Safety of baclofen versus tizanidine for older adults with musculoskeletal pain.

BACKGROUND: Baclofen and tizanidine are both muscle relaxants that carry the risk for neuropsychiatric events in older adults but there is a lack of data directly comparing their safety. This study aimed to investigate the relative risk between these two medications in causing injury and delirium in older adults. METHODS: This was a retrospective cohort study that was completed in an integrated healthcare system in the United States and included patients aged 65 years or older who started baclofen or tizanidine for the treatment of musculoskeletal pain from January 2016 through December 2018. Outcomes included new incidence of injury (concussion, contusion, dislocation, fall, fracture, or other injuries) and delirium. The cohort was followed from the initiation of therapy until the first occurrence of any of the following events: end of the index drug exposure, end of health plan membership, death, or the study end date of December 31st, 2019. Descriptive statistics were used to compare baseline patient characteristics between baclofen and tizanidine treatment groups. Cox proportional hazards model was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals. RESULTS: The final study cohort included 12,101 and 6,027 older adults in the baclofen and tizanidine group respectively (mean age 72.2 ± 6.2 years old, 59% female). Older adults newly started on baclofen had a greater risk of injury (HR = 1.54, 95% CI = 1.21-1.96, P = < 0.001) and delirium (HR = 3.33, 95% CI = 2.11-5.26, p = <0.001) compared to those started on tizanidine. CONCLUSION: The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.

Opioid Adjuncts: Optimizing Opioid Therapy With Nonopioid Medications.

In this article, we describe a variety of medications that physicians managing outpatient chronic pain should familiarize themselves with to better aid their approach to multimodal pain therapy. Physicians should always consider the use of an adjuvant or coanalgesic drug as first-line treatments. Although many of these medications are not primarily analgesics, in clinical practice they have independent analgesic effects or synergistic analgesic properties when used with opioids. The use of adjunct analgesics reduces opioid-related adverse effects and optimizes pain management. Although there may be some medication overlap with this section and the ERAS section, the purpose of this article is to understand prolonged use in the outpatient setting to reduce opioid use or limit opioid dose with adjuvant therapy.

Results of the post-registration clinical study "PARUS" on efficiency and safety assessment of Mydocalm-Richter for local injection therapy of a myofascial trigger zone.

AIM: The "PARUS" program included investigation of the analgesic, muscle relaxant and sedative effects of Mydocalm-Richter which acts as central muscle relaxant in patients with myofascial pain syndrome, taking into account its registered indication for use - the hypertonus and cross-striated muscle spasm. MATERIALS AND METHODS: Fifty patients with myofascial trigger points, the mean age of 41.67±11.86 years, have been enrolled in the study. All patients had undergone clinical examination that allowed the diagnosis of myofascial pain syndrome. The intensity of pain syndrome was evaluated using the pain visual analogue scales and McGill pain questionnaire. Visualization of area in spasm and evaluation of blood circulation was carried out using the ultrasound scan of target muscle. In order to objectively evaluate any conceivable hypotensive and sedative effects of Mydocalm-Richter we used the orthostatic test, Schulte's test for attention span and perfor-mance distribution and Munsterberg's test for attention discrimination and concentration. RESULTS: The analgesic and muscle relaxant effects of Mydocalm-Richter become apparent by day 3 post-injection, and the muscle relaxation effect is reaching its maximum on day 10 post-injection. Cardiovascular function following administration of Mydocalm-Richter was evaluated using the orthostatic test which revealed good orthostatic tolerance. Single injection of tolperisone hydrochloride possessing a central muscle relaxant activity has no sedative effect and does not influence patient response time. The ultrasound examination data demonstrated the improvement and in some cases restoration of blood circulation in the myofascial trigger points. CONCLUSION: Clinical study "PARUS" conducted in patients with myofascial pain has demonstrated a positive muscle relaxant and analgesic effect of Mydocalm-Richter that resulted in restoration of peripheral circulation in the myofascial trigger pointsconfirmed by ultrasound examination. An important benefit of this drug product is the absence of sedative effect and arterial hypotension.

Clinical case reviews and poster sessions in multiple sclerosis spasticity: main outcomes and highlights.

BACKGROUND: Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary : Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex®) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic 'priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity.

Randomised clinical trial: arbaclofen placarbil in gastro-oesophageal reflux disease--insights into study design for transient lower sphincter relaxation inhibitors.

