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Background Many clinical toxicology laboratories receive urine specimens in urine cups that contain point of care (POC) drug testing strips. We conducted this study to evaluate the effect on the stability of commonly measured drugs in the clinical toxicology laboratory when urine is exposed to POC urine drug testing cups. Methods Drug free urine was spiked with 85 drugs that were measured by a validated liquid chromatography mass spectrometry (LCMS) method after exposure to POC urine drug testing cups at ambient and 2–6 °C temperatures. Alterations ≥20% were defined as significant changes in the drugs concentration. Results Concentrations of amitriptyline, cyclobenzaprine, fentanyl, fluoxetine, flunitrazepam, nortriptyline, paroxetine, and sertraline were significantly reduced when urine specimens were stored inside POC urine drug testing cups for 24 h at ambient temperature. Storage of urine in urine chemistry dipsticks reduced the concentration of several drugs. When spiked urine was exposed to an increasing number of POC urine drug testing strips, the concentrations of some drugs were reduced in a dose-dependent manner. The drugs that were absorbed by POC urine drug testing strips were partially back extracted from the strips. Conclusion Exposure of urine specimens to POC urine drug testing strips reduces the concentration of several drugs measured by LCMS method.

As part of early drug development, preformulation studies are used to comprehensively explore the properties of new drugs. In particular, this includes the biopharmaceutical characterization and evaluation of impacting factors (e.g. excipients, microenvironmental conditions etc.) by permeation studies. To overcome the limitations of current studies, a novel standardized ex vivo procedure using esophageal mucosa as surrogate has been established successfully and applied to preformulation studies for oromucosal delivery of cyclobenzaprine hydrochloride, a tricyclic muscle relaxant with potential for psychopharmacotherapeutic use. By using the standardized ex vivo permeation process, a twofold enhancement of permeability (0.98 ± 0.16 to 1.96 ± 0.10 * 10-5 cm/s) was observed by adjustment and controlling of microenvironmental pH, empowering a targeted and effective development of sublingual formulations. Predictivity and suitability were superior compared to in vitro experiments using artificial biomimetic membranes, revealing a determination coefficient (R2) of 0.995 vs. 0.322 concerning pH-dependent permeability of cyclobenzaprine. In addition, diffusion properties were extensively examined (e.g. influence of mucosal thicknesses, tissue freezing etc.). The alignment of the study design regarding physiologically/clinically relevant conditions resulted in ex vivo data that allowed for the estimation of plasma AUC levels in the extend of reported in vivo ranges.

Made available in DSpace on 2022-04-28T19:30:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-05-20 The present work describes the performance of a new voltammetric sensor based on the modification of glassy carbon electrodes (GCE) with carbon black (CB) and botryosphaeran (BOT) (CB-BOT/GCE) for the electroanalytical determination of cyclobenzaprine. BOT is a fungal exocellular (1→3)(1→6)-β-ᴅ-glucan, which was used to improve the adherence of CB onto the surface of GCE. The electrochemical characterisation was performed by electrochemical impedance spectroscopy which showed an improvement in the transfer of electrons on the surface of the sensor developed in relation to the unmodified (bare) GCE. The voltammetric behaviour of cyclobenzaprine was studied using bare GCE, BOT/GCE, CB/GCE, and CB-BOT/GCE. All electrodes presented an oxidation peak (+ 1.0 V) for cyclobenzaprine, while the cyclobenzaprine peak intensity on CB-BOT/GCE was found to be 480% higher than the bare GCE. Through employing square-wave voltammetry, the analytical curve was found to be linear over the concentration range of 2.0 to 20.6 μmol L−1 (in 0.1 mol L−1 NaCl solution) with a detection limit (based on 3-sigma) of 0.63 μmol L−1. The developed electrochemical sensor exhibited excellent sensitivity and selectivity and was successfully applied for the voltammetric determination of cyclobenzaprine in pharmaceutical, biological, and environmental samples for the first time using the CB-BOT/GCE electrochemical sensing platform. Departamento de Química Centro de Ciências Exatas Universidade Estadual de Londrina, Rodovia Celso Garcia Cid, 445 Km 380 Faculty of Science and Engineering Manchester Metropolitan University, Chester Street Departamento de Química e Bioquímica Escola de Ciência e Tecnologia Universidade do Estado de São Paulo Programa de Pós-Graduação em Ciências Fisiológicas Departamento de Ciências Fisiológicas Centro de Ciências Biológicas Universidade Estadual de Londrina Beta-Glucan Produtos Farmoquímicos EIRELI UTFPR Câmpus Londrina, Lote 24A, Bloco Zircônia, Avenida João Miguel Caram 731

