BACKGROUND: Trihexyphenidyl and clonazepam are commonly used to treat dystonia in children with cerebral palsy (CP). However, there is a notable gap in the literature when it comes to studies that combine these first-line agents for the management of dystonia.
METHODS: This open-label, randomized controlled trial aimed to compare the efficacy of adding oral clonazepam to trihexyphenidyl (THP + CLZ) versus using trihexyphenidyl alone (THP) in reducing the severity of dystonia, as measured by the Barry-Albright Dystonia (BAD) score. The study was conducted over a 12-week therapy period in children with dystonic CP aged two to 14 years.
RESULTS: Each group enrolled 51 participants. The THP + CLZ group showed significantly better improvement in dystonia severity at 12 weeks compared with the THP group alone (-4.5 ± 2.9 vs -3.4 ± 1.7, P = 0.02). Furthermore, the THP + CLZ group exhibited superior improvement in the severity of choreoathetosis, upper limb function, pain perception by the child, and quality of life, with P values of 0.02, 0.009, 0.01, and 0.01, respectively. The number of participants experiencing treatment-emergent adverse events was comparable in both groups (P = 0.67). Importantly, none of the participants in any of the groups reported any serious adverse events.
CONCLUSIONS: A combination of oral THP + CLZ proves to be more efficacious than using THP alone for the treatment of dystonic CP in children aged two to 14 years in terms of reducing the severity of dystonia.

OBJECTIVE: Burning mouth syndrome (BMS) is a chronic pain disorder characterized by intraoral burning or dysaesthetic sensation, with the absence of any identifiable lesions. Numerous treatments for BMS have been investigated, though without conclusive results. An analysis was conducted of the efficacy of treatment with a low-level diode laser and clonazepam in patients with BMS, and a study was carried out on the levels of different salivary biomarkers before and after treatment.
METHODS: A randomized, single-blind clinical trial was carried out involving 89 patients divided into the following groups: group 1 (laser, The Helbo® Theralite Laser 3D Pocket Probe + clonazepam) (n = 20), group 2 (sham laser placebo) (n = 19), group 3 (laser) (n = 21) and group 4 (clonazepam) (n = 18). Symptom intensity was scored based on a visual analogue scale (VAS). Sialometry was performed before and after treatment, and the Xerostomia Inventory, Oral Health Impact Profile-14 (OHIP-14) and Mini-Nutritional Assessment (MNA) questionnaires were administered. The following markers were measured in saliva samples: interleukins (IL2, IL4, IL5, IL6, IL7, IL8, IL1β, IL10, IL12, IL13, IL17, IL21 and IL23), proteins (MIP-3α, MIP-1α and MIP-1β), GM-CSF, interferon gamma (IFNγ), interferon-inducible T-cell alpha chemoattractant (ITAC), fractalkine and tumor necrosis factor α (TNFα).
RESULTS: A significant decrease in the VAS scores was observed after treatment in group 1 (laser + clonazepam) (p = 0.029) and group 3 (laser) (p = 0.005). In turn, group 3 (laser) showed a decrease in the salivary concentration of fractalkine (p = 0.025); interleukins IL12 (p = 0.048), IL17 (p = 0.020), IL21 (p = 0.008), IL7 (p = 0.001) and IL8 (p = 0.007); proteins MIP1α (p = 0.048) and MIP1β (p = 0.047); and TNFα (p = 0.047) versus baseline. Following treatment, group 1 (laser + clonazepam) showed significant differences in IL21 (p = 0.045) and IL7 (p = 0.009) versus baseline, while group 4 (clonazepam) showed significant differences in IL13 (p = 0.036), IL2 (p = 0.020) and IL4 (p = 0.001). No significant differences were recorded in group 2 (sham laser placebo).
CONCLUSIONS: The low-level diode laser is a good treatment option in BMS, resulting in a decrease in patient symptoms and in salivary biomarkers. However, standardization of the intervention protocols and laser intensity parameters is needed in order to draw more firm conclusions.

