Oral Medications

Baclofen, a derivative of gamma aminobutyric acid (GABA), is widely used as the first line of pharmacological treatment for spasticity in people with SCI[1] (Kirshblum 1999; Taricco et al. 2006). Baclofen, also identified as Lioresal^â, CIBA Ba-34647 and b-(parachlorophenyl) gamma aminobutyric acid, crosses the blood-brain barrier more readily than GABA itself and is believed to reduce spasticity by enhancing inhibitory influences on the spinal stretch reflex by increasing presynaptic inhibition (Kirshblum 1999).

In typical practice, baclofen requires a careful dose titration period with a usual maximal recommended dose of 20 mg qid (Burchiel & Hsu 2001) which is also the dosage employed in the majority of studies involving people with SCI (Aydin et al. 2005; Nance 1994). Veerakumar et al. (2015), in an analysis of a single provider’s patient database over 25 years, reported a significant but marginal increase in baclofen dosage over the 25-year span and patients with gunshot related SCI receiving earlier baclofen initiation than patients with SCI related to motor vehicle accident. Baclofen may be especially effective in reducing flexor spasms (Shahani & Young 1974; Duncan et al. 1976; Gracies et al. 1997) although these effects may also act to impair specific functional tasks such as walking or standing (Kirshblum 1999; Burchiel & Hsu 2001). The mechanism for impairment in functional tasks may require further exploration as Chu et al. (2014) did not record substantial decreases in voluntary electromyographic activity despite baclofen’s effectiveness in reduced stretch reflexes. A variety of adverse events may limit the use of baclofen including lowering of seizure threshold, sedatory effects (i.e., drowsiness), insomnia, dizziness, weakness, ataxia, anxiety and mental confusion (Hinderer 1990; Gracies et al. 1997; Kirshblum 1999; Burchiel & Hsu 2001). A significant side effect of antispasmodics, with baclofen being the most commonly used, is the potential for reduced torque during routine activities and for activity-dependent interventions such as locomotor treadmill training (Roy & Edgerton 2012; Harkema et al. 2012). Baclofen also increases cough threshold in cervical spinal cord subjects (Dicpinigaitis 2000). Sudden discontinuation or withdrawal of baclofen can result in seizures, confusion, hallucinations and rebound muscle overactivity with fever (Gracies et al. 1997). For the most part, tolerance with sustained use of baclofen is possible (Knutsson et al. 1974), but is not a major issue (Roussan et al. 1985; Gracies et al. 1997; Kirshblum 1999).

Benzodiazepines (i.e. diazepam/valium, clonazepam) are used for multiple problems encountered post-SCI such as anxiety, musculoskeletal pain and spasticity. Although Valium has been prescribed, since the 1960s (Neill et al 1964, Kerr et al 1966, Wilson & McKehnie 1966), for being superior to placebo in treatment of SCI related spasticity, benzodiazepines are not FDA approved for spasticity. However, they are sometimes prescribed for short-term treatment of spasticity (e.g. nocturnal spasticity). This class of drug acts by inhibiting afferent pathways to relax skeletal muscle or inhibiting gamma-aminobutyric acid (GABA) pre- and post-synpatically to depress the central nervous system. Given that excessive CNS depression was often cited as an unwanted side effect, diazepam is not as commonly prescribed as a first line treatment for spasticity as it once was before newer more effective classes of medications became available (e.g. baclofen). Other common side effects of benzodiazepines are ataxia, dyscoordination, fatigue, weakness, hypotension, sedation, depression, memory impairment and risk of addiction. Despite the known sedative effect of valium, it was shown to be superior to Amytal (barbiturate used as sedative or hypnotic) and placebo in reducing SCI related spasticity (Corbett et al 1972).

Oral baclofen

Despite the general acceptance and clinical experience of using oral baclofen to reduce spasticity in people with SCI, at least two systematic reviews have noted a relative paucity of high quality studies (i.e., RCTs) demonstrating specific or comparative efficacy (Chou et al. 2004; Taricco et al. 2006). Taricco et al. (2006) conducted a Cochrane Review of all pharmacological interventions for spasticity following SCI. Only one study examining the effect of oral baclofen (Burke et al. 1971) met the review inclusion criteria (i.e., RCT with at least 50% of participants with SCI published up to July 2004). The reviewers deemed this study to have been relatively poor quality with small sample size (n=6) so did not provide a positive assessment of the efficacy of oral baclofen.

Since the 2006 Cochrane Review, two additional RCTs (Aydin et al. 2005, n=21; Chu et al. 2014, n=10) published demonstrating effective reduction in spasticity with oral baclofen as measured using the Ashworth Scale, Spasm Frequency Scale, deep tendon reflex score, FIM and Functional Disability Scores, and electromyographical measures. An earlier RCT (Duncan et al. 1976) demonstrated reduced spasticity as measured by the Ashworth Scale and Spasm Frequency Scale. Further support for the efficacy of oral baclofen was provided by a pre-post study by Nance (1994) in which baclofen was compared to clonidine and cyproheptadine in 25 subjects with SCI. In general, all three agents were shown to be effective in relieving spasticity with baclofen among the most effective for each of the measures. Chu et al. (2014; N=10) compared baclofen and tizanidine and reported that baclofen was preferentially effective for flexors and tizanidine for extensors. This finding suggests that tailoring of antispastic drug therapy to spasticity characteristics of individual patients may be possible.

