49* Pain at palpation 0 2.00 ± 0.64 2.07 ± 0.64 2.04 ± 0.72 3 1.34 ± 0.67 1.46 ± 0.64 1.17 ± 0.49* 7 0.79 ± 0.77 0.96 ± 0.77 0.59 ± 0.59* Muscular contracture 0 2.17 ± 0.59 1.76 ± 0.69 1.73 ± 0.53 3 1.34 ± 0.67 1.36 ± 0.62 1.00 ± 0.52*° 7 0.76 ± 0.74 0.71 ± 0.69 0.48 ± 0.60* Impaired working 0 1.90 ± 0.48 1.93 ± 0.69 1.65 ± 0.49 capacity 3 1.52 ± 0.51 1.61 ± 0.57 1.52 ± 0.59*° 7 1.31 ± 0.47 1.31 ± 0.47 1.09 ± 0.43*° Hand-to-floor 0 35.17 ± 13.44 37.43 ± 16.21 28.92 ± 13.96 distance 3 23.11 ± 14.89 27.61 ± 14.62 15.61 ± 9.82* 7 13.48 ± 13.36 18.73 ± 16.15 7.38 ± 6.37* relevant acute LBP arisen oversince less activity the investigator informed the than 48 hours, and a muscular contrac- patient about the nature and purposes ture of mild to severe intensity. Criteria of the study, and any possible risk that for exclusion were: a) history of hyper- might have occurred during the treat- sensitivity to ; b) any ment. Patients were also informed that anti-inflammatory and/or drug they could suspend the trial at any given in the last 24 hours; c) pregnant or moment without any justification. nursing mothers; d) disturbances of noci- According to a randomization ception and/or proprioception that could sequence, the patients were allocated to negatively affect neuronal reflexes and a double-blind oral treatment with motility; e) severe cardiovascular dis- either diazepam 5 mg three times daily eases; f) history and/or presence of any (t.i.d.) (DIA), eperisone 50 mg t.i.d. hepatic or renal disease, or other condi- (EPE150) or eperisone 100 mg t.i.d. tions which could affect the drugs’ (EPE300), for seven consecutive days. absorption and disposition; g) ongoing The investigational medicinal products infective ; h) chronic rheumatic were manufactured in a way to guaran- diseases; i) neoplasias of the vertebral tee the full blindness for both patients column. and investigators. According to the Helsinki The efficacy of the treatments was Declaration and the recommendations evaluated by the physicians according to of the Spanish Medical Deontological the following parameters: a) intensity of Codex (“Codigo Deontologico Medico pain in rest position and on palpation Espaniol”), before any trial-related measured by means of a 4-point scale (0

The Journal of Applied Research • Vol. 9, No. 1 & 2, 2009 25 = none; 1 = mild; 2 = moderate; 3 = test was used to confirm the homogene- severe); b) intensity of muscular contrac- ity of the variances. Afterwards, the most ture by a 5-point scale (0 = none; 1 = appropriate parametric tests (post-hoc minimum; 2 = mild; 3 = moderate; 4 = Bonferoni test) were used for normally severe); c) the impact on muscular con- distributed variables, while the non- tracture on working capacity by a 4- parametric tests were used for the other point scale (1 = no limitation of activity; variables. 2 = partial limitation, but able to per- For non- parametric tests the homo- form usual activities; 3 = not self-suffi- geneity of qualitative variables was ini- cient, needs help; 4 = bedridden). tially evaluated; then, the Friedman and The muscle relaxant activity of the Wilcoxon tests were used for intragroup two medications was also evaluated by comparative analysis, while the Kruskal- the investigators who asked the patients Wallis and Mann Whitney U tests were to bend forward and try to touch the used for comparison between groups. floor with their fingers; the remaining The level of significance for all the sta- distance between fingers and ground tistical decisions was of p < 0.01 for (“hand-to-floor”) was measured by studies of two tails. means of a ruler (cm). In addition, the limitation of the lumbar motility was RESULTS measured by the degree of side flexion The three groups of patients proved to of the spinal column that the patient be homogenous at the enrolment visit in could reach towards both sides (as terms of demographic characteristics. degrees). Thirty patients were fully evaluated in The patients were evaluated by the the DIA (18 M / 12 F; mean age: 39.27 ± investigators at the screening/enrolment 13.35; range: 19-74) and in the EPE150 visit (basal) and after 3 (intermediate) (15 M / 15 F; mean age: 45.40 ± 13.74; and 7 days (end) of treatment. At each range: 24-65) groups, while the third visit the patients were asked to report EPE300 group was formed by 26 fully any occurred adverse effect to medica- evaluated patients (11 M / 15 F; mean tions, as well as any treatment was need- age: 35.69 ± 11.89; range: 18-67) since ed for its relief, and taking note of them four patients were lost at follow-up on the case report form. At the basal (these patients were unable to come control visit any concomitant disease back at visits and, when contacted by was noted together with any