Muscle relaxants tizanidine: Drug Database | Medication Decision Support

27.08.202329.06.2023 by alexxlab

Содержание

Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr

Comparative Study

. 2012 Mar;17(1):102-9.

doi: 10.1177/1074248410395020.

Epub 2011 Feb 11.

Nisrin Kaddar¹, Patrick Vigneault, Sylvie Pilote, Dany Patoine, Chantale Simard, Benoit Drolet

Affiliations

Affiliation

¹ Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC Canada.

PMID:
21317414
DOI:
10.1177/1074248410395020

Comparative Study

Nisrin Kaddar et al.

J Cardiovasc Pharmacol Ther.

2012 Mar.

. 2012 Mar;17(1):102-9.

doi: 10.1177/1074248410395020.

Epub 2011 Feb 11.

Authors

Nisrin Kaddar¹, Patrick Vigneault, Sylvie Pilote, Dany Patoine, Chantale Simard, Benoit Drolet

Affiliation

¹ Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC Canada.

PMID:
21317414
DOI:
10.1177/1074248410395020

Abstract

Background:

Tizanidine (Zanaflex) is a centrally acting imidazoline muscle relaxant that is structurally similar to clonidine (α(2)-adrenergic agonist) but not to other myorelaxants such as baclofen or benzodiazepines. Interestingly, cardiac arrhythmias and QT interval prolongation have been reported with tizanidine.

Objective:

To evaluate the effects of tizanidine on cardiac ventricular repolarization.

Methods:

(1) Whole-cell patch-clamp experiments: HERG- or KCNQ1+KCNE1-transfected cells were exposed to tizanidine 0.1-100 µmol/L (n = 29 cells, total) to assess drug effect on the rapid (I(Kr)) and slow (I(Ks)) components of the delayed rectifier potassium current. (2) Langendorff retroperfusion experiments: isolated hearts from male Hartley guinea pigs (n = 6) were exposed to tizanidine 1 µmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo wireless cardiac telemetry experiments: guinea pigs (n = 6) implanted with radio transmitters were injected a single intraperitoneal (ip) dose of tizanidine 0. 25 mg/kg and 24 hours electrocardiography (ECG) recordings were made.

Results:

(1) Patch-clamp experiments revealed an estimated IC(50) for tizanidine on I(Kr) above 100 µmol/L. Moreover, tizanidine 1 µmol/L had hardly any effect on I(Ks) (5.23% ± 4.54% inhibition, n = 5 cells). (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, tizanidine 1 µmol/L prolonged MAPD(90) by 8.22 ± 2.03 (6.7%) and 11.70 ± 3.08 ms (8.5%), respectively (both P < .05 vs baseline). (3) Tizanidine 0.25 mg/kg ip caused a maximal 11.93 ± 1.49 ms prolongation of corrected QT interval (QTc), 90 minutes after injection.

Conclusion:

Tizanidine prolongs the QT interval by blocking I(Kr). Patients could be at risk of cardiac proarrhythmia during impaired drug elimination, such as in case of CYP1A2 inhibition during drug interactions.

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Inappropriate Use of Skeletal Muscle Relaxants in Geriatric Patients

US Pharm. 2020;45(1):25-29.

ABSTRACT: Falls in geriatric patients cost the United States billions of dollars each year and contribute to morbidity and mortality in this population. Polypharmacy can significantly contribute to the fall risk, especially those medications that are on the Beers Criteria list. Skeletal muscle relaxants are on this list, and an increased risk of falls is associated with their use. These medications are inappropriately used as an alternative to conventional pain medications and can be as harmful as opioids in the geriatric population. Education of patients and prescribers is necessary in order to prevent inappropriate muscle-relaxant use and to lessen the risk of falls.

In the United States, an estimated 29 million falls occurred in 46 million people older than age 65 years in 2014, and 7 million of those falls resulted in injuries.¹In 2015, estimated medical costs related to fatal and nonfatal falls totaled more than $49 billion.² It is estimated that the U.S. geriatric population will increase to 74 million in 2030, and 49 million falls are predicted (with 12 million of these falls incurring injuries).¹ Well-known risk factors for falls in geriatric patients are polypharmacy and adverse effects of medications. Community pharmacists are uniquely positioned to reduce costs related to falls and increase patient safety by scrutinizing prescriptions for high-risk medications before these drugs are given to their patients. One class of medications with the potential for inappropriate prescribing in geriatric patients is skeletal muscle relaxants. Most skeletal muscle relaxants appear in both the National Committee for Quality Assurance’s list of high-risk medications in the elderly and the Beers Criteria list of potentially inappropriate medications in older adults.^3,4 In 2017, cyclobenzaprine, diazepam, tizanidine, baclofen, and carisoprodol appeared on the top-200 list of medications dispensed to patients.⁵