BACKGROUND: Arbaclofen placarbil is a pro-drug of the gamma-aminobutyric acid-B agonist R-baclofen that has been shown to reduce reflux episodes in patients with gastro-oesophageal reflux disease (GERD). AIM: To evaluate the efficacy and safety of arbaclofen placarbil vs. placebo as adjunctive therapy in subjects with troublesome GERD symptoms despite therapy with once-daily doses of a proton pump inhibitor (PPI) and to identify the characteristics of patients who were responders. METHODS: Patients (n = 460) with symptomatic GERD experiencing troublesome symptoms on once-daily PPI therapy were enrolled in this phase II, randomised, multicentre, double-blind, placebo-controlled, dose-ranging study. Patients were randomised to receive placebo or arbaclofen placarbil (20 or 40 mg once daily, 20 or 30 mg twice daily) with their current PPI for 6 weeks. Patients recorded heartburn and other GERD symptoms in a daily diary and rated severity of each event. The primary endpoint was percent change from baseline in heartburn events per week. RESULTS: In the primary analysis, there was no significant difference between arbaclofen placarbil and placebo. Post hoc analyses removing mild and very mild heartburn events resulted in greater percent reductions for all arbaclofen placarbil doses with nominal P values <0.05 for each dose compared with placebo. There was a dose-related increase for the most common adverse events. CONCLUSIONS: Arbaclofen placarbil was not superior to placebo in the primary analysis. Post hoc analyses suggest that subjects with more clinically relevant moderate or severe symptoms are more likely to respond to arbaclofen placarbil (clinicaltrials.gov NCT00978016).

Safety of subcutaneous microinjections (mesotherapy) in musicians.

OBJECTIVE: Determine the safety and tolerance of mesotherapy as a technique for the treatment of musculoskeletal complaints in musicians. METHOD: 67 patients (55.2% women) were subjected to a total of 267 mesotherapy sessions. A mesotherapy needle or normal needle was used randomly. The drugs employed were thiocolchicoside and diazepam as muscular relaxants, pentoxifylline or buflomedil as vasodilators, and piroxicam as an anti-inflammatory, as directed. A visual analogue scale was used to quantify the pain produced by the microinjections as well as the degree of immediate and midterm side effects as reported on a standard questionnaire. RESULTS: A mean of 155.5 microinjections were performed per session, of which 45.6% were perceived as painful by the patient with a mean severity of 4.3 out of 10. The pain reduced to 0.5 out of 10 after 24 hours. The most sensitive areas were the levator scapulae and splenius muscles. Systemic symptoms were reported by 5.99% of the musicians after the mesotherapy sessions (muscular weakness 1.5%, rash 1.5%, drowsiness 1.1% and itching 1.1%, being the most frequent). The mean severity of these symptoms was 2.77 out of 10. In all cases the symptoms had completely disappeared after 24 hours. No patient referred to signs of local or systemic infection. CONCLUSIONS: The application of drugs by means of subcutaneous injections (mesotherapy) in musicians is a technique that is safe, well tolerated, and without any severe complications.

Pharmaceutical therapy for radiculopathy.

Pharmaceutical treatments for radiculopathy include opioid, antiinflammatory (steroidal and nonsteroidal), neuromodulating, topical, and adjuvant treatments. These medications act locally, peripherally, or centrally on the neural axis. This article reviews the history of medication use for radiculopathy and the available literature along with the breadth of current treatment and indications.

Intrathecal baclofen in multiple sclerosis: too little, too late?

The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management.

Malignant hyperthermia: a pharmacogenetic disorder.

Malignant hyperthermia (MH) is a pharmacogenetic disorder triggered by volatile anesthetics or depolarizing muscle relaxants in predisposed individuals. Exercise or stress-induced MH episodes, in the absence of any obvious pharmacological trigger, have been reported, but these are rare. A considerable effort has taken place over the last two decades to identify mutations associated with MH and characterize their functional effects. A number of different, but complementary systems, have been developed and implemented to this end. The results of such studies have identified commonalities in functional affects of mutations, and also uncovered unexpected complexities in both the structure and function of the skeletal muscle calcium-release channel. The following review is an attempt to provide a summary of the background to current MH research, and highlight some recent advances in our knowledge of the molecular basis of the phenotypic expression of this disorder.

[Physical and other methods therapy of the spasticity in children]. / Neurorehabilitacja i inne sposoby leczenia spastycznosci u dzieci.

BACKGROUND: Spasticity is a very bothering symptom, which aggravates disability and prevents in many cases a successful treatment. THE AIM: The aim of this paper was to remind different methods of treatment of spasticity, with a special attention to neurorehabilitation. RESULTS: In the research the complex pathogenesis of spasticity was referred, as well as factors influenced its aggravation and associated symptoms. Methods of evaluation of degree of spasticity were also recalled. The advantage and disadvantage of neurorehabilitation were also discussed. NDT-Bobath method as well as other kinesiotherapy methods were described with the necessity to make individualised program. The methods of rehabilitation which help in the reduction of muscle tone were refered, as well as the importance of botulin toxin, in the context of lack of efficacy of drugs in the reduction of spasticity, which cannot in fact help to reach better results of rehabilitation. The effectiveness of spasticity therapy with baclofen pump and other surgical methods were also mentioned. CONCLUSIONS: The decision to treat spasticity must be justified and depended on its intensity. It is necessary to develop new methods to obtain the durable effect of therapy of spasticity.

Outcome of non-invasive treatment modalities on back pain: an evidence-based review.