Tissue-based ex-vivo studies on the oromucosal permeability of drugs are often insufficiently adapted to physiological and clinical conditions, which limits their predictivity. Moreover, the scientific community demands for the standardization of ex-vivo studies, since conceptual limitations (e.g. low sensitivity of analytical methods, insufficient monitoring, different designs) restrict the wide implementation in preclinical drug development. Therefore, an innovative ex-vivo permeation process consisting of novel Kerski diffusion cell coupled to fully automated sampling and sample preparation with LC-MS/MS quantification was developed and standardized. Novel assays for routine examination of tissue integrity and viability were developed and embedded in a comprehensive analytical control system. The high level of standardization and automation reduced the differences of between-run to within-run precision to ≤ 0.27 % CV. Successful validation proved a broad calibration range of 0.93-952.38 ng/mL of the model drug cyclobenzaprine with guideline-compliant relative errors from -7.9-12.6 % (between-run accuracy). Consequently, the method allowed the physiological-clinical alignment of the study conditions to therapeutic doses and the short residence time of intraoral drugs (sampling times 1-60 min). Applicability was demonstrated by assessing the oromucosal permeability for different sublingual cyclobenzaprine hydrochloride formulations representing the excipient selection as a common aspect during galenic development. Thereby, expressive evaluation of the dosage forms was achieved resulting in an improved permeation by replacing croscarmellose into polyvinylpyrrolidone (cumulative amount of 42.6 vs. 112.6 μg/cm²). Thus, the automated permeation process ensured lean, standardized and reproducible assessment of oromucosal permeability within quality-controlled academic and regulatory environments. Simultaneously, the improved ex-vivo predictivity through physiological-clinical adjustments facilitates the reduction of costly in-vivo studies.

The aim of this study was to investigate the effect of backing films on transdermal delivery of cyclobenzaprine patch. Different backing films were chosen to prepare the cyclobenzaprine transdermal patch. The cumulative amount of cyclobenzaprine released from different patches was evaluated in vitro. To investigate the interaction between cyclobenzaprine and backing films, the partitioning experiments and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy were performed. The cumulative amount of cyclobenzaprine released from the patch with Cotran™ 9700 as backing film was less than that of other patches with different backing films. Furthermore, the cumulative amount of cyclobenzaprine released from the patch with Cotran™ 9700 as backing film decreased significantly after 7 d storage at room condition. The partitioning experiments indicated a strong adsorption of cyclobenzaprine onto the Cotran™ 9700, which could explain the decrease of cumulative amount of cyclobenzaprine released from the patch with Cotran™ 9700 as backing film. According to the ATR-FTIR results, there was no interaction between Cotran™ 9700 and cyclobenzaprine. The effect of backing films on the release behavior of cyclobenzaprine transdermal patch was attributed to the adsorption of cyclobenzaprine onto the Cotran™ 9700.

BACKGROUND CONTEXT Recent studies suggest as much as 25% of patients undergoing spine surgery are still on opioids two years later. In response, we developed protocols to minimize opioid consumption following elective spine surgery. Our goal was to evaluate patients undergoing single-level Anterior Lumbar Interbody Fusions (ALIF ± posterior fixation) on MMPC compared to patients who were not (nonMMPC). PURPOSE To determine if the combination of an oral preoperative pain cocktail with transverse abdominis plane (TAP) block (multi-modal pain control: MMPC) will reduce length of stay (LOS), ileus, and in-hospital opioid consumption. STUDY DESIGN/SETTING Retrospective chart review. PATIENT SAMPLE Consecutive patients undergoing single-level ALIF for degenerative lumbar conditions by a single-surgeon. OUTCOME MEASURES Length of stay (LOS), incidence of ileus and in-hospital opioid consumption. METHODS A retrospective review of a prospective, single-surgeon, surgical database was utilized for consistency in technique. Consecutive patients undergoing single-level ALIF for degenerative lumbar conditions were identified before and after initiation of the MMPC. The MMPC consisted of a preop oral regimen of cyclobenzaprine (10mg), gabapentin (600mg), acetaminophen (1g) and methadone (10mg). Postoperatively they received a bilateral transverse abdominis plane (TAP) block with 0.5% Ropivicaine. Our primary outcome was total, in-hospital opioid consumption (morphine milligram equivalents: MME). RESULTS There were 68 patients in the MMPC cohort and 39 in the nonMMPC cohort. There was no difference in baseline demographics such as sex, BMI, smoking, or preoperative opioid use between the two groups. The MMPC cohort was older (56.7 vs 51.1 years, p=0.026). Similar rates of ileus (4 vs 6, p=0.102), no difference in LOS (3.8 vs 4.5, p=0.246) and no difference in index hospital costs was found. Although there was no difference in day of surgery MMEs (58.5 vs 68.9, p=0.387), cumulative MMEs each day after surgery was significantly lower in the MMPC cohort, with final cumulative MMEs being reduced by 62% (120.2 vs 314.8, p CONCLUSIONS The use of a MMPC regimen in patients undergoing single-level ALIF for degenerative conditions reduced opioid consumption starting on POD 1, resulting in a cumulative reduction of 62%. Further research should strive to minimize opioid use and the downstream effects. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

