Tizanidine vs. Zolpidem in Primary Insomnia: A Randomized Trial

Efficacy of Tizanidine (0.1 mg/Kg/HS) versus Zolpidem 10 mg HS in Primary Insomnia: Double Blind Randomized Controlled Trial

Literature review:

Insomnia: Prevalence and Impact

Around 10% of adults have an insomnia disorder, while another 20% experience occasional insomnia symptoms (1). Women, older adults, and those facing socioeconomic challenges are more prone to insomnia. Insomnia often persists over time, with a 40% persistence rate over five years (1). Insomnia is a significant public health concern requiring individual clinical care and broad population-level interventions to improve sleep health (1).

The Individual and Public Health Ramifications of Insomnia

On an individual level, insomnia has significant repercussions on daily life, including impaired daytime function, emotional distress, reduced productivity, increased healthcare utilization, and heightened accident risk (2). Along with physiological hyperarousal, cardiometabolic morbidities such as hypertension, and diabetes, neurocognitive impairment such as short-term memory impairment, and psychological impairment such as depression, and anxiety (2)(3). Additionally, untreated insomnia tends not to improve over time (3).

On a public level, insomnia impacts various aspects of society. It contributes to an increased economic burden through decreased work productivity and higher healthcare costs due to increased healthcare service utilization (4). Additionally, insomnia heightens the risk of accidents, including traffic accidents, jeopardizing public safety (4). Its association with mental health disorders adds to the healthcare burden of managing these conditions, while the increased risk of chronic medical diseases further strains healthcare systems (5). Given that the untreated economic costs of insomnia far exceed that of treated insomnia (4), efforts should be focused on developing clinical trials aimed at assessing the cost-benefit, and cost-effectiveness of various insomnia therapies.

Defining Primary Insomnia According to DSM-5 Criteria

Primary insomnia, as defined in the DSM-5 criteria (6), refers to a sleep disorder characterized by difficulty initiating or maintaining sleep, or experiencing non-restorative sleep, for at least one month. Individuals with primary insomnia often report significant distress or impairment in social, occupational, or other important areas of functioning due to their sleep difficulties. The DSM-5 criteria further specify that insomnia is not better explained by another sleep disorder, such as narcolepsy, or circadian rhythm sleep disorder, etc., and not due to another mental disorder. Additionally, the diagnosis of primary insomnia requires that the sleep disturbance does not occur due to the physiological effect of a medical condition or substance use (6).

Current FDA-Approved Medications for Insomnia

Current FDA-approved medications for insomnia include benzodiazepines, such as Triazolam, and Temazepam, as well as non-benzodiazepines (Z drug) such as zolpidem, and zaleplon. Additionally, melatonin agonist ramelteon, tricyclic antidepressant doxepin, and orexin antagonists such as suvorexant are also among the approved options for managing insomnia (7).

Zolpidem was the first Z drug to be developed. In studies investigating zolpidem adverse events that arose during treatment, such as drowsiness, nausea, dizziness, nightmares, and agitation, have led to the discontinuation of the zolpidem (7). Additionally, some patients experienced anterograde amnesia (7). Moreover, concerns about the frequent use of benzodiazepine for insomnia include the risk of dependence, drug-seeking behavior, and abuse in the context of inadequate medical supervision (8). Evaluating any new pharmacological treatments against conventional benzodiazepine and z-drugs intake is crucial, as there is limited data on the benefit-to-risk ratio of such treatment strategies, necessitating head-to-head trials.

Therapeutic Applications of Tizanidine

Tizanidine, a centrally acting alpha-2 agonist, is commonly prescribed to manage spasticity induced by conditions such as multiple sclerosis, stroke, and spinal cord injury. Beyond its labeled indications, it finds off-label use in alleviating chronic neck and back pain as well as chronic migraines (9).

Clinical Trials of Tizanidine in the Context of Insomnia

Tizanidine has shown promise in previous studies for its efficacy in sleep disturbances. In a study where 24 subjects with Myofascial pain syndrome received tizanidine, which was titrated up to 12 mg over 3 weeks and maintained for 2 weeks. the study results showed Pain intensity and disability decreased significantly from baseline at weeks 3 and 5 and after washout (P \< .001). Pressure threshold and sleep improved for all study periods (P \< .001). The Sleep in this study was assessed via a visual analog scale (VAS) (10).

In a randomized controlled clinical trial assessing the efficacy of adding either tizanidine or cyclobenzaprine in treating jaw pain, 45 patients diagnosed with myofascial pain were randomly assigned to three groups: a placebo group, a tizanidine group (4 mg), and a cyclobenzaprine group (10 mg). Patients were assessed for changes in pain intensity using the modified Severity Symptoms Index and changes in sleep quality using the Pittsburgh Sleep Quality Index. Results showed that all three groups experienced a reduction in pain symptoms and an improvement in sleep quality when comparing pretreatment and treatment scores (11).

