7.1 Introduction

When the craniomandibular and craniocervical musculature becomes painful and it is possible to feel by palpation that the muscles are firm or tight, then the relaxation of these presumed “hyperactive” skeletal muscles is a common goal of therapy.¹ For this reason, skeletal muscle relaxants are often prescribed in the treatment of acute temporomandibular disorders (jaw locking, trismus, masticatory, and cervical myofascial pain). This is done in an attempt to reduce pain, improve any limitations in range of motion, reduce trismus and hyperactivity (e.g., taut bands), and help the patient perform the prescribed rehabilitation exercises. Palpating muscles for taut bands is not easy, and two separate investigations have shown that clinician differences are quite large when conducting this examination.^2,3 Moreover, while needle electromyography can identify hyperactive endplates in myofascially involved muscles, this is a nonspecific electrophysiological finding, and therefore⁴ surface electromyography is not sufficiently discriminatory for diagnosing these intramuscular phenomena.⁵ Fortunately, new methods have been developed that provide a more quantitative measure of muscle stiffness and taut bands. These methods hold great promise for more quantification of focal muscle hyperactivity and careful assessment of treatments designed to reduce muscle hyperactivity. For example, one 2003 study reported on the correlation between muscle activity recorded with electromyography (EMG) and muscle stiffness recorded using magnetic resonance elastography (MRE).⁶ These authors claimed that MRE, which generates a wave of activity in muscles, can then be used to noninvasively determine muscle activity. The authors used six healthy volunteers and imaged their muscles while they held varying degrees of isometric muscle activity in the muscle. They compared the elastographic wavelengths with the EMG-based activity in the muscle and found that the elastography wavelengths were linearly correlated to the muscular activity as defined by electromyography. A more recent study used this method to determine the mechanical properties of myofascial taut bands.⁷ This study involved eight human subjects (four who had myofascial pain). The data showed that there was a statistically significant increase of shear stiffness in the taut band regions of the involved subjects relative to that of the controls or in nearby uninvolved muscles. This method has not yet been used in clinical trials looking at various therapies for these taut bands, such as muscle relaxants.

While the use of analgesics in the treatment of acute and chronic orofacial pain disorders is well documented by randomized, double-blind, placebo-controlled trials, there is scant data on the efficacy of muscle relaxants in this population.^8,9 Theoretically, there is some evidence that generalized hyperexcitability of the central nervous system pathways, either causal or as a consequence of chronic orofacial conditions, may be seen and therefore it may be argued that there is a role of centrally acting muscle relaxants in treatment.¹⁰

Within a chronic pain population, there are always some cases of true spasticity or involuntary movement disorder, although these are far less common. Regardless of the diagnosis, there is a need for caution when using skeletal muscle relaxants, mainly because many of the drugs discussed in this chapter have side effects such as sedation and weakness and when used, especially in the elderly, there is real risk of serious adverse events. Moreover, some of the medications have strong drug–drug interaction poten­tial, and some produce a physical dependency and can induce addiction behavior.¹¹ Risk is always balanced against benefit so this chapter presents the available data on the efficacy and adverse events associated with skeletal muscle relaxants. First, we must point out that there are several drugs not covered in this chapter that are used primarily for involuntary movement disorders such as dyskinesia and dystonia and for sleep-related motor behaviors such as bruxism and myoclonus. These drugs include the anticholinergics, dopaminergics, botulinum toxin, and several others that are instead discussed in Chapters 19 and 11. There are also a variety of smooth muscle relaxants, also called antispasmodics, which are primarily used for gastrointestinal and bronchial tube spasm, but they are not discussed here.

