Pharmacological Treatment - There is insufficient evidence to assist clinicians in a rational approach to antispastic treatment for SCI. Further research is urgently needed to improve the scientific basis of patient care (Taricco, et al 2005). Spasticity-related interventions need to be aimed at what matters most to the patient. It is critical for clinicians to understand patients' experiences to make accurate assessments, effectively evaluate treatment interventions, and select appropiate management strategies. When providers reconfigure patients' descriptions to fit neatly with a biomedical understanding of spasticity without carefully assessing the descriptions in terms of what matters most to patients, a potential risk for misappropriating interventions may arise (Mahoney, et al 2007).

1. Baclofen (Lioresal), an analog of GABA (gamma-aminobutyric acid), is probably the drug of choice in spinal forms of spasticity. It inhibits both monosynaptic and polysynaptic reflexes by inhibiting calcium influx into presynaptic terminals, which suppresses the release of neurotransmitters. Baclofen is effective in reducing flexor spasms, increasing range of motion, and decreasing spastic hypertonia. There is a low incidence of side effects, which may include hallucinations, confusion, sedation, hypotonia, and ataxia. Chronic baclofen therapy may diminish cough reflex sensitivity (Dicpinigaitis, et al 2000). It is equivalent to diazepam in efficacy, but has a less sedative effect and is safe and effective in long-term use. Acute withdrawal can induce the development of neurological symptoms, including seizure disorder, psychosis, hallucinations, and visual disturbances (Rivas, et al 1993).

2. Baclofen (Intrathecal) can treat spastic hypertonia in patients, who are refractory to or cannot tolerate oral baclofen, by surgically placing the drug near the spinal cord structures of desired action without the CNS side effects of increased oral intake. A pump may be planted subcutaneously in the abdomen wall, a catheter may be surgically placed into the subarachnoid space, and the pump filled monthly by a transcutaneous injection. In addition to treating spasticity, intrathecal baclofen increases bladder capacity and decreases external sphincter spasticity, but does not result in normal voiding patterns. Since intrathecal administration of baclofen achieves higher concentrations in the spinal cord with smaller doses than oral baclofen, the adverse CNS effects of oral baclofen at higher doses are significantly reduced. Overdoses, however, may cause reversible coma. Abrupt withdrawal of intrathecal baclofen can cause hallucinations, confusion, manic-psychotic episodes, seizures, autonomic dysreflexia, hyperthermia, and rebound severe spasticity which can be treated with oral baclofen or dantrolene (Khorasani, 1995). Tolerance to intrathecal baclofen has been reported (Lewis & Mueller, 1993). Clonidine can be added to the baclofen pump and both drugs administered intrathecally if baclofen alone is ineffective or there is increasing tolerance to baclofen (Middleton, et al 1996). Intrathecal morphine can also reduce spasticity and pain in SCI without the development of tolerance to or loss of beneficial effects in long-term follow-up.

3. Diazepam (Valium) is a successful treatment for spastic hypertonia in SCI. It facilitates postsynaptic effects of GABA, which result in an increase in presynaptic inhibition. Diazepam is generally safe and well tolerated, except for its sedative effect, which makes it unsuitable for patients with brain injury. Its sedative effects can involve attention, memory, intellectual impairment, and reduced motor coordination. Other side effects include psychological addiction and synergistic depression when administered with alcohol. Weight gain has been reported in SCI patients while taking diazepam (Frisbie & Aguilera, 1995).

4. Dantrolene sodium (Dantrium) is preferred for cerebral forms of spasticity, but may be a useful adjunct in spinal forms of spasticity in that it is less likely to cause lethargy or cognitive disturbances than baclofen or diazepam. It intervenes in spastic hypertonia at a muscular (rather than a segmental reflex level), by reducing muscle action potential-induced release of calcium into the sarcoplasmic reticulum, which decreases the force produced by excitation-contraction coupling. It reduces the activity of phasic more than tonic stretch reflexes, affects fast more than slow muscle fibers, and has little effect on smooth muscle. Its most pronounced effect may be a reduction in clonus and muscle spasms resulting from innocuous stimuli. Side effects include mild to moderate lethargy, malaise, nausea, vomiting, dizziness, diarrhea, and hepatotoxicity. Liver function tests are therefore monitored periodically.

