Open Experience with a New Myorelaxant Agent for Low Back Pain

S. Sartini, A. Ferrini* L. Guerra**

Service of Rehabilitation and Functional Reeducation, S. Orsola-Malpighi Hospital, Bologna (Italy) *Division of Orthopaedics and Traumatology, Hospital of Vignola (Modena, Italy); **Medical Service Alfa Wassermann, Bologna (Italy).

1 KEY WORDS: Myyrelasant, Eperisone were reported, such as lightheadness, hydrochloride, and Chronic low back occasional vertigo and/or loss of equilib- 3 2 pain rium, mild somnolence, and epigastric pain.1 In almost all cases, there was no need to interrupt the treatment, and the ABSTRACT reactions spontaneously recovered. Eperisone hydrochloride has been It is noteworthy to mention that both recently proposed as a muscle relaxant the activities with eperisone, ie, analge- for treatment of muscle contracture and sia and muscle relaxation, were achieved chronic low back pain (LBP), being with 1 drug only, while it is common devoid of clinically relevant sedative practice in rheumatology to combine a effects on central nervous system (CNS). painkiller with a muscle relaxant in This view has been confirmed by our order to achieve a satisfactory result experience in a series of 100 patients with both symptoms. Moreover, because with LBP and spinal muscle contracture, of the lack of significant effects on the treated with a full eperisone dose (300 CNS such as drowsiness, eperisone rep- mg/day) for ten consecutive days. resents a valuable alternative to the tra- The treatment achieved a consistent ditional centrally acting muscle analgesic and muscle relaxant activity relaxants, whose use has been signifi- across all of the patients. Both “sponta- cantly limited in recent years by their neous pain” and “pain on movement” CNS adverse effects in spite of a well- were significantly decreased, as did the documented therapeutic efficacy. resistance encountered by the investigator to passive movements, the antalgic INTRODUCTION rigidity and the muscle contracture. As a Chronic low back pain (LBP) is one of consequence, the treatment with the most common debilitating condi- eperisone resulted in a lower rigidity of tions reported by patients, and repre- low back and an improved motility for sents a substantial burden on the patients. healthcare system,1 with approximately Only 7 cases of adverse reactions 45% of the adult population experienc-

226 Vol. 8, No. 2, 2008 • The Journal of Applied Research ing LBP annually. Direct cost for diag- market for the management of painful nosis and treatment is reported to be conditions sustained by a muscle con- higher than 23 billion dollars in the tracture.14,15,16 U.S.A. in 1990.2 Together with knee and According to results achieved with hip osteoarthritis, LBP is one of the other compounds belonging to the same leading causes of disability in European pharmacological class, the mechanism of countries3 as well, and it is the 10th most action of eperisone is believed to be a common complaint in outpatient office blockade of sodium channels; in addi- visits.4 tion, these compounds, including Analgesics such as non-steroidal eperisone, are reported to have a anti-inflammatory drugs (NSAIDs), marked effect on voltage-gated calcium paracetamol, and opioids are the most channels.17 These data suggest that largely used medications for sympto- eperisone and its analogues may exert matic treatment of LBP. However, tradi- their spinal reflex inhibitory action pre- tional NSAIDs are associated with an dominantly via a presynaptic inhibition increased risk for serious upper gas- of the transmitter release from the pri- trointestinal (GI) complications, includ- mary afferent endings via a combined ing bleeding and perforation; action on voltage-gated sodium and cal- nephrotoxicity, including oedema, hyper- cium channels.18 tension, and acute renal failure; conges- More importantly, eperisone appears tive heart failure; and adverse to be devoid of clinically relevant seda- reproductive outcomes5,6,7. Paracetamol tive effects on CNS, as it has been is generally considered to be safer and reported in trials involving patients with better tolerated than NSAIDs when myelopathy or tropical spastic parapare- used at therapeutic doses, but the results sis;19 patients with neurogenic bladder;xx of a recent epidemiological study seem and patients with muscle cramps second- to indicate that high doses of paraceta- ary to liver diseases.20 The lack of seda- mol may involve the same risk for upper tive effects, together with the lack of GI complications as traditional those GI adverse effects that are typical NSAIDs.8 Opioids such as oxymor- of traditional NSAIDs, represent the phone,9 oxycodone,10,11 tramadol,12 or most important advantage of eperisone, tramadol, in combination with paraceta- keeping in mind that patients with LBP mol,13 are effective analgesics. However, are not usually young and, therefore, at somnolence or other detrimental effects high risk for NSAID-induced GI toxicity. on CNS, and constipation, are observed in a percentage of patients ranging PATIENTS AND METHODS between 3% and 20%. We have screened 100 consecutive Central muscle relaxants (CMRs) patients of both sexes, among those are most often used for treating muscle seeking our centres for medical advise spasticities of neurological origin, while and healthy assistance because of LBP. their use for minor complaints, such as Forty patients were enrolled at the acute LBP, has been limited by their Service of Rehabilitation and Functional adverse CNS effects. Among these com- Reeducation, S. Orsola-Malpighi pounds, eperisone hydrochloride has Hospital, Bologna (Italy), and 60 recently emerged as antispastic agent patients at the Division of Orthopaedics with an improved profile of safety com- and Traumatology, Hospital of Vignola pared to other drugs of the same phar- (Modena, Italy). macological class; in particular, Main criteria for inclusion were eperisone has been introduced on the acute or relapsing LBP, moderate to