Although these medications may be useful for treating acute low back pain, evidence for safe and effective prolonged use is limited.^6,7These agents may be inappropriately prescribed on a long-term basis, as an alternative to opioids or nonsteroidal anti-inflammatory drugs (NSAIDs), based on a mistaken belief that they are safer. Carisoprodol and diazepam are the only skeletal muscle relaxants that carry a risk of addiction, but all of them have some risk of central nervous system depression, which can be problematic in geriatric patients.^7-9

Types of Skeletal Muscle Relaxants

Skeletal muscle relaxants, also called muscle relaxers, may be divided into two classes: antispasmodics and antispastics. Antispasmodics are agents that specifically treat muscle spasms. Muscle spasm occurs as a result of injury to muscles, tendons, or ligaments and is often synonymous with low back sprain or strain.^10,11Antispastics (sometimes referred to as spasmolytics) are agents that specifically treat muscle spasticity. Muscle spasticity is a condition in which the patient experiences continuous muscle spasms as a result of spinal motor neuron overactivity. This overexcitation manifests as clonus; stiffness; rigidity and tightness; and difficulty with walking, movement, and, occasionally, talking.^12,13 A systematic review of studies on leg spasticity epidemiology reported a prevalence of 28% to 38% in stroke patients, 41% to 66% in multiple sclerosis patients, and 13% in patients with traumatic brain injury.¹³TABLE 1 highlights key differences between antispasmodic and antispastic agents. A summary of available antispasmodics and antispastics is presented in TABLE 2.

According to the American College of Physicians (ACP), first-line therapy for acute low back pain (pain lasting <4 wk) consists of nonpharmacologic measures such as stretching, heat, and physical therapy. Antispasmodics, antispastics, and NSAIDs are all considered second-line therapy.¹⁴ Patient characteristics will influence the drug choice. Unlike NSAIDs, however, skeletal muscle relaxants do not have any disease-modifying properties for low back pain and provide only symptomatic improvement.¹⁴Chronic use of these medications is not recommended because little to no data exist on their safety and efficacy with long-term use.⁶ The ACP does not recommend skeletal muscle relaxants in patients with chronic low back pain (pain lasting >12 wk) because of a lack of efficacy and safety data.¹⁴

The Geriatric Lexi-Drugs database recommends the avoidance of muscle relaxants other than diazepam and tizanidine in patients older than age 65 years because efficacy and safety have not been established in geriatric patients. ⁹ However, all muscle relaxants, including tizanidine and diazepam, are on the Beers Criteria list.³

Potential for Harm in Geriatric Patients

Because antispastics and antispasmodics work within the central nervous system, their side effects can pose a unique risk for geriatric patients. Compared with the average adult, geriatric patients are at increased risk for falls because of unsteady gait, loss of coordination or muscle strength, and other age-related declines in mobility and cognition. Common side effects of antispastic and antispasmodic medications include dizziness, drowsiness, and hypotension; therefore, a geriatric patient’s risk for falls and fractures can increase when skeletal muscle relaxants are used. One study showed that geriatric patients who took muscle relaxants were 2.25 times more likely to visit the emergency department for a fall or fracture and 1.56 times more likely to be hospitalized for a fall or fracture than patients who did not take these medications. ¹⁵ Another study found that skeletal muscle relaxant users older than age 65 years were 1.32 times more likely to have an injury than patients who did not use skeletal muscle relaxants. More specifically, patients who took carisoprodol, cyclobenzaprine, and methocarbamol, respectively, were 1.73 times, 1.22 times, and 1.42 times more likely to have experienced injury compared with patients without a history of skeletal muscle relaxant use.¹⁶

Possible Alternative Therapies

There are several alternative therapies to skeletal muscle relaxants, depending on the reason for use. TABLE 3 gives a summary of possible alternatives.¹⁷For patients with lower back pain, it is important to understand that most pain resolves on its own and does not require medical treatment. Nonpharmacologic therapies such as superficial heat, transcutaneous electrical nerve stimulation, and massage may be employed, along with rest.^14,18 If pharmacologic therapy is deemed appropriate, ibuprofen may be used instead of skeletal muscle relaxants in patients without heart failure, renal dysfunction, or a history of gastrointestinal issues. ¹⁹ Recommendations for ibuprofen should be made cautiously in patients with cardiovascular history because of potential drug-disease interactions.⁶ Bleeding risk should also be evaluated because older adults have an increased risk of gastrointestinal bleeds.²⁰ The patient’s profile should be assessed prior to initiation, with particular attention paid to aspirin, clopidogrel, warfarin, and factor Xa inhibitors.²¹Recommendation of a trial of short-term pharmacologic therapy on an as-needed basis, along with nonpharmacologic options and physical therapy, can reduce polypharmacy and increase positive health outcomes in many patients.