5. Tizanidine is equivalent to baclofen as an antispasmotic agent in both cerebral and spinal forms of spasticity, but may be better tolerated, and is as efficacious as and better tolerated than diazepam in patients with chronic hemiplegia. An imidazoline derivative, tizanidine has an agonistic action at some adrenergic receptor sites, prevents the release of excitatory amino acids from the presynaptic terminals of spinal interneurons, and may facilitate the action of glycine, an inhibitory neurotransmitter. It enhances vibratory inhibition of the H-reflex, reduces abnormal cocontraction, and increases the torque of spastic muscle. Like baclofen, it is more effective in extensor than flexor musculature. Common side effects include mild hypotension, sleepiness, weakness, and dry mouth. No significant alterations in muscle strength or vital signs have been reported (Nance, et al 1994).

6. Clonidine has been used with fair success in SCI patients. Now available in an adhesive patch for weeklong transdermal delivery, it may cause syncope, hypotension, nausea, and vomiting, but not usually abuse. Other possible side effects include constipation and bradycardia (Rosenblum, 1993). Intrathecal clonidine may be a useful conservative treatment of both severe bladder hyperreflexia and spinal spasticity, with short-term effects evaluated through bolus injection in subcutaneous port before definitive pump implantation (Chartier-Kastler, et al 2000). Clonidine can also be added to the baclofen pump and both drugs administered intrathecally in patients where baclofen alone is ineffective or there is an increasing tolerance to baclofen (Middleton, et al 1996). Clonidine can be a powerful anti-spasmodic drug in addition to improving locomotion in a limited number of SCI subjects (Barbeau & Norman, 2003).

7. Other agents:
   • Chlorpromazine may have important modulatory effects on spastic hypertonia due largely to its effects on the brain stem reticular formation. Combination with phenytoin may be more efficacious, than when used alone, and may permit the dose of chlorpromazine to be lowered, decreasing its sedative effect.
   • Cyproheptadine, a 5-HT2 antagonist, has been demonstrated to be an antispasmotic agent (Nance, 1994). Drug absorption (and therefore dosing) vaires among SCI patients withlesions above and below the sympathetic outflow (T6) (Segal, et al 2000).
   • Fampridine-SR (sustained release 4-aminopyridine) significantly reduced spasticity in SCI patients with incomplete injuries with minimal side effects, such as transient lightheadedness and nausea (Potter, et al 1998).  4-Aminopyridine may also be useful to restore useful motor function (Segal & Brunnemann, 1998), improve impaired central motor conduction of some patients with incomplete SCI (Wolfe, et al 2001), enhance pulmonary function (Segal, et al 1999), and improve glucose tolerance (Segal, et al 2007). Drug absorption (and therefore dosing) varies among SCI patients with lesions above and below the sympathetic outflow (T6) (Segal, et al 2000). Intrathecal administration at a rate of 5 microg/h offers the potential to focus therapeutic effects to the lesion while minimizing systemic side effects (Halter, et al 2000). Fampridine-SR can improve Subject Global Impression (SGI) in motor-incomplete SCI and show potential benefit on spasticity. It is well tolerated, but adverse effects include hypertonia, generalized spasm, insomnia, dizziness, pain, constipation and headache (Cardenas, et al 2007).
   • Gabapentin may be useful in the management of spasticity associated with SCI (Gruenthal, et al 1997), and specifically for some features of spasticity (Priebe, et al 1997).
   • Ketazolan is as effective as and less sedating than diazepam in spinal forms of spasticity, may have a similar pharmacologic action, and can be administered in a single daily dose. It is not available in the U.S.
   • Progabide and Tetrahydroisoxazolopyridin, GABA agonists, are possible antispasticity drugs that reduce spastic hypertonia, tendon reflexes, and flexor spasms. Progabide does not significantly improve voluntary strength and, in higher doses, may cause fever, weakness, and elevated liver enzymes.
   • Threonine has a modest but definite antispastic effect, in patients with spinal spasticity, with minimal side effects (Lee & Patterson, 1993).
   • Valproic acid has been demonstrated to greatly diminish the frequency of myoclonic jerks with minimal side effects in a patient who failed or was intolerant to baclofen, dantrolene, and diazepam (Andary, et al 1997).