A rapid and sensitive liquid chromatography–tandem mass spectrometry method was developed and validated for the quantification of cyclobenzaprine in dog plasma. After extracted with organic solvent, post-treatment samples were separated on an Agela C18 column interfaced with a triple quadrupole tandem mass spectrometer in positive electrospray ionization mode. Multiple reaction monitoring was performed using the transitions of m / z 276.2 → 216.1 and m / z 325.1 → 109.0 to quantify cyclobenzaprine and escitalopram (internal standard), respectively. The mobile phase consisted of acetonitrile: 5 mM ammonium acetate: formic acid (90:10:0.01, v/v/v) at a flow rate of 0.3 ml/min. The total analysis time was 2.4 min. The method was linear over the concentration range of 0.0200–10.0 ng/ml. The intra- and inter-day precision was within 12.8% in terms of relative standard deviation (RSD%) and the accuracy within 5.6% in terms of relative error. This method was successfully applied in a pharmacokinetic study of extended-release cyclobenzaprine in dogs.

Background Pain, swelling and trismus are undesirable effects of extraction of impacted mandibular third molars. The authors conducted a study to evaluate the effectiveness of the muscle relaxant cyclobenzaprine when used as a supplement to cryotherapeutic, antibiotic and steroidal anti-inflammatory treatment with the aim of reducing undesirable consequences after third-molar extraction. Methods The authors conducted a prospective, randomized, double-masked, placebo-controlled clinical trial involving 50 participants aged 18 to 29 years randomly assigned to receive cyclobenzaprine or the placebo. The authors used a split-mouth design, so each participant acted as his or her own control. For each participant, the authors extracted one impacted mandibular third molar on each side of the mouth at different times. Participants received 10 milligrams of cyclobenzaprine or a placebo once per day the day before surgery, the day of surgery and the first day after surgery. The authors assessed the participants' postoperative pain by means of a visual analog scale at four, six, eight, 12, 24 and 48 hours. They measured the participants' swelling and maximal interincisor distance at 48 hours and seven days. Results The authors assessed both sides of each participant's mouth for differences in pain, swelling and trismus. They found no statistically significant differences between sides of the mouth regarding these three variables. Conclusions The results of this trial indicate that the influence of cyclobenzaprine over pain, swelling and trismus does not justify prescribing additional medication for patients undergoing third-molar extraction. Clinical Implications The muscle relaxant cyclobenzaprine was ineffective in reducing pain, swelling and trismus after third-molar extraction.

