INTRODUCTION
Several neurological disorders , including spine injury, stroke, movement disorders, traumatic brain injury, and multiple sclerosis, often manifest with abnormal muscle tone and motor activity. Such pathophysiological conditions are characterized by spasticity that results from impaired muscle function and remains non-progressive.[ 1 ] Spasticity results in moderate-to-severe discomfort and stiffness. On the other hand, spasms are more severe muscle-toned states that result in impaired functions along with pain. Spasticity may also result in difficulty in mobility, shifting, washing, and picking up objects, dressing, and participating in sexual activities.[ 2 ] Studies also demonstrated that spasticity and spasms might affect emotional behavior by altering mood, stress, and anxiety. Spasticity and spasms can also affect one’s sitting posture and cause muscle weakness.[ 3 ] Accurate diagnosis of spasticity in a timely manner is very important. Missing or delayed diagnosis of spasticity affects the development and functioning of the muscles, tendons, and related soft tissues. Treatment of spasticity requires antispasticity therapeutics that offer symptomatic relief from abnormal muscle tone and spasms. Spasticity management also requires non-medication approaches such as physical therapy, self-exercise, and care delivered by a multispecialty team.
Education of all stakeholders, including the patient, family, caregivers, and health professionals, is a critical component of management. There is no accepted evidence-based paradigm for the management of spasticity . Much of such care is based on a logical and pragmatic approach.[ 4 ] Furthermore, the effects of spasticity on an individual are either mild or severe; patients must know about spasticity , its associated features, and how they can help themselves manage and prevent its symptoms.[ 5 ] Far too often, pharmacological treatment is escalated before appropriate strategies to control bladder and bowel function, skin integrity, soft tissue length, and positioning are instigated. Attention to these essential but straightforward areas is paramount at all stages of management. Non-progressive spasticity is a complication of cerebrovascular disease, spinal cord injury, head trauma, cerebral palsy, and progressive neurological disorders such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS).[ 6 ] It is common, can severely impair normal daily functions such as walking, eating, and dressing, and contributes to patient disability. Several drugs with antispastic effects are available and work through various mechanisms of action. For example, baclofen, tizanidine, benzodiazepines, gabapentin, clonidine, and cannabinoids are centrally acting drugs. Dantrolene and botulinum toxin A have peripheral actions.[ 3 ] Botulinum toxin A has local action and a long-lasting effect. It is used to treat focal spasticity or localized spasms.[ 2 ]
The treatment of spasticity requires an external intervention of antispasticity therapeutics via different routes. The most common therapeutic drugs for managing spasticity include baclofen, benzodiazepines, dantrolene, clonidine, tizanidine, and gabapentin, which are often administered via the oral route.[ 2 ] The intrathecal route is also effective but remains associated with severe complications, including side effects and adverse reactions.[ 7 ] Baclofen is a GABAB receptor agonist and has shown an inhibitory effect on the secretion of glutamate and aspartate, which are excitatory neurotransmitters.[ 8 ] However, tizanidine acts as an inhibitor of alpha 2 receptors at the polysynaptic spinal excitatory pathway.[ 4 ] Dantrolene sodium is also available for clinical use in the case of spasticity , where it acts via the inhibition of Ca++ release from the sarcoplasmic reticulum of muscle. Benzodiazepines such as diazepam are GABA agonists and a common therapeutic for spasticity conditions.[ 1 ] Baclofen pump in combination with clonidine, morphine, fentanyl, midazolam, and lidocaine is often given via the intrathecal route for the management of spasticity . Another class of antispasticity drugs known as neurolytic agents is also available for clinical use toward managing spasticity .[ 2 ] However, these therapies are associated with moderate-to-severe complications. The study provides a comprehensive synthesis of the scientific evidence on the safety and efficacy of oral antispasticity drugs in non-progressive neurological diseases. The effect of several oral antispasticity therapeutic drugs was analyzed in the meta-analysis , and their effectiveness was compared. The study also provides an association between the route of administration of antispasticity drugs and its effectiveness.
