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Combined Gait Training and Pharmacological Interventions

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Drugs such as clonidine (a noradrenergic agonist), cyproheptadine (a serotonergic antagonist), baclofen (GABA agonist), GM-1 ganglioside, L-Dopa and 4-aminopyridine have been used in association with attempts to improve ambulation in individuals with SCI. The results from animal studies indicate that some of these drugs may act on the receptors in the spinal cord which facilitate interaction with a locomotor central pattern generator (spinal circuits which produce coordinated locomotor movement) (Chau et al. 1998; Rossignol et al. 1996; Barbeau and Rossignol 1990). Although not conclusive, there is some evidence that similar “central pattern generator” circuits exist in humans (Bussel et al. 1996; Illis 1995; Calancie et al. 1994; Bussel et al. 1989; Bussel et al. 1988) and provide the rationale for clinical use of these drugs.

Table 18: Studies of Pharmacological Interventions effects on gait outcomes

Discussion

The interactions of these pharmacological interventions are complex and appear to affect walking ability and spasticity to varying effects. The studies on clonidine (oral or intrathecal), cyproheptadine and baclofen demonstrate improvements in various aspects of gait (i.e. walking speed, posture, spasticity), but no improvements led to significant functional changes in walking.  Norman et al. (1998) found the greatest improvements in more severely disabled subjects and in many cases, the effects were retained following washout of clonidine. Bradycardia and hypotension, common side-effects of oral clonidine can be ameliorated with intrathecal injection of clonidine (150-450µg) (Filos et al. 1994). The combined effect of different drugs has not been well explored.  One very small study (not tabled due to its small sample size, Fung et al., 1990) showed that a combination of clonidine, cyproheptadine and treadmill training improved SCI locomotion in its 2 participants.

Conflicting evidence exists on the use of GM-1 ganglioside for neurologic recovery for walking in SCI.  A large scale multicenter RCT (n=760) (Geisler et al., 2001) suggested that although GM-1 treatment may have accelerated initial SCI recovery (at 8 weeks), it did not improve the final extent of recovery (26 weeks). However, walking ability was not assessed.

Immediate release, 4-AP capsules have been shown to have no benefit to ambulation as indicated by 2 RCTs (van der Bruggen et al. (2001), n=20; DeForge et al. (2004), n=15).  However, the study of van der Bruggen et al. (2001) was not directed solely at exploring the effects on walking and therefore the heterogenous nature of the subject groups may have confounded the ambulation results. Furthermore, differences in intervention (i.e. up-titration to 15-45mg/day over 4 weeks in van der Bruggen et al. (2001) vs. up to 10mg 4X/day for 2 weeks in DeForge et al. (2004)) and the lack of consistent clinically relevant outcome measures complicates the interpretation of the available evidence.

Effect Size Forest Plots of RCTs with Available Data
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Effect size SMD forest plot for DeForge et al. 2004, 4-aminopyridine, 4-AP, fampridine

Two of the studies noted above used a combination of pharmacological and physical therapy gait training interventions. One small RCT (Walker & Harris, 1993) (N=9) provided some evidence that a combination of physical therapy (including gait training) and GM-1 ganglioside improved motor scores, walking distance, and walking speed in chronic SCI participants compared to physical therapy plus placebo (though Klose and Calancie (1994) posted a critique and re-calculated their results with different conclusions). Other results from the pre-test/post-test study conducted by Fung et al. (1990) provide level 5 evidence that clonidine and cyproheptadine in conjunction with BWSTT may be effective in enabling nonambulatory incomplete SCI patients to achieve overground ambulation with assistive devices.

A more recent study examined the effects of combining L-Dopa (dopamine precursor) with gait retraining in a group of individuals with acute/sub-acute incomplete SCI (Maric et al., 2008). Unlike the promising effects of L-Dopa on motor recovery following stroke (Scheidtmann et al., 2001), there was no added benefit in this SCI group. Although spinal neural circuits can certainly undergo plastic changes, the results of this study suggest that dopaminergic neurons may not have been sufficiently stimulated by the dosage used here, or that they may not contribute to motor recovery associated with gait retraining.

There is limited evidence that oral Baclofen may improve walking after SCI from two Level 5 pre-post studies that examined the effects of Baclofen on gait (total N = 21, 0.5-27 years post-injury (Azouvi et al., 1996; Norman et al., 1998). Avouzi et al. (1996) showed increases in the Functional Independence Measure (FIM™) walking scores in 5 of 18 patients, and 2 people acquired the ability to climb stairs following Baclofen administration. Participants in the Norman et al. (1998) study only showed minor changes in walking when using this drug.

Conclusion

There are nine Level 1 and 2 studies (DeForge et al. 2004; Duffell et al. 2015 (2); Leech et al. 2014; van der Bruggen 2001; Grijalva 2010; Maric 2008 ; Stewart et al. 1991; Wainberg et al. 1990) that found no significant differences of the effects of medication on walking ability.

 There is level 1 evidence (Walker & Harris, 1993), limited by a small sample size, that GM-1 ganglioside combined with physical therapy improves walking ability in chronic incomplete SCI patients (though Klose and Calancie (1994) posted a critique and re-calculated their results with different conclusions).

There are two level 4 studies (Azouvi et al. 1996; Segal and Brunnemann 1998) that found significant differences in aspects of gait after baclofen administration.

  • There is limited evidence for the benefits of combining the use of certain pharmacological agents with gait training on ambulation in individuals with SCI.