concomi- phone, they reported that reasons for tant pharmacological treatment; then, at withdrawal were independent from the each visit the patients were asked to medications). report the presence of any new con- The radiological examinations per- comitant disease. formed at the enrolment showed eleven The statistical analysis was per- cases of pre-existing lumbar diseases formed by an independent subject (four cases each in the DIA and (Europharma 2000 s.r.l. Firenze, Italy) EPE150 groups and three in the by means of the SPSS-PC Version 9.0.1 EPE300 group); all of them were of mild package. Descriptive statistics areis severity. The neurological examination reported as data ± standard deviation or showed no abnormal findings in any frequencies as appropriate. patient. Initially, the Kolmogorov-Smirnoff All the tested medications exerted a test was applied on the quantitative vari- statistically significant analgesic effect in ables to verify whether they followed a terms of “pain at rest” (Table 1). While normal distribution; then, the Bartlett no difference was observed among the

26 Vol. 9, No. 1 & 2, 2009 • The Journal of Applied Research three groups at the basal visit, DIA, was significantly better than that EPE150 and EPE300 reduced the “pain obtained with EPE150 (p<0.01). It is at rest” by 30%, 28% and 45%, respec- noteworthy that the score observed with tively, after three days of treatment, and EPE300 was also significantly better by 66%, 56% and 79%, respectively, than that with DIA both at day 3 and after seven days of treatment. The inter- day 7 of treatment (p<0.01). group comparison showed that, both The treatment with DIA increased after 3 and 7 days of treatment, the the lateral flexion to right by 17% and reduction of “pain at rest” observed in 43%, respectively, after 3 and 7 days of the patients treated with EPE300 was treatment, and the lateral flexion to left significantly higher than that achieved by 18% and 37% at the two control vis- with EPE150 (p<0.01). its; at the same times (day 3 and day 7), The treatment with diazepam and the improvement achieved with EPE150 eperisone achieved also a significant in the lateral flexion was of 19% and reduction of “pain on palpation”. The 49% towards the right side, and 21 and pain was reduced by 33%, 29% and 54% towards the left side, while the 45%, respectively, with DIA, EPE150 improvement achieved with EPE300 and EPE300, after three days of treat- was of 24% and 55% towards right and ment, and by 60%, 53% and 71%, 23% and 52% towards left. The statisti- respectively, after seven days of treat- cal analysis showed a statistically signifi- ment. Similarly to “pain at rest”, the sta- cant difference (p < 0.01) in the right tistical analysis showed a significantly side flexion between the EPE150- and higher efficacy of EPE300 vs. EPE150 EPE300-treated patients on day 3; the both after 3 and 7 days of treatment difference continued to be significant on (p<0.01 at both times). day 7 (data not shown). The “muscular contracture” was sig- Similar results were obtained in the nificantly and progressively reduced by hand-to-floor distance. In the patients the treatments; the intergroup compari- treated with DIA the distance signifi- son showed a statistically significant dif- cantly decreased by 34% and 62%, ference of EPE300 vs. EPE150 both respectively, after 3 and 7 days of treat- after 3 and 7 days of treatment (p<0.01 ment; the improvements observed at the at both times), and a significant differ- same times with EPE150 were of 26% ence between EPE300 and DIA after and 50%, and those with EPE300 were three days of treatment (p<0.01). of 46% and 74%. Once more, the The evaluation of the “impaired response achieved with EPE300 was sig- working capacity” as a result of the mus- nificantly better than that obtained with cular contracture, showed that a signifi- the lower dosage of eperisone (p<0.01) cant improvement was achieved in the (Table 1). patients treated with DIA both after 3 Finally, in the DIA-treated group 23 and 7 days of treatment, while in the patients (77%) reported the following patients treated with EPE150 the differ- adverse reactions: (19) asso- ence was significant only at the visit per- ciated with depression in one case, and formed at day 3. The patients treated with epigastric pain in the other one; with EPE300 obtained a significant tachycardia with vertigo (1), epigastric improvement in the working capacity pain (2) and diarrhoea (1). Somnolence, after seven days of treatment. However, as well as the depression and vertigo, the comparison between groups showed were of moderate-severe intensity, being that both on day 3 and day 7 the the remaining symptoms of mild intensi- improvement achieved with EPE300 ty.

