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10 Articles in Volume 16, Issue #5
A Review of Skeletal Muscle Relaxants for Pain Management
Applying Kinesiology as a Multi-Prong Approach to Pain Management
Arachnoiditis: Diagnosis and Treatment
Bench to Bedside: Clinical Tips from APS Poster Presentations
Conversation With David Williams, PhD, President of the American Pain Society
Letters to the Editor: Prince Fentanyl Overdose, High-Dose Opioids, Mystery Care
Los Angeles Times Versus Purdue Pharma: Is 12-Hour Dosing of OxyContin Appropriate?
My Experience With OxyContin 12-Hour Dosing
Technology: Changing the Delivery of Healthcare
The Neuroscience of Pain

A Review of Skeletal Muscle Relaxants for Pain Management

Spasticity and spasm: 2 distinct reactions to motor neurons that require unique and sometimes complementary therapies.

Although grouped under a single drug class, skeletal muscle relaxants are a heterogeneous group of structurally unrelated medications with variable pharmacologic and safety profiles.1-3 Skeletal muscle relaxants are used commonly for the treatment of 2 conditions: spasticity and local musculoskeletal spasms. Approximately 2 million Americans, including more than 300,000 people over 60 years of age, are prescribed muscle relaxants.3

Spasticity and spasms are distinct etiologies, and each condition responds differently to certain medications. Spasticity is a disorder of motor neurons that manifests as increased muscle tone and stiffness.4 Spasms are involuntary localized muscle contractions that arise from acute trauma or muscle strain.3,5 Although antispasmodics and antispasticity agents generally are not interchangeable, diazepam (Valium) is approved by the Food and Drug Administration (FDA) for both conditions.6,7

In this article, the authors review the etiologies of, and treatment options for, painful spasticity and muscle spasm.

Skeletal Muscle System

Table 1 highlights the basic differences between spasticity and spasms, including the etiology, symptoms, causes, and FDA-approved therapies.8

Two types of motor neurons regulate skeletal muscle excitability: upper motor neurons (UMNs), which originate from the cerebral cortex, and lower motor neurons (LMNs), which originate in the spinal cord and brain stem.9-11 UMNs innervate the LMNs in the spinal cord, where they directly innervate skeletal muscles, and in the brain stem (cranial nerves), where they innervate the facial muscles. UMNs can stimulate or inhibit skeletal muscle contraction by direct innervation to LMNs. UMN lesions can result in muscle weakness, spasticity, or both, but LMN lesions may develop into muscle weakness and paralysis.

How Skeletal Muscle Contracts

A single α-motor neuron can innervate up to 200 muscle fibers, forming a complex called motor unit (Figure 1).10 With movement, an action potential originates from the UMN in the motor cortex.9 This action potential depolarizes the motor neuron terminal, resulting in the opening of voltage-gated calcium (Ca2+) channels and the subsequent release of the neurotransmitter acetylcholine (Ach) into the synaptic cleft. In the synaptic cleft, Ach binds to nicotinic cholinergic receptors on the muscle fiber membrane, leading to an influx of sodium (Na+) and a discharge of potassium (K) across the muscle fiber’s membrane, which results in depolarization of the muscle fiber.11 This depolarization opens voltage-gated Ca2+ channels on the sarcoplasmic reticulum (via ryanodine and inositol triphosphate receptors), allowing for Ca2+ influx into the cytoplasm of striated muscle cells.12  The Ca2+ then binds to troponin C, which exposes myosin-binding sites on actin filaments. A cross-link forms between actin and myosin, leading to muscle contraction. The pumping of Ca2+ back into the sarcoplasmic reticulum, using adenosine triphosphate, leads to cessation of contraction.

Neuromuscular System

There are 2 pathways that regulate skeletal muscle excitability and contraction: the monosynaptic and polysynaptic reflex pathways.8,10,13 In the monosynaptic reflex, afferent signals from muscle cells return to the spinal cord, resulting in negative feedback on motor movements. The Golgi tendon (Figure 2), a proprioceptive sensory receptor organ, senses muscle tension and sends an inhibitory signal to the spinal cord.9 In the polysynaptic reflex, type IA afferent neurons synapse on inhibitory neurons in the dorsal horn and inhibit contraction of the targeted area.8,10,13 For example, if a person touches a hot surface, the brain sends an excitatory signal to stimulate the bicep muscles to contract, allowing for the desired motion, and then sends an inhibitory signal.