Guidelines from the National Institute for Health and Care Excellence (NICE) for the management of multiple sclerosis, the most common cause of spasticity, recommend physical therapy for the management of spasticity in all patients. Pharmacotherapy is recommended only when spasticity causes pain, significant discomfort, loss of independence, or limitations in activities. ¹³ For patients who experience adverse effects with muscle relaxants, it may be beneficial to discuss alternative options, such as physical therapy, physiotherapy, or as-needed dosing with a muscle relaxant. Patients should be educated about the potential for falls and other adverse events and encouraged to weigh the pros and cons of taking a skeletal muscle relaxant. Another option to reduce medication burden, and therefore reduce fall risk, would be to tailor therapy to the time of day that muscle relaxation is needed. Patients often do not need medication when walking and being active, but they may require relaxation when going to bed because changing positions can aggravate spasticity. The first-line therapy (baclofen) and one second-line therapy (dantrolene), according to the NICE guidelines, are not on the Beers Criteria list, but both medications can increase the risk of falls.¹³ Tizanidine, the other second-line therapy, is on the Beers list owing to potential urinary retention, and it can also increase the risk of falls. ^3,12

The Pharmacist’s Role

Community pharmacists spend a significant amount of time ensuring that their patients receive medications that are both safe and effective for their medical conditions. Often, this involves contacting the prescriber after receiving a new prescription to verify the drug choice or dosing information. Pharmacists use clinical judgment every day to determine whether interventions necessitate calling the provider or counseling the patient. By educating patients and prescribers on the alternative pharmacologic and nonpharmacologic therapeutic options to skeletal muscle relaxants, the use of these medications can be drastically reduced. Also, patients should be educated on the risks associated with muscle relaxants, particularly falls.

If an older patient has a genuine need for one of these high-risk medications, it is important that the duration of medication use be kept as short as possible. Patients should also be educated about nonpharmacologic measures that can help prevent falls. ²² Patients with vision difficulties should avoid areas that are not well lit and should remove any tripping hazards, including rugs.²³ Assistive devices, particularly those with nonskid rubber ends, should be used if the patient feels unsteady while walking.²⁴ While taking skeletal muscle relaxants, patients should be particularly careful to avoid ingesting alcohol because coadministration increases the risk of central nervous system depression and falls.⁸

Conclusion

Skeletal muscle relaxants are a sedating class of medications used to treat spasticity and pain. Their sedative properties can pose a risk for geriatric patients who are predisposed to falls. It is important for the pharmacist to assess the patient before dispensing medications. Short-term use of skeletal muscle relaxants may be appropriate for certain conditions but should not be used long-term, regardless of interaction. Alternative pharmacologic options exist, but most have drawbacks. Nonpharmacologic therapy may be a better option in both the short term and the long term. Nonpharmacologic education on fall prevention is essential in patients being given skeletal muscle relaxants, regardless of duration of therapy. Not only will appropriate use of skeletal muscle relaxants improve patient outcomes, it can also improve star ratings for both insurance providers and pharmacies.

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14. Qaseem A, Wilt TJ, McLean RM, et al. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166:514-530.
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16. Spence MM, Shin PJ, Lee EA, Gibbs NE. Risk of injury associated with skeletal muscle relaxant use in older adults. Ann Pharmacother. 2013;47:993-998.
17. Humana. Medications to avoid in the elderly. http://apps.humana.com/marketing/documents.asp?file=3128346. Accessed October 1, 2019.
18. Chou R, Huffman LH. Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann Intern Med. 2007;147:492-504.
19. Hanlon JT, Semla TP, Schmader KE. Alternative medications for medications in the use of high-risk medications in the elderly and Potentially Harmful Drug–Disease Interactions in the Elderly quality measures. J Am Geriatr Soc. 2015;63:e8-e18.
20. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risk of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008;52:1502-1517.
21. Hamrick JW, Nykamp D. Drug-induced bleeding. US Pharm. 2015;40(12):HS17-HS21.
22. Jeon MY, Jeong H, Petrofsky J, et al. Effects of a randomized controlled recurrent fall prevention program on risk factors for falls in frail elderly living at home in rural communities. Med Sci Monit. 2014;20:2283-2291.
23. Gillespie LD, Robertson MC, Gillespie WJ, et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2012;(9):CD007146.
24. National Institute on Aging. Prevent falls and fractures. www.nia.nih.gov/health/prevent-falls-and-fractures. Accessed November 27, 2019.

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Nonbenzodiazepine muscle relaxants: focus on safety

06/22/2018

PDF article

Muscle relaxants are widely used in neurological practice for the treatment of syndromes accompanied by painful muscle spasm. However, arguments in favor of the effectiveness of muscle relaxants are often based on the results of studies with imperfect design. At the same time, there is strong evidence for their adverse effects (S. See, 2008). Therefore, important conditions for the effective and safe use of muscle relaxants are an individual approach to the selection of the drug and its dose, determining the duration of administration, as well as the use of rational combinations and the exclusion of undesirable interactions with other drugs (E.V. Lukina et al., 2013).

Comparative efficiency

Muscle relaxants are a heterogeneous group of drugs used to treat spasticity as well as muscle pain or peripheral musculoskeletal spasms. A systematic review summarized and evaluated the evidence for the comparative efficacy and safety of muscle relaxants (R. Chou, K. Peterson, 2004).