The Journal of Applied Research • Vol. 9, No. 1 & 2, 2009 27 Among the EPE150-treated patients, experience confirm the efficacy of only 5 adverse reactions (17%) were eperisone as muscle relaxant in patients reported, i.e. epigastric pain of severe with chronic LBP. Both “pain at rest” intensity (3) occurring after about four and “pain on palpation” were signifi- days of treatment, and associated in one cantly reduced by all the treatments, but case with dyspnoea; somnolence of mod- it is noteworthy to mention that the erate intensity (1) and of mild analgesic activity was significantly better intensity (1). with the highest dosage of eperisone In the group of patients treated with (300 mg/day) than with the lower dose EPE300 mg, the reported adverse reac- (150 mg/day) and with diazepam. The tions were six (23%): somnolence of superiority of the higher dose compared slight intensity (2), epigastric pain of to the lower dose of eperisone is con- severe intensity (1), vertigo (1) and uri- firmed also by the results on “muscle nary retention (1) with a doubtful rela- contracture”, “impaired working capaci- tionship to the medication since the ty” and “hand-to-floor distance”. patient had a history of nephritic colic, Moreover, a statistically significant dif- and slight anorexia (1). ference was also observed between eperisone at the highest dose and DISCUSSION diazepam as far as regards “muscle con- Clinical trials of eperisone in the treat- tracture” and “impaired working capaci- ment of LBP are relatively few. A ty”. Medline search at the time of trial plan- Although the lack of a placebo arm ning looking for “back pain” and certainly represents certainly a weakness “eperisone” has shown only a double- of the study, the significant differences blind, randomized, placebo-controlled we observed between the low and high trial reporting a benefit of eperisone in doses of eperisone and, in some patients with cervical spondylosis, with instances between high eperisone and reduction of pain in the nuchal region, diazepam as well, effectively substitute back pain, pain in arms and shoulders, for the lack of placebo arm and show and stiffness15. proof of efficacy of eperisone much bet- More recently, a randomized con- ter than if it would be simply a non-infe- trolled trial has been published report- riority trial vs. diazepam in terms of ing the effects of eperisone in patients efficacy. with chronic LBP. VAS for pain was sig- On the other handway, diazepam nificantly reduced after 4 weeks of treat- could be considered something more ment compared to controls; moreover, than a pure “placebo” since reports have the relative change of oxygenated hemo- been published on the use of diazepam globin during lumbar extension at 4 in the treatment of spasticity16-17, weeks was significantly higher in the although it’s use is limited by the fre- eperisone group compared to control quent appearance of undesired side (no treatment) and McKenzie therapy effects caused by the concentration of alone. Thus, administration of eperisone the in the brain18-19. for 4 weeks significantly affected both In this regard, we would like to the VAS pain and the muscle hemody- underline that the incidence of adverse namics, and improved the intramuscular effects was much lower in both groups oxygenation during lumbar extension of patients treated with eperisone as and flexion in patients with chronic compared to the patients treated with LBP10. diazepam. The lack of a significant effect The results achieved in our clinical of eperisone on attention and other cog-

