Methocarbamol versus diazepam in acute low back pain in the emergency department: a randomised double-blind clinical trial.

BACKGROUND: Acute low back pain (LBP) is a common complaint in the emergency department and achieving effective analgesia can be challenging. METHODS: In this multicentre randomised double-blind clinical trial conducted at three EDs in Iran from August to November 2020, we assessed the efficacy and adverse effects of two muscle relaxants in patients aged 18 years or older who suffered LBP in the last 6 weeks. Group 1 received intravenous methocarbamol and group 2 received intravenous diazepam followed by a weight-based dose of intravenous morphine in both groups. Exclusion criteria mainly included non-spine aetiologies, cord compression, acute gastrointestinal bleeding, renal/hepatic insufficiency, pregnancy, breast feeding and unstable vital signs. Pain scores and adverse events were measured by a Numeric Rating Scale (NRS) at baseline and after 30 and 60 min by one of the researchers who was not involved with patient visits and was blinded to the intervention. We used t-test to assess the mean difference of NRS at 30 and 60 min. RESULTS: Out of 101 enrolled patients, 50 participants received methocarbamol and 51 diazepam. The baseline mean pain scores and demographic characteristics were not different between the study groups. Pain scores were reduced by both agents after 60 min, with slightly greater pain reductions in the diazepam group in comparison with methocarbamol (mean difference -6.1, 95% CI -6.5 to -5.7 vs mean difference -5.2, 95% CI -5.7 to -4.7, respectively, p<0.001). ED length of stay of patients did not differ between the groups (methocarbamol 5.9 vs diazepam 4.8 hours, p=0.365). Patients receiving diazepam were more likely to report drowsiness (2 (4.0%) vs 15 (29.4%), p=0.001). CONCLUSIONS: In patients with LBP, the pain was relieved in the methocarbamol and diazepam groups after 60 min. Although diazepam was more effective, its use was associated with a slightly higher risk of drowsiness. TRIAL REGISTRATION NUMBER: The protocol of this clinical trial was prospectively registered in the irct.ir (IRCTID: IRCT20151113025025N4; https://irct.ir/trial/50148) .

Methocarbamol blocks muscular Nav 1.4 channels and decreases isometric force of mouse muscles.

BACKGROUND: The muscle relaxant methocarbamol is widely used for the treatment of muscle spasms and pain syndromes. To elucidate molecular mechanisms of its action, we studied its influence on neuromuscular transmission, on isometric muscle force, and on voltage-gated Na+ channels. METHODS: Neuromuscular transmission was investigated in murine diaphragm-phrenic nerve preparations and muscle force studied on mouse soleus muscles. Nav 1.4 channels and Nav 1.7 channels were functionally expressed in eukaryotic cell lines. RESULTS: Methocarbamol, at 2 mM, decreased the decay of endplate currents, slowed the decay of endplate potentials and reduced tetanic force of soleus muscles. The drug reversibly inhibited current flow through muscular Nav 1.4 channels, while neuronal Nav 1.7 channels were unaffected. CONCLUSIONS: The study provides evidence for peripheral actions of methocarbamol on skeletal muscle. Muscular Na+ channels are a molecular target of methocarbamol. Since Nav 1.7 currents were unaffected, methocarbamol is unlikely to exert its analgesic effect by directly blocking Nav 1.7 channels.

Interaction of methocarbamol and yeast sucrase induces enzyme inhibition.

BACKGROUND: Methocarbamol is a skeletal muscle relaxant and is widely used to relieve pain in muscles. Many drugs may have interactions with each other when used at the same time. Yeast sucrase is taken as a drug by patients with congenital sucrase-isomaltase deficiency (CSID). METHODS: In this study, the interaction between methocarbamol and yeast sucrase was investigated. RESULTS: Our results showed that methocarbamol can inhibit sucrase activity and reduce the maximum reaction velocity (Vmax) of the enzyme by a non-competitive pattern. Measurement of IC50 and Ki of the drug revealed that methocarbamol did not bind the enzyme with high affinity. Fluorescence measurement showed that the drug binds to free enzyme and enzyme-substrate complexes that were accompanied by structural changes on the enzyme. Guaifenesin, which has a similar structure to methocarbamol, does not affect the activity of sucrase. CONCLUSIONS: Methocarbamol inhibits sucrase activity and its carbamate group plays a main role in the binding of drug to sucrase.

Muscle relaxant activity of methocarbamol enantiomers in mice.

