UNASSIGNED: Healthcare providers may be utilizing central nervous system (CNS) depressants to reduce opioid use due to recent changes in public policy. Combination use of these agents with opioids increases the risk of respiratory depression and death. Healthcare expenditures by individuals using these drug combinations have not been previously quantified. We sought to characterize healthcare costs and expenditures associated with a population reporting concurrent CNS depressants and opioid use compared with nonopioid analgesics in the United States from 2009 to 2019.
UNASSIGNED: A serial cross-sectional design was used to compare the healthcare expenditures of adult Medical Expenditure Panel Survey respondents who were prescribed nonopioid analgesics, opioids only, opioids/benzodiazepines (BZD), opioids/BZD/skeletal muscle relaxants (SMR), or opioids/gabapentin (gaba) using pooled data from 2009 to 2019. Expenditure (cost and resource utilization) categories included inpatient, outpatient, office-based, and prescription medicine. Average marginal effects were used to compare survey-weighted annual costs and resource utilizations across the groups as compared to nonopioid analgesic respondents, adjusted for covariates.
UNASSIGNED: A weighted total of 34 241 838 individuals were identified. Most were opioid-only respondents (46.5%), followed by nonopioid analgesic (43.4%), opioid/BZD (5.3%), opioid-gaba (3.5%), and opioid/BZD/SMR respondents (1.3%). In comparison to the study groups with nonopioid analgesics, opioid-gaba users had the highest significant incremental cost difference among the different pairings (+$11 684, P < .001). Opioid-gaba, opioid/BZD, and opioid/BZD/SMR respondents had significantly higher inpatient, emergency department, and prescription drug costs and use compared to nonopioid analgesic respondents. Opioid-only respondents had higher outpatient and office-based costs and visits compared to nonopioid analgesic respondents.
UNASSIGNED: As healthcare providers seek to utilize fewer opioids for pain management, attention must be paid to ensuring safe and effective use of concurrent CNS depressants to mitigate high healthcare costs and burden.

BACKGROUND: Low back pain (LBP) is a leading cause of disability worldwide and has posed numerous health and socioeconomic challenges. This study compared whether nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with tramadol, tizanidine or placebo would be the best treatment regime to improve the Roland Morris Disability Questionnaire (RMDQ) scores at 1 week.
METHODS: This was a multi-center, double-blind, randomized, and placebo-controlled trial including adult patients with acute LBP and sciatica in three emergency departments in Hong Kong. Patients were randomized to the receive tramadol 50 mg, tizanidine 2 mg, or placebo every 6 hours for 2 weeks in a 1:1:1 ratio. The RMDQ and other secondary outcomes were measured at baseline, Day 2, 7, 14, 21, and 28. Data were analyzed on an intention to treat basis. Crude and adjusted mean differences in the changes of RMDQ and NRS scores from baseline to Day 7 between tizanidine/tramadol and placebo were determined with 95% confidence intervals.
RESULTS: Two hundred and ninety-one patients were analyzed with the mean age of 47.4 years and 57.7% were male. The primary outcome of mean difference in RMDQs on Day 7 (compared with baseline) was non-significant for tizanidine compared with placebo (adjusted mean difference - 0.56, 95% CI -2.48 to 1.37) and tramadol compared with placebo (adjusted mean difference - 0.85, 95% CI -2.80 to 1.10). Only 23.7% were fully compliant to the treatment allocated. Complier Average Causal Effect analysis also showed no difference in the primary outcome for the tizanidine and tramadol versus placebo.
CONCLUSIONS: Among patients with acute LBP and sciatica presenting to the ED, adding tramadol or tizanidine to diclofenac did not improve functional recovery.

UNASSIGNED: The objective of this case series is to describe the clinical signs and outcome of cyclobenzaprine ingestion in two dogs treated with intralipid emulsion (ILE) and supportive care.
UNASSIGNED: Two dogs presented for evaluation of cyclobenzaprine ingestion. A 4-year-old female spayed Rat Terrier (dog 1) presented within 4 h of ingestion of cyclobenzaprine (between 9.7 and 25.9 mg/kg). The dog experienced abnormal behavior, agitation, tremors, tachycardia, and hypertension. There were no significant clinicopathological abnormalities. The dog was treated with ILE, cyproheptadine, and activated charcoal. All clinical signs resolved after treatment. A 5-month-old female intact mixed-breed dog (dog 2) presented after ingestion of an unknown amount of cyclobenzaprine 2-3 h prior to presentation. The dog experienced dull mentation, tremors, loss of gag reflex, tachycardia, and hypertension. There were no significant clinicopathological abnormalities. Orogastric decontamination was performed via gastric lavage, and activated charcoal was given via orogastric tube, followed by ILE. All clinical signs resolved after therapeutic intervention.
UNASSIGNED: This is the first report documenting clinical signs of cyclobenzaprine toxicity in two dogs followed by successful treatment with gastric emptying, ILE, and supportive care.