Tizanidine, cyclobenzaprine, dantrolene, carisoprodol, baclofen, orphenadrine, and diazepam were compared with placebo in 14 randomized clinical trials analyzed. Seven studies showed a significant reduction in the severity of dorsalgia, muscle tension and improvement in functional status after the use of these drugs for 1-2 weeks, and their effectiveness was comparable.

There is strong evidence that baclofen, tizanidine and dantrolene are effective compared with placebo in patients with spasticity (primarily those with multiple sclerosis). Cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are comparable to placebo in patients with musculoskeletal disorders (primarily acute back pain and neck pain).

Systematic reviews and meta-analyses also support the use of muscle relaxants for the short-term relief of acute low back pain when non-steroidal anti-inflammatory drugs (NSAIDs) are not effective and are poorly tolerated. Centrally acting muscle relaxants (M.W. Van Tulder, 2003) of various pharmacological groups have the highest efficiency (level of evidence 1A), while a high level of effectiveness of nonbenzodiazepine muscle relaxants was noted for pain in the lower back. It should be noted that comparative studies have not demonstrated the superiority of one or another muscle relaxant (F.A. Beebe, 2005; S. See, 2008).

The efficacy of cyclobenzaprine (10 mg) and tizanidine (4 mg) was compared in a randomized, placebo-controlled study in patients with myofascial pain and, in particular, jaw pain. Analysis of changes in the intensity, frequency and duration of pain in the cyclobenzaprine and tizanidine groups also did not reveal any significant differences (F.G. Alencar, 2014).

Safety profile

The use of all muscle relaxants may be accompanied by side effects, which patients should be informed about. Based on comparable efficacy, a muscle relaxant should be chosen individually, taking into account the safety profile and possible drug interactions (S. See, 2008). Dizziness and drowsiness are known to be common side effects of muscle relaxants, and it is noted that the sedative properties of tizanidine and cyclobenzaprine may benefit patients with insomnia caused by severe muscle spasms.

At the same time, other possible adverse effects of these drugs show significant differences. Thus, the use of cyclobenzaprine may be accompanied by an anticholinergic effect: dry mouth, urinary retention, increased intraocular pressure. Rare but serious side effects such as convulsions, heart rhythm disturbances, myocardial infarction are also possible.

Therefore, cyclobenzaprine is contraindicated in patients with arrhythmias, recent myocardial infarction, or congestive heart failure. It is noted that cyclobenzaprine has a long half-life, and can also enter into unwanted drug interactions with CYP450 inhibitors, tramadol and anticonvulsants.

Cyclobenzaprine should be avoided in the elderly and patients with glaucoma.

In turn, tizanidine has favorable pharmacokinetic properties. When taken orally,
is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum concentrations in blood plasma are created after 1-2 hours. The drug binds to blood plasma proteins by no more than 30% and, thus, has a quick effect, does not have a cumulative toxic effect (G. B. Kadrzhanova et al., 2013) .

Tizanidine may cause dose-dependent hypotension and dry mouth. Co-administration with strong CYP1A2 inhibitors such as ciprofloxacin, fluvoxamine, and alcohol is not recommended. Also, against the background of the use of tizanidine, a decrease in the effectiveness of the use of oral contraceptives is possible (S. See, 2008).

With sudden withdrawal of the drug, some increase in muscle tone may occur, so the withdrawal should be gradual. The “rebound” syndrome is also observed with the rapid cancellation of some other muscle relaxants (V.V. Badokin, 2013).

In general, the side effects of tizanidine are less pronounced than with other muscle relaxants (B. Bass et al., 1988; X. Lataste et al., 1994; J. D. Wallace, 1994; D. A. Gelber et al., 2001).

It should be noted that 90% of patients determined the tolerability of tizanidine as “good” or “very good”, which allows us to recommend it as the drug of choice among muscle relaxants for the treatment of pain caused by muscle spasm (A. V. Sergeev, 2013).

In combination with NSAIDs

As is known, patients suffering from diseases of the musculoskeletal system almost constantly take NSAIDs, which often leads to the development of drug-induced gastropathy and enteropathy, increased blood pressure and other cardiac symptoms, as well as nephrotoxicity (V.V. Badokin, 2013).

At the same time, some muscle relaxants can be used as an alternative to NSAIDs in patients who are at risk of gastrointestinal or renal complications, and also have a gastroprotective effect when used together with NSAIDs (S. See, 2008; V.V. Badokin, 2013 ).

In particular, tizanidine, which has both a muscle relaxant and a central analgesic effect, has a gastroprotective effect, which is associated with its adrenergic and antispasmodic activity (M. Emre, 1998; A.V. Sergeev, 2013).

When taking the drug, the basal and induced secretion of acid in the stomach decreases, the balance of glycoproteins in the gastric mucosa and gastric secretion is restored.