Documented studies support the emerging idea that drug enantiomers could have different pharmacological activity. Our bibliographical data have shown that so far no report has been published on the pharmacological activity of individual enantiomers of methocarbamol. This study was conducted to characterize the muscle relaxant activity of methocarbamol enantiomers. The rotarod test was used to compare the muscle relaxant activity of racemic methocarbamol and pure enantiomers after intraperitoneal administration of the enantiomers to mice. The results show that (+)-R-methocarbamol has higher muscle relaxant activity compared with racemic methocarbamol or (-)-S-methocarbamol.

Does methocarbamol affect fatigue markers in the low-back electromyogram?

Many low-back patients undergo electromyography (EMG)-based evaluations of muscle performance but present to the clinic after being prescribed muscle relaxants. The question that needed to be addressed was, do centrally acting muscle relaxants (methocarbamol; Robaxin) affect the EMG spectral indices of muscle fatigue that are often used to assess muscle performance. Participants performed an isometric spine extension protocol involving a 30 s fatigue exertion trial, then 1 min rest, and finally a 10 s long repeat exertion trial, at a 60% maximum voluntary contraction (MVC) level of exertion. Seven men were tested on two separate days (approximately 3-7 days apart), one day while medicated (six doses) with Robaxin and on another while not medicated. Specifically, the following parameters were studied in the bilateral multifidus (L5), lower erector spinae (L3) and upper erector spinae (T9): the slope of median power frequencies (MPFs) over the duration of the trial and the initial y-intercept of the MPF. The results generally suggest that methocarbamol (Robaxin) does not have any significant affect on the EMG median power frequency of the extensors during a fatiguing contraction followed by a repeat exertion, at least in normal people (one exception was observed--one side of multifidus at L5). However, given that this appears to be the first study of its kind, and that a relatively small number of subjects were used in this study, further investigation is needed to make a definitive conclusion about the effects of this drug on the several features of the electromyogram, over a broad spectrum of the clinical population performing a wider variety of tasks.

Drug discrimination analysis of midazolam under a three-lever procedure: I. Dose-dependent differences in generalization and antagonism.

Twelve rats were trained to discriminate two doses of midazolam, 0.32 and 3.2 mg/kg, from no drug under a three-lever, multiple-trials procedure (15-min time-out, 5-min fixed-ratio-10 schedule of food reinforcement). In tests, midazolam (0.0032-10 mg/kg), administered cumulatively within a session or acutely across sessions, produced dose-dependent increases in responding on the low-dose lever after 0.1 to 1.0 mg/kg and on the high-dose lever at higher doses in all rats. Flumazenil dose-dependently antagonized the discriminative stimulus effect of 3.2 mg/kg of midazolam in all rats but antagonism of the lower midazolam training dose was not obtained in all rats. Pentobarbital dose-dependently produced responding on the levers associated with the no-drug and 0.32-mg/kg midazolam conditions but not on the lever associated with 3.2 mg/kg of midazolam. These results differed from those that would have been predicted from studies in midazolam-trained rats in two-lever procedures. The muscle relaxant methocarbamol and nonsedative/anxiolytic drugs (morphine, caffeine and d-amphetamine) did not produce responding on the lever associated with either the low or high midazolam training dose. However, cocaine produced partial responding on the lever associated with the low midazolam dose. Thus, the discriminative stimulus effects of 3.2 mg/kg of midazolam were benzodiazepine-like and not a function of general sedative or muscle-relaxant effects. The 0.32-mg/kg midazolam training dose, in this context, appeared less specific than 3.2 mg/kg of midazolam. Taken together, the results suggest that not all differences among the training stimuli in this three-lever context reflect simple differences in dose.

Subjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability.

The effects of orally administered placebo, diphenhydramine, lorazepam, methocarbamol and placebo were studied in volunteers with histories of recreational substance abuse including sedative/hypnotics. Placebo, diphenhydramine (100, 200 and 400 mg), lorazepam (1 and 4 mg) and methocarbamol (2.25 and 9 g) were tested in a randomized, double-blind crossover study using 14 subjects. Psychomotor and cognitive performance and subject- and observer-rated responses were measured daily before and for 5.5 hr after drug administration. The results showed that each of the drugs exhibited a different profile of effects on the test battery. Lorazepam produced significant increases in subjects' ratings of drug effect and liking, increases in measures of sedation and impairment of psychomotor performance. Methocarbamol also produced significant increases in subjects' ratings of drug effect and liking and measures of sedation, but it produced only minor impairment of psychomotor and cognitive performance. Diphenhydramine increased subjects' and observers' ratings of drug effect and measures of sedation, but it produced less psychomotor performance impairment and liking than lorazepam. Diphenhydramine produced the most side effects. The present study clearly differentiated the behavioral and subjective profiles of diphenhydramine, lorazepam and methocarbamol. Consistent with its recognized low abuse liability, diphenhydramine produced fewer increases in measures of positive mood and more adverse effects. The considerable overlap in subjective effect measures of positive mood make further differentiation with respect to abuse liability difficult.