28 Vol. 9, No. 1 & 2, 2009 • The Journal of Applied Research nitive functions is clinically relevant with cutaneous administration in rats. Jpn J regards to the compatibility of this treat- Pharmacol 1997; 73: 215-20. ment for muscle contracture with the 7. Iwase S, Mano T, Saito M, Ishida G. Effect of a centrally-acting muscle relaxant, eperisone normal- day-life activities. In fact, it hydrochloride, on muscle sympathetic nerve should be taken into consideration that, activity in humans. Funct Neurol 1992; 7: 459- while a few decades ago an acute LBP 70. almost completely prevented the subject 8. Farkas S. : a centrally acting muscle from heavy activities related to job or relaxant. CNS Drug Rev 2006; 12: 218-35. normal- day-life, today such a distur- 9. Kocsis P, Farkas S, Fodor L, Bielik N, Thán M, bance is not incompatible with some Kolok S, Gere A, Csejtei M, Tarnawa I. Tolperisone-type drugs inhibit spinal reflexes activities performed at home, such as via blockade of voltage-gated sodium and cal- communication, e-mailing, etc. Thus, the cium channels. J Pharmacol Exp Ther 2005; maintenance of a standard level of 315: 1237-46. attention and cognitive capacities is wel- 10. Sakai Y, Matsuyama Y, Nakamura H, Katayama Y, Imagama S, Ito Z, Okamoto A, come. Ishiguro N. The effect of muscle relaxant on In conclusion, our results seem to the paraspinal muscle blood flow: a random- indicate that, in comparison with ized controlled trial in patients with chronic diazepam eperisone seems to represent low back pain. Spine 2008; 33: 581-7. a significant advancement among the 11. Nakagawa M, Nakahara K, Maruyama Y, Kawabata M, Higuchi I, Kubota H, Izumo S, centrally active muscle relaxant agents Arimura K, Osame M. Therapeutic trials in both in terms of efficacy and safety. A 200 patients with HTLV-I-associated myelopa- daily dosage of 100 mg t.i.d. appears to thy/ tropical spastic paraparesis. J Neurovirol 1996; 2: 345-55. be appropriate for the management of patients with acute painful spinal muscle 12. Murayama K, Katsumi T, Tajika E, Nakamura T. Clinical application of eperisone hydrochlo- contracture. ride to neurogenic bladder. Hinyokika Kiyo 1984; 30: 403-8. REFERENCES 13. Tariq M, Akhtar N, Ali M, Rao S, Badshah M, Irshad M. Eperisone compared to physiothera- 1. Gautschi OP, Hildebrandt G, Cadosch D. py on muscular tone of stroke patients: a Acute low back pain: assessment and manage- prospective randomized open study. J Pak ment. Praxis (Bern 1994) 2008; 97: 58-68. Med Assoc 2005; 55: 202-4. 2. Abbruzzese G. The medical management of 14. Kobayashi Y, Kawasaki T, Yoshimi T, Nakajima spasticity. Eur J Neurol 2002; 9 (Suppl 1): 30-4. T, Kanai K. Muscle cramps in chronic liver dis- 3. Gracies JM, Nance P, Elovic E, McGuire J, eases and treatment with antispastic agent Simpson DM. Traditional pharmacological (eperisone hydrochloride). Dig Dis Sci 1992; treatments for spasticity. Part II: General and 37: 1145-6. regional treatments. Muscle Nerve Suppl 1997; 15. Bose K. The efficacy and safety of eperisone in 6: S92-120. patients with cervical spondylosis: results of a 4. Taricco M, Pagliacci MC, Telaro E, Adone R. randomized, double-blind, placebo-controlled Pharmacological interventions for spasticity trial. Methods Find Exp Clin Pharmacol 1999; following injury: results of a 21: 209-13. Cochrane systematic review. Eura Medicophys 16. Cz∏onkowski A, Mirowska D. 2006; 42: 5-15. Pharmacotherapy for spasticity. Ortop 5. Morikawa K, Oshita M, Yamazaki M, Ohara Traumatol Rehabil 2002; 4: 54-6. N, Mizutani F, Kato H, Ito Y, Kontani H, 17. Kita M, Goodkin DE. Drugs used to treat Koshiura R. Pharmacological studies of the spasticity. Drugs 2000; 59: 487-95. new centrally acting muscle relaxant 4’-ethyl- 2-methyl-3-pyrrolidinopropiophenone 18. Dones I, Nazzi V, Broggi G. The guidelines for hydrochloride. Arzneimittelforschung 1987; 37: the diagnosis and treatment of spasticity. J 331-6. Neurosurg Sci 2006; 50: 101-5. 6. Matsunaga M, Uemura Y, Yonemoto Y, Kanai 19. Waldman HJ. Centrally acting K, Etoh H, Tanaka S, Atsuta Y, Nishizawa Y, relaxants and associated drugs. J Pain Yamanishi Y. Long-lasting muscle relaxant Symptom Manage 1994; 9: 434-41. activity of eperisone hydrochloride after per-

The Journal of Applied Research • Vol. 9, No. 1 & 2, 2009 29

Top View