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Tizanidine is a centrally acting alpha2-adrenergic agonist that was approved as an antispastic drug by the United States Food and Drug Administration in 1996.
Important points of the pharmacodynamics and pharmacokinetics of tizanidine are as follows:
Pharmacology. Tizanidine is an agonist at alpha2-agonist receptor sites and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. In animal models, tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction and no major effect on monosynaptic spinal reflexes. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons. The main clinical effects are a reduction in tonic stretch and polysynaptic reflexes. Tizanidine remains a useful medication for patients suffering from spasticity caused by multiple sclerosis, traumatic brain injury, or spinal cord injury.
The imidazoline chemical structure of tizanidine is related to that of the antihypertensive drug clonidine and other alpha2-adrenergic agonists. Pharmacological studies in animals show similarities between the 2 compounds, but tizanidine was found to have one-tenth to one-fiftieth the potency of clonidine in lowering blood pressure.
Pharmacokinetics. The essential features are the following:
• Following oral administration, tizanidine is essentially completely absorbed and has a half-life of approximately 2.5 hours.
• There are ethnic differences in clearance of tizanidine. The metabolic clearance of tizanidine 5.9 l/h/kg in Japanese subjects is lower in than rate of 8.1 to 10.9 l/h/kg in Caucasians (12).
• Peak plasma concentration is reached at 1.5 hours after dosing. Food increases the maximum concentration by approximately one-third and shortens time to peak concentration by approximately 40 minutes, but the extent of tizanidine absorption is not affected. Tizanidine has linear pharmacokinetics over a dose of 1 to 20 mg.
• The absolute oral bioavailability of tizanidine is approximately 40% due to extensive first-pass metabolism in the liver. Approximately 95% of an administered dose is metabolized. Tizanidine metabolites are not known to be active.
• Tizanidine is widely distributed throughout the body; mean steady-state volume of distribution is 2.4 L/kg following intravenous administration in healthy adult volunteers. Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively.
• Tizanidine is approximately 30% bound to plasma proteins, independent of concentration over the therapeutic range.
Formulations. A pharmacokinetic study of tizanidine showed that the tablet and capsule formulations were bioequivalent in the fasting state, but action of the capsule was delayed if taken with food. A pharmacokinetic study to compare 2 proprietary preparations of tizanidine concluded that each Tizanidine 4 mg tablet from Pharma International Company is bioequivalent to Sirdalud® 4 mg tablet from Novartis (02).
The bioavailability of the tizanidine intranasal formulation is higher than that of tizanidine oral tablets (19). A nasal formulation of tizanidine is being considered for phase II clinical trials.
Because of the short half-life of oral tizanidine given as tablets requiring frequent administration, efforts are being made to develop sublingual formulations that improve bioavailability as shown in clinical trials. One clinical trial has shown that tizanidine, encapsulated in a chitosan lactate wafer for buccal delivery, increases the bioavailability of tizanidine 2.27-fold (07). A drug-in-adhesive patch of tizanidine is prepared by employing ion-pair and permeation enhancer to increase drug-polymer miscibility and drug release (22).
The capacity of tizanidine to reduce increased muscle tone associated with spasticity was demonstrated in several earlier well-controlled studies in patients with multiple sclerosis or spinal cord injury.
The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome), but also did not lead to any consistent advantage of tizanidine-treated patients on measures of activities of daily living. In an open trial on patients with incomplete spinal cord injury, tizanidine was shown to improve walking speed and endurance in high-functioning participants (05).
A double-blind, randomized, placebo-controlled study showed that overnight sublingual tizanidine provides improvement in spasticity on the following day without sleepiness as a side effect (18).
A randomized study has compared the efficacy of tizanidine with eperisone, both in combination with tramadol, in patients with chronic low back pain (16). Both combinations were effective, but eperisone/tramadol has better compliance.
Most of the clinical trials of tizanidine have been completed or terminated. In the latest reported trial, tizanidine was combined with upper cervical block for relief of pain after thyroidectomy (ClinicalTrials.gov identifier: NCT02725359). This combination reduced postoperative opioid consumption, posterior neck pain, and occipital headache (01).
The primary indication for tizanidine is for acute and intermittent management of increased muscle tone associated with spasticity due to multiple sclerosis and spinal cord injury.
• Treatment of addiction in combination with dextromethorphan.
• Combination of tizanidine with amitriptyline for chronic tension headaches.
• Spasticity associated with hemiplegia due to stroke.
• Acute low-back pain in combination with ibuprofen.
• For decreasing spasticity associated with traumatic brain injury during rehabilitation.
• Myofascial pain.
• Refractory sleep disturbance in spastic quadriplegic patients.
• Treatment of alcohol withdrawal (03).
• A prospective randomized open-labeled trial has shown tizanidine to be a safe and effective treatment of children with dysfunctional voiding due to pelvic floor sphincter dysfunction (06).
• A retrospective study has shown that continuous infusion of tizanidine via a feeding tube is useful for the treatment of severe generalized spasticity that cannot be adequately controlled by intermittent use of oral muscle relaxant drugs (09).
• Tizanidine is an alternative muscle relaxant therapy in stiff person syndrome where benzodiazepine may have to be withdrawn either due to lack of efficacy or adverse effects (21).
• Postoperative pain management as adjunct to reduce dose of analgesic medications (20).