BACKGROUND: The prevalence of neurological disorders is high among the Mexican population. Clonazepam is primarily indicated to treat panic disorders, certain kinds of epilepsy such as status epilepticus, childhood motor seizures (petit mal absence, Lennox-Gastaut syndrome, and infantile spasms), anxiety, and muscle spasm. This study was performed to compare bioequivalence between two oral tablet formulations of clonazepam 2 mg in healthy Mexican volunteers under fasting conditions.
METHODS: This phase I, randomized, open-label, two-treatment, crossover study included 30 healthy volunteers. Subjects were randomly assigned to either test or reference formulation of clonazepam 2 mg. Each study period was separated by 21-day washout period. Blood samples were collected at pre-dose and up to 72 h after drug administration. Clonazepam concentrations were determined using a validated ultra-flow liquid chromatography-tandem mass spectrometric method. Pharmacokinetic parameters were determined using a non-compartmental method. Two formulations were considered bioequivalent if geometric mean ratios (test/reference) were between 80% and 125%. Safety was evaluated by recording adverse events.
RESULTS: Pharmacokinetic parameters were comparable between test and reference formulations. The mean maximum plasma concentration (Cmax) was ≈ 13 ng/mL, area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC0-t) was ≈ 360 ng h/mL, time to reach maximum plasma concentration (Tmax) was ≈ 3 h, and elimination half-life (t1/2) was ≈ 43 h. Geometric mean ratios (90% confidence interval) of Cmax (99.2-115.3%), AUC0-t (100.6-110.6%), and AUC0-∞ (98.5-111.6%) were within the bioequivalence range. Seven non-serious adverse events (mostly asymptomatic hypotension) were recorded.
CONCLUSIONS: The test and reference formulations of clonazepam 2 mg were bioequivalent and well tolerated in healthy Mexican volunteers under fasting conditions.
UNASSIGNED: 213301410B0051 (Approved on April 13, 2021).

To evaluate the effectiveness of high-dose clonazepam (1 mg) versus low-dose clonazepam (0.5 mg) with cognitive behavioral therapy for insomnia (CBT-i) in older adults with moderately severe insomnia.
A prospective cohort study was conducted in patients who did not respond to low-dose clonazepam for insomnia secondary to chronic medical conditions. After starting with 0.25 mg of clonazepam, their dose was increased to 0.5 mg, then to 1 mg (Group A), or to the same dose with additional CBT-i (Group B). They were followed for 24 weeks, and scores of the insomnia severity index (ISI) and subjective units of distress scale (SUDS) were recorded. Patient adverse drug reactions (ADRs) were documented and assessed for their causality. ISI and SUDS scores were considered primary outcome measures.
Between-group analysis revealed a significant decline in the mean score of ISI at week 16 (P < 0.05) and for SUDS at week 20 (P < 0.05) in group B compared to group A. Similarly, within-group analysis also revealed a statistically significant reduction of the mean score in ISI and SUDS scores at week 4 and 8 (P < 0.05) in both groups. ADRs occurred more frequently in group A (14%) than in group B (5%). Assessments of causality showed that the majority of cases were possible.
For individuals who were resistant to 0.5 mg of clonazepam, adding CBT-i with low-dose clonazepam is a viable alternative to increasing the dose to 1 mg.

Objective: The current study aimed to compare the impact of acupressure and clonazepam tablets on the quality of sleep in hemodialysis patients in light of the rising prevalence of chronic kidney disease (CKD), the high prevalence of sleep disturbance in these patients, and the side effects of hypnotic drugs. Method : A total of 60 patients were selected for this randomized, controlled clinical trial and randomly assigned to two groups. For two weeks during the researcher\'s evening shift, one group received acupressure (six spots bilaterally for three minutes each day). The opposing group was administered clonazepam tablets (0.5 mg) for two weeks. The Pittsburgh Sleep Quality Index (PSQI), which measures sleep quality, was used to compare sleep in the two groups before and after the intervention. Results: There was no statistically significant difference between the two groups prior to the intervention (P = 0.75) in terms of the mean pre-intervention PSQI scores for the acupressure and clonazepam groups, which were 15.83 ± 1.51 and 16.17 ± 0.91, respectively. However, the average PSQI scores after the intervention in the clonazepam and acupressure groups were 13.25 ± 2.88 and 8.97 ± 4.29, respectively, indicating a statistically significant difference (P < 0.0001). Both the acupressure and the clonazepam groups showed improvements in their post-intervention sleep quality among the patients. However, when the percentage changed in the mean scores of the total score and all of the PSQI components were calculated for each group, it became clear that acupressure was more effective at enhancing sleep than clonazepam tablets. Conclusion: The findings of the present investigation demonstrate that acupressure has a greater impact on patients\' sleep quality compared to clonazepam tablets. Depending on the circumstances, acupressure can be used as a simple, safe, and non-drug way to enhance hemodialysis patients\' quality of sleep.

