Baclofen, a derivative of gamma aminobutyric acid (GABA), is widely used as the first line of pharmacological treatment for spasticity in people with SCI (Kirshblum 1999; Taricco et al. 2006). Baclofen, also identified as Lioresalâ, 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 via 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; Hinderer et al. 1990). 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). 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). 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).
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.
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.
There is Level 1a evidence that oral baclofen improves muscle spasticity secondary to SCI. This conclusion is based on the results from five positive small-scale RCTs (Chu et al. 2014; Nance et al. 2011; Aydin et al. 2005; Duncan et al. 1976; Burke et al. 1971) 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.
- Oral baclofen reduces muscle spasticity in people with SCI.