Spasticity

Spasticity is defined as a velocity-dependent increase in muscle tone caused by the increased excitability of the muscle stretch reflex.4 Clinical manifestations include muscle stiffness, co-contraction of flexors and extensors, and increased resistance to muscle stretching. The etiology of spasticity is not fully known, but it is thought to be due to excessive stimulation or lack of inhibition of α-motor neurons, leading to increased muscle tone.2,4

Spasticity is associated with increased activity of excitatory neurotransmitters or decreased activity of inhibitory neurotransmitters (Table 2).13 Causes of spasticity include multiple sclerosis (MS), cerebral palsy, spinal cord injury, traumatic brain injury, and post-stroke syndrome.4,10,13

Antispasticity medications reduce muscle tone by acting either on the central nervous system (CNS) or directly on skeletal muscles (Figure 3).2 Agents that work on the CNS include baclofen (Gablofen, Lioresal, others), tizanidine (Zanaflex, others), gabapentinoids (gabapentin [Gralise, Horizant, others], pregabalin [Lyrica]), riluzole (Rilutek, others), and benzodiazepines (diazepam [Diazepam Intensol, Valium, others]), whereas peripheral agents include dantrolene (Dantrium, Revonto, others), and botulinum toxin (Table 3).14-16

Central Agents

Baclofen is a structural analogue of GABA that binds to GABAB receptors, which are coupled to presynaptic and postsynaptic Ca2+ and K+ channels.2,17 Therefore, baclofen acts presynaptically and postsynaptically to inhibit spinal reflexes. Presynaptic activation of GABAB receptors results in hyperpolarization and decreased Ca2+ influx, which reduces glutamate release, leading to a decrease in α-motor neuron activity. Postsynaptic activation of GABAB increases K+ conductance in the IA afferent neuron terminals, hyperpolarizing the membrane and enhancing presynaptic inhibition. Baclofen also is thought to inhibit substance P release into the spinal cord, which may reduce pain.18

Baclofen is available as an oral medication, as an intrathecal injection, or for use in an intrathecal pump; the latter form is reserved for cases of severe spasticity.19 Baclofen has been evaluated for other conditions, including cluster headache, intractable hiccups, and nicotine, cocaine, and alcohol dependence.20-24

Common adverse effects (AEs) include dry mouth and transient sedation that subside with chronic use.17 Withdrawal syndrome has been reported following abrupt stoppage of intrathecal and/or oral baclofen.25,26 Symptoms associated with abrupt withdrawal of baclofen include auditory and visual hallucinations, agitation, delirium, anxiety, fever, tremors, tachycardia, and, potentially, seizures.25,26

Tizanidine is a centrally acting α2 agonist that is structurally similar to clonidine.2,6 Tizanidine inhibits presynaptic release of excitatory neurotransmitters, reducing the excitability of postsynaptic α-motor neurons.2 In addition, tizanidine can potentiate the actions of glycine.27 Tizanidine has been shown to suppress the polysynaptic reflex and reduce abnormal co-contraction of opposing muscle groups.28 Tizanidine also has been evaluated as an adjunct for prophylaxis of several types of headache, including migraine and tension headache.29

Tizanidine is available as capsules and tablets, which are bioequivalent only when taken on an empty stomach.6 When tizanidine is administered with food, the amount absorbed from the capsule is approximately 80% of that of the tablet. In addition, food increases the plasma concentration of the tablet by 30% and decreases the plasma concentration of the capsule by 20%. Ingesting the contents of the capsule with applesauce results in a 15% to 20% increase in plasma concentration and area under the curve (AUC), compared to ingesting the capsule while fasting. Therefore, it is important to note that the capsules and tablets are not interchangeable.

Tizanidine is metabolized through CYP1A2, and the inactive metabolites are excreted in the urine (60%) and feces (20%).6 CYP1A2 inhibitors, such as fluvoxamine and ciprofloxacin, can increase plasma levels of tizanidine and the incidence of AEs.30 Studies have shown that concurrent use of oral contraceptives also increased the plasma concentration and hypotensive effects of tizanidine.31

AEs include weakness, dry mouth, increased spasm or tone, hypotension, and mild liver function test (LFT) elevations.6 Withdrawal symptoms, including reflex tachycardia, hypertension, hypertonicity, tremor, and anxiety, have been reported with abrupt discontinuation.32 To minimize withdrawal symptoms, the manufacturer recommends that the dose be tapered slowly (2-4 mg/day), especially in patients receiving high doses (>20 mg/day) for long periods (>9 weeks).6