Reduced ulcerogenic effect of acetylsalicylic acid, indomethacin, meloxicam, nimesulide and naproxen (N.K. Jain, 2002), ibuprofen (B. Bass et al., 1988) when combined with tizanidine. In patients treated with the combination of ibuprofen and tizanidine, the frequency of gastrointestinal side effects, including bleeding, was significantly lower (p = 0.002) than in patients treated with the combination of ibuprofen and placebo (H. Berry, D.R. Hutchinson, 1998).

Also proved the gastroprotective effect of tizanidine when using diclofenac in a multicenter randomized clinical trial in which 405 patients participated. Gastropathy was detected in 12% of patients who received the combination of diclofenac and tizanidine, and in the group of patients who took diclofenac and placebo, in 32% (Sirdalud ternilin Asia-Pacific study group, 1998).

It has been established that tizanidine improves the tolerability of NSAIDs (in particular diclofenac) and potentiates their analgesic effect. The use of piroxicam, diflunisal and diclofenac in combination with tizanidine (4 mg/day), administered for 10-12 days, showed a significant reduction in pain and improvement in spinal mobility in the latter group.

At the same time, the indicators of the Oswestry questionnaires recommended by the World Health Organization for patients with back pain improved by 25%, and the pain score on the visual analogue scale (VAS) decreased from 56 mm to 34 mm. Tolerability of diclofenac and tizanidine in their combined use was good (V.A. Nasonova, 2004).

Tizanidin demonstrates a gastroprotective effect in ankylosing spondylitis, and also has a pronounced muscle relaxant, analgesic effect and potentiates the action of NSAIDs (V.V. Badokin, 2013).

The duration of the course use of muscle relaxants is 1-3 weeks. In clinical practice, for the rapid relief of pain in the back, it is advisable to use a combined scheme: NSAIDs + muscle relaxant (tizanidine) (V.A. Parfenov, 2010).

Thus, the use of tizanidine makes it possible to more effectively relieve pain, reduce the doses of NSAIDs and the frequency of adverse reactions associated with their use (A.V. Sergeev, 2013).

Pediatric

Despite the fact that muscle relaxants are widely used mainly in adult patients, there is evidence of the use of tizanidine in pediatric practice. In particular, the use of low doses of tizanidine in children with severe spastic diplegia is accompanied by positive effects in the motor, autonomic and emotional spheres.

The use of tizanidine was studied in 300 children with spastic and hyperkinetic forms of cerebral palsy (ICP) (G.B. Kadrzhanova et al., 2013). The drug was prescribed in small doses from 0.5 to 1 mg/day for 12-14 days. In severe forms of cerebral palsy, the course of treatment with tizanidine was extended to 30 days with a gradual withdrawal of the drug.

The main indications for the appointment of tizanidine were spasticity, dystonic muscle attacks with persistent hyperkinesis and severe anxiety, sleep disturbance.

During treatment with tizanidine, a pronounced sedative effect, a decrease in muscle spasm, and an improvement in sleep were noted during the first three days of using the drug. It was shown that tizanidine led to a significant decrease in muscle tone in 70-75% of children, a decrease in hyperkinesis in 85% of children, and normalization of sleep in 70% of children.

A positive effect was noted in patients with severe spastic-hyperkinetic forms of cerebral palsy, accompanied by severe dystonic attacks. The use of tizanidine also contributed to the reduction of such vegetative-visceral dysfunctions as excessive sweating, regurgitation, hyperthermia. The most pronounced effect was noted in young children (from 6 months to 1.5 years) with severe hyperkinetic forms of cerebral palsy. Thus, the experience of using tizanidine in the rehabilitation of children with cerebral palsy has demonstrated a positive effect on the motor sphere, the autonomic nervous system, as well as an improvement in emotional tone.

No serious side effects were noted when taking tizanidine, except for some drowsiness during the first days. In general, the drug was well tolerated. The results of ongoing studies of tizanidine may become an argument for expanding indications for its use in pediatric practice.

Based on the available data, the following conclusions can be drawn:

– tizanidine has a number of advantages over other centrally acting muscle relaxants: in addition to the muscle-relaxing effect, which is not accompanied by a decrease in muscle strength, it has an analgesic effect and potentiates the action of NSAIDs;

– the gastroprotective effect of tizanidine makes it possible to neutralize the negative effects of NSAIDs on the gastrointestinal tract, and the side effects of tizanidine itself are less pronounced compared to other muscle relaxants with a similar mechanism of action;

– tizanidine is widely used to treat muscle spasms, as well as in the complex therapy of pain syndromes of various etiologies. The drug has proven its effectiveness in the treatment of trigeminal neuralgia, myofascial, headache, neuropathic pain, dorsopathy pain, as well as pain syndrome in patients with spastic paresis;

– tizanidine is also used in the treatment of trigeminal neuralgia, myofascial pain of masticatory muscles, phantom pain, as well as in rheumatological practice (A.B. Danilov, 2010; E.V. Lukina et al., 2013; V.V. Badokin, 2013; F. G. Alencar, 2014; A. Ahiskalioglu et al., 2018).