BACKGROUND: This report describes the successful rescue of a 12-year-old girl who ingested large quantities of clonazepam tablets.
METHODS: The patient was promptly treated with flumazenil and hemoperfusion to alleviate the symptoms of central depression. Therapeutic drug monitoring was used to evaluate detoxification efficacy. The authors analyzed the rescue protocol for clonazepam poisoning based on the pathophysiology, clinical manifestations, and pharmacokinetics of clonazepam overdose.
RESULTS: The patient responded well to the treatment and was discharged from the hospital without adverse events.
CONCLUSIONS: This case study demonstrated the effectiveness and safety of combining flumazenil with hemoperfusion as a treatment for clonazepam poisoning. This study aimed to provide insights into more effective methods for treating clonazepam overdose and contribute to the ongoing issue of managing this condition.

Antiseizure medications (ASMs) are among the most commonly prescribed teratogenic drugs in women of childbearing age. Limited data exist on utilization patterns across different indications for therapy and for the newer-generation ASMs in this population. Thus, we assessed the pattern of ASM use in women of childbearing age with epilepsy and nonepilepsy indications (pain and psychiatric disorders).
We conducted a retrospective analysis of deidentified administrative data submitted to the Optum Clinformatics database. Eligible participants included women aged 12-50 years who filled ASMs between year 2011 and 2017. Participants were followed from date of index prescription filled to study end or insurance disenrollment, whichever came first. For the overall cohort and potential therapy indications, we assessed the type and frequency of ASMs filled; proportion of participants on monotherapy, polytherapy, or treatment switching; and duration of continuous use. Trends were characterized using annual percent change from study start to study end.
Our analysis included 465,131 participants who filled 603,916 distinct ASM prescriptions. At baseline, most of the participants had chronic pain (51.0%) and psychiatric disorders (32.7%), with epilepsy the least common (0.9%). The most frequently dispensed were diazepam (24.3%), lorazepam (20.1%), gabapentin (17.4%), clonazepam (12.7%), topiramate (11.3%), and lamotrigine (4.6%). Significant linear increase in trends were observed with gabapentin (annual percent change [95% CI]: 8.4 [7.3-9.4]; p < 0.001) and levetiracetam (3.4 [0.7-6.2]; p = 0.022) and decreasing trends for diazepam (-3.5 [-2.4 to 4.5]; p < 0.001) and clonazepam (-3.4 [-2.3 to 4.5]; p = 0.001). No significant change in trend was observed with valproate (-0.4 [-2.7 to 1.9]; p = 0.651), while nonlinear changes in trends were observed with lorazepam, topiramate, lamotrigine, and pregabalin.
Decreasing trends were observed with older ASMs in the overall cohort and across the potential indications for therapy. Conversely, increasing trends were seen with the newer ASMs. Considering the risk of teratogenicity associated with the newer medications largely unknown, counseling and education in addition to a careful consideration of the benefits vs potential risks should remain pivotal when prescribing ASMs for women of childbearing age.