The pharmacology and pharmacokinetics of high-dose methocarbamol in horses.

The haemodynamic, respiratory and behavioural effects and pharmacokinetics of methocarbamol were studied in eight healthy, adult horses after intravenous (i.v.) and oral administration of large dosages. Heart rate, cardiac output, mean pulmonary arterial blood pressure, systolic, diastolic and mean aortic blood pressure, respiratory rate and arterial blood gases did not change after either i.v. (30 mg/kg bodyweight [bwt]) or oral (50 and 100 mg/kg bwt) dosages of methocarbamol. Mild to moderate depression was observed in five of eight horses administered i.v. methocarbamol, and in all horses administered oral methocarbamol. Plasma methocarbamol concentration declined very rapidly during the initial or rapid disposition phase after i.v. administration; the terminal elimination half-life ranged from 59 to 90 mins. Peak plasma methocarbamol concentrations following oral administration occurred within 15 to 45 mins and oral bioavailability ranged from 50.7 to 124 percent.

Evaluation of the abuse potential of methocarbamol.

The subjective and behavioral effects of p.o. administered methocarbamol, lorazepam and placebo were studied in a nonresidential group of adult male volunteers with histories of recreational substance abuse including sedative/hypnotics. In the first phase of the investigation, a dose run-up of methocarbamol (up to 12 g) was conducted in six subjects to determine appropriate doses. In the second phase, a randomized block cross-over study using 14 subjects was conducted. The following drug conditions were tested in the cross-over phase: placebo, lorazepam 1, 2 and 4 mg, and methocarbamol 2.25, 4.5 and 9 g. Drug conditions were tested under double-blind conditions. Psychomotor and cognitive performance measures and subject- and observer-rated behavioral responses were measured daily before dosing and for 5.5 hr after drug administration. The results showed that both lorazepam and methocarbamol produced statistically significant dose-related increases in subjects' ratings of drug effect and liking, although only lorazepam increased morphine-benzedrine group (MGB) scale scores. Methocarbamol also increased ratings on measures indicating the emergence of dysphoric and other side effects at high doses. Both drugs impaired psychomotor and cognitive performance, with lorazepam generally producing greater effects than methocarbamol. The results indicate that methocarbamol, at doses well above those used therapeutically, has some potential to be abused by persons with histories of sedative/hypnotic abuse; however, this potential for abuse is probably decreased by the accompanying side effects at high doses and is probably less than that of lorazepam.

A comparison of diazepam stimuli in aged and adult rats.

Young adult rats (5 months) were compared with aged (28 months) rats in their ability to learn and perform in a diazepam drug discrimination. Both groups of rats were drug naive at the onset of the experiment. Adult and aged animals learned to discriminate diazepam. In general, the response rates under both drug and vehicle conditions were significantly lower for the aged group. The diazepam stimuli were dose-dependent in each group. Similar dose-dependent generalization with chlordiazepoxide, pentobarbital, and methocarbamol was also noted in both the aged and adult animals. These data suggest that aged animals, who have experienced anxiolytic compounds over a period of time (in this case, repeated administration of diazepam in the discrimination procedure), respond in a similar fashion to drug treatment as do young adult animals, verifying the reliability and validity of results obtained in aging rats who are repeatedly exposed to drug treatment.

2-Amino-7-phosphonoheptanoic acid (AP7) produces discriminative stimuli and anticonflict effects similar to diazepam.

The N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, was evaluated in two animal test procedures known to be sensitive to the effects of diazepam. In rats trained to discriminate diazepam from vehicle, AP7 produced dose-dependent generalization to the diazepam interoceptive stimuli. This NMDA antagonist also increased the rates of conflict responding in a chronic test procedure used to identify compounds with potential anxiolytic effects. A comparison of AP7 with diazepam and two muscle relaxants (methocarbamol and baclofen) showed that excitatory amino acid antagonists (of the receptor site stimulated by NMDA) produce a muscle relaxant effect (drug discrimination) and may represent a new class of compounds for the treatment of anxiety-related disorders (conflict test).