MATERIALS AND METHODOLOGY
Standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed when conducting the meta-analysis . The most pertinent scientific research was used in a thorough literature search to reach the desired goals. The Cochrane Central Register of Controlled Trials (CENTRAL), SciELO, and PubMed databases were all examined. The most pertinent scientific studies on oral antispasmodics in non-progressive neurological disorders are thoroughly examined. To research the most relevant studies, various databases and resources were explored, namely randomized control trials (RCTs), meta-analyses, and expert opinions. In order to emphasize my specific aim, several targeted searches in different databases were utilized to look for a close relationship between oral antistatic medications and non-progressive neurological illnesses in relation to safety and efficacy.
Procedure
The studies associated with RCTs and meta-analyses were incorporated in this section. Different keywords were used in search of the most relevant studies. The keywords included “oral antispasticity drug”, “non-progressive neurological diseases”, “therapeutics for non-progressive neurological disease”, “intervention of oral non-progressive neurological disease”, “oral antispasticity drugs and efficacy profiles”, and “oral antispasticity drugs and safety profiles”. In the search for the most relevant studies, keywords were used alone or in combination. Further, search keywords, including RCTs, meta-analyses, and human studies used for study design, protocol, and participants, and full-length studies fulfilling inclusion and exclusion criteria were selected for the study.
Inclusion/exclusion criteria
Table 1 provides a summary of the inclusion and exclusion criteria that were applied in the current study. In the analysis of the hypothesis on the connection between oral antispastic medications and non-progressive neurological illnesses, the study strictly incorporated RCTs exclusively. The analysis and synthesis of all pertinent studies focused solely on theories in the English language. However, papers with inadequate definitions or those with only an abstract were eliminated from the study.
Table 1: Inclusion and exclusion criteria
Meta-analysis Retrieved scientific information was used to analyze and interpret the safety and efficacy of oral antispastic drugs and their efficacy profile in non-progressive neurological diseases. Here, the study analyzed effectiveness with respect to non-reoccurrence of spasticity . To synthesize a valid scientific argument, a recent study focused on RCT studies. The inclusion and exclusion criteria were also considered during the analysis. The results were interpreted under PRISMA guidelines. The study also highlighted the difficulties in finding relevant scientific data and how they affected my investigation. The discussion and conclusion of the study took into account earlier systematic reviews and meta-analyses. My goal was to emphasize findings that had either not been previously examined or had been poorly handled in other investigations. Based on the findings of this investigation, a meta-analysis draws conclusions and emphasizes suggestions. A meta-analysis of selected studies was carried out using MedCalc Statistical Software. Here, analysis was carried out using multiple variables, including odds ratio , risk analysis, and risk difference. Finally, the analysis was carried out via forest and funnel plot analysis.
Data extraction and bias assessment
Bias assessment was performed as per the PRISMA statement, and data from most eligible studies were retrieved. Data included information on the study population, various oral antispasticity drugs , the intervention (dose and duration), and the control (placebo). The outcome and efficacy data were based on the absence of symptoms after the intervention and follow-up period in each study.
RESULT
In the present study, 252 original records were retrieved from different predefined databases on oral antispasticity drugs and their association with non-progressive neurological disorders . Among these records, 238 studies were collected from PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and SciELO databases, and 14 additional records were obtained from non-predefined sources. Eligibility criteria were applied, and the most relevant studies were segregated from the pool of collected studies. A total of 154 records were non-eligible for meta-analysis based on their information, that is, their lacking of information on oral antispasticity drugs associated with non-progressive neurological diseases. In the second phase of screening, nine records were excluded as reported duplicates. Furthermore, 77 studies failed to meet predefined eligibility criteria and were excluded. The screening found that these 77 studies did not provide information on oral antispasticity drugs and did not associate them with non-progressive neurological diseases. After several steps of screening, 12 studies were found eligible for meta-analysis . A detailed search strategy and study selections are shown in Figure 1 as per the PRISMA statement. Tables 2 and 3 provide information on clinical data from the most relevant studies. Here, Table 2 demonstrates the effect of various drugs under oral antispasticity drugs , treatment dose, follow-up, and efficacy. On the other hand, Table 3 provides detailed information about the treatment group and control group with the measured outcome. The outcome in both groups was determined based on efficacy.