Thus, tizanidine (Sirdalud) is an effective and safe drug for the treatment of pain syndromes associated with increased muscle tone, which allows it to be used as the drug of choice for monotherapy of acute myofascial pain and for the treatment of chronic myofascial pain in combination with other drugs.

Prepared by Alexandra Demetskaya

Thematic issue “Neurology, Psychiatry, Psychotherapy” No. 2 (45) cherv 2018

Number:
Thematic issue “Neurology, Psychiatry, Psychotherapy” No. 2 (45) cherven 2018

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Clinical pharmacology of muscle relaxants uMEDp

Muscle relaxants are currently widely used in the treatment of spasticity and various pain syndromes. This article is devoted to a review of the clinical pharmacology of three muscle relaxants – tizanidine, baclofen and tolperisone. Particular attention is paid to the safety and tolerability of these drugs.

Table 1. Pharmacokinetic characteristics of oral tizanidine in different patient populations

Table 2. Pharmacokinetic characteristics of tolperisone at a single dose of 150 mg

Table 3. The frequency of the most common adverse reactions in patients with spasticity when using tizanidine, baclofen or diazepam

Table 4. Head-to-head safety studies of tizanidine and baclofen in patients with spasticity

Table 5. Overall tolerance of tizanidine, baclofen and diazepam in comparative clinical studies in patients with spasticity, % of patients

Introduction

Muscle relaxants are widely used in the complex treatment of spasticity in multiple sclerosis or after a stroke, as well as pain syndromes.

Scientists from the USA found that only 16% of patients with multiple sclerosis had no spasticity, in 31% of cases it was expressed to a minimum degree, in 19% – in mild, in 17% – moderate, in 13% – severe, in 4% cases – was of a total nature, making everyday activity impossible [1].

Another group of patients who require the appointment of muscle relaxants are stroke survivors [2]. Thus, in the first three months after a stroke, more often hemorrhagic, spasticity was observed in 17–25% of patients [3].

Muscle relaxants are also used for pain in the lower back, mostly acute and associated with muscle spasm [4]. According to different researchers, the prevalence of pain in the lower back ranges from 1.4 to 20.0% [5]. In the Russian Federation, according to the World Health Organization, pain in the lower back among people over 50 years of age occurs in 56% of cases [6]. At the same time, it has been established that from 50 to 80% of the adult population experience such pain at least once in their lives [7, 8].

To compare the effectiveness of muscle relaxants for pain in the lower back, R. Chou et al. conducted a systematic review [9]. Scientists noted that there are not enough high-quality clinical studies to evaluate this [9].

Since the most effective muscle relaxant in the treatment of low back pain has not been determined, consideration should be given to its tolerability and safety profile when choosing a drug.

Good tolerability in outpatient treatment is especially important, since the development of adverse drug reactions may be accompanied by a decrease in compliance and even discontinuation of the drug [10].

The article considers the pharmacology of the most studied and widely used muscle relaxants in clinical practice: tizanidine, baclofen and tolperisone.

Pharmacodynamics and pharmacokinetics

Tizanidine

Tizanidine is a centrally acting muscle relaxant. The drug is an alpha-2-adrenergic receptor agonist. Their stimulation in the region of the presynaptic membrane leads to a decrease in the secretion of amino acids (glutamate and aspartate) that activate the motor neurons of the spinal cord [11, 12]. As a result, the polysynaptic reflexes of the spinal cord responsible for muscle hypertonicity are inhibited. Along with this, inhibition of interneuronal activity, also caused by stimulation of alpha-2-adrenergic receptors, causes additional antinociceptive and anticonvulsant activity [12].

The pharmacokinetic profile of tizanidine has been studied in a number of clinical studies, both in healthy volunteers and in patients with spinal cord injury or multiple sclerosis. It has been established that when taken orally, tizanidine is rapidly absorbed (53-66% of the dose taken). The maximum plasma concentration (C _max ) at a single oral dose of 5 and 8 mg varies from 3.2 to 25.8 µg/l, respectively [13]. Time to reach maximum concentration (T _max) in blood plasma is 0.75–2.00 hours (Table 1) [13].

A study involving healthy volunteers demonstrated that food intake had no significant effect on the pharmacokinetics of tizanidine [13].

The absolute bioavailability of tizanidine when taken orally is from 20 to 34%, which is due to the pronounced effect of the first passage through the liver [12].

Tizanidine is metabolized in the liver by oxidation with the participation of isoenzymes of the cytochrome P450 system (CYP1A2) with the formation of inactive metabolites, 19-23% of which are excreted with faeces, 53-66% – with urine. Less than 3% of the dose of tizanidine is excreted unchanged in the urine [14].

Most clinical studies have shown that the half-life (T _1/2) of tizanidine is 2.1-4.2 hours [13]. In case of impaired renal function (creatinine clearance less than 1.5 l / h (25 ml / min)) the half-life with a single dose of 4 mg increases to 13.6 hours [13].