At present, there is an increasing international trend towards evidence-based health care. The field of low back pain (LBP) research in primary care is an excellent example of evidence-based health care because there is a huge body of evidence from randomized trials. These trials have been summarized in a large number of systematic reviews. This paper summarizes the best available evidence from systematic reviews conducted within the framework of the Cochrane Back Review Group on non-invasive treatments for non-specific LBP. Data were gathered from the latest Cochrane Database of Systematic Reviews 2005, Issue 2. The Cochrane reviews were updated with additional trials, if available. Traditional NSAIDs, muscle relaxants, and advice to stay active are effective for short-term pain relief in acute LBP. Advice to stay active is also effective for long-term improvement of function in acute LBP. In chronic LBP, various interventions are effective for short-term pain relief, i.e. antidepressants, COX2 inhibitors, back schools, progressive relaxation, cognitive-respondent treatment, exercise therapy, and intensive multidisciplinary treatment. Several treatments are also effective for short-term improvement of function in chronic LBP, namely COX2 inhibitors, back schools, progressive relaxation, exercise therapy, and multidisciplinary treatment. There is no evidence that any of these interventions provides long-term effects on pain and function. Also, many trials showed methodological weaknesses, effects are compared to placebo, no treatment or waiting list controls, and effect sizes are small. Future trials should meet current quality standards and have adequate sample size.

Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs.

INTRODUCTION: Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect and side effects in behaving rodents, which may hinder the development of new drugs. Here we report on the establishment of a simple pharmacological test battery, which was used to compare efficacies and side effect profiles of 11 compounds with central muscle relaxant action, in mice (intraperitoneal application). METHODS: For measuring muscle relaxant activity, (1) a new tremor model (GYKI 20039-induced tremor) and (2) the morphine-induced Straub-tail assay were used. The former, newly developed method has advantages over harmaline- or LON-954-induced tremor. For detecting side effect liability (ataxia, sedation, impairment of voluntary motor functions), (1) the rota-rod test, (2) measurement of spontaneous motility, (3) the weight-lifting test and (4) the thiopental sleep test were used. RESULTS: Among the 11 muscle relaxant compounds tested (tolperisone, eperisone, silperisone, diazepam, baclofen, tizanidine, afloqualon, mephenesin, zoxazolamine, memantine and carisoprodol), the calculated safety ratios (i.e. ID50 for side effect/ID50 for muscle relaxant effect) varied in a wide range. Silperisone seems to have the most advantageous profile (safety ratios range between 1.7 and 3.3 in the different pairs of assays) compared to the other tested drugs with lower (one or more ratios below 1.5, and often far below 1) and more varying ratios. DISCUSSION: Therapeutic indices calculated from the results of these in vivo experiments for the clinically used muscle relaxants are in agreement with their adverse effect profiles in humans. Thus the present test battery seems to be suitable for predicting the possible clinical utility of newly synthesized compounds.

Generalized periarticular myositis ossificans as a complication of pharmacologically induced paralysis.

To our knowledge, no previous direct associations have been made between generalized myositis ossificans and pharmacological therapy. We report a case of generalized periarticular myositis ossificans associated with the use of curare and diazepam. The previously reported associations of myositis ossificans with tetanus and burns may be misleading. It is possible that it is not the disease process itself (e.g., tetanus, severe burn) that precipitates heterotopic ossification, but the treatment of these ailments. These observations suggest the importance of early mobilization and restrained use of immobilizing drugs. Further investigation is warranted with regard to the predisposing factors of generalized myositis ossificans and to its prevention.

[Combined use of non-depolarizing muscle relaxants in clinical anesthesiology]. / Kombinirovannoe primenenie nedepoliarizuiushchikh miorelaksantov v klinicheskoi anesteziologii.

Clinical observations in 99 patients and 74 experiments in cats enabled the authors to suggest that nondepolarizing myorelaxants when used in combination affected different portions of cholinergic receptors of the end plate of motor nerves causing greater inhibition of neuromuscular transmission. So an associated simultaneous application of such myorelaxants as tubocurarine and tercuronium as well as tercuronium and Arduan in special sub-blocking doses gives a complete relaxation of skeletal muscles without side effects which allows such methods to be recommended in surgical practice for anesthetic maintenance of operations on high risk patients.

Muscle relaxants for out-patient procedures.

The requirements for muscle relaxation in out-patient anesthesia are: a short total relaxation enabling the induction of an endotracheal tube followed by a period of 15-20 minutes of clinical relaxation. Reversal should be spontaneous. The new short acting muscle relaxants vecuronium and atracurium enable such a procedure, provided small doses are used (0.045 mg/kg for vecuronium or 0.2 mg/kg for atracurium. These small doses require a longer waiting time before intubation is easily performed (5 min for vecuronium and 6 min for atracurium). Spontaneous reversal of these small doses is achieved within 20-30 minutes. Potentiation of the relaxation by inhalational agents is not recommended.