Figure 1: PRISMA flow chart demonstrating search strategy and study selection
Table 2: Data on the most eligible studies based on eligibility criteria. The table depicts sample size, treatment, dose information, and efficacy of the treatment
[ 9–20 ] Table 3: Summary of comparative details of treatment group with outcome over control group for those studies found eligible based on applied inclusion and exclusion criteria
The effectiveness of the oral antispasticity drug was analyzed in the present meta-analysis , where selected studies included interventions with tizanidine, diazepam, dantrolene, baclofen, and gabapentin with a control (placebo). The analysis was based on the odds ratio , where the total random effect of selected drugs was reported to be 3.45–11.11 and 3.45–11.11, and the relative risk was 2.10–13.66. Oral antispasticity drugs represent a class of therapeutics administered via the oral route, and hence there are several therapeutics classified as Oral antispasticity drugs represent different classes of therapeutics administered via the oral route, and the efficacy of these therapeutics was evaluated using odds ratio , risk difference, and relative risk analysis. Non-progressive neurological illnesses may respond differently to antispasticity treatments given intravenously, intramuscularly, or intrathecally (other than oral methods). Odds ratio analysis, where the quantity of treatments and controls that yield positive results is crucial, provides a scientific foundation for pharmacological efficacy. The efficacy of oral antispasticity was demonstrated in the risk difference and relative risk analysis. As a result, as shown in Table 4 and Figure 2 , the selected oral antispasticity drugs reported effectiveness based on a P value, that is, P < 0.001 (significant). The result demonstrates a varying relative risk and risk difference in the meta-analysis , that is, the highest in one report[ 18 ] , where efficacy was found to be minimal. 1991, where efficacy was found to be minimal. The relative risk and difference are heavily influenced by the outcomes of the treatment and control groups. For example, a 95% confidence interval (CI) in odds ratio , relative risk, and risk difference analysis reported varying results [Table 4 ]. The 95% CI value reported a significantly low-risk difference analysis compared to the other modes, that is, odds ratio and relative risk. The heterogeneity (inconsistency I2 ) test and the significance level were reported as 0.00% and P = 0.5130 in the odds ratio analysis. Publication bias was also tested via the Eggers and Begg tests for the Kendall Tau analysis. The publication bias was analyzed in the present study, and an intercept of 3.5447 with 95% Cl (0.749–6.3) was reported with a significance level of P = 0.0180. Further, in the Begg test, the significance level was much higher (P = 0.0549), with Kendall’s tau value of −0.4242.
Figure 2: Meta-analysis of oral antispasticity drugs for the management of non-progressive neurological disorders based on odds ratio among intervention and control group along with relative risk and risk difference
Table 4: Table demonstrate Odds ratio among intervention and control group as shown significant (P <0.001) with high weightage, relative risk and risk difference
DISCUSSION
Spasticity represents the clinical manifestation of an upper motor neuron lesion that affects muscle tone and generally results in impaired excitability. In cases of spasticity , muscle spasm is one of the causes of decreased mobility, which is also linked to pain. Spasticity is also considered a neurological disorder that primarily affects muscle tone. Antispasticity therapeutics are used to tackle the muscle tone associated with neurological disorders , primarily non-progressive ones.[ 1 ] A number of antispasticity drugs are available for clinical use, but their efficacy is dependent on the route of administration. These therapies can be delivered via oral, intrathecal, intramuscular, inhalational, etc., routes. The effectiveness varies among the routes of administration and the nature of the antispasticity drug. Oral antispasticity drugs represent the therapeutic class and offer a differential effect on non-progressive neurological disorders . My study demonstrated the use of oral antispasticity drugs , where a few selective therapeutics that were analyzed based on clinical data were compelling. Here, the treatment group showed significantly improved spasticity conditions compared to the control group. The differential effect of selected antispasticity drugs has been reported and depends on several factors, including type and nature of the drug, the treatment and control group, and the neurological disorder involved.