The Journal of Applied Research • Vol. 8, No. 3, 2008 227 Table 1. Effects of a 10-day treatment with eperisone in 100 patients with low back pain of sci- atic origin. Results are reported as means ± standard deviation either of a 10-cm VAS (spontaneous pain and pain on movement); a 5-point scale (resistance to passive movements; antalgic rigidity, muscular contracture, joint functional impairment); or centimetres (“hand-to- floor” distance). Statistically significant differences: * p<005 and ** p<0.01 vs. baseline; °° p<0.01 vs. day 3.

BASELINE DAY 3 DAY 10 Spontaneous pain (VAS) 6.49 ± 0.12 5.40 ± 0.15** 3.54 ± 0.18°° Pain on movement (VAS) 7.28 ± 0.12 6.08 ± 0.17** 4.06 ± 0.20°° Resistance to passive movements 2.98 ± 0.07 2.45 ± 0.08** 1.63 ± 0.08°° Antalgic rigidity 3.18 ± 0.07 2.56 ± 0.07** 1.66 ± 0.09°° Muscle contracture 3.17 ± 0.07 2.56 ± 0.08** 1.62 ± 0.09°° Spine functional impairment 2.74 ± 0.10 2.24 ± 0.09** 1.54 ± 0.09°° “Hand-to-floor” distance (cm) 58.03 ± 3.21 48.71 ± 2.58* 36.55 ± 2.44°° severe, with no finding of severe spinal movement induced by the investigator) diseases at a Rx examination of lumbar were assessed by means of a 10-cm visu- spinal tract, such as spondilitis, fractures, al analogue scale (VAS); the patient was cancers, severe arthrosis and osteoporo- asked to score the pain by ticking off the sis. Muscular diseases, such as myositis, scale between 0 (no pain) and 10 polimyositis, muscular dystrophia and (unbearable pain). myotonia, were criteria for exclusion, as In addition, the resistance to passive well as any other severe disease affect- movement, the antalgic rigidity, and the ing neurological or cardiovascular sys- muscle contracture, were evaluated by tems, liver and kidney. Other criteria for the investigator by means of a 5-digit exclusion were history of hypersensitivi- scale (0 = absent; 1 = minimum; 2 = ty to the test compound; any anti-inflam- mild; 3 = moderate; 4 = severe); the matory and/or analgesic drug given in functional impairment was also scored the last 24 hours; pregnant or nursing by means of semiquantitative scale (0 = mothers; disturbances of nociception none; 1 = ≤ 25%; 2 = between 25 and and/or proprioception that could nega- 50%; 3 = between 50% and 75%; 4 = > tively affect neuronal reflexes and motil- 75%). Finally, the patients were asked to ity; any condition that could affect bend forward and try to touch the floor drugs’ absorption and disposition; and with fingers. The remaining distance ongoing infective diseases. between fingers and ground (“hand-to- The patients gave their informed floor” distance) was measured (cm). consent to taking part into the trial, and All these assessments were repeated then they were treated with eperisone after 3 and 10 days of treatment. At hydrochloride 100 mg 3 times daily (tid.) these times, the patients were asked a for 10 consecutive days. The medication non-leading question such as “Have you was given at 6:00 AM., 2:00 PM. and felt different in any way since starting 10:00 PM. Other non-analgesic medica- treatment or since the last visit?” in tions were allowed during the study for order to identify any adverse event specific diseases, but their dosage occurring during treatment. At the end remained unchanged for all the trial. of the study, a full lab examination At baseline (day 0), the “sponta- (hematology, blood chemistry, and uri- neous pain” and the “pain on move- nalysis) was performed, and the physi- ment” (pain provoked by a passive cians were asked to give their judgment