Background: Low back pain is a leading reason for primary care visits. Many treatment options are available, but some lack scientific support. Objective: The aim of this review was to discuss the etiology of low back pain and the relative risks and benefits of muscle relaxants commonly prescribed for the management of back pain. Methods: We searched Intercontinental Marketing Services data for January 2003 through January 2004 to determine the most commonly prescribed agents for the management of musculoskeletal pain. Carisoprodol, cyclobenzaprine hydrochloride, and metaxalone represented >45% of all such prescriptions. Cochrane Library, MEDLINE, and EMBASE databases were searched (time frame: 1960 through January 2004; search terms: back pain, carisoprodol, cyclobenzaprine, metaxalone, muscle relaxants , and pharmacotherapy ) and reference lists of identified articles were hand-searched. Results: Three trials of carisoprodol (N = 197) were located in the Cochrane Library database. Two double-blind, randomized, placebo-controlled trials evaluating the safety and efficacy of cyclobenzaprine hydrochloride (N = 1405) were identified in the literature. Three double-blind, placebo-controlled trials were identified for metaxalone (N = 428) in 2 reports. The types of adverse events seen with these agents involved the central nervous system, including drowsiness/sedation, fatigue, and dizziness. However, the efficacy of cyclobenzaprine hydrochloride was shown to be independent of its sedative effects, which were dose related. The potential for abuse with carisoprodol is of growing concern. Conclusions: Analgesic pain management for low back pain due to muscle spasm may be combined with a muscle relaxant. Cyclobenzaprine hydrochloride has the most recent and largest clinical trials demonstrating its benefit, but carisoprodol and metaxalone also appear to be effective. However, carisoprodol's usefulness is mitigated by its potential for abuse.

Study objective: We evaluate the analgesic and side effects of adding cyclobenzaprine to ibuprofen in emergency department patients with acute myofascial strain. Methods: A randomized, prospective, double-blind study was conducted at an urban teaching ED with an annual census of 44,000. One hundred two patients aged 18 to 70 years with acute myofascial strain caused by minor trauma within the prior 48 hours were included, and 77 patients completed the protocol. Each patient received a single dose of 800 mg of ibuprofen in the ED and a vial of 6 capsules containing 800 mg of ibuprofen to take every 8 hours as needed after discharge from the ED. In addition, 51 patients received a single dose of 10 mg of cyclobenzaprine and a vial of 6 capsules containing 10 mg of cyclobenzaprine to take every 8 hours as needed after discharge from the ED; the remaining 51 patients received an identically labeled placebo capsule and vial of placebo capsules to take every 8 hours as needed after discharge from the ED. Patients rated the intensity of their pain on a 100-mm visual analog scale (VAS) at baseline; 30, 60, 90, 120, and 180 minutes; and 24 and 48 hours after treatment. Telephone follow-up was obtained at 24 and 48 hours, and side effects were elicited at 24 and 48 hours by means of open-ended questioning. Results: The patients in each group were similar with regard to diagnosis and baseline pain score. The number of patients who did not complete the protocol and the number of those who required additional analgesia were similar in both groups. Over the 48 hours of the protocol, the mean VAS score for the combination group decreased from 60.4 to 35.6, and the mean VAS score for the ibuprofen alone group decreased from 62.2 to 35.4. The mean VAS scores between groups across time was not statistically significant (P=.962, repeated-measures analysis of variance). At both 24 and 48 hours, central nervous system side effects were reported more frequently in the patients receiving cyclobenzaprine (16 [42%] versus 7 [18%] at 24 hours and 15 [39%] versus 5 [13%] at 48 hours, respectively). Conclusion: In ED patients with acute myofascial strain, the addition of cyclobenzaprine to ibuprofen does not improve analgesia but is associated with a greater prevalence of central nervous system side effects.

The deceased was a 35 year old female who was found by her husband in the bathtub with her head and face submerged in the water. Autopsy findings were unremarkable. Toxicological analysis revealed the presence of ethanol (215 mg/dL) and cyclobenzaprine (1.786 mg/l) in the blood. This high concentration of cyclobenzaprine (Flexeril®) in combination with alcohol proved to be fatal.

Summary Electrocardiograph artifacts are known to occur in uncontrolled muscle activity, classically in seizures. With the use of therapeutic hypothermia in post cardiac arrest patients in modern ICUs, occurrence of EKG artifact is common due to shivering in patients. We present a 52-year-old admitted to the intensive care unit post cardiac arrest secondary to cyclobenzaprine overdose been treated with therapeutic hypothermia for cerebral protection. Within 5h of cooling, his cardiac monitor started to show persistent wide complex tachycardia with a rate of more than 300/min. It was decided to give loading dose of amiodarone. Before starting amiodarone it was seen that the arterial line showed a normal waveform with a rate of 70/min and BP of 140/70mmHg. The paradoxical waveform was presumptively attributed to shivering of patient. Patient was paralyzed with vecuronium and the cardiac monitor changed to normal sinus rhythm with a rate of 70/min almost immediately. Arrhythmias are unique among transient pathologies because even in the absence of symptoms and other clinical correlations, they often lead to intensive investigations and treatments. When artifacts mimic arrhythmias, these tests are unnecessary and can be potentially dangerous.

