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Experiments were performed on intact and spinalized rats anesthetized with urethane and alpha-chloralose. In intact rats, administration of tizanidine (0.1 mg/kg, i.v.) decreased the mono- (MSR) and polysynaptic reflex potentials (PSR). Blood pressure was initially elevated and then lowered by tizanidine. Although pretreatments with hexamethonium and phentolamine prevented the tizanidine-induced decrease in blood pressure, the depressant effects of tizanidine on the reflexes remained. The alpha 2-antagonist idazoxan inhibited the tizanidine-induced decrease in spinal reflexes, suggesting that central alpha 2-adrenoceptors are involved in the depression of the reflexes. In spinalized rats, tizanidine transiently increased the MSR and gradually decreased the PSR. Blood pressure was elevated transiently by tizanidine. Although the hypertensive effect of tizanidine was inhibited by phentolamine, the effect of tizanidine on the PSR did not change. Prazosin blocked the stimulatory effect of tizanidine on the MSR and caused a rapid decrease of the PSR, suggesting that spinal alpha 1-adrenoceptors are involved in the enhancement of the reflexes. These results suggest that the depressant effects of tizanidine on spinal reflexes are due to the supraspinal and spinal effects of the drug, and not to changes in blood pressure.
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A double-blind, double-dummy, randomized, 3-treatment, 2-way crossover, comparative, placebo-controlled study was conducted in a neuroimmunology clinic of a university-affiliated medical center (December 2005 to March 2006). Enrolled patients received placebo once nightly and were then randomized to receive oral tizanidine HCl following sublingual tizanidine HCl or sublingual tizanidine HCl following oral tizanidine HCl, each arm for 7 days. The patients were evaluated for spasticity (Ashworth scale), mobility, Global Assessments of Disease Severity and Change, and safety parameters, including next-day somnolence (Epworth Sleepiness Scale), fatigue, hypotension, and hepatotoxicity.
A total of 40 patients with a mean±SD age of 7±2.6 years were enrolled. The clinical and urodynamic parameters were comparable between both groups. At the last follow-up visit, both groups had had similar improvement in the severity of symptoms, satisfaction scale, and noninvasive flowmetry parameters. In the doxazosin group, urge episodes was the only symptom that showed a significant reduction compared with the baseline values (P=.028). However, the incidence of nocturnal enuresis, urgency attacks, and daytime incontinence were significantly reduced compared with baseline in the tizanidine group (P=.003, P=.008, and P=.017, respectively). Adverse effects were recorded in 6 patients (15%). Epigasteric pain was reported in 2 children (10%) who received doxazosin. In the tizanidine group, a loss of appetite was noted in 2 children (10%), epigastric pain in 1 (5%), and headache in 1 (5%).
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The site of action of tizanidine (5-chloro-4-(2-imidazolin-2-yl-amino)2,1,3-benzothiadiazole) was investigated in a tail-flick test in comparison with clonidine and morphine. Tizanidine and clonidine produced a profound and linear dose-dependent antinociceptive action by i.c.v. administration. The ED50 values for tizanidine, clonidine and morphine were increased 2-4-fold 1 or 3 days after spinalization at C5-C6. These results indicate that the antinociceptive activity of tizanidine arises mainly from activity at the supraspinal level, similar to clonidine and morphine, but these drugs act also at the spinal level at high doses.
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The effects of alpha2-adrenoceptor agonists, clonidine, tizanidine and UK-14304 on alpha1-adrenoceptor-mediated contractile responses were studied in isolated tail arteries and thoracic aorta of the rat. When applied during sustained contractile responses to almost maximum concentration (10 microM) of phenylephrine, clonidine (0.3 microM to 100 microM) produced concentration-dependent relaxations in both tissues. The maximum relaxation was smaller in tail arteries than in thoracic aorta. Clonidine up to 100 microM failed to relax both tissues precontracted with KCl (60 microM) or U-46619 (1 microM), a thromboxane mimetic. The clonidine-induced relaxation in tail arteries, was reversed by alpha2-adrenoceptor antagonists, yohimbine and idazoxane. Effects of the alpha2-adrenoceptor antagonists were concentration-dependent (0.1 microM to 1 microM), but not in a competitive manner. On the other hand, the relaxation in thoracic aorta was not significantly antagonized by these alpha2-adrenoceptor antagonists. Tizanidine and UK-14304 also relaxed both tail arteries and thoracic aorta precontracted with phenylephrine. The characteristics of the relaxation and their antagonism by yohimbine in both arteries were similar to those induce by clonidine. In tail arteries, NG-nitro-L-arginine, a nitric oxide synthase inhibitor, at a concentration that completely inhibited acetylcholine-induced relaxations did not significantly affect the relaxation induced by clonidine. In contrast, the relaxation of thoracic aorta in response to clonidine was partly reduced in the presence of NG-nitro-L-arginine. These results indicate that the alpha2-adrenoceptor agonists selectively inhibit the contractions induced by phenylephrine in both tissues. Regional differences in the modes of the inhibition by the alpha2-adrenoceptor agonists exist.