228 Vol. 8, No. 3, 2008 • The Journal of Applied Research about the efficacy of the treatment by line, to 48.71 cm at day 3 (-16%) and to means of a 5-digit scale (nil; light; mod- 36.55 cm at day 10 (-47%) (p < 0.01) erate; good; excellent efficacy). (Table 1). Thus, the analgesic and muscle Demographic and baseline data were relaxant activities of eperisone resulted described statistically. The analysis of in a lower rigidity of the low back and variance was used for “between-times” an improved motility of the patients. comparison. Then, the Student’s t test According to the investigators, the and the Mann-Whitney’s U test were treatment with eperisone was very suc- used, respectively, for paired data of cessful in 41% of patients and relatively continuous normally distributed vari- good in other 36%. However, the most ables and for non-parametric variables. interesting findings observed with The ¯Ç test was for analysis of the effica- eperisone refer to its safety of use. cy judgement done by the investigator. Only 7 adverse drug reactions (ADRs) were observed on a total of 100 RESULTS treated patients (Table 2). One patient A total of 100 patients were enrolled complained of minimal lightheadness into the study. There were 41 males and from day 4 to the end of treatment. 59 females between 18 and 70 years of There were 3 intermittent cases of light age (mean ± s.e.m.: 47.62 ± 1.46 years), to mild vertigo and/or loss of equilibri- and weighed between 48 and 100 kg um, and 2 patients reported mild somno- (mean ± s.e.m. 67.68 ± 1.16 kg). lence. In all these cases, the ADR was The treatment with eperisone considered as likely related to the treat- achieved a consistent beneficial anal- ment, but no action was undertaken and gesic and muscle relaxant activity across no treatment was given for ADRs. More all patients. Both “spontaneous pain” importantly, no ADR was severe enough and “pain on movement” (induced by to require withdrawal from the study, the manoeuvres of the investigators) sig- and they all abated spontaneously. nificantly decreased during the study; In only 1 case, the patient was the VAS values of spontaneous pain obliged to stop treatment, that because were respectively reduced by 17% and of epigastric pain. However, this patient 46%, after three and ten days of treat- had already manifested a similar symp- ment with eperisone, while the values tomatology with other treatments, so the for pain on movement showed a 16% investigator preferred to withdraw the and 44% decrease at the same observa- patient from the study. Also in this case, tion times. Similarly, the resistance the ADR abated after suspension of encountered by the investigator to pas- eperisone. sive movements, the antalgic rigidity, and No finding of systemic poor tolera- the muscle contracture showed an 18%, bility was observed at the lab examina- 19%, and 19% reduction, respectively, tion performed at the end of the trial. after 3 days of treatment. At the end of the treatment, the reductions for the DISCUSSION same 3 parameters were 45%, 48%, and Although our experience was not con- 49% respectively (Table 1). trolled with placebo or active reference The score for spine functional drug, the results we obtained in a rela- impairment was reduced from 2.74 at tively large series of patients confirm the baseline to 2.24 at day 3 (-18%), and to efficacy of eperisone, as it has been 1.54 at day 10 (-44%) (p < 0.01). Also, reported in several published reports. the “hand-to-floor” distance was signifi- A randomized, double-blind, clinical cantly reduced from 58.03 cm at base- trial in patients with cervical spondylosis

The Journal of Applied Research • Vol. 8, No. 3, 2008 229 Table 2. Adverse drug reactions (ADR) observed in a 100 patient-population treated for 10 days with eperisone 300 mg/day.