UNASSIGNED: Many natural bioactive chemicals have been shown to have functional activity, suggesting that they could be useful in the treatment and management of a wide range of chronic conditions. Flavonoids, which include gallic acid (GA), are the most abundant polyphenols found in nature. Skeletal muscle relaxants are drugs that reduce undesired spasms while maintaining awareness and reflexes unaffected. The purpose of this investigation was to determine if GA has any skeletal muscle relaxant properties in experimental animal models.
UNASSIGNED: The muscle relaxant activity of three dosages of GA (5, 10, and 20 mg/kg) was compared to that of normal diazepam (5 mg/kg) utilizing climbing, chimney, and modified Kondziela\'s inverted tests. An analysis of variance (ANOVA) and a post-ANOVA Tukey multiple comparisons test were used to assess the data.
UNASSIGNED: Animals given 10 and 20 mg/kg of GA had a great deal of trouble climbing up the chain, presumably because their muscles were relaxed. Similarly, rats given a high dose of GA (20 mg/kg) had a significantly (P < 0.05) longer response time in the chimney test, indicating a lack of attention and slowed muscle tone, resulting in problems with motor coordination. In inverted testing, animals given a high dose of GA had a significantly (P < 0.01) reduced holding capacity on the mesh for a longer period of time. A decrease in holding time is caused by a decrease in muscular contraction. The low dose of GA, on the other hand, failed to show muscle relaxant effect in any of the three models.
UNASSIGNED: As a conclusion, our data show that GA has a dose-dependent skeletal muscle relaxant effect when administered orally to mice.

BACKGROUND: A series of phenylurea derivatives were designed and synthesized, The target compounds were subjected to pharmacological studies. Various other parameters such as physicochemical properties, computational studies, and % similarity were also calculated.
METHODS: The synthesis of the target compounds has been carried out by reaction of Phenylurea with chloroacetyl chloride to afford 1-(2-chloroacetyl)-3-phenylurea, which further reacted with substituted anilines. All the reactions were monitored by TLC. All the target compounds were purified by recrystallization and characterized by spectroscopic methods. Physicochemical parameters and Log P values of the synthesized derivatives were also calculated. It identified compounds that have the prospect to cross the blood-brain barrier (BBB) and are CNS active. Skeletal muscle relaxant activity was also carried out using the Rotarod method.
RESULTS: The data of Log P indicated that the synthesized compounds have the potential to cross the BBB, so they are CNS active. Pharmacological activities of the derivatives showed that the compounds containing chloro group have moderate skeletal muscle relaxant activity. The test compounds possess significant differences between the control group and the treated group.
CONCLUSIONS: The synthesized derivatives containing chloro group were found to be more potent when compared to standard drug Diazepam. Various others parameters studied revealed that the drug has the potency to cross the blood-brain barrier.

Tolperisone is a nonopioid, centrally acting muscle relaxant in clinical development in the USA for the treatment of symptoms associated with acute, painful muscles spasms of the back. CLN-301, RESUME-1, is a 14-day double-blind, randomized, placebo-controlled, parallel-group Phase III study of the efficacy and safety of tolperisone administered orally three-times daily in 1000 male and female subjects at approximately 70 clinical sites in the USA experiencing back pain due to or associated with muscle spasm of acute onset. Tolperisone is a promising therapeutic for managing acute, painful muscle spasms of the back as it appears to lack the off-target CNS effects often seen with conventional skeletal muscle relaxants. Clinical Trials registration number: NCT04671082.

UNASSIGNED: Use of skeletal muscle relaxants (SMRs) for acute muscle spasm is confounded by central nervous system adverse events (AEs), including somnolence. Tolperisone is an SMR that does not appear to be associated with somnolence. The aim of this study was to assess the safety and efficacy of tolperisone versus placebo in subjects with acute muscle spasm of the back.
UNASSIGNED: STAR (NCT03802565) was a double-blind, randomized, placebo-controlled phase 2 study in subjects with back pain due to acute muscle spasm. Subjects were randomized 1:1:1:1:1 to tolperisone 50, 100, 150, or 200 mg three times daily (TID) or placebo for 14 days. The primary efficacy endpoint was subject-rated pain \"right now\" using a numeric rating scale on day 14.
UNASSIGNED: Subjects (tolperisone, n=337; placebo, n=78) were enrolled at 38 US clinical sites. Tolperisone was well tolerated, with AEs in 18.1% of subjects receiving tolperisone versus 14.1% of subjects receiving placebo. Headache (7.1%) and diarrhea (2.4%) were the most frequent AEs in tolperisone-treated subjects versus 3.8% and 0%, respectively, in placebo-treated subjects. Somnolence was reported in 1.2% and 2.6% of subjects treated with tolperisone and placebo, respectively. Mean change from baseline in numeric rating scale score of pain \"right now\" on day 14 was -3.5 for placebo versus -4.2, -4.0, -3.7, and -4.4 for tolperisone 50, 100, 150, and 200 mg TID, respectively (linear test of trend on the least-squares mean difference [treatment-placebo]; p=0.0539). In an analysis of pairwise estimates (treatment-placebo), the greatest numerical difference and significance were observed for tolperisone 200 mg TID (p=0.0040). Several secondary endpoints trended toward significance for tolperisone 200 mg TID versus placebo.
UNASSIGNED: Tolperisone 200 mg TID may be a promising treatment for acute muscle spasm, without the somnolence associated with SMRs. The safety and efficacy of tolperisone should be evaluated in a phase 3 trial.