Yan et al (2018) directly compared Baclofen (BA) to botulinumtoxin A (BTI) and reported trial participants’ modified Ashworth scores (MAS) reflected significant anti-spasmodic performance of both BA and BTI at 2 weeks (p=0.003 and p=0.02, respectively) compared to baseline. At 4 weeks, the control group’s MAS score was also significantly decreased (p<0.001 for all 3 treatments). However, at 6 weeks post treatment, only the BTI group had significantly reduced spasticity (p>0.05) compared to baseline. These results confirm the known immediate efficacy of BA that could also be susceptible to resistence development. On the other hand, this trial demonstrates the persistence of BTI neurotransmitter release inhibition. Interestingly, only the BA group was significantly improved functionally as assessed by the Disability Assessment Scale (DAS; p=0.05). However, the DAS was specifically developed for use in stroke, not SCI. Both BA and BTI administration produced side effects such as asthenia and sleepiness, and bronchitis and elevated blood pressure, respectively.

Luo et al (2017) compared baclofen to tolperisone (a centrally acting muscle relaxant) for the treatment of spasticity secondary to SCI. As with the comparison to BTI, after initial significant efficacy, MAS continued to significantly decline b6 week 6 only with the comparator (tolperisone). Thomas et al 2010 attributes long-term use of baclofen with reduced muscle activity and maximal tetanic forces. Accordingly, Luo et al (2017) surmise that long-term use of baclofen weakens the whole muscle that in turn introduces fatigue.

Arbaclofen placarbil (AP) is a prodrug of R-baclofen in an extended-release oral formulation that is well absorbed throughout the gastrointestinal tract (Lal et al. 2009). Efficacy and safety of AP was studied (Nance et al. 2011) and results indicated that 20/30mg of AP every 12 hours for 26 days, significantly improved Ashworth scores and reduced severity of spasticity ratings compared to the placebo group. However, there was no significant difference in muscle strength between the AP and placebo group. Chu et al. (2014) also reported that neither baclofen or tizanidine had a negative impact on strength and postulated that patient reported weakness secondary to drug administration by be due to decreased motivation secondary to drowsiness.

In contrast to these studies, a counter-therapeutic response to baclofen was found by Hinderer (1990). In this RCT (n=5) the effect of baclofen on spasticity was studied by examining the viscous stiffness (resistance torque) following a 5° sinusoidal ankle perturbation at 3-12 Hz. No difference was noted between baclofen and placebo on this measure. No other outcome measures were assessed. Chu et al. (2014) noted that baclofen had a stronger inhibitory effect on knee flexors. These studies illustrate one of the limitations in establishing the efficacy for any spasticity-relieving agent–the heterogeneity of reported outcomes and outcome measures used across studies (Chou et al. 2004; Taricco et al. 2006). Spasticity is multi-dimensional with a variety of clinical manifestations and much day-to-day and diurnal variation within an individual. A battery of measures is needed to obtain valid and reliable measurement of spasticity within a given trial (Priebe et al. 1996). The range of studies outlined in the present review demonstrates various physiological, clinical and functional measures, yet there is minimal consistency of outcome measure selection across trials.

Interesting findings from a retrospective analysis of a single provider’s 25-year patient database (Veerakumar et al. 2015, n=115) revealed that baclofen use varied with etiology of the SCI, time since injury and concomitant antispasmodic use. These findings provide further evidence that baclofen use requires careful dose titration and monitoring based on the unique spasticity profile of individual patients.

Benzodiazepines

Although Valium proved to be superior to Amytal and placebo for controlling SCI related spasticity, only 2/22 participants did not require other treatment methods (e.g. physiotherapy, hydrotherapy) to fully control their spasticity (Corbett et al 1972, RCT). Neill et al (1964) confirmed anti-spasmodic efficacy (compared to placebo) on 13/20 people with SCI and the prominence of drowsiness as the most frequent side effect. However, Neill et al concluded that the greatest benefit was recorded in participants with traumatic cervical SCI. This latter claim should be interpreted with caution given the small cohort of participants (N=20). Diazepam’s effectiveness for treatment of spasticity in people with SCI was further supported with an observational survey of 35 participants where 30 reported good to excellent relief. Only 3 participants complained of drowsiness but did not require discontinuation or diminution of the dosage.

Conclusions

There is Level 1a evidence that oral baclofen improves muscle spasticity secondary to SCI. This conclusion is based on the results from eight RCTs (Yan et al 2018, Luo et al 2017, Chu et al. 2014; Nance et al. 2011; Aydin et al. 2005; Duncan et al. 1976; Burke et al. 1971, Jones et al 1970) although is minimally muted by a single negative finding from one small RCT (Hinderer et al. 1990) with an overall lack of homogeneity in outcome measures and study participants. Additional evidence from a prospective controlled trial (Dicpinigaitis et al. 2000), a cohort (Veerakumar et al. 2015) and pre-post study (Nance 1994) also provide support for the use of oral baclofen in reducing spasticity.

There is Level 1b evidence (Yan et al 2018, N=336, Luo et al 2017, N=150) supporting the immediate effect of baclofen for the treatment of spasticity but that at 6 weeks post treatment, baclofen is inferior to botulinumtoxin A and tolperisone.

There is level 1b evidence (Corbett et al 1972, RCT, N=9) supported by 2 other trials ( level 2 evidence (Level 2, Neill et al 1964, Cohort, N=20) confirming that valium (diazepam) is effective in decreasing spasticity secondary to SCI.

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Oral baclofen reduces muscle spasticity in people with SCI.

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Oral baclofen is inferior to botulinumtoxin A injection and oral tolperisone by 6 weeks of spasticity treatment in people with SCI.

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Diazepam is effective for the treatment of spasticity secondary to SCI