Earlier, Sawa and Paty,[ 8 ] in a double-blinded, cross-over, placebo-controlled trial conducted in 1979, had shown the efficacy of baclofen in treating the spasticity of multiple sclerosis (MS). The study showed that baclofen intervention was effective in the treatment group compared to the other oral antispasticity therapeutics and control. However, baclofen remains associated with side effects, including drowsiness, dizziness, weakness, tiredness, headache, sleep problems (insomnia), nausea, and constipation. The drug was well-tolerated and led to a significant (P < 0.001) reduction in spasticity compared to the control group in MS patients. Baclofen is one of the most effective oral antispasticity drugs available for clinical use. Dario and Tomei,[ 7 ] in an open-label study on oral baclofen, reported improved motor function of toned muscles and reduction of nearly 90% of spasticity conditions in non-progressive neurological diseases compared to a control group. The study also showed that oral baclofen was well tolerated, and adverse effects were dose-dependent and seen in 15% of patients. It is noteworthy to add here that baclofen can also be used via other routes, such as intrathecal, where the drug’s efficacy is compromised. Hoogstraten et al. ,[ 4 ] in a combined study using a partially blind cross-over with tizanidine and baclofen, reported no significant difference in the outcome. However, these drugs differ in side-effect profile, where Baclofen does not have serious complications compared to tizanidine. Another clinical manifestation of spasticity is GABA dysfunction, and the use of diazepam and other neurotransmitters may not be effective.
Spasticity treatment can be achieved via neurolytic agents such as carbolic acid, phenic acid, phenylic acid, phenyl hydroxide, hydroxybenzene, and oxybenzone.[ 5 ] The clinical outcome of neurolytic agents differs from that of oral antispasticity drugs in terms of efficacy and side effects. Oral antispasticity medications were reported as effective and safe, and my study also showed a similar pattern. The analysis also indicates the modest impact of oral antispasticity drugs in managing non-progressive neurological disease. Management of spasticity here was considered in association with antispasticity oral medicines. These therapeutics represent a small class of different medications that show varying responses and differ in clinical outcome and efficacy. The meta-analysis required clear and distinct clinical data. Since clinical data from different therapeutics were used in the present study, the outcome remained moderate. Spasticity is a multi-factorial pathophysiological sequelae of different non-progressive neurological disease. Hence, other factors need to be addressed, and more clinical data are required to validate the outcome of oral antispasticity drugs .
CONCLUSION
The current meta-analysis provided insight into the efficacy of oral antispasticity drugs for managing non-progressive neurological disorders . Here, the meta-analysis on the intervention of tizanidine, diazepam, dantrolene, baclofen, and gabapentin with a control (placebo) group was analyzed and reported as moderately effective. These therapeutics may be administered via other routes; however, the oral route offers not only moderate effectiveness but also fewer side effects and adverse reactions. The analysis was carried out based on available clinical data where spasticity was evaluated with regard to oral antispasticity drugs . Spasticity remains a multi-factorial pathophysiological event; muscle motor activity and tone are not the only risk factors for spasticity . The effect of neurotransmitters such as GABA needs a revisit for its role in spasticity . Then a complete profile of oral antispasticity can be effectively evaluated.
Study limitations
The absence of clinical studies using specific oral antispasticity medications to treat non-progressive neurological illnesses was drawback of this study. Additionally, a variety of pharmacological classes were included in the available data from clinical studies. Additionally, failed follow-up and drug withdrawal continued to be linked to the majority of clinical studies that were used in the current meta-analysis .
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgements
I would like to thank the Deanship of Scientific Research at Shaqra University, Saudi Arabia.
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