The comparative study of clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury.

In the present study we compared the clinical efficacy and safety of baclofen vs tolperisone in spasticity caused by spinal cord injury. A total of 150 patients were enrolled in the present study and were divided into two groups with 75 patients in each group, receiving baclofen or tolperisone, respectively. We used Modified Ashworth Scale, Medical research council scale, Barthel Index, and Coefficient of efficacy to measure clinical efficacy. After 6-week treatment, both groups demonstrated significant improvement in muscle tone, muscle strength and functional outcome (Group I, 1.55 ± 0.053, 2.79 ± 0.032, 59.31 ± 1.32; Group II, 1.57 ± 0.053, 3.04 ± 0.032, 73 ± 1.32 respectively). There was no significant difference regarding improvement in muscle tone and muscle strength between the two groups (Group I, 1.055 ± 0.053 vs Group II, 1.57 ± 0.053; Group I, 2.79 ± 0.032 vs Group II, 3.04 ± 0.032, p > 0.05). However, the improvement in functional outcomes was greater in group II as compared to that in group I (Group I, 59.31 ± 1.32 vs Group II, 73 ± 1.32, p < 0.05). In addition, overall efficacy coefficient was greater for group II as compared to group I (Group I, 3.6 vs Group II, 2.3, p < 0.05). Group I had more side effects compared to Group II. Compared to baclofen, tolperisone offers greater improvement in activities of daily living compared to baclofen.

RCT Entities:   Population Interventions Outcomes

Introduction

As a typical sign of upper motor neuron dysfunction, spasticity happens due to disruptions in inhibitory descending spinal motor pathways (Lance, 1980). The characteristics of spasticity appear due to hyper excitability of the stretch reflex including exaggerated tendon jerks and a velocity dependent increase in muscle tone (Lance, 1980). Currently, there are 12 million patients suffering from spasticity worldwide. The commonest causes of spasticity include cerebral palsy (CP), and spinal cord injury (Wang et al., 2015, Lance, 1980, Halim et al., 2017).

A variety of underlying mechanisms of spasticity have been reported for spasticity, including damage of descending inhibitory pathways and creation of new synapses by motor neurons which have lost their supraspinal innervations (Young, 1994). Spasticity can be classified into two categories including positive and negative spasticity, depending upon the upper motor neuron signs. Positive spasticity signs include hyperreflexia, clonus, spasms, and postural abnormalities, while negative spasticity signs include loss of dexterity, loss of strength, fatigue, and pain. The spasticity treatment is usually focused on the positive upper motor neuron signs (Luo et al., 2016, Dietz and Sinkjaer, 2007). The spasticity treatment objectives are to facilitate rehabilitation, increase daily activities, prevent contractures, and relieve pain. The previous studies have shown that the maintenance of a certain level of spasticity may be beneficial for some patients to support body posture (Taricco et al., 2000, Shakespeare et al., 2003). Currently, all reviews based on clinical trials demonstrated limited evidence for evaluating the clinical efficacy of a variety of drugs to relieve spasticity.

As one of the most common drug used for the treatment of spasticity, oral baclofen has been used on a long term basis (Dario and Tomei, 2004), which is a γ-aminobutyric acid receptor B (GABA-B) agonist. Although there are a variety of GABA-B receptors in the spinal cord (Liu et al., 2015, Yine et al., 2015, Yang et al., 2001), baclofen preferentially binds to pre-synaptic receptors, resulting in a decrease of release of neurotransmitters (Khaliq et al., 2016, Price et al., 1984). In addition, baclofen increases the total persistent inward current in motoneurons as it increases more of sodium current compared to the calcium flow reduction (Bennett, 2004). The previous studies have shown that baclofen decreases hyperreflexia, muscle tone and contractions of paralyzed muscles (Li et al., 2005, Taricco et al., 2006) and just one-week treatment has shown positive impact on voluntary muscle strength for patients with multiple sclerosis (Pedersen et al., 1970, Nielsen and Sinkjaer, 2000).

Recently, tolperisone has been to be an effective and safe muscle relaxant for patients with spasticity. It stabilizes nerve membrane and inhibits pathologic mono- and polysynaptic reflex activity (Dulin et al., 1998, Pratzel et al., 1996). Unlike other muscle relaxants, tolperisone has no substantial affinity to cholinergic, serotonergic, dopaminergic or adrenergic receptors in the central nervous system, thus without sedation or withdrawal phenomenon (Dulin et al., 1998). However, there are very few trials available which ensures the clinical efficacy and safety of tolperisone. In addition, only few studies are available assessing the clinical efficacy and safety of tolperisone in spasticity after stroke and no studies are available for SCI and CP related spasticity (Stamenova et al., 2006, Rahman et al., 2017, Sarfraz et al., 2017). The aim of the present study is to compare and evaluate the clinical efficacy and safety of baclofen vs tolperisone for spasticity of patients with spinal cord injury.