Baclofen

Baclofen is also a centrally acting muscle relaxant. The drug is a lipophilic derivative of gamma-aminobutyric acid (GABA) and has a high affinity for its B-receptors. It activates GABA B receptors on mono- and polysynaptic neurons in the spinal cord and brain. By acting on B-receptors, baclofen causes a decrease in spasticity.

As is known, GABA affects two types of receptors – A and B [15]. A receptors are ionotropic. When GABA binds to them, an ion channel opens in the nerve cell membrane, chloride ions penetrate the cell, reducing its reactivity. This type of receptor is the target of benzodiazepines, barbiturates, volatile anesthetics, and alcohol [15]. B receptors are metabotropic. Indirectly, through the G-protein system, they reduce the level of excitation in the cell. A decrease in cell sensitivity to excitatory effects is provided due to the effect on calcium and potassium channels. B receptors can be located both presynaptically and postsynaptically [16].

It is believed that the inhibitory effect on the brain upon activation of B receptors is realized by reducing the release of excitatory amino acids (for example, glutamate), as well as by hyperpolarization of postsynaptic neurons [16].

It should be noted that baclofen is characterized by a withdrawal syndrome. This can manifest as hallucinations, disorientation, confusion, tachycardia, tremors, seizures and muscle rigidity, as well as hypertension and hyperthermia. The development of these conditions is due to the rapid cessation of the inhibitory effect of the drug on GABA receptors. Risk factors for the occurrence of withdrawal syndrome are considered to be high doses, long-term therapy and its rapid withdrawal [17].

When administered orally, baclofen is rapidly absorbed from the gastrointestinal tract, with a bioavailability of 70–85% [18]. However, as the dose increases, absorption may decrease. With a single oral dose of 50 mg C _max in healthy volunteers was 737.6 ng/ml, T _max was 1.9 ± 0.3 hours [19].

It should be noted that the results of a prospective study in which 15 male volunteers aged 19up to 30 years [20], suggested the absence of significant pharmacokinetic interactions between baclofen and tizanidine. The study consisted of three periods: the first – taking tizanidine 4 mg three times a day for seven days, the second – taking baclofen 10 mg three times a day for seven days, the third – the joint administration of tizanidine and baclofen in the above doses also in within seven days. Washing periods of four days were carried out between these periods. C _max of baclofen when taken separately reached 211 ng/ml, when combined with tizanidine – 208 ng/ml [20].

Baclofen has a relatively short T _1/2 – from two to six hours.

About 15% of baclofen is metabolized in the liver by deamination. In clinical studies using a drug labeled with a radioactive isotope, it was found that about 85% is excreted unchanged, mainly with urine, as well as with faeces [18].

Complete elimination of the drug from the body is observed 72 hours after administration.

Tolperisone

Tolperisone is a centrally acting muscle relaxant, similar in chemical structure to local anesthetics (lidocaine). The drug is mainly used in European countries. It is not registered in the USA.

The mechanism of action of tolperisone is not fully understood. However, it has been found that it blocks voltage-dependent sodium and potassium channels at the level of the spinal cord, causing inhibition of the presynaptic release of neurotransmitters [21]. In addition, the drug suppresses mono- and polysynaptic reflexes at the level of the spinal cord, provides lidocaine-like analgesia, and stabilizes nerve cell membranes [21]. Along with this, tolperisone enhances peripheral blood flow, facilitates voluntary muscle movements [21].

Tolperisone is rapidly and almost completely absorbed from the gastrointestinal tract. Due to the effect of the first passage through the liver, its absolute bioavailability is 17–20% [21, 22]. The time to reach the maximum concentration is from 0.5 to 1.0 hours [21]. The elimination half-life averages 1.7 hours [22].

A distinctive feature of tolperisone is the significant variability of pharmacokinetic parameters depending on genetic characteristics. So, in the study by M. Pawlowska et al. (2015) [22] involved 28 healthy Caucasian men aged 27.3 ± 7.7 years [22]. Volunteers received a single oral dose of tolperisone at a dose of 150 mg. Using a real-time polymerase chain reaction, they were found to be carriers of alleles of the CYP2D6 and CYP2C19 genescytochrome P450, which are responsible for the metabolism of tolperisone.

C _max of the drug ranged from 4. 47 to 336.43 ng/ml, on average it was 90.88 ± 86.04 ng/ml (Table 2) [22].

The study also found that the frequency of genetic polymorphisms of the genes that provide slow / slow metabolism of tolperisone in healthy volunteers for CYP2D6 and CYP2C19 isoenzymes was 46.43 and 0%, respectively [22]. The results of the study by Z. Desta et al. indicate that the number of Caucasians with a genetically determined slow metabolism of tolperisone does not exceed 6% [23]. To obtain accurate information, a broader study of the problem in different populations and countries is required.

Similar data on the variability of the pharmacokinetic parameters of tolperisone were presented by J.W. Bae et al. (2007) [24]. The study was conducted with the participation of 15 healthy volunteers of the Mongoloid race (Koreans). The average age of men is 23.6 ± 1.3 years. Tolperisone was administered orally at a dose of 450 mg once. C _max ranged from 64.2 to 784.9 ng/ml. Area under the pharmacokinetic curve (AUC), from zero to infinity (AUC _0-∞), – from 125. 9up to 1241.3 ng × h/ml [24].