A 65-year-old woman with chronic pain was admitted to the hospital for severe recurrent major depression complicating Parkinson's disease (PD). Pain complaints were closely related to the fluctuating motor syndrome of PD. Specifically, pain was experienced in conjunction with hypomobility, and, as a result, she self-medicated with extra carbidopa/levodopa. A regimen of tramadol and cyclobenzaprine, along with sustained-release carbidopa/levodopa for PD and buproprion for her depression resulted in sustained symptomatic and functional improvement. Craving for, and self-medication with, supplemental carbidopa/levodopa ceased. Theoretical support for synergism among dopamine and opioid neurotransmitter systems can be found in recent literature.

The fungus, Cunninghamella elegans, was used as a microbial model of mammalian drug metabolism to biotransform a tricyclic antidepressant, cyclobenzaprine. Seventy-five percent of this drug at a concentration of 1 mM was metabolized within 72 h by C. elegans grown on Sabouraud dextrose broth. Milligram amounts of fungal metabolites were isolated by reversed-phase high performance liquid chromatography (HPLC) and their structures were characterized by 1H NMR spectroscopy, mass spectrometry, and UV spectroscopy analyses. The major fungal metabolites of cyclobenzaprine were 2-hydroxycyclobenzaprine (59%), N-desmethylcyclobenzaprine (21%), cyclobenzaprine trans-10,11-dihydrodiol (5%), N-desmethyl-2-hydroxy-cyclobenzaprine (3%), 3-hydroxycyclobenzaprine (3%), and cyclobenzaprine N-oxide (1%). These fungal metabolites were used as standards to investigate the metabolism of cyclobenzaprine by rat liver microsomes. Rat liver microsomes also biotransformed cyclobenzaprine to produce similar metabolites as the fungus. The isotope labeling of 2-hydroxycyclobenzaprine by 18O2 and the trans-configuration of the dihydrodiol suggested that these reactions were catalyzed by cytochrome P-450 monooxygenases in C. elegans. These results also demonstrated that the fungal biotransformation system could be used to predict and synthesize the mammalian drug metabolites.

The centrally acting muscle relaxant cyclobenzaprine was thought to be an alpha 2-adrenoceptor agonist that reduced muscle tone by decreasing the activity of descending noradrenergic neurons. In the present study, we examined the effects of cyclobenzaprine on descending neurons by measuring the monosynaptic reflex in rats. Cyclobenzaprine reduced the monosynaptic reflex amplitude dose dependently and this effect was not inhibited by the alpha 2-adrenoceptor antagonists idazoxan and yohimbine. Cyclobenzaprine-induced monosynaptic reflex depression was not attenuated by noradrenergic neuronal lesions produced by 6-hydroxydopamine. However, cyclobenzaprine inhibited monosynaptic reflex facilitation induced by (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, a 5-HT2 receptor agonist, in spinalized rats markedly, and 5-HT depletion by DL-p-chlorophenylalanine inhibited the depressive effect of cyclobenzaprine on the monosynaptic reflex. These results suggest that cyclobenzaprine is a 5-HT2 receptor antagonist and that its muscle relaxant effect is due to inhibition of serotonergic, not noradrenergic, descending systems in the spinal cord.

Cyclobenzaprine (CBP) has a cyclic structure similar to amitriptyline. In overdose, CBP has been suggested to produce the cardiovascular and neurologic toxicity found with the cyclic antidepressants. To examine this possibility, a retrospective chart review of all cases of CBP exposure reported to five regional poison centers was performed for the years 1989-93. There were a total of 750 charts identified for CBP exposure, of which 523 had data sufficient for evaluation. There were 121 polydrug ingestions leaving 402 pure CBP ingestions. Ages ranged from 7 mo to 77 yrs, with a mean of 20 yrs; 26% were 6 yrs or less. Females comprised 63% of the patient group. No deaths occurred. Dysrhythmias beyond sinus tachycardia were infrequent, and none were life-threatening. No seizures occurred. Common effects were lethargy, sinus tachycardia, and agitation, and both hypertension and hypotension were seen. All symptomatic cases with a known time of ingestion were symptomatic within 4 h of ingestion. Doses ingested ranged from 5-1000 mg, with a mean of 133 mg. Asymptomatic and symptomatic patients had a mean dose ingested of 45 mg and 183 mg, respectively. Treatment was primarily gastrointestinal (GI) decontamination and supportive care. Other therapies required were mechanical ventilation, dopamine, fluid bolus, sedation, and foley catheter. Symptoms requiring treatment beyond GI decontamination did not occur with ingestions less than 100 mg. In conclusion, cyclobenzaprine does not appear to produce the life-threatening cardiovascular or neurologic effects of the cyclic antidepressants in doses less than 1 g. Lethargy and anticholinergic effects are prominent, though serious toxicity is infrequent.