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In this case report, we present a 42-year-old man with history of chronic low back pain after a work-related injury. The patient failed multiple therapeutic modalities both conservative and interventional, including numerous spinal injections and placement of a spinal cord stimulator. Finally, an intrathecal morphine pump was placed to control his pain in addition to oral pain medications. The course of the treatment included adding a muscle relaxant, tizanidine (Zanaflex), to control spasms in the lower extremities. Six weeks after starting tizanidine, a large pleural effusion was noted incidentally on a computerized tomography scan of the thoracic and lumbar spine. The patient underwent work-up for the pleural effusion; all tests came back negative. Finally, a drug reaction to tizanidine was suspected. The drug was discontinued, and 4 weeks later the pleural effusion resolved.
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Systematic searches identified 15 interventions for the treatment of spasticity and 15 interventions for treatment of pain. The quality and outcomes of the studies were evaluated. Reviews of the treatment of spasticity and pain when due to other aetiologies were also sought.
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Our findings demonstrate that tizanidine acts to reduce reflex mechanical responses substantially, without inducing comparable changes in intrinsic muscle properties in individuals with spinal cord injury. Thus, the pre-post difference in joint mechanical properties can be attributed to reflex changes alone. From a practical standpoint, use of a single "test" dose of Tizanidine may help clinicians decide whether the drug can helpful in controlling symptoms in particular subjects.
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Previous studies in anesthetized or reduced preparations of nonprimate animals revealed that the alpha 2-adrenergic agonist tizanidine, clinically used as an antispastic drug, effectively reduces polysynaptic flexor reflexes. To further clarify the invoked adrenergic mechanism for physiological motor functions, and in view of the clinical relevance of tizanidine, the effect of this substance was reinvestigated in awake, nonanesthetized monkeys. Systemic applications of tizanidine dose-dependently reduced the magnitude of the electromyographic response of the flexor reflex that was induced by nonnoxious stimulation of cutaneous afferents. Whereas the effects on the flexor response were consistent, the changes of the background electromyogram were much more variable, often not paralleling those of the reflex. The reflex depression produced by tizanidine could be prevented by pretreatment with the alpha 2-antagonist yohimbine. It is concluded that the action of tizanidine on spinal reflexes, and therefore probably also on hyperactive reflexes of spastic patients, is mediated via the alpha 2-adrenergic properties of the drug. On the basis of the present results, taken together with previous observations that tizanidine transiently inactivates neurons of the nucleus locus coeruleus, it is proposed that the reflex depression may be caused by a removal of a descending noradrenergic facilitation exerted on spinal reflex transmission. This interpretation leaves open further possible actions of tizanidine exerted directly on spinal interneurons.
To demonstrate clinically the effectiveness of tizanidine in the decrease of the spasticity.
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The multimodal approach to perioperative analgesic management, which includes concurrent administration of intravenous acetaminophen and opioids, is effective in reducing the total average amount of opioids administered on postoperative days 1-2 and perioperatively. Limitations of this study include its short duration, retrospective design, and single-site setting. These results may not be generalized to patients undergoing other types of obstetric-gynecologic surgeries.
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There is substantial evidence to show that plasma tizanidine concentrations are linearly related to dose in healthy subjects and patients, although there is a high degree of intersubject variability. The most common adverse events and pharmacodynamic effects are related to plasma concentrations. The clinical implications of the large interpatient variability in plasma tizanidine concentrations and its narrow therapeutic index make it necessary to individualise patient therapy. Practical advice on tizanidine dosing and/or switching between formulations is provided.
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Tizanidine used in back pain accompanied by muscle spasm results in quick pain relief (initial relief on the 2nd day of treatment, complete relief after 4 days, vs. initial relief on the 3rd day of treatment, complete after 7 days in the control group). The daily dosage and cumulative dose needed to achieve analgesic effect is low (lowest recommended dose by the producer). Tizanidine is well tolerated: adverse effects were rare (<6%, vs. 13% in the control group) and transient. The clinical effect of tizanidine was prompt in acute pain and more delayed in chronic disease.
Spinal cord injury (SCI) results in significant impairments in function and ankle joint spasticity is a common secondary complication. Various interventions have been trialed to improve function and reduce spasticity after SCI, with variable results. We investigated the effects of a pharmacological (an anti-spastic medication - tizanidine) and a physical intervention (robotic-assisted locomotor training - Lokomat) on function in people with incomplete SCI over 4-week of training. The outcome measures were walking speed, endurance and mobility. Subjects were randomized into one of three groups; no intervention (control), Lokomat (Lok) and tizanidine (Tiz). To account for variability, we used growth mixture modelling (GMM) to class subjects based on their recovery patterns. GMM identified two classes of recovery: high and low function. Significant improvements were seen in walking speed and mobility in high and low functioning subjects in the Lok group, and in walking endurance in high functioning subjects in the Tiz group. However, changes with training were clinically important only for approximately 10% of subjects, who achieved a minimal important difference (MID) in functional outcomes as a result of the training. We used mixed model ANOVAs to compare the group effects. Improvements with training were seen in both classes, however no differences between interventions were found. The GMM had classed all subjects that achieved the MID as high functioning. GMM can be used to successfully class subjects; however larger subject numbers and longer interventions are required to fully utilize this technique. Our results demonstrate that both interventions have potential to improve walking capacity, but more intense training for a longer period may need to achieve MID.