• Reduction of night sweats due to dysautonomia in syringomyelia (11).
• Antinociceptive effects of tizanidine has been shown on a rat model of neuropathic pain through inhibition of the production of proinflammatory cytokines by suppression of the activation of TLR4/NF-κB p65 signaling pathway (14).
Tizanidine is contraindicated in patients with known hypersensitivity to tizanidine or its ingredients.
Tizanidine is a short-acting drug for the acute and intermittent management of increased muscle tone associated with spasticity. The reduction of muscle tone that follows the oral administration of a single dose of tizanidine has its peak effect 1 to 2 hours after dosing, and the effect dissipates between 3 to 6 hours; therefore, use must be individualized, directed to those activities and times when relief of spasticity is most important and titrated to avoid intolerance. Generally, therapy is initiated at low dosages and then increased gradually to avoid adverse effects. Optimal therapy is the lowest effective dosage. Evidence demonstrating the effectiveness of tizanidine is derived from a single-dose study and from a 7-week multiple-dose study conducted in patients with multiple sclerosis and spinal cord injury, respectively. The effect of long-term treatment is not known.
A single 8 mg dose of tizanidine can be repeated at 6 to 8 hour intervals, as needed, to a maximum of 3 doses in 24 hours. The total daily dose should not exceed 36 mg.
The contents of the tizanidine capsule sprinkled in applesauce are not bioequivalent to the intact 6 mg capsule. Therefore, in switching from the intact capsule to the capsule contents, monitoring for adverse events is recommended, and dose adjustment may be necessary.
Pediatric. No adequate and well-controlled studies are available to document the safety and efficacy of tizanidine in children.
Geriatric. Tizanidine should be used with caution in elderly patients because renal clearance is decreased.
Pregnancy. Tizanidine increases gestation duration in rats as well as prenatal and postnatal pup loss and developmental retardation. Tizanidine has not been studied in pregnant women, and it should be given to pregnant women only if clearly needed.
Renal insufficiency. Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance less than 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. Therefore, tizanidine should be used with caution in patients with impaired renal function.
In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. Coprescription of strong CYP1A2 inhibitors increases the risk of hypotensive episodes associated with the use of tizanidine in routine clinical practice (04).
Alcohol. Alcohol increases the area under the curve of tizanidine by approximately 20% and increases its maximum concentration by approximately 15%. This is associated with an increase in side effects of tizanidine. The CNS depressant effects of tizanidine and alcohol are additive.
Oral contraceptives. No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and tizanidine; however, retrospective analysis of population pharmacokinetic data following single and multiple dose administration of tizanidine showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared to women not on oral contraceptives.
Antihypertensive agents. Tizanidine may interact with antihypertensive agents (ie, angiotensin converting enzyme inhibitors) during treatment of either hypertension or spasticity in hypertensive patients, and this may cause hypotension. The addition of tizanidine in a patient receiving long-term treatment with lisinopril was associated with severe hypotension and bradycardia (15). Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy; tizanidine should not be used with other alpha2-adrenergic agonists.
Fluvoxamine. Pharmacokinetics of tizanidine is seriously affected by an interaction with fluvoxamine, which increases the intensity and duration of its effects.
Mexiletine. Coadministration of mexiletine increases tizanidine blood levels and enhances tizanidine action in terms of reduction in blood pressure and adverse symptoms (13).
Hypotension. As an alpha2-adrenergic agonist (like clonidine), tizanidine can produce hypotension. The chance of significant hypotension may possibly be minimized by titration of the dose and by focusing attention on signs and symptoms of hypotension prior to dose advancement. In addition, patients moving from a supine to a fixed upright position may be at increased risk for hypotension and orthostatic effects.
Bradycardia. Bradycardia is a rare side effect of tizanidine and usually reverses after discontinuation of the drug. A case of irreversible profound symptomatic bradycardia requiring pacemaker placement after using tizanidine/loxoprofen (a nonsteroidal anti-inflammatory drug) combination therapy for pain has been reported, and caution is advised in using these drugs together (10).
Tizanidine withdrawal syndrome. This is rarely observed after sudden discontinuation of tizanidine therapy and is caused by adrenergic discharge due to its alfa2-agonist mechanism, which is characterized by hypertension, reflex tachycardia, hypertonicity, and anxiety (17). This can be successfully managed by restarting tizanidine followed by weaning by slow downward titration of dose.
Risk of liver injury. Tizanidine occasionally causes liver injury, most often hepatocellular in type. A patient who was taking tizanidine developed drug-induced hepatitis, from which he recovered, but there was repeated recurrence of this adverse reaction after resumption of the drug (08). After permanent discontinuation of tizanidine the symptoms resolved, with return of liver function tests to normal. Monitoring of aminotransferase levels is recommended during the first 6 months of treatment (eg, baseline 1 month, 3 months, and 6 months) and periodically thereafter based on clinical status. Because of the potential toxic hepatic effect of tizanidine, the drug should be used only with extreme caution in patients with impaired hepatic function.
Sedation. In controlled clinical studies, 48% of patients receiving any dose of tizanidine reported sedation as an adverse event. The effect appears to be dose related.
Hallucinations. Tizanidine use has been associated with hallucinations in 3% of the patients in controlled clinical studies. These hallucinations usually clear up on discontinuation of therapy but can occasionally persist.
K K Jain MD
Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.See Profile
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