Valeriana officinalis L. root extracts are traditionally taken for their sedative and anxiolytic properties and are also used for muscle relaxation. Relaxant effects were clearly observed on smooth muscle whereas data on effects on skeletal muscle are scarce and inconsistent. The aim of this study was to assess whether a standardized extract (SE) of V. officinalis had myorelaxant effects by decreasing skeletal muscle strength and/or neuromuscular tone in mice. Mice received an acute dose of V. officinalis SE (2 or 5 g/kg per os) or tetrazepam (10 mg/kg ip), a standard myorelaxant drug. Thirty minutes later, the maximal muscle strength was measured using a grip test, while global skeletal muscle function (endurance and neuromuscular tone) was assessed in a wire hanging test. Compared to tetrazepam, both doses of V. officinalis SE induced a pronounced decrease in skeletal muscle strength without any significant effects on endurance and neuromuscular tone. This study provides clear evidence that the extract of V. officinalis tested has a relaxant effect on skeletal muscle. By decreasing skeletal muscle strength without impacting endurance and neuromuscular tone, V. officinalis SE could induce less undesirable side effects than standard myorelaxant agents, and be particularly useful for avoiding falls in the elderly.

A simple, sensitive and reproducible reversed phase ultra performance liquid chromatography (RP-UPLC) coupled with a photodiode array detector method was developed for the quantitative determination of metaxalone (META) in pharmaceutical dosage forms. The method is applicable to the quantification of related substances and assay of drug product. Chromatographic separation was achieved on an Acquity(®) HSS-T3 (100 mm x 2.1 mm, 1.7 μm) column. The optimized isocratic mobile phase consists of a mixture of water, methanol, acetonitrile and triethylamine in the ratio of 50:25:25:0.1 % v/v (pH adjusted to 6.3 with orthophosphoric acid). The eluted compounds were monitored at 230 nm for META assay and 205 nm for related substances, the flow rate was 0.3 mL/min, and the column oven temperature was maintained at 45°C. The developed method separated META from its two known and two unknown impurities within 6.0 min. Metaxalone was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Metaxalone was found to degrade significantly in base stress condition, degrade slightly in oxidative stress condition and remain stable in acid, hydrolytic, thermal and photolytic degradation conditions. All impurities were well resolved from each other and from the main peak, showing the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines.

METHODS: We performed a multicentric, randomized, comparative clinical trial. Eligible patients were randomly assigned to receive 150 mg of Tolperisone thrice daily or 8 mg of Thiocolchicoside twice daily for 7 days.
OBJECTIVE: To assess the efficacy and tolerability of Tolperisone in comparison with Thiocolchicoside in the treatment of acute low back pain with spasm of spinal muscles.
BACKGROUND: No head on clinical trial of Tolperisone with Thiocolchicoside is available and so this study is done.
METHODS: The assessment of muscle spasm was made by measuring the finger-to-floor distance (FFD), articular excursion in degrees on performing Lasegue\'s maneuver and modified Schober\'s test. Assessment of pain on movement and spontaneous pain (pain at rest) of the lumbar spine was made with the help of visual analogue scale score.
RESULTS: The improvement in articular excursion on Lasegue\'s maneuver was significantly greater on day 3 (p = 0.017) and day 7 (p = 0.0001) with Tolperisone as compared to Thiocolchicoside. The reduction in FFD score was greater on day 7 (p = 0.0001) with Tolperisone. However there was no significant difference in improvement in Schober\'s test score on day 3 (p = 0.664) and day 7 (p = 0.192). The improvement in pain score at rest and on movement was significantly greater with Tolperisone ((p) = 0.0001).
CONCLUSIONS: Tolperisone is an effective and well tolerated option for treatment of patients with skeletal muscle spasm associated with pain.