Materials and methods

Patients

A total of 150 patients with spasticity due to spinal cord injury were enrolled in the present study. Patients were enrolled from January 2011 to Dec 2014. The study protocol was reviewed approved by the Medical Ethics Committee of West China Hospital (Chengdu, Sichuan, China). All patients provided written consent forms. The patients were randomly divided into two groups including group I – patient receiving baclofen and group II – patients receiving tolperisone.

Inclusion criteria

(a) lower limb muscles spasticity including medial hamstring and hip adductors muscle; (b) diagnosis of severe chronic spastic hypertonia in the lower extremities for ≥six-month duration; (c) the degree of spasticity ≥level 3 according to the Ashworth Scale; (d) muscle strength ≤2 according to the medical research council scale (MRC); (e) functional outcomes ≤50 according to the Barthal Index (BI).

Exclusion criteria

(a) Concomitant neurological disease, orthopedic illness or any other disease likely to alter muscle tone, hamper motility, or influence the aim of the trial otherwise; (b) allergy to tolperisone or baclofen; (c) women in reproductive age without safe contraception, pregnancy or lactation period.

Treatment

In group I, baclofen was initiated at 5–10 mg 2 or 3 times per day, and the dosage was gradually increased at 5–10 mg per week, until up to 80 mg per day. In group II, tolperisone was initiated at 150–450 mg per day until up to 600 mg per day. The data were measured before treatment, at week 2, 4, and 6.

Outcome measures

Muscle tone

Muscle tone was measured by MAS (Bohannon and Smith, 1987) with 0 = No increase in muscle tone, 1 = Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end range of motion when the part is moved in flexion or extension/abduction or adduction, etc, 1 +  = Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the range of motion (ROM), 2 = More marked increase in muscle tone through most of the ROM, but the affected part is easily moved, 3 = Considerable increase in muscle tone, passive movement is difficult, 4 = Affected part is rigid in flexion or extension (abduction or adduction, etc.).

Muscle strength

Muscle strength was measured by MRC (Paternostro-Sluga et al., 2008) with 0 = No contraction, 1 = Flicker or trace of contraction, 2 = Active movement with gravity eliminated, 3 = Active movement against gravity, 4 = Active move-ment against gravity and resistance, 5 = Normal power.

Functional outcomes

Functional outcomes were measured by BI (Collin et al., 1988) in the form of 0–100 scores with 0 = total dependence and 100 = total independence.

Safety

The adverse events and side effects were observed and recorded by attending physicians and nurses by daily monitoring.

Statistical analysis

SPSS 17.0 package was used for statistical analyses. Parameters were expressed in mean ± standard deviation (x ± s) using repeated measures analysis of variance. When the spherical test condition (α = 0.1) was unsatisfied, Greenhouse-Geisser adjustment was applied. Paired t test or paired rank sum test method were used for the self-comparison in each time point. T test or rank sum test method was used for the comparison of the changes of parameters with the significance level of P < 0.05. Sigmaplot 10.0 software was used for plotting.

Results

Baseline characteristics

As shown in Table 1, Group I had 75 patients with mean age 36.6 ± 1.7 years and group II had 75 patients with mean age 35.5 ± 1.5 years. The body weight for group I and group II were 57.7 ± 5.6 kg and 55.2 ± 5.0 kg, respectively. There were no significant differences regarding age and body weight between the two groups.

Table 1

Demographic and baseline characteristics of all patients.

Indexes	Group I (n = 75)	Group II (n = 75)	P value
Sex (M/F)	20/55	27/48
Age (years)	36.6 ± 1.7	35.5 ± 1.5	0.105
Body weight (kg)	57.7 ± 5.6	55.2 ± 5.0	0.175
Mean dosage	24.33 ± 12.5 mg/day	378.2 ± 102.1 U

Values are expressed as Mean + SEM.