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Two independent reviewers extracted data and the findings of the trials were summarised. Missing data were collected by correspondence with principal investigators. A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed.
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Research laboratory in a rehabilitation hospital.
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Tizanidine (TZD) is an alpha-2-adrenergic drug with potential spinal analgesic action and could be a substitute or additive for intrathecal (i.t.) opiates in chronic pain treatment. However, long-term tolerability and tissue compatibility are not yet established.
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Spasticity is a sign of upper motor neurone lesion, which can be located in the cerebrum or the spinal cord, and be caused by stroke, multiple sclerosis, spinal cord injury, brain injury, cerebral paresis, or other neurological conditions. Management is dependent on clinical assessment. Positive and negative effects of spasticity should be considered. Ashworth score and the modified Ashworth score are the most used scales for assessment of spasticity. These and other spasticity scales are based on assessment of resistance during passive movement. The main goal of management is functional improvement. A novel 100-point score to assess disability, function related to spasticity (Rekand disability and spasticity score) is proposed. Management of spasticity should be multimodal and should always include physiotherapy or exercise. Oral medications such as baclofen and tizanidine have limited efficacy and considerable side effects, but are easiest to use. Botulinum toxin combined with physiotherapy and/or orthopaedic surgery is effective treatment of localized spasticity. Treatment with intrathecal baclofen via programmable implanted pump is effective in generalized spasticity, particularly in the lower extremities. Neurosurgical and orthopaedic procedures may be considered in intractable cases.
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There is no doubt that spasticity is a significant cause of disability in the elderly. Regrettably, it is a condition that is often poorly treated and can result in a range of unnecessary complications which can cause further problems for the disabled person and their family. There are now a number of effective treatment options. However, before such options are defined the specific goals of rehabilitation need to be clarified and an appropriate outcome measure chosen in order to determine when such goals are being met. The treatment should be multidisciplinary and input from both the physician and a physiotherapist is essential. Involvement of the elderly person with spasticity, and often their family, is also important in the education process. Simple physiotherapy interventions can be remarkably helpful, including attention to positioning and seating. The role of the physician initially focuses on oral medication. Although we still have older drugs including diazepam, baclofen and dantrolene there are now more modern drugs including tizanidine and, more recently, gabapentin. However, most spasticity is focal in origin and thus requires focal treatment. Although phenol nerve blocks are sometimes helpful the use of botulinum toxin is now to be highly recommended. There is now clear evidence of the efficacy of botulinum toxin, which has been a significant advance in our management of spasticity. More advanced and difficult to treat problems can be alleviated by intrathecal baclofen or sometimes intrathecal phenol or, as a last resort, surgical intervention. The advent of lycra garments for the overall management of more diffuse spasticity is now becoming both fashionable and effective.
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The majority of patients were female and most had secondary progressive MS. Baclofen (76-80%), tizanidine and benzodiazepines were the most common antispastic drugs administered. A variety of spasticity rating scales were employed, and they demonstrated the same general trends. MS progressed, with the composite score for spasticity and mobility deteriorating in 46.4% of patients, and there were no marked differences between antispasticity drugs. The annual healthcare-related cost of treating an MSS resistant patient in the Spanish healthcare system was €15,405, largely attributable to the cost of disease-modifying drugs and care provision. Other aspects, such as medical visits and antispastic treatments, formed only a small portion of cost.
Treatment of spasticity poses a major challenge given the complex clinical presentation and variable efficacy and safety profiles of available drugs. We present a systematic review of the pharmacological treatment of spasticity in multiple sclerosis (MS) patients.
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Double-blind, placebo-controlled, crossover, before-after trial, pilot study.
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Events that threaten tissue integrity including noxious stimulation activate central noradrenergic circuits, particularly locus coeruleus and its projections. Recent advances in theory hold that an adaptive, defensive shift in brain activity takes place in response to threat. In principle, this shift may accentuate the autonomic and central biomarkers of the perception of painful events and the experience of pain itself. We have examined the effects of an alpha-2 agonist on pupil dilation responses, skin conductance responses, near field somatosensory evoked potentials and pain reports in normal volunteers undergoing repeated trials of painful fingertip stimulation delivered at low, medium and high intensities. In a double-blinded study, 114 healthy male and female volunteers underwent repeated noxious stimulation under baseline, placebo and active drug conditions where the active drug was the alpha-2 agonist tizanidine 4 mg. In contrast to baseline and placebo conditions, tizanidine 4 mg significantly reduced the magnitudes of the mean pupil dilation response, the mean skin conductance response, the mean near field somatosensory evoked potential peak-to-peak amplitude and the mean pain intensity rating. Stimulus intensity significantly altered all three biomarkers and the pain report in a graded fashion. There were no sex differences. These findings support the hypotheses that painful events activate central noradrenergic circuits, and that these circuits play a role in the autonomic and central arousal associated with pain.
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The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing. The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.