tizanidine/Zanaflex (US trade name)
Tizanidine/Zanaflex is an interesting agent that may be effective for neurogenic flushing & has been recently shown helpful for chronic headaches like clonidine & propranolol. It has a shorter half life than clonidine like moxonidine but a long-acting formulation is being studied and a broad dose titration is readily possible. For those who can not get a prescription for moxonidine & can't tolerate clonidine, Zanaflex may be worth consideration with the supervision of your doctor.
http://www.rxlist.com/cgi/generic/tizanidine.htm - Full RxList Monograph
The imidazoline chemical structure of tizanidine is related to that of the anti-hypertensive drug clonidine and other alpha2-adrenergic agonists. Pharmacological studies in animals show similarities between the two compounds, but tizanidine was found to have one-tenth to one-fiftieth (1/50) of the potency of clonidine in lowering blood pressure. (http://www.rxlist.com/cgi/generic/tizanidine_cp.htm)
Guanfacine Hydrochloride - Full RxList Monograph (Tenex trade name) is another available clonidine alternative that some find more tolerable but is much more similar to clonidine than tizanidine.
Tizanidine, an imidazoline derivative, is the newest of drugs approved for the management of spasticity. It is an alpha2-adrenergic agonist active at both alpha2-adrenergic and imidazoline receptors in the spinal cord.38,39 It is thought to have several mechanisms of action resulting in a decrease in polysynaptic spinal cord reflex activity, including inhibition of the release of excitatory neurotransmitters from presynaptic sites and of Substance P from nociceptive sensory afferents.40–42 Tizanidine also decreases neuronal firing at the level of the locus ceruleus.39 Tizanidine has been shown to be effective in reducing spasticity and spasms in patients with multiple sclerosis, and other brain and spinal cord diseases with efficacy similar to baclofen.39,43 It is currently under investigation for the treatment of neuropathic pain, and detrusor-sphincter dyssynergia, which are often seen in multiple sclerosis patients. The major advantage of tizanidine over baclofen is that tizanidine does not cause muscle weakness. Therefore, tizanidine may be of particular benefit, and may be the drug of first choice, in patients with marginal strength.
The sedative side effects of tizanidine are somewhat equivalent to that of baclofen, but less than benzodiazepines.43 Other side effects include dry mouth and hypotension, which is generally dose related.44 The side effects are minimized by slow titration of dosage. Slight elevation of liver enzymes have been noted in 5% of patients; these generally normalize with a decrease in dosage or discontinuation of medication.43 It is recommended that liver enzymes be monitored during the first 6 months of treatment and that the drug be avoided in patients with liver disease. Initial dosage is 2 to 4 mg/d and is slowly titrated upwards in 2 to 4-mg increments every 3 to 4 days to a maximum of 36 mg/d divided tid-qid.35 Peak effect is in 1 to 2 hours with 3- to 6-hour duration of action.33 A sustained release formulation of tizanidine is currently under investigation for the management of spasticity in multiple sclerosis patients.
Clonidine is an alpha2-adrenergic agonist similar to tizanidine, but is limited in its use by orthostatic hypotension. It is started orally at 0.05 mg bid and increased by 0.1 mg/d weekly to a maximum of 0.4 mg/d.47
The data, presented today at the
World Congress of Neurology, show that the drug tizanidine (Zanaflex®)
significantly reduced the frequency, intensity, and duration of headaches in
patients experiencing an average of 23 days of headache/month. Most (75
percent) had been suffering with chronic daily headache for three years or
longer, and experienced a combination of both frequent migraines and chronic
daily pain.
Overall headache frequency for the group receiving tizanidine declined by an
average of eight days/month (P<0.02), and severe headaches dropped by 55
percent (P<0.02). Average headache intensity (P<0.01), peak intensity
(P<0.002), and mean headache duration (P<0.01) each declined by at least
33 percent, with mean duration dropping from 6.8 to 4.4 hours/headache.
Based on a headache index combining frequency, average intensity, and duration, the average percentage improvement was 51 percent for those receiving tizanidine, compared to 34 percent for placebo (P<0.0025). Patients were only allowed to use a limited amount of analgesic and abortive medication, and could not add new abortives once they entered the single-blind baseline phase of the study.
Changes in headache intensity and
duration were not due to more frequent use of abortives, which actually declined
during the course of the study. Patients receiving tizanidine also rated their
overall headaches as significantly better at the end of the study than those who
received placebo (P<0.007).
"Medical literature focused on chronic daily headache (CDH) is limited, so
most of what we know about treatment strategies is based on anecdotal
information," says Alvin E. Lake III, Ph.D., Director of the Behavioral
Medicine Division at the Michigan Head Pain and Neurological Institute and study
co-investigator.
"This study is important
because it gives clinicians scientific evidence regarding a new approach to
treating an often difficult-to-treat condition." The multicenter study
involved co-investigators including Joel R. Saper, M.D., FACP (Director of the
Michigan Head Pain and Neurological Institute), Alvin E. Lake III, Ph.D.
(Division Director, Behavioral Medicine, Michigan Head Pain & Neurological
Institute), Paul K. Winner, D.O. (Director, Premier Research Institute/West Palm
Beach Headache Center, West Palm Beach, Florida), and others.
Tizanidine hydrochloride is an alpha(2)-adrenergic agonist that inhibits the
release and effectiveness of norepinephrine at both central sites (e.g., the
locus coeruleus) and the spinal cord. It acts as a central muscle relaxant and
exhibits antinociceptive effects with little or no interaction with serotonin,
dopamine, or GABA receptors.
Ninety-two patients completed a four-week single-blind placebo baseline, with 45
then randomly assigned to tizanidine and 47 to placebo. Forty-four of the
tizanidine group and 41 who were given placebo then completed all 12 weeks of
planned treatment. Dosing was titrated from 2mg at bedtime to a median daily
dose of 20mg during the treatment weeks 9-12 (mean = 18.4, SD = 6.4, range =
2-24, divided over three doses per day).
"Not only did treatment with
tizanidine reduce the amount of analgesic required by patients, it seemed to
work more effectively on reducing the frequency of the most severe headaches,
which dropped by 55 percent compared to a 32 percent decline in the overall
frequency of headaches," said Dr. Lake. "A post-hoc analysis found
that those who unquestionably met IHS criteria for migraine were just as
likely to be treatment responders as those with chronic tension-type headache."
Mild-to-moderate adverse events reported by more than 10 percent of the patients
that were significantly more common in the tizanidine group included somnolence,
dizziness, insomnia, dry mouth, and asthenia. Past research with tizanidine has
shown elevated liver enzymes in a small minority of patients, which return to
normal when the drug is discontinued. Liver enzymes should be monitored.
The complete analysis of this data supports recently published preliminary
results from an open-label study (Saper JR, Winner PK, Lake AE. An open-label
dose-titration study of the efficacy and tolerability of tizanidine
hydrochloride tablets in the prophylaxis of chronic daily headache. Headache 2001;
41:357-368).
SOURCE: Michigan Head Pain and Neurological Institute- WCN Zanaflex (Tizanidine) Provides Well-Tolerated, Effective Treatment for Chronic Headache
| Neuropharmacology 1991 Jun;30(6):585-9 | Related Articles, Books |