Muscle tone

As shown in Table 2, Table 3 and Fig. 1A, MAS was significantly decreased over the six-week period in both groups, from 3.34 ± 0.05 to 1.55 ± 0.05 and 3.33 ± 0.03 to 1.57 ± 0.05, for group I and II, respectively. In addition, compared with those in group II, MAS at week 2 and 4 in group I were significantly lower (1.77 ± 0.05 vs 2.39 ± 0.03; 1.59 ± 0.08 vs 2.21 ± 0.08; p = 0.003 and 0.02, respectively). However, at the week 6, the difference was not significant (1.55 ± 0.05 vs 1.57 ± 0.05, p = 0.25).

Table 2

Effect of baclofen on muscle strength, muscle tone and functional outcomes.

Indexes	Time points	Values	P values
MAS	Baseline	3.34 ± 0.05
	Week 2	1.77 ± 0.05*	0.001
	Week 4	1.59 ± 0.08*	0.045
	Week 6	1.55 ± 0.05*	0.048
MRC	Baseline	1.31 ± 0.05
	Week 2	2.90 ± 0.09*	0.001
	Week 4	3.11 ± 0.03#	0.043
	Week 6	2.79 ± 0.03†	0.033
BI	Baseline	36.05 ± 1.41
	Week 2	42.05 ± 2.34*	0.045
	Week 4	52.32 ± 2.05#	0.039
	Week 6	59.31 ± 1.32†	0.041

Values are expressed as Mean ± SEM.

Abbreviations: MAS, Modified Ashworth Scale; MRC, Medical Research Council; BI, Barthel Index.

Note: Significantly different from baseline (P < 0.05).

Significantly different from 2nd week (P < 0.05).

Significantly different from 4th week (P < 0.05).

Table 3

Effect of tolperisone on muscle strength, muscle tone and functional outcomes.

Indexes	Time points	Values	P values
MAS	Baseline	3.33 ± 0.03
	Week 2	2.39 ± 0.03*	0.012
	Week 4	2.21 ± 0.08*	0.035
	Week 6	1.57 ± 0.05†	0.002
MRC	Baseline	1.41 ± 0.06
	Week 2	1.71 ± 0.09*	0.023
	Week 4	2.46 ± 0.03#	0.040
	Week 6	3.05 ± 0.03†	0.014
BI	Baseline	38.53 ± 1.41
	Week 2	51.53 ± 2.34*	0.001
	Week 4	63.80 ± 2.50#	0.021
	Week 6	73.35 ± 1.32†	0.034

Values are expressed as Mean ± SEM.

Abbreviations: MAS, Modified Ashworth Scale; MRC, Medical Research Council; BI, Barthel Index.

Note: Significantly different from baseline (P < 0.05).

Significantly different from 2nd week (P < 0.05).

Significantly different from 4th week (P < 0.05).

Fig. 1

Differences between the groups (a) Change in MAS, (b) Change in MRC score, (c) Change in BI index. Values are expressed as Mean + SEM.

Muscle strength

As shown in Table 2, Table 3 and Fig. 1B, MRC was significantly increased over the six-week period in both groups, from 1.31 ± 0.05 to 2.79 ± 0.03 and 1.41 ± 0.06 to 3.05 ± 0.03, for group I and II, respectively. In addition, compared with those in group II, MRC at week 2 and 4 in group I were significantly higher (1.77 ± 0.05 vs 2.39 ± 0.03; 1.59 ± 0.08 vs 2.21 ± 0.08; p = 0.003 and 0.02, respectively). However, at the week 6, there was no significant difference between the two groups at week 6 (2.79 ± 0.03 vs 3.05 ± 0.03, P = 0.07).

Functional outcome

As shown in Table 2, Table 3 and Fig. 1C, There were significant increases in BI score at week 6 as compared to the baseline for both groups, from 36.05 ± 1.41 to 59.31 ± 1.32 and from 38.53 ± 1.41 to 73.35 ± 1.32 for group I and II, respectively. In addition, compared with those in group I, BI scores in group II were significantly higher at week 2, 4, and 6, respectively (42.05 ± 2.75 vs 51.53.80 ± 1.63; 52.32 ± 2.75 vs 63.8 ± 1.63; 59.31 ± 1.43 vs 73 ± 1.24, P = 0.035, 0.022, 0.037).

Adverse events and side effects

As shown in Table 4, asthenia was the most frequent adverse event both in the group I (26.7% of patients) and in the group II (4%) followed by sleepiness in the group I (6.7%) and in group II (1.3%). In all cases, adverse events were of mild intensity and resolved rapidly.

Table 4

Adverse events and side effects during the study.