Study objectives: Musculoskeletal spasm and pain is a leading cause of physician visits and a frequent cause of disability in people younger than 45 years. Many patients with musculoskeletal spasm and pain are treated only with high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) without muscle relaxants. There are few published studies comparing the efficacy of a muscle relaxant alone or in combination with NSAIDs to support a specific treatment regimen. We are conducting a community-based trial comparing cyclobenzaprine 5 mg (Flexeril 5 mg) administered 3 times daily (tid) alone (Cyc5) or in combination with ibuprofen 400 mg tid (Motrin-IB; Cyc5/Ibu400) or ibuprofen 800 mg tid (Cyc5/Ibu800) to determine whether either over-the-counter or prescription doses of NSAIDs improve treatment outcomes when used in combination with a muscle relaxant. In 2 previous double-blind studies of acute muscle pain, cyclobenzaprine 5 mg tid alone was shown to have efficacy equivalent to 10 mg tid and superior to placebo, and to have fewer adverse events (principally sedation and dry mouth). We test the hypothesis that cyclobenzaprine 5 mg tid plus ibuprofen (400 or 800 mg tid) is not superior to cyclobenzaprine 5 mg tid alone in the treatment of acute muscle spasm and pain. Methods: This was a prospective, randomized, open-label, multicenter, 7-day study of Cyc5 versus Cyc5/Ibu400 or Cyc5/Ibu800 in patients with acute muscle spasm of the back or neck of 14 days' duration or less. Patients' spasm and pain were assessed using an 11-point (0 to 10) patient-rated numeric pain rating score collected by an interactive voice recognition system after 3 and 7 days of therapy. Patients were men and women aged 18 to 65 years. Results: Interim data from 316 patients with acute muscle spasm and pain who completed up to 7 days of therapy (Cyc5, n=102; Cyc5/Ibu400, n=115; Cyc5/Ibu800, n=99) were assessed at baseline and after 3 days (D3) and 7 days (D7) of therapy. The percentages of changes from baseline for muscle spasm and pain scores were as follows: spasm score changes: Cyc5: –35% D3; –55% D7; Cyc5/Ibu400: –37% D7; –59% D7; and Cyc5/Ibu800: –35% D3; –57% D7; and pain score changes: Cyc5: –32% D3; –52% D7; Cyc5/Ibu400: –33% D3; –56% D7; and Cyc5/Ibu800: –32% D3; –53% D7. All 3 treatments had statistically significant improvements from baseline after 3 and 7 days of therapy for spasm and pain ( P P Conclusion: Preliminary results indicate that all treatment arms provide similar improvements in acute muscle spasm and pain. These findings support the hypothesis that cyclobenzaprine 5 mg tid plus ibuprofen (400 or 800 mg tid) is not superior to cyclobenzaprine 5 mg tid alone in the treatment of acute muscle spasm and pain.

back pain in 2000. Among individual drugs, ibuprofen and naproxen accounted for most of the prescriptions for traditional NSAIDs (60%), whereas two-thirds of the prescriptions for muscle relaxants were attributable to cyclobenzaprine, carisoprodol and methocarbamol. Prescription of COX-2 inhibitors or muscle relaxants demonstrated wide variations across different regions. Several individual characteristics including age, race and educational level were associated with the prescription of some of the medications. CONCLUSIONS: Neither traditional NSAIDs, nor COX-2 inhibitors, nor muscle relaxants dominated prescriptions for back pain. However, a small number of individual drugs were attributable to most of the prescriptions for traditional NSAIDs or muscle relaxants. The prescription of some of the medications demonstrated wide variations across different regions or different racial and educational groups. More studies are needed to understand why the variations occurred and how to standardize the prescriptions. Head-to-head comparisons of the relative costs and effectiveness among different categories of the medications, especially those drugs that have been most widely prescribed should also be warranted. DISCLOSURES: No disclosures. CONFLICT OF INTEREST: No Conflicts.