Gabapentinoids are anticonvulsant medications that have shown benefit as antispasticity agents in studies in involving patients with spinal cord injuries.2,33-35 Both gabapentin and pregabalin inhibit the α2δ subunit of L-type voltage-gated Ca2+ channels, which are thought to inhibit glutamate release.36,37 Both agents have demonstrated efficacy in treatment of neuropathic pain and spasticity in patients with MS.35,38

Gabapentin has been shown to have a dose-related efficacy in controlling spasticity at dosages of 1,200 mg to 3,600 mg/day.33 Gabapentin has variable interindividual bioavailability, and exhibits saturable oral absorption; its bioavailability decreases as the dose increases.2,36 Gabapentin also is available in extended-release formulations with improved absorption, a tablet (Gralise),39 and a gastroretentive prodrug, gabapentin enacarbil (Horizant).40 Gralise is indicated for the management of postherpetic neuralgia,39 whereas Horizant is approved for the treatment of postherpetic neuralgia and moderate-to-severe primary restless legs syndrome.40

Pregabalin has a more predictable pharmacokinetic profile compared to gabapentin because it exhibits linear absorption.37 In a retrospective case series that evaluated pregabalin (75 to 300 mg bid) as a monotherapy for spasticity in 22 patients, 12 patients perceived improvements in spasticity, and 8 patients experienced AEs that lead to discontinuation.35

Overall, the role of gabapentinoids as monotherapy for spasticity remains unclear. They may be beneficial adjuncts in patients who have spasticity and neuropathic pain.  

Diazepam is the only benzodiazepine that is FDA approved for treatment of spasticity and muscle spasms.7 Diazepam binds to GABAA receptors and potentiates GABAergic activity by increasing chloride conductance, which results in presynaptic inhibition in the spinal cord.2,7 Diazepam has demonstrated efficacy in the management of spasticity associated with spinal cord injury, hemiplegia, and MS. However, it is not often recommended as a first-line agent due to risks of sedation and a potential for dependence or abuse.

Diazepam is metabolized to the active metabolites desmethyldiazepam, temazepam, and oxazepam, the last 2 of which are available commercially.7 AEs include lethargy, sedation, anterograde amnesia, cognitive impairment, and dependence. Withdrawal syndrome can occur with abrupt cessation of diazepam, and may lead to seizures.

Riluzole is a glutamatergic drug that is indicated for treatment of spasticity associated with amyotrophic lateral sclerosis (ALS).41 The etiology of ALS is unknown, but one hypothesis is that neurons become vulnerable through genetic predisposition or environmental factors, and excitotoxicity occurs secondary to excessive stimulation of glutamate receptors. Riluzole inhibits voltage-gated Na+ channels on glutaminergic nerve terminals, thereby inhibiting glutamate release. Riluzole also regulates glutamate release and postsynaptic receptor activation. These actions also contribute to inhibition of glutamate release.2,41

Riluzole’s absorption is reduced by administration with high-fat meals, which results in a 20% reduction in AUC and a 45% reduction in peak plasma concentration.41 Riluzole undergoes hepatic metabolism through CYP1A2 followed by glucuronidation, and is excreted as glucuronide metabolites in the urine (85%).41

In clinical trials, riluzole demonstrated disease-specific efficacy, showing benefit in patients with ALS but not patients with Huntington’s disease.42-45 Riluzole prolonged tracheostomy-free survival by 2 to 3 months in patients with ALS and showed a small beneficial effect on bulbar and limb function but not on muscle strength.43,44 However, when evaluated in patients with Huntington’s disease, riluzole had no benefit in symptoms or neuroprotection effects.45

Common AEs reported during clinical trials included nausea, vomiting, dyspepsia, flatulence, dry mouth, and weight loss.41-44 Riluzole was reported to cause dose-related LFT elevations during clinical trials (3-fold increase in serum alanine transferase), and the manufacturer recommends using caution in patients with hepatic impairment.41,43

Peripheral Agents

Dantrolene is a hydantoin derivative structurally related to phenytoin that blocks the ryanodine channel, which inhibits Ca2+ release from the sarcoplasmic reticulum, thus reducing muscle contraction.12,46 Dantrolene has been approved for “controlling the manifestations of clinical spasticity” that is the result of UMN disorders.46

AEs include skeletal muscle weakness, dyspnea, dysphasia, somnolence, and dose-dependent diarrhea. There have been reports of life-threatening hepatotoxicity.47,48 Dantrolene carries a black box warning of hepatotoxicity associated with high doses (>800 mg/day) and long-term use (3 to 12 months).46 Due to the risk of hepatotoxicity, it is not commonly used in practice for treatment of chronic spasticity and is mainly reserved for acute conditions such as neuroleptic malignant syndrome and malignant hyperthermia.