The curve-shift paradigm in self-stimulation.

Eleven rats were trained to press a lever in an operant chamber in order to earn rewarding trains of cathodal rectangular pulses of fixed intensity and variable frequency. The rate-frequency functions were examined under administration of two neuroleptics (pimozide and chlorpromazine) and three manipulations that interfered with bar pressing (muscular relaxation with methocarbamol, increased lever weight, and limitation of maximum response rates by an F1 reinforcement schedule). Chlorpromazine, and pimozide at low dosages produced a near parallel shift of the rate-frequency functions on the logarithmic axis of pulses, suggesting that these drugs decreased the reinforcing efficacy of the stimulation. The three conditions that interfered with bar-pressing decreased the asymptotic rates and produced small or moderate lateral shifts. Changes in the reinforcing efficacy of the stimulation following the above manipulations were inferred from the shift in the number of pulses required at zero and half-maximal performance (theta 0 and M50 indices, respectively). In the cases of the manipulations that interfered with bar-pressing, M50 indicated a larger artifactual change in the efficacy of the stimulation, compared to theta 0. This phenomenon was mainly due to the fact that the asymptote of the altered functions was shifted towards higher pulse numbers.

Response decrement patterns after neuroleptic and non-neuroleptic drugs.

Previous work has shown that administration of pimozide and other neuroleptic drugs can produce within-session response decrement patterns of appetitively-reinforced behaviour. This phenomenon has been described as an extinction-like pattern of responding and used as evidence for the hypothesis that these drugs attenuate the rewarding properties of food, water and electrical stimulation of the brain. The present study was carried out to investigate within-session patterns of responding maintained by food presentation or shock avoidance after administration of a variety of neuroleptic and non-neuroleptic drugs. Haloperidol, metoclopramide, pimozide and butaclamol produced within-session response decrements of both food-reinforced lever pressing and one-way shock avoidance. The atypical antipsychotic drug clozapine did not consistently produce similar effects nor did the alpha-adrenoceptor agonist clonidine, the opiate agonist morphine, the benzodiazepine anxiolytic chlordiazepoxide and the muscle relaxant methocarbamol, although all these drugs were tested up to doses which markedly disrupted responding. Thus, within-session response decrement patterns are a characteristic effect of dopamine-blocking neuroleptic drugs. However, because of the generally similar effects of these drugs on appetitively- and aversively-motivated behaviour, these effects are probably best interpreted as actions on motor, rather than motivational, mechanisms.

Efectos del diacepam y del metocarbamol sobre los signos EEG de la "conducta de relajación" inducida por la ingestión de leche en gatos / Effects of diazepam and methocarbamol on EEG signs of relaxation behavior induced by milk slurping in cats

Se investigaron los efectos de diferentes dosis de diacepam (0.1,0.3,1.0,3.0 mg/kg IM) o metocarbamol (30,100,300 mg/kg IM) en diez gatos que mostraban comportamiento aprensivo y escasas proporciones de sincronización del EEG parietal y parietooccipital durante la ingestión de leche, un signo electrografico confiable de la "conducta de relajación" en el gato. Las proporciones de sincronización del EEG parietal y parietooccipital aumentaron significativamente luego de la administración de estos fármacos; al parecer este efecto del diacepam se relaciona principalmente con los efectos del fármaco sobre la conducta que también suprimió el comportamiento aprensivo. El efecto del metocarbamol, aumentó de la sincronización del EEG durante la ingestión de leche, podría ser causado principalmente por cambios del estado de ánimo resultantes de la relajación muscular. Estos hallazgos deben considerarse para el análisis de los mecanismos nerviosos que relacionan el estado de ánimo, el tono muscular y los signos electrográficos de la "conducta de relajación

Pharmacologic and pharmacokinetic properties of methocarbamol in the horse.

The hemodynamic, respiratory, and behavioral effects, as well as the pharmacokinetic properties of methocarbamol, were determined in horses. Heart rate, cardiac output, arterial and venous blood pressures, respiratory rate, and arterial blood gases did not change after IV methocarbamol (4.4, 8.8, 17.6 mg/kg) administration. There were no signs of behavior modification or ataxia observed. Analysis of plasma concentration time data indicated that the disposition of methocarbamol may be dose-dependent. Clearance and steady-state volume of distribution decreased as the dose increased. Plasma concentrations of guaifenesin, a metabolite of methocarbamol, were never greater than 0.5% of the plasma concentration of methocarbamol.

