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Other Anti-Spasmodics

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Other potential anti-spasmodics which have been tested in the SCI population include Traditional Chinese Medicine (TCM), Riluzole, L-threonine, and orphenidrine citrate.

TCM is believed to have medical benefits and scientific documentation of these benefits, specifically with respect to spasticity, pain and sleep, have begun.

Riluzole is an antiglutamatergic agent approved to slow the progression of Amyotrophic Lateral Sclerosis. Due to its spinal locus of activity where it acts more strongly on polysynaptic reflex pathways but not on direct motoneuron excitabilty, riluzole was investigated and shown to decrease spastic flexion reflexes in response to cutaneous stimuli in spinal cord injured rats (Kitzman 2009).

L-threonine is an α-amino acid with a putative mechanism of anti-spastic action through increasing spinal glycine levels (Paisley et al. 2002).

Orphenadrine citrate is a non-competitive NMDA-type (N-Methyl-D-aspartate) glutamate antagonist which acts centrally as an anticholinergic and non-opioid analgesic (Clark 2002).

Although diazepam and dantrolene continue to be used in SCI spasticity, no new evidence is available to support continued recommendation for use in the presence of current first line treatments.

Other drugs that have been assessed against spasticity treatment in SCI include the opiod antagonist, Naloxone and the anti-epileptic, levetiracetam.

Table 24: Effect of Other Potential Anti-Spasmodics for Reducing Spasticity

Discussion

Traditional Chinese Medicine

Liu et al. (2014) reported significant improvements in pain, spasticity and sleep after a randomized, double blind, study comparing an herbal bath of six traditional Chinese medicines (TCM) to a placebo of perfumed bath water. No treatment related side effects or allergies were observed in 160 participants during the year long study. Outcome assessments included the Ashworth Scale, the Visual Analog Scale for pain, subject and clinician global impression scales and the Pittsburg Sleep Quality Index. Liu et al. (2014) concluded that the treatment was effective and economical for long-term use. However, they acknowledge that even though the herbs used in this study are believed to have medical benefits after more than 1000 years of use, a detailed chemical analysis is needed to understand the mechanism of action.

Orphenadrine

Casale et al. (1995) were able to demonstrate a significant reduction of spasticity (p<0.0001) as measured by Ashworth in favour of intravenous administration orphenadrine citrate versus placebo. This anti-spasmodic effect was demonstrated by an increased flexion reflex threshold as early as 30 minutes post administration. The authors suggest that this drug, given its immediate action, could be used as a preparatory solution for physical therapy sessions in spastic patients. Given its known side effect profile, this treatment may be appropriate for short term application.

Riluzole

Theiss et al. (2011) demonstrated significantly reduced spasticity without a generalized reduction in strength, uniformly among seven patients with chronic, motor-complete SCI. Although the study was randomized, double-blinded and controlled, measurements were made only on a single dose and outcome assessments were not clinically feasible (e.g. stimulus thresholds and torque measurements). At least one confirmatory RCT would be beneficial before consideration that continued use of riluzole is beneficial for spasticity treatment in SCI. In the interim, riluzole may be appropriate to trial on individuals who do not respond to or tolerate other anti-spasmodics.

L-Threonine

A randomized, controlled study of L-threonine (Lee & Patterson 1993) showed minimal effects on spasticity. Interestingly there was no correlation between the reduction in spasm score and tone reduction suggesting that these components of the disordered upper motor neurone syndrome may have different pathophysiological causes and therefore may require different pharmacological treatments. This is especially important to note since many patients do not experience satisfactory control of spasticity using first line treatments for reasons other than intolerance.

Naloxone

An inadvertent side effect discovered during an investigation of neuroendocrine function in SCI using naloxone was the profound increase in spasticity after naloxone treatment in all three SCI subjects compared to no such activity in the three able-bodied study volunteers (Brackett et al. 2007). This interesting finding agrees with a previous suggestion that a relationship between opioid receptors and spasticity in patients exists where morphine is found to be effective when intrathecal baclofen tolerance is an issue.

Levetiracetam

Levetiracetam, an anti-epileptic (i.e., Keppra), was studied by Finnerup et al. (2009) for its effect on neuropathic pain, evoked pain or spasms and spasticity. Although well tolerated, no effects were recorded for spasm severity or pain.

Although diazepam and dantrolene continue to be used in the treatment of SCI related spasticity, no new evidence has been found to support their continued use given that Level 1 evidence supports treatments now routinely used for spasticity in SCI (Nance et al. 1989). See Table 20 for data regarding a study focusing on clonidine in SCI. However, an earlier crossover study (Corbett et al. 1972) showed that effects of diazepam and placebo were not different from pre-treatment and that Valium was more effective than amytal and placebo in reducing spasticity (p<0.02-0.05)

Conclusions

There is level 1b evidence (from one RCT; Liu et al. 2014) that traditional Chinese medicine is a safe, effective and economical long-term treatment for spasticity in SCI.

There is level 2 evidence (from one prospective controlled trial; Casale et al. 1995) for short-term use of intravenous orphenadrine citrate for treatment of spasticity secondary to SCI.

There is level 1b evidence (from one RCT; Theiss et al. 2011) that riluzole is effective in treating spasticity post SCI.

There is level 1b evidence (from one RCT; Lee & Patternson 1993) that L-threonine produces minimal anti-spasmodic effects post SCI. 

There is level 4 evidence (from one pre-post study; Brackett et al. 2007) that naloxone causes a profound increase in spasticity in individuals with SCI.

There is level 1b evidence (from one RCT; Finnerup et al. 2009) that Levitiracetam is not effective for treating spasm severity in SCI.

Continued use of diazepam and dantrolene for reducing SCI-related spasticity is not supported with up to date evidence and would benefit from new controlled comparison studies. Whether effective or not, replicating results in well-designed trials is warranted before alternative recommendations for new or older treatments will be accepted into current practice.

  • TCM, intravenous orphenadrine cirate, riluzole, and L-threonine may be effective in treating SCI-related spasticity.
  • Levitiracetam, diazepam, dantrolene and naloxone may not be effective for treating SCI-related spasticity, but would benefit from confirmatory studies.