Botulinum toxin (BTX) is produced from Clostridium botulinum and is injected locally to inhibit presynaptic release of Ach in the neuromuscular junction, resulting in paralysis of the muscle.49,50 The onset of effect varies depending on the indication but is typically 14 days for spasticity and cervical dystonia—the effect typically lasts approximately 3 months.50 The effect diminishes when motor neurons develop new nerve terminals that start releasing Ach.51 Resistance to the paralytic effect could develop with repeated injections due to development of antibodies against the toxin.52,53 Adverse effects include rash and muscle weakness at the injection site, flu-like symptoms, and headache.

There are 2 antigenically distinct serotypes of BTX on the market: BTX-A and BTX-B. BTX-A is available as onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin).49,50 The only available BTX-B on the market is rimabotulinumtoxinB (Myobloc). Each agent has different FDA indications. All agents are approved for cervical dystonia; however, BTX-A has been shown to have a longer duration of effect than BTX-B.54 OnabotulinumtoxinA is approved for treatment of upper and lower limb spasticity, whereas abobotulinumtoxinA is approved for upper limb spasticity.55,56

Muscle Spasms

A muscle spasm is a sudden involuntary contraction of a muscle group that involves jerking and twitching.1,2,5 Unlike spasticity, which is a disorder of the CNS, muscle spasms arise from a variety of peripheral musculoskeletal conditions, such as mechanical low back pain. Common skeletal muscle conditions that cause spasms include fibromyalgia, myofascial pain syndrome, and mechanical low back or neck pain.1

Antispasm Agents

Most of the agents discussed here are FDA approved for adjunctive use to treat muscle spasms and pain associated with acute musculoskeletal conditions (Table 4). Health data from 2003 to 2004 revealed that cyclobenzaprine (Amrix, Fexmid, others), carisoprodol (Soma, others), and metaxalone (Metaxall, Skelaxin, others) accounted for more than 45% of medications prescribed for acute musculoskeletal pain.3

Although skeletal muscle relaxants are recommended for short-term use in the treatment of musculoskeletal pain, approximately 44.5% of users remain on them for more than a year.3 Due to CNS depression, cyclobenzaprine, metaxalone, orphenadrine (Norflex, others), methocarbamol (Robaxin, others), carisoprodol, and chlorzoxazone (Lorzone, Parafon Forte DSC, others) are on the American Geriatrics Society’s Beers List of inappropriate drugs for elderly patients.5 Despite this, approximately 300,000 annual prescriptions for skeletal muscle relaxants (15%) are issued to patients older than 65 years of age.3,5

Cyclobenzaprine has no direct activity on skeletal muscle, and its mechanism in myorelaxation has not been elucidated fully but is thought to be due primarily to its sedative effects.2,15,57 Cyclobenzaprine is highly sedating,  which could be beneficial in patients with acute muscle spasms who are also experiencing difficulty sleeping, but the toxicity that comes with its significant anticholinergic risks cannot be overstated.1,15

Cyclobenzaprine is structurally similar to tricyclic antidepressants (TCAs), differing from amitriptyline by only 1 bond in the central ring.58 A meta-analysis evaluating cyclobenzaprine in fibromyalgia patients showed that the medication was superior to placebo; however, it has been shown to be inferior to its chemically related TCA counterparts.59,60

Long-term use beyond 3 weeks is not recommended due to lack of data on efficacy for prolonged use.61 Cyclobenzaprine undergoes hepatic metabolism through CYP3A4, CYP1A2, and CYP2D6 and is mainly excreted in the urine as glucuronide conjugates and, to a lesser extent, as unchanged drug in the feces. Its AE profile is similar to amitriptyline and includes anticholinergic AEs (dry mouth, confusion, urinary retention), fatigue, tachycardia, and cardiac conduction disturbances. It is not recommended in patients with arrhythmias or cardiac conduction abnormalities.