Relationship with Treatment ADR Treatment ADRs (n) Eperisone Withdrawal Resolution for ADR given Lightheadness (1) Probable No Yes No Vertigo (2) Probable No Yes No Lost equilibrium (1) Probable No Yes No Somnolence (2) Probable No Yes No Epigastric pain (1) Probable Yes Yes No N° of patients = 100 ADR incidence = 7% has shown that eperisone has a benefi- cles in the lumbar spine may represent cial activity on pain in arms and shoul- an aggravating factor leading to LBP.30 ders, stiffness, and other symptoms In this regard, preclinical studies related to cervical spondylosis.22 In addi- have shown that eperisone exerts sever- tion, eperisone was found to be compa- al activities on the saphenous artery and rable to physiotherapy in reducing veins, thus regulating the blood flow to spasticity in patients with cerebral the skeletal muscles of the lower limbs. stroke23 and cramps secondary to It would then follow that eperisone chronic liver diseases.24 A trial involving relaxes the saphenous arteries and veins patients with myelopathy or tropical previously contracted by norepineph- spastic paraparesis showed that motor rine, serotonin, acetylcholine, potassium, disability was significantly improved in or barium. Moreover, a treatment with 50% of patients treated with eperisone eperisone attenuates the contractions hydrochloride alone, and, to a lesser induced by norepinephrine and sero- extent, in patients treated with other tonin in the arteries, as well as the con- muscle relaxants or anti-inflammatory tractions induced by clonidine and drugs.25 phenylephrine in the veins.31 In healthy It is noteworthy that both activities volunteers, a single dose of 300 mg of observed in our patients, ie. analgesia eperisone has a sympatho-suppressive and muscle relaxation, were achieved action and enhances the blood flow in with 1 drug only (eperisone), while it is resting skeletal muscles of healthy vol- common practice in rheumatology to unteers with no effect on the sympathet- prescribe a pain-killer (eg, paracetamol ic nerve activity in actively contracting or an NSAID) with a muscle relaxant muscles, eg, standing or hand-gripping.32 (eg, tramadol, thiocholchicoside, dantro- Thus, in patients with LBP, eperisone is lene), even in fixed combinations,26 in expected also to improve the blood flow order to achieve a satisfactory result on to muscles and improve the hypoxic both pain and muscle contracture.27,28 condition. In addition, the spinal muscle con- Our study was mostly aimed at eval- tracture underlying LBP is usually com- uating the safety of eperisone. In this plicated by a reduced blood flow to the regard, the drug resulted was well toler- muscles, whose metabolic requirements ated. Adverse drug reactions were rare are further increased by the (7%), and of minor clinical relevance. In contraction.29 It has been therefore sug- particular, there were only 2 reports of gested that in some cases various somnolence, and they were not severe degrees of ischemia of the extensor mus- enough to oblige the patients to cease