An open-label dose-titration study investigated the effectiveness and tolerability of tizanidine hydrochloride tablets in preventing chronic daily headaches. The dosage was gradually increased from 2 mg at bedtime to a median daily dose of 14 mg (mean 13.5; SD 4.3; range 4 to 20), divided over three doses per day by the fourth week of treatment. Significant improvements were observed in overall headache status, mood, sleep, quality of life (P \< .00001), as well as sexual function (P = .0075), and the Beck Depression Inventory-II scores (P = .00073). Mild-to-moderate adverse events reported by 10% of patients included somnolence, asthenia, and dry mouth. Three patients discontinued treatment due to somnolence, dry mouth, or constipation. Additionally, one patient experienced elevated liver enzymes which normalized after discontinuing the medication (12).

Adverse Effects and Pharmacokinetic Considerations of Tizanidine

Adverse reactions associated with tizanidine include hypotension, bradycardia, or excessive sedation requiring gradual dose reduction or stopping therapy (9). Given its extensive hepatic metabolism, tizanidine's pharmacokinetics can be significantly altered in patients with hepatic impairment. Thus, special attention must be given to the dosing and monitoring of tizanidine in such individuals to mitigate risks (9). Similarly, patients with renal impairment, particularly those with a creatinine clearance below 25 mL/min, require careful management when using tizanidine. Initiation at lower doses, along with close monitoring of therapeutic response, is recommended (9). Any decision to prescribe tizanidine during pregnancy should involve a thorough risk-benefit assessment to ensure the safety of both the mother and the fetus. Moreover, considering tizanidine's lipid-soluble nature, potential transfer into breast milk raises concerns regarding its use during lactation (9). Smoking has been identified as a factor that reduces tizanidine's plasma concentration and exposure, as observed in studies such as Al-Ghazawi et al. (13)

Following oral administration of tizanidine, the peak plasma concentrations occurred 1 hour after with a half-life of approximately 2 hours. (14). The doses employed in the present study constitute an initial dose of 2 mg HS, and it will be titrated up by 2 mg every 4 days, as per response and tolerability, up to a maximum dose of 0.1 mg/kg/HS administered before bedtime. This proposed dose was found effective in a clinical trial assessing the effects of tizanidine for refractory sleep disturbance in disabled children with spastic quadriplegia. The clinical trial included 21 children diagnosed with spastic quadriplegia and experiencing severe sleep disturbances. All these children exhibited abnormalities in both falling asleep and staying asleep. Tizanidine was administered at a dosage ranging from 0.1 to 0.2 mg/kg/day, divided into two or three doses. If daytime drowsiness was significant, tizanidine administration was limited to just before bedtime. Improvement in sleep induction and/or maintenance was observed in 13 patients (61.9%). Moreover, the families of the patients expressed satisfaction with the treatment (15).

The objective of this study was to compare in a double-blind design the subjective hypnotic efficacy and safety of Tizanidine (0.1 mg/kg/day), and a Zolpidem 10 mg HS over 12 weeks in adult patients with primary insomnia.

Study Objectives

Primary Objective:

To evaluate the efficacy of Tizanidine compared to Zolpidem in improving sleep quality among patients with primary insomnia.

Secondary Objectives:

* To assess the safety and side effect profile of Tizanidine. * To compare patient tolerance and satisfaction between Tizanidine and Zolpidem treatments.

Hypotheses

Main Hypothesis:

Tizanidine is effective in the treatment of primary insomnia, offering a better safety profile with fewer side effects.

Secondary Hypotheses:

* Patients treated with Tizanidine will report fewer side effects compared to those treated with Zolpidem. * Tizanidine will demonstrate higher patient tolerance and satisfaction in the treatment of primary insomnia.

Methodology

Study Design:

This study will be conducted as a double-blind, randomized controlled trial. Participants will be randomly assigned to receive either Tizanidine or Zolpidem for 12 weeks.

The trial design is a parallel-group randomized controlled trial. Participants will be randomly assigned to either one of the two treatment groups: the Tizanidine group or the Zolpidem group. This design allows for the comparison of the efficacy and safety of Tizanidine versus Zolpidem in the treatment of primary insomnia. The allocation ratio will be 1:1, ensuring an equal distribution of participants between the two treatment arms.

Trial setting:

The data were collected at the outpatient sleep clinic affiliated with Al-Masarah Hospital, Muscat, Oman.

Randomization:

The method used to generate the random allocation sequence:

• Frequency and Severity of Side Effects [Time frame: 4 weeks, 8 weeks, 12 weeks]