More MS news articles for March 2000

Q&A: Zanaflex for Treating Spasticity

Question:
Canadians have recently been approved for the use of Zanaflex for spasticity control. I have found little information on the actual physiological effects (what it does to actual receptors etc) of the drug. I am on a three-week trial now as the government has not approved medical coverage yet. If someone could post as much info as possible on it, or their experience with it, it would be appreciated. Thanks, Jason

Answer, from Dr. Wise Young, M.D., Ph.D.:
Tizanidine hydrochloride or Zanaflex was approved by the FDA for treating spasticity in people with spinal cord injury and multiple sclerosis. An alpha(2)-adrenoceptor agonist, the drug has been reported to have anti-nociceptive (anti-pain) effects as well in rats [1], with somewhat less potency than clonidine or dexmedetomidine. The drug costs are typically in the range of $2800 per year [2].

Tizanidine has also been reported to have anti-convulsive activity (anti-seizure) [3]. It may be useful for the treatment of trigeminal neuralgia [4]. It also prevents against convulsions induced by electroshock [5] and lidocaine [6]. Tizanidine is sometimes used in combination with baclofen and the two drugs do not interact pharmacokinetically [7].

Many studies have been carried out comparing the various anti-spasticity drugs [8-9] and tizanidine has usually held its own during such comparisons. The availability of tizanidine is viewed generally as increasing the therapeutic options of spasticity [10-11]. The mechanisms of tizanidine action are not well understood but are generally considered to be similar to those of clonidine, another alpha-adrenergic agonist; both drugs apparently affect gamma motoneuronal response to group II stretch reflex inputs and thereby lower the threshold for such reflexes [12].

One animal study suggests that pre-treatment with tizanidine 2 hours before will reduce ischemic brain damage, i.e. stroke [13]. Tizanidine has been given intrathecally to sheep and it appears to be relatively safe and well tolerated [14]; therefore it may well be a suitable drug for intrathecal administration for both spasticity and pain. Alpha-2 adrenoceptor agonists also are known to initiate locomotor activity [15].

Groves, et al. 1998 [16] did a review of 10 published clinical trials and found that tizanidine appears to improve muscle strength more than baclofen and other drugs that it was compared against. Tizanidine may also be useful for the treatment of opiate withdrawal in cases of intrathecal morphine where a drug holiday may be desired to reduce the accelerated dosing schedule often required when treating neuropathic pain [17]. The effects of tizanidine depend on dose [18], significantly reducing spasticity in human subjects, as measured by the Ashworth scale and the knee swing pendulum test [19], reducing mean muscle tone scores by about 37 percent compared to 4-9 percent in placebo treated subjects [20]. In rats, both clonidine and tizanidine significantly reduce allodynia (sensitivity to touch-induced pain) [21]. In animal studies, the drug appears to be similar to baclofen in its ability to depress spasticity [22].

Tizanidine may cause liver damage in some people [23]. It can also reduce blood pressure [24-25]. In overdoses, tizanidine may cause cardiac arrhythmias [26]. In normal subjects, tizanidine reduces metabolic rate and oxygen consumption by 12-15 percent after 6-12 mg oral doses [27]. More patients experienced adverse events during tizanidine treatment than did patients receiving placebo; the most common adverse events reported were dry mouth, somnolence, asthenia, and dizziness [28]. These effects vary substantially at doses that have central effects on spasticity-inducing spinal cord activities [29].

Tizanidine is a very old drug. Over 20 double-blind randomized clinical trials were carried out between 1977 and 1987 [30]. Combined with the more recent studies, the weight of the evidence for its antispasticity effects is very substantial. The safety record of drug is also quite reasonable. It is a valuable addition to the armamentarium of anti-spasticity treatments that are now available for spinal cord injury [31] and multiple sclerosis [32].

ENDNOTES
 

Wise Young, Ph.D., M.D., Professor II & Director
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey
Nelson Biological Laboratories, 604 Allison Rd
Piscataway, New Jersey 08854-8082
tel: 732-445-2061, fax: 732-445-2063
efax: 425-984-7563, email: wisey@pipeline.com

(This story was posted on 19 Mar 2000)