Cyclobenzaprine reduced segmental evoked monosynaptic potentials to a much greater degree in decerebrate as compared with spinal cats. Post-tetanic potentiated responses were also reduced, but to a lesser degree so that the PTP ratio tended to exhibit a dose-related increase, especially in decerebrate preparations. Tonic vibration reflex responses were evaluated in decerebrate and decerbrate-decerebellate cats. In both preparations, reflex contractions elicited by various frequencies of longitudinal muscle vibration appeared equally sensitive to the action of cyclobenzaprine. Consequently, the slope of the line for change in muscle tension, per Hz increase in frequency of vibration in these preparations, exhibited a similar dose-related reduction after cyclobenzaprine. Reflex contractions elicited by vibration amplitudes ranging from 10 to 100μ peak-to-peak were also equally sensitive to drug action. These findings therefore support the concept that the predominant muscle relaxant action of cyclobenzaprine is at the supraspinal level reducing both γ- and α-motoneurone efferent activity. This action does not appear to involve presynaptic mechanisms. It is further suggested that cyclobenzaprine exerts its pharmacologic action upon reticulospinal rather than on vestibulospinal pathways.

Experiments were performed on decerebrate cats to determine whether CBZ acted as a general depressant to spinal cord neurones or whether the depression was selective to certain groups of neurones. At doses which appreciably affected motoneurone pools, CBZ had no depressant effect on Renshaw or IA inhibition; most spontaneously active neurones in Rexed layers V and VI, and brainstem reticular formation cells were depressed by CBZ. These results indicate that CBZ does not have a general depressant action on spinal cord neurones. Although some direct action on the spinal cord may be present, the major effects are secondary to an apparent action on specific neurones in the brainstem.

The muscle relaxant activity of cyclobenzaprine relative to chlorpromazine and diazepam in several animal models manifesting hypertonic skeletal muscle activity is described. In mice subjected to electrical and chemical induced tonic-extensor seizures, only cyclobenzaprine achieved a protective index greater than unity in all preparations. Cyclobenzaprine also appeared to be highly potent and selective in abolishing local tetanus in rabbits. Relative to the other compounds, cyclobenzaprine was consistently active in γ- and α-decerebrate as well as in ischemic spinal cord rigid cat preparations, at doses which produced no signs of motorincoordination (ataxia) or behavioural depression. Consequently, only cyclobenzaprine exhibited high protective indices and those of greater than unity for all three cat preparations. Furthermore, in contrast with chlorpromazine and diazepam, repeated administration of cyclobenzaprine to ischemic spinal cord rigid cats failed to induce tachyphylaxis. Cyclobenzaprine was also well absorbed orally in mice and cats. These observations suggest that cyclobenzaprine may be useful in the treatment of human pathological conditions manifested by excessive tonic skeletal muscle activity. The potential usefulness of cyclobenzaprine as a pharmacological tool for further studies involving somatic motor systems is also suggested.

The therapeutic role of medications in fibromyalgia is reviewed. The tricyclics, amitriptyline and cyclobenzaprine, have been the most extensively evaluated, and in controlled studies have proven to be more effective than placebo or NSAIDs. Their mode of action is not known, but their effect may relate to a number of potential mechanisms. However, neither the tricyclics nor any other medication has provided long-term, clinically meaningful improvement in the majority of patients.

Fibrositis (fibromyalgia) is best treated by attaining patient acceptance of and compliance with a comprehensive treatment program. This includes education, physical therapy, muscle and mental relaxation, examination and adjustment of goals and priorities, and pacing of activities, as well as pharmacotherapeutics. Of the medications in use, anti-inflammatory agents with a high degree of analgesia are more effective than "pure" anti-inflammatory agents. Tricyclic derivatives are beneficial muscle relaxants. The use of long-acting agents improves compliance and is therefore favored. Local agents are of adjunctive value in some cases. Double-blind, placebo-controlled studies show cyclobenzaprine to be an effective medication in the treatment of fibrositis (fibromyalgia).