230 Vol. 8, No. 3, 2008 • The Journal of Applied Research treatment. On the other hand, only 1 steroidal antiinflammatory drugs; population case of epigastric pain was reported, but based observational study and case-control study. Brit Med J 200; 322: 266-270. it was not certainly related to eperisone, 8. Garcia Rodriguez LA, Hernandez-Diaz S. since it was reported by the patients The relative risk of upper GI complications with other medications as well. among users of acetaminophen and nonsteroidal antiinflammatory drugs. These findings are noteworthy, if we Epidemiology 2001; 12 (in press). keep in mind that traditional NSAID 9. Hale ME, Dvergsten C, Gimbel J. Efficacy have a consistently worse tolerability; and safety of oxymorphone extended release in chronic low back pain: results of a random- also the more recent generations of ized, double-blind, placebo- and active-con- NSAIDs, such as the selective inhibitors trolled phase III study. J Pain 2005; 6: 21-8. of cyclooxygenase-2 (COXIB), which 10. Hale ME, Fleischmann R, Salzman R, Wild J, Iwan T, Swanton RE, Kaiko RF, Lacouture seemed to have a better GI tolerability PG. Efficacy and safety of controlled-release than traditional NSAIDs, have been versus immediate-release oxycodone: ran- reported to be responsible of an domized, double-blind evaluation in patients with chronic back pain. Clin J Pain 1999; 15: increased risk for cardiovascular acci- 179-83. dents and withdrawn from the market in 11. Salzman RT, Roberts MS, Wild J, Fabian C, 200433. Moreover, NSAIDs have an anal- Reder RF, Goldenheim PD. Can a controlled- release oral dose form of oxycodone be used gesic and anti-inflammatory activity, but as readily as an immediate-release form for they are devoid of muscle relaxant the purpose of titrating to stable pain con- effects. trol? J Pain Symptom Manage 1999; 18: 271-9. 12. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. In conclusion, because of lack of sig- Efficacy of tramadol in treatment of chronic nificant CNS-related effects uch as low back pain. J Rheumatol 2000; 27: 772-8. drowsiness, eperisone represents a valu- 13. Ruoff GE, Rosenthal N, Jordan D, Karim R, Kamin M. Tramadol/acetaminophen combi- able alternative to traditional CMRs, nation tablets for the treatment of chronic whose use has been significantly limited lower back pain: a multicenter, randomized, in the last years because of their CNS double-blind, placebo-controlled outpatient study. Clin Ther 2003; 25: 1123-41. adverse effects in spite of a well-docu- 14. Morikawa K, Oshita M, Yamazaki M, Ohara mented therapeutic efficacy.34,35,36,37 N, Mizutani F, Kato H, Ito Y, Kontani H, Koshiura R. Pharmacological studies of the new centrally acting muscle relaxant 4’-ethyl- REFERENCES 2-methyl-3-pyrrolidinopropiophenone 1. Reginster JY. The prevalence and burden of hydrochloride. Arzneimittelforschung 1987; arthritis. Rheumatology 2002; 41 (Suppl 1): 3- 37: 331-6. 6. 15. Matsunaga M, Uemura Y, Yonemoto Y, Kanai 2. Jackson KC 2nd. Pharmacotherapy in lower K, Etoh H, Tanaka S, Atsuta Y, Nishizawa Y, back pain. Drugs Today (Barc) 2004; 40: 765- Yamanishi Y. Long-lasting muscle relaxant 72. activity of eperisone hydrochloride after per- 3. Centers for Disease Control. Prevalence of cutaneous administration in rats. Jpn J diabilities and associated health conditions – Pharmacol 1997; 73: 215-20. United States, 1999. MMWR Morb Mortal 16. Iwase S, Mano T, Saito M, Ishida G. Effect of Wkly Rep 2001; 50: 120-125. a centrally-acting muscle relaxant, eperisone 4. Cherry DK, Woodwell DA. National hydrochloride, on muscle sympathetic nerve Ambulatory Medical Care Survey; 2000 sum- activity in humans. Funct Neurol 1992; 7: 459- mary. Advance data vital and health statistics; 70. n° 328. Hyattsville, MD: National Center for 17. Farkas S. Silperisone: a centrally acting mus- Health Statistics, 2002. cle relaxant. CNS Drug Rev 2006; 12: 218-35. 5. Hernandez-Diaz S, Garcia Rodriguez LA. 18. Kocsis P, Farkas S, Fodor L, Bielik N, Thán M, Epidemiological assessment of the safety of Kolok S, Gere A, Csejtei M, Tarnawa I. conventional nonsteroidal Tolperisone-type drugs inhibit spinal reflexes 6. Garcia Rodriguez LA, Hernandez-Diaz S. via blockade of voltage-gated sodium and cal- The epidemiology of myocardial infarction cium channels. J Pharmacol Exp Ther 2005; and heart failure among users of nonsteroidal 315: 1237-46. antiinflammatory drugs. Epidemiology 2000; 19. Nakagawa M, Nakahara K, Maruyama Y, 11: 382-386. Kawabata M, Higuchi I, Kubota H, Izumo S, 7. Nielsen GL, Sorensen HT, Larsen H, Arimura K, Osame M. Therapeutic trials in Pedersen L. Risk of adverse birth outcome 200 patients with HTLV-I-associated and miscarriage in pregnant users of non-

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