Adverse events/side effects	Group I (n = 75)	Group II (n = 75)
Amenorrhea	1(1.3)	0(0.0)
Anorexia	1(1.3)	0(0.0)
Asthenia	20(26.7)	3(4.0)
Cramps	0(0.0)	1(1.3)
Dyspepsia	0(0.0)	1(1.3)
Eczema	0(0.0)	1(1.3)
Epigastric pain	0(0.0)	2(2.7)
Headache	0(0.0)	1(1.3)
Hypochondrial pain	1(1.3)	0(0.0)
Hyposthenia in lower limbs	4(5.3)	0(0.0)
Hypotonia	0(0.0)	1(1.3)
Insomnia	0(0.0)	1(1.3)
Itching	0(0.0)	1(1.3)
Paresthesia	1(1.3)	0(0.0)
Sciatica	1(1.3)	0(0.0)
Sleepiness	5(6.7)	1(1.3)
Sweating	1(1.3)	0(0.0)
Vertigo	1(1.3)	1(1.3)
Total	36(48.0)	14(18.7)

Discussion

In present study, both groups demonstrated significant decline in MAS, suggesting that both drugs have beneficial effects on muscle tone. However, the beneficial effects of baclofen were short term and not significant between week 2 and week 4 & week 4 and week 6, which was consistent with the previous study (Bresolin et al., 2009). The previous study suggested that baclofen showed 50% reduction in MAS after 2-week treatment. However, the difference between week 2 and week 6 became insignificant (Safi et al., 2015, Atta et al., 2017). The possible reasons might be that the long-term application of baclofen increases the motor unit weakness which make the whole muscle weaker and fatigable. Thomas et al. (2010) have shown that the long-term use of baclofen reduced muscle activity and maximal tetanic forces.

In addition, the improvement of MAS by tolperisone treatment were consistent with the previous studies (Stamenova et al., 2010). Stamenova et al. (2010) have shown that tolperisone at 300–450 mg per day resulted in 42% improvement of the Ashworth score in patients with stroke. Furthermore, The Ashworth score was reduced by 1.03 ± 0.71 in tolperisone subjects vs 0.47 ± 0.54 in placebo subjects (p < 0.001). Van Denburg et al. (2008) have found a 33% change in the Ashworth score to correlate with a 1-point change in the Physician’s global assessment score in patients with post-stroke spasticity, indicating clinical relevance (Zhao and Ashraf, 2016, Huang et al., 2015, Ishaq and Jafri, 2017).

To date, there is only one comparative trials (Koval’chuk et al., 2008) comparing the clinical efficacy of baclofen vs tolperisone. The results found that, compared with baclofen, tolperisone was a more effective muscle relaxant, causing reliable improvement in muscle tone for patients with stroke. Baclofen did not cause significant positive effect for muscular tone for patients with stroke. In the present study, we found that both groups had significant improvement of muscle strength. However, there was a MRC decline from the week 4 to week 6 in group I. In addition, compared with that of group I, MRI of group II was significantly higher.

Furthermore, we found the significant changes regarding BI scores in both the groups. At week 6, the group II showed significantly higher BI score compared with that of the group I, which was consistent with previous studies (Koval’chuk et al., 2008, Muhammad et al., 2017). Fehér et al. (1985) have shown that, compared with those in baclofen group, the Rivermead and the Barthel scales was higher in tolperisone group, with the difference being statistically significant for the Rivermead scale (P < 0.05). Koval’chuk et al. (2008) have found that patients receiving tolperisone treatment demonstrated higher level of daily domestic skills compared with those receiving baclofen. Therefore, baclofen was found to be inferior to tolperisone in terms of exerting reliable significant positive effect on the level of domestic adaptation for patients with stroke.

However, there were some limitations in the present study. Firstly, the present study was conducted using relatively small sample size of patients in a single institution. Therefore, multiple-centered studies with larger sample size of penitents will be needed to verify our results and conclusions. Secondly, in the present study, baclofen and tolperisone were given based on our clinical experience. However, the best regimen for baclofen and tolperisone administration has been unknown. Therefore, we recommended conduct further studies to verify our results and conclusion and determine the best regimen for baclofen and tolperisone administration.

Conclusions

In conclusion, baclofen is inferior to tolperisone in terms of efficacy and safety in the treatment of spasticity for patients with spinal cord injury. On long-term treatment, baclofen demonstrated negative effect on muscle tone and strength, while tolperisone showed high efficacy for improvement in daily domestic adaptation and quality of life. In addition, tolperisone had lesser adverse events and side effects compared to baclofen.