Tizanidine is a myotonolytic agent FDA-approved for the management of spasticity, which may be caused by multiple sclerosis, an acquired brain injury, or a spinal cord injury. It has also been shown to be clinically effective in the management of patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes.[1] Animal studies have shown that tizanidine provides benefits in the perioperative period and the management of neuropathic pain such as trigeminal neuralgia, similar to the effects of clonidine under similar circumstances. Clinicians also prescribe it off-label for migraine headaches, insomnia, and as an anticonvulsant. Tizanidine can also be part of a detoxification therapy regimen in patients exhibiting analgesic rebound headaches to assist with analgesic withdrawal.

Clinical Studies

Spasticity is a common symptom of upper motor neuron disorders. Tizanidine is widely used as a spasmolytic agent for the management of these debilitating conditions. However, the data regarding the efficacy and safety of tizanidine compared to other approved skeletal muscle relaxants such as baclofen, dantrolene, and diazepam is limited and of older date.

Placebo-controlled studies confirm the significant efficacy of tizanidine in reducing spasticity in patients with spinal cord-induced spasticity. Literature suggests that patients with more severe spasticity are more likely to benefit from the therapy. Drug comparison studies have shown no differences in the efficacy of tizanidine compared with baclofen or diazepam. The Tizanidine treatment group did not report increased weakness when compared with controls. Furthermore, patients using tizanidine experienced fewer adverse effects than those using controlled substances.[2]

Other comparison studies showed that tizanidine, baclofen, and diazepam were equally effective in decreasing excessive muscle tone in patients with multiple sclerosis or cerebrovascular lesions. Muscle strength improved in all three treatment groups, but the improvement was greatest with tizanidine.[3]

Shakespeare et al. also reported similar findings showing no differences in efficacy between tizanidine, baclofen, and dantrolene when compared to diazepam.[4] However, diazepam was associated with more sedation. Another study by Lataste et al.[5] showed no significant differences between tizanidine and baclofen or diazepam for muscle tone, muscle spasms, clonus, muscle strength, or overall anti-spastic effect. However, tizanidine tolerance slightly better than diazepam and baclofen.

Groves et al.[3] report no significant differences between tizanidine or baclofen or diazepam for spasticity by “Ashworth score.” However, applying “global tolerability to treatment” favored tizanidine compared to baclofen and diazepam. Wallace et al.[2] evaluated the efficacy and tolerability of tizanidine, baclofen, and diazepam and reported increased withdrawal symptoms due to adverse events to tizanidine. 

Tizanidine, an imidazoline derivative is a central acting noradrenergic alpha-2 receptor agonist resulting in impairment of excitatory amino acids like glutamate- and aspartate-release from spinal interneurons and increasing presynaptic inhibition of motor neurons with the greatest effect on spinal polysynaptic pathways.[6] The overall effect of these actions is thought to reduce the facilitation of spinal motor neurons. Similar alpha-2 receptor-mediated inhibition of interneuronal activity appears to underlie the additional anti-nociceptive and anticonvulsant activities of tizanidine. Spasm frequency and clonus are also reduced by tizanidine.[7] Tizanidine also has an affinity for the alpha-1 receptors but to a lesser degree, which may explain its mild and transitory effect on the cardiovascular system compared to clonidine despite their structural and biochemical similarity.[6]

Pharmacokinetics  

Tizanidine has a significant, first-pass hepatic metabolism with an oral bioavailability of 20% to 34%. Tizanidine has an elimination half-life of 2.5 hours, and it follows linear pharmacokinetic principles. The steady-state concentration of tizanidine is reached within 24 to 48 hours after administration, and there is no noticeable change in its pharmacokinetic behavior with repeated intake.[8]

Tizanidine is metabolized extensively in the liver by CYP450: 1A2 to inactive metabolites and excreted 60% through urine and 20% through feces.

Tizanidine is administrated orally as 2 mg, 4 mg, and 6 mg capsules or as 2 mg and 4 mg tablets. Dosage starts with 2 mg orally and may repeat every 6 to 8 hours as needed. The dosage may gradually increase by 2 to 4 mg per dose of 1 to 4 days in between until there is a noticeably significant reduction of spasticity. Maximum dosing is three doses every 24 hours, up to 36 mg daily. Tizanidine can be taken with food or on an empty stomach. If it is used for more than 9 weeks or given in high doses ranging from 20 mg to 36 mg daily, then one may consider discontinuing by tapering the dose 2 to 4 mg per day to reduce the risk of tachycardia, rebound hypertension, and increased spasticity. The patient may open capsule, and its content sprinkled into food. However, absorption of the drug is increased significantly when administered under fasting conditions.

Tizanidine is generally well-tolerated. However, reports exist of potential adverse effects on several organs such as cutaneous, gastrointestinal, neurologic, cardiovascular, endocrine, and respiratory systems.

Common adverse effects include xerostomia, drowsiness, asthenia, dizziness, hypotension, bradycardia, constipation, urinary frequency, blurred vision, dyskinesia, nervousness, hallucination, and rhinitis.

Serious adverse effects include hepatotoxicity, severe bradycardia, QT interval prolongation, severe hypotension, syncope, Stevens-Johnson syndrome, anaphylaxis, and exfoliative dermatitis. Tachycardia, rebound hypertension, and increased spasticity may occur when discontinuing the drug abruptly. 

Drug Interactions

Concomitant use of tizanidine with fluvoxamine or ciprofloxacin is contraindicated due to significant hypotension and increased psychomotor impairment.

Because of potential drug interactions, using tizanidine with other CYP1A2 inhibitors such as oral contraceptives containing ethinyl estradiol and gestodene, dronedarone, pimozide, saquinavir, cimetidine, famotidine, acyclovir, and ticlopidine should be avoided due to decreased clearance of tizanidine. If tizanidine is clinically necessary, therapy should be initiated with 2 mg and increased 2 to 4 mg daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive sedation occur, the dose should be reduced or discontinued. The use of alcohol should be avoided. Tizanidine should be used cautiously in patients on other alpha-2 adrenergic receptor agonists.

Tizanidine is contraindicated in patients reporting allergies to the drug itself or any other component of the formulation used.

Tizanidine use requires caution in patients with hepatic or renal impairment. In such patients, individual dosing should be decreased. If high doses are necessary, increase the individual dose rather than the dose frequency.