This study delves into the interaction between benzodiazepine (BZD) drugs and 2-hydroxypropyl-β-cyclodextrin (2HPβCD), a cyclodextrin (CD) known to improve drug delivery and enhance therapeutic outcomes. We find that the 2HPβCD\'s atoms become more rigid in the presence of chlordiazepoxide (CDP), clonazepam (CLZ), and diazepam (DZM), whereas they become more flexible in the presence of nordazepam (NDM) and nitrazepam (NZP). We also investigated the structure of 2HPβCD and found that loading these drugs increases both the area and volume of the 2HPβCD cavity, making it more suitable for drug delivery. Moreover, this research found that all drugs exhibited negative values for the binding free energy, indicating thermodynamic favorability and improved solubility. The binding free energy order of the BZDs was consistent in both molecular dynamics and Monte Carlo methods, with CDP and DZM having the highest affinity for binding. We also analyzed the contribution of different interaction energies in binding between the carrier and the drugs and found that Van der Waals energy is the primary component. Our results indicate that the number of hydrogen bonds between 2HPβCD/water slightly decreases in the presence of BZDs, but the hydrogen bond\'s quality remains constant.

BACKGROUND: Hemifacial spasm (HFS) is an involuntary intermittent twitching of the facial muscles. Medical and surgical treatments can be considered for HFS. Among medical treatments, clonazepam is a benzodiazepine used to treat epilepsy, psychiatric symptoms, and movement disorders. This study aimed to investigate the efficacy and safety of clonazepam for the treatment of HFS.
METHODS: This randomized double-blind placebo-controlled trial prospectively enrolled patients with HFS aged 20-79 years. The patients were randomly assigned in a 1:1 ratio to receive either clonazepam (0.5 mg twice daily) or a placebo for 4 weeks. All participants underwent clinical assessment and laboratory tests at baseline and visit 2. The primary endpoint was the clinical global impression-improvement (CGI-I) score at visit 2.
RESULTS: A total of 34 patients with HFS assessed for eligibility were enrolled between April 2015 and November 2016. Among them, two patients were withdrawn before randomization. Thus, the intention-to-treat analysis included 32 patients with HFS. The median CGI-I scores at visit 2 did not differ significantly between the clonazepam (3; range 1-6) and placebo (3.5; range 3-5) groups. In the safety analysis, only mild or no serious adverse events were observed.
CONCLUSIONS: The results of this study demonstrated the safety of clonazepam in patients with HFS. However, clonazepam did not show a statistically significant effect on HFS. Further studies are needed to provide evidence of the clinical benefits in patients with HFS.

BACKGROUND: Sleep disturbances are common non-motor symptoms of Parkinson\'s disease (PD). We aimed to compare the safety and efficacy of trazodone with melatonin and clonazepam in patients with PD and sleep complaints.
METHODS: This single-center, double-blind, randomized clinical trial was conducted on PD patients with subjective sleep complaints. Eligible patients were randomized 1:1:1 to receive melatonin 3 mg/day, clonazepam 1 mg/day, or trazodone 50 mg/day for 4 weeks. The primary outcome measure was the changes in Pittsburgh Sleep Quality Index (PSQI) scores. The mean change in Epworth Sleepiness Scale (ESS) and RBD screening questionnaire (RBDSQ) was considered as the secondary outcome measures.
RESULTS: A total of 112 eligible patients were randomized and 93 participants, melatonin (n = 31), trazodone (n = 31), and clonazepam (n = 31), completed the study. There was a significant decrease in PSQI scores after 4 weeks of treatment in all groups. The mean changes of PSQI from baseline were similar among the treatment arms (P = 0.325). Mean changes of RBDSQ and ESS from baseline were significantly different between study arms (P < 0.05). Melatonin intake was associated with a higher decrease in RBDSQ score compared to trazodone (P = 0.011) and clonazepam (P = 0.004). Trazodone intake was associated with a higher decrease in ESS score compared to clonazepam (P = 0.010). Mild adverse events were reported in three patients in the clonazepam, two patients in the trazodone group, and none in the melatonin group.
CONCLUSIONS: Trazodone 50 mg/day, clonazepam 1 mg/day, and melatonin 3 mg/day were all tolerable and effective in improving sleep quality in patients with PD.
BACKGROUND: Iranian Registry of Clinical Trials (registration number; IRCT20170821035819N2).