Methocarbamol is a centrally acting muscle relaxant that is a carbamate derivative of guaifenesin (Liquibid, Mucinex, others).2,62 Its muscle relaxant mechanism is unknown but is presumed to be due to sedation. In a head-to-head trial comparing methocarbamol to cyclobenzaprine, methocarbamol was associated with less sedation (38% vs 58%), but the percentage of patients who stopped therapy due to AEs was similar for the 2 agents (6% vs 7%, respectively).63 The risk of respiratory depression may be increased when patients also are taking opioids, benzodiazepines, or barbiturates. A unique AE of the medication is brown or green urine discoloration. Muscle coordination abnormalities and grand mal seizures also have been reported.

Similar to the other agents in this class, carisoprodol also is a centrally acting muscle relaxant.64 In animal studies, carisoprodol exhibited its muscle relaxant effects by altering interneuronal activity in the spinal cord and the descending reticular formation of the brain.64 It also has been found to have analgesic properties by reducing perception of pain.64

Carisoprodol undergoes extensive hepatic metabolism through CYP2C19 to several metabolites, including meprobamate, which exerts barbiturate-like activity at the GABAA receptors.65 Poor CYP2C19 metabolizers (prevalent in 5%-15% of Asians and 3%-5% of Caucasians and African Americans) have experienced up to a 4-fold increase in exposure to carisoprodol and 50% reduction in exposure to meprobamate.66

AEs include drowsiness, headache, vertigo, insomnia, and an increased risk of respiratory depression, especially in patients on concomitant opioids, benzodiazepines, or barbiturates. Compared to cyclobenzaprine, carisoprodol is associated with less frequent dry mouth but more frequent dizziness.67 Of particular danger is the risk of psychological dependence with prolonged use, which is likely due to the meprobamate metabolite.68 Withdrawal symptoms have been reported with abrupt cessation of therapy.

Orphenadrine is an anticholinergic agent that is structurally similar to diphenhydramine but has a stronger antagonistic effect on the histamine H1 receptor.69 Orphenadrine appears to inhibit antimuscarinic Ach and N-methyl-D-aspartate receptors in the CNS. It undergoes hepatic metabolism, and the metabolites are primarily eliminated in the urine. The most common AEs are related to its anticholinergic profile and dose. AEs include dry mouth, sedation, constipation, ocular hypertension, palpitations, and sinus tachycardia. Rare cases of aplastic anemia have been reported but no causal relationship has been established.

The mechanism of action of metaxalone has not been established. It has no direct effect on skeletal muscles or nerve fibers, but CNS depression may be responsible for its effects.70 When taken with a high-fat meal, the bioavailability and AUC of metaxalone is increased. Metaxalone undergoes hepatic metabolism by CYP1A2, CYP2D6, CYP2E1, and CYP3A4, and its metabolites are excreted through the kidneys. Metaxalone is contraindicated in patients with renal or hepatic impairment. 70

AEs include dizziness, headache, nervousness, epigastric discomfort, and increased risk for respiratory depression in patients taking opioids, benzodiazepines, and barbiturates. Compared to other agents within the class, metaxalone has a relatively low risk of drowsiness or cognitive defects.71 Paradoxical muscle cramping has been documented with its use.71

Chlorzoxazone was FDA approved in 1958 as an adjunct for relief of discomfort associated with acute musculoskeletal conditions.72 Data from animal studies showed that it acts primarily at the level of the spinal cord and subcortical areas of the brain, which results in inhibition of multisynaptic reflex arcs involved in muscle spasms. It undergoes hepatic glucuronidation into an inactive metabolite that is excreted in the urine.73 Chlorzoxazone can cause orange, red, or purple urine discoloration.72

AEs include dizziness, somnolence, and occasional overstimulation. Rare cases of idiosyncratic hepatocellular toxicity have been reported.74 The manufacturer recommends immediate discontinuation if symptoms, including fever, rash, dark urine, or jaundice develop. Periodic LFT monitoring is recommended for patients on chronic therapy.72

Conclusion

Skeletal muscle relaxants represent a diverse pharmacotherapeutic group of medications across several chemical classes that are structurally dissimilar. These agents are effective for spasticity, skeletal muscle spasms, or both. Because of the breadth of pharmacologic mechanisms and variable pharmacokinetics, the drugs have a huge range of AEs and potential drug interactions. Considering that these agents are most often used in the elderly and also as adjuvants for the treatment of chronic pain patients with multiple comorbidities who are likely receiving a polypharmaceutical regimen (including opioids), skeletal muscle drug selection for each patient requires careful attention to these factors.

Last updated on: April 11, 2017
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Applying Kinesiology as a Multi-Prong Approach to Pain Management

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