Methods employing solvent extraction, thin-layer chromatography, gas-liquid chromatography, and UV spectrophotometry are described for the quantitative determination of halofenate, cyclobenzaprine and sulindac in rodent diet mixtures. Halofenate was hydrolyzed to its free acid derivative and converted to a methyl ester prior to assay. The drugs were shown to be stable when stored in food mixtures at room temperature for seven days. Diet mixtures containing the three drugs were demonstrated to be uniformly mixed by the procedure employed.

The effects of cyclobenzaprine on spinal synaptic transmission were studied in spinal unanesthetized cats. The drug, in cumulative doses up to 20 mg/kg, depressed monosynaptic reflexes evoked by stimulation at 0.2 Hz to a moderate degree. Polysynaptic reflexes were depressed to a similar extent. Monosynaptic reflexes evoked repeatedly at 5 and 10 Hz were depressed even after 5 mg/kg of cyclobenzaprine. Maximum potentiation of monosynaptic responses after tetanization was not affected. Neither direct postsynaptic nor recurrent inhibition was influenced by the drug. Presynaptic inhibition was slightly reduced. It is suggested that direct effects of cyclobenzaprine at the spinal level do not represent the primary site of action responsible for its antispastic activity.

Tissue slices 400 μ thick were taken from the brain stem, at the level of the locus coeruleus, of 150–250 g Sprague-Dawley rats. Microe1ectrodes were placed in the locus coeruleus under visual control, and a cell whose discharge rate would decrease with microiontophoretic application of norepinephrine or clonidine was sought. Cyclobenzaprine (CBZ) was then introduced into the perfusion medium at a concentration equivalent to 1 mg/kg body weight of the whole animal. Discharge rates before and during CBZ administration were compared. The six cells with initial discharge rates between 2 and 10 Hz decreased firing with CBZ, whereas the four cells with initial rates between 0.5 and 1.5 Hz increased their rates with CBZ.

1. 1. Nine different evaluation systems were used to assess the efficacy of cyclobenzaprine (Flexeril®) and benzotropine methanesulfonate (Cogentin®) in 24 men with Parkinson's disease. 2. 2. A randomized double-blind cross-over clinical trial was followed by an extension study, with patients permitted to choose either medication. 3. 3. Both medications were judged beneficial to a majority of patients. Of the 9 evaluation systems used, 8 revealed cyclobenzaprine was better, while the ninth indicated that neither drug affected cognition. Differences between the two medications were slight and not significant. 4. 4. In the extension study, 71% of patients selected cyclobenzaprine and 29% selected benzotropine methanesulfonate. 5. 5. The chemical structure of cyclobenzaprine differs from other anti-parkinsonian agents, and this drug may be effective for patients who do not tolerate or benefit appreciably from levodopa or other medicants.

A sensitive method for the determination of cyclobenzaprine in biological samples is described. The extraction procedures used are different for urine and blood serum. The pH is a very important factor affecting the purity of the extract and the reproducibility of the recovery data, particularly for urine. By means of extraction, purification is achieved, while separation by thin-layer chromatography increases the specificity of the determination considerably. With a Vitatron TLD-100 densitometer, the substances separated can be measured as fluorescent spots from the thin-layer plates directly and quantitatively, with good reproducibility. The sensitivity is 1 ng and a linear relationship was obtained between 1 and 25 ng. extensive recovery studies were made in view of the forthcoming clinical evaluation of cyclobenzaprine. A number of experiments showed that this method has so far produced better results than can be obtained with the most sensitive gas chromatographic detection methods.

A convenient high-performance liquid chromatographic method for the quantitative determination of cyclobenzaprine hydrochloride in tablets is described. Samples were dissolved in 0.05 N sulfuric acid and diluted with methanol. The cyclobenzaprine hydrochloride was chromatographed using an octylsilane column and the eluent acetonitrile-0.6% dibasic potassium phosphate aqueous buffer (pH 3.0) (75:25) at a flow rate of 1.5 ml/min. Naphazoline hydrochloride was used as an internal standard. The UV detector response at 254 nm was linear for cyclobenzaprine hydrochloride in the 0.005-0.03 mg/ml range under conditions of the analysis.

A case of cyclobenzaprine (Flexeril ® ) overdose in a 31-year-old woman is presented. The treatment rendered was analogous to treatment protocols implemented for tricyclic overdose. A review of the pharmacology of cyclobenzaprine, as well as the management of patients who overdose on this drug, is presented.