Thus, depending on the genetic characteristics of a person, the maximum concentration of tolperisone in blood plasma can vary significantly. As a result, either the ineffectiveness of therapy (at low concentrations due to a high level of metabolism of tolperisone), or a high risk of developing unwanted and toxic reactions (at a low level of metabolism, leading to high concentrations of the drug in the blood).

Tolperisone is excreted mainly by the kidneys (85%). At the same time 98% of the drug is eliminated from the body within 24 hours after ingestion [21].

Adverse reactions

Tizanidine

Tizanidine is generally well tolerated. According to the results of clinical studies, in patients with spasticity taking tizanidine ≤ 36 mg / day, the most common adverse reactions were dry mouth (23-57%), drowsiness (24-48%), muscle weakness (18-48%) and dizziness (10–19%). In 5-7% of cases, there was a clinically significant increase in the level of liver enzymes, which resolved after discontinuation of the drug [25-27].

In comparative studies, among the most common side effects while taking tizanidine ≤ 32 mg / day, drowsiness, dry mouth and muscle weakness were also indicated [13]. At the same time, the incidence of drowsiness in those who received tizanidine and those who took baclofen was comparable – from 15 to 67% (Table 3) [13].

It should be noted that baclofen (0–25%) had the highest rate of drug withdrawal due to muscle weakness, followed by diazepam (4–6%) and tizanidine (0–6%) (Table 4) [ 28–33].

Serious adverse reactions during tizanidine therapy were recorded in 0.18% of patients [34]. These were represented by hallucinations and severe liver dysfunction. In most cases, liver damage during tizanidine therapy manifests itself in the form of an increase in the level of liver enzymes (alanine aminotransferase and aspartate aminotransferase) – 5% of patients.

In addition to the safety profile, tolerability is considered an important characteristic of any drug. A survey of patients with spasticity treated with tizanidine showed that the overall tolerability of the drug was good or excellent in 44-100% of cases (Table 5) [13].

In comparative studies, tizanidine was better tolerated than baclofen and diazepam, which may affect adherence to therapy, especially in outpatient settings [13].

Baclofen

The incidence of adverse reactions with oral baclofen ranges from 10% to 75% [35]. The most common include drowsiness, excessive general weakness, severe muscle weakness and dizziness.

In patients with impaired renal function, the drug should be administered with caution due to a higher risk of adverse reactions. Data on this was received by F.T. Muanda et al. in a large retrospective cohort study of 15,942 elderly patients (66 years and older) with chronic kidney disease (estimated glomerular filtration rate (eGFR)

We also compared the relative risk of hospitalizations due to encephalopathy in those taking and not taking baclofen (n = 284,263). The weighted relative risk of hospitalization while taking the drug at a dose of less than 20 mg / day was 5.9(with 95% confidence interval (CI) 3.59–9.70), at a dose of 20 mg/day or more – 19.8 (95% CI 14.0–28.0).

Thus, it was found that in patients with impaired renal function, baclofen during the first 30 days of administration contributed to the development of encephalopathy requiring hospitalization, therefore, when prescribing it to such patients, the benefit / risk ratio should be assessed [36].

Tolperisone

Most often, weakness and muscle pain, dizziness, urticaria, nausea, vomiting, and dry mouth are observed during tolperisone therapy [21]. These reactions usually subside after discontinuation of the drug. However, the literature also describes severe adverse reactions, such as anaphylactic shock [37]. It should be noted that tolperisone does not have a sedative effect [6].

According to post-registration studies and the spontaneous reporting system, allergic reactions occurred in about 50% of cases, followed by adverse reactions from the gastrointestinal tract [38]. Among allergic reactions, the most common were urticaria (5.1%), itching (4.8%), shortness of breath (4.2%), angioedema (3%), erythema (2.6%), rash (1.8 %) and anaphylactic shock (1.2%). About 30% of allergic reactions developed when tolperisone was used with other drugs, most often with non-steroidal anti-inflammatory drugs [38]. Allergic reactions on the background of tolperisone therapy became the basis for the European Medical Agency to recommend to refrain from prescribing oral forms of tolperisone, with the exception of adult patients with spasticity after a stroke (2012) [39]. This statement was made after evaluating the benefit / risk ratio for various diseases.

Data from post-registration studies and spontaneous reporting systems also revealed serious side effects in the form of hypersensitivity reactions, as well as a lack of data confirming the effectiveness of tolperisone in the treatment of a number of diseases. In this regard, experts from the European Medical Agency recommended limiting the use of oral tolperisone, except for the treatment of spasticity after a stroke, in which the benefits of using the drug outweigh the potential risk [39].

Muscle relaxants tizanidine: Drug Database | Medication Decision Support

Tizanidine (Zanaflex): a muscle relaxant that may prolong the QT interval by blocking IKr

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