Self-stimulation response decrement patterns differentiate clonidine, baclofen and dopamine antagonists from drugs causing performance deficit.

Fouriezos and co-workers have reported that rats treated with the neuroleptics, pimozide or d-butaclamol, barpress at baseline rates at the start of an intracranial self-stimulation (ICSS) session, but cease responding within a few minutes. They suggested that this response decrement pattern (RDP) resembles natural extinction, indicating attenuation of reward by neuroleptic treatment. In the present experiments, the RDPs produced by several different drug classes were systematically compared. Two dopamine receptor antagonists, haloperidol and metoclopramide, produced an extinctionlike RDP. In contrast, the alpha-1 adrenoceptor blocker, prazosin, and the muscle relaxant, methocarbamol, caused uniformly low response rates that did not decrease further as the session progressed. Clonidine, an alpha-2 adrenoceptor agonist, and baclofen, a novel GABAB receptor agonist, were associated with RDPs that resembled those of the dopamine antagonists tested. Analysis of drug-induced RDPs is characterized as a valuable tool for exploring the nature of drug effects on ICSS responding.

Effects of various catecholamine receptor antagonists, muscle relaxation and physical hindrance on shuttlebox self-stimulation.

Certain drugs, particularly clozapine and clonidine, have been reported to increase selectively the latency to initiate brain stimulation (the ON latency) in a shuttlebox test of self-stimulation, suggesting a preferential attenuation of the "reward" component. The pharmacological selectivity of this reported effect was systematically evaluated. At doses that blocked bar-pressing self-stimulation, metoclopramide (3 mg/kg), prazosin (3 mg/kg) clonidine (0.1mg/kg), clozapine (3 mg/kg)and haloperidol (0.3 mg/kg), all elevated the ON latency to a greater extent than the OFF latency. Methocarbamol (200 mg/kg), and a muscle relaxant, also elevated the ON latency preferentially but the magnitude of this preferential effect was smaller than that produced by the other drugs. A hurdle in the center of the shuttlebox increased the ON and OFF latencies nonselectively. The shuttlebox procedure does not clearly discriminate among various substances that interfere with noradrenergic or dopaminergic neurotransmission, but the common profile produced by the these substances is distinguishable to some degree from simple motor disruption.

Differential effects of drug treatments on nose-poke and bar-press self-stimulation.

To assess the possibility of dissociating drug-induced gross performance deficits from effects on brain stimulation reward, the nose-poke and bar-press operants were systematically compared. Pentobarbital and methocarbamol (a muscle relaxant) reduced bar-pressing more strongly than nose-poking. In contrast, clonidine and haloperidol, which disrupt noradrenergic and dopaminergic neurotransmission respectively, had no differential effect on these operants. The nose-poke operant appears less vulnerable to drug-induced gross motor impairment and may be more suitable for pharmacological studies of self-stimulation.

[Electroencephalographic effects of chlorphenesin carbamate, a new central muscle relaxant, in rabbits (author's transl)].

Electroencephalographic (EEG) effects of chlorphenesin carbamate were investigated in rabbits with chronic electrode implants, and compared with those of chlormezanone and methocarbamol. Chlorphenesin carbamate (50 mg/kg i.v., 100 mg/kg i.d.) induced a drowsy pattern of spontaneous EEG consisting of high voltage slow waves in the cortex and amygdala, and desynchronization of hippocampal theta waves. Chlormezanone also elicited similar EEG changes but such were much more potent than chlorphenesin carbamate. Methocarbamol showed no effect on spontaneous EEG. Chlorphenesin carbamate caused sedation in this period and muscle relaxation was more potent than that of chlormezanone. The EEG arousal response to auditory stimulation and to electric stimulation of the posterior hypothalamus, centromedian thalamus and mesencephalic reticular formation was slightly depressed by chlorphenesin carbamate. Chlorphenesin carbamate, as with chlormezanone, markedly depressed the limbic afterdischarges elicited by hippocampal stimulation. These EEG effects of chlorphenesin carbamate were qualitatively similar to but much weaker than those of chlormezanone, whereas the muscle relaxant effect of chlorphenesin carbamate was more potent than that of chlormezanone.