7.1.A Skeletal Muscle Relaxants Versus Antispasticity Drugs

In this chapter we review 10 drugs and 1 drug class (benzodiazepines), which reduce skeletal muscle contraction or tension levels. These drugs are broadly called spasmolytics, and all except one (dantrolene) are centrally acting and can be subdivided into two main subcategories: skeletal muscle relaxants and antispasticity medications.¹² The antispasicity drugs are usually reserved for those patients with spasticity secondary to neurological conditions (e.g., multiple sclerosis) or spinal cord injury. Spasticity is defined as an upper motor neuron disorder characterized by muscle hypertonicity and involuntary movements or clonic jerks.¹³ Upper motor neurons are those that originate in motor region of the cerebral cortex or the brain stem and carry motor information toward the next neuron in the pathway. By definition, upper motor neurons are not directly responsible for stimulating the target muscle.¹⁴ Lower motor neurons are those that actually connect the brain stem and spinal cord directly to muscle fibers; their axons travel through a foramen and terminate on an effector (muscle). The antispasticity drugs include baclofen, tizanidine, dantrolene, and tiagabine, as well as the benzodiazepines (diazepam, lorazepam, alprazolam, and clonazepam). Botulinum toxin is being used for spasticity and dystonia, but this drug is discussed in another chapter (see Chapter 11).

In contrast there are six so-called muscle relaxants (cyclobenzaprine, methocarbamol, metaxalone, ophendrine, chlorzoxazone, and carisoprodol). These drugs are primarily used to treat painful musculoskeletal conditions, which exhibit muscle spasms, secondary muscle guarding, bracing, tightening, or trismus.¹⁵ Muscle spasm is a painful and involuntary muscular contraction that cannot be released voluntarily and is caused by pain stimuli to the lower motor neuron. These agents are also sometimes used to treat habitual (presumed to be volitional) behaviors such as anxiety-associated clenching and other muscle-specific habits, which are thought to contribute to the pain. Most clinicians endorse the idea that muscle pain induces some degree of muscle hyperactivity, which can in turn cause more pain. Although pain in a focal area does mandatorily induce tightening of the surrounding muscles, sometimes the opposite is true. Pain may inhibit rather than facilitate reflex contractile activity, so the decision to treat a patient with a muscle relaxant should not be based solely on pain but also on physical signs that include muscle tightness and/or taut bands. For acute pain of musculoskeletal origin, nonsteroidal anti-inflammatory drugs (NSAIDs) are used with much greater frequency than oral skeletal muscle relaxants or opioids. Unfortunately, there is very little evidence-based medicine available to guide the choice of a medication for an acute, uncomplicated musculoskeletal disorder since only a limited number of high-quality, randomized, controlled trials (RCTs) provide evidence of the effectiveness of muscle relaxants. As mentioned previously, the distinction between antispasticity drugs and muscle relaxants is based not on their site of action (e.g., central vs. peripheral) since most of these drugs act centrally, but on their relative ability to suppress upper and lower motor neuron activity. Because spasticity is quite disabling, the more potent antispasticity drugs, which also have more side effects and more associated adverse-event risk, are used in these cases. With minor skeletal muscle spasms such as a tight, sore, and stiff muscle, muscle relaxants are typically used since they are better tolerated, with relatively fewer adverse events. Finally, these agents have also been shown in some studies to demonstrate analgesia equivalent to either acetaminophen or aspirin. It remains uncertain if muscle spasm is a prerequisite to their efficacy as analgesics.¹⁶

7.2 Muscle Relaxants

Six drugs are discussed in this section (carisoprodol, cyclobenzaprine, methocarbamol, metaxalone, ophendrine, and chlorzoxazone). These drugs are used mostly for muscle spasm and muscle hyperactivity, which occurs as a secondary phenomenon in association with musculoskeletal pain. The Cochrane Library database contains other reviews that have looked at muscle relaxants for treatment of acute and nonspecific low back pain.¹⁷ These reviews focused on cyclobenzaprine, benzodiazepines, carisoprodol, or metaxalone and generally have concluded that there was enough evidence to support their short-term use for acute musculoskeletal pain. For a more chronic disease state, such as fibromyalgia, there is also some evidence that cyclobenzaprine is better than placebo (see Sec. 7.2.B). Finally, a non–Cochrane Library review of muscle relaxants for myofascial face pain was published.¹⁸ This systematic review concluded that the use of muscle relaxants in patients with myofascial pain involving the masticatory muscles seems to be justified but that current research can only be judged as weak and that the risk–benefit ratio of these medications must be considered.

7.2.A Carisoprodol

Description, Mechanism of Action, and Primary Indications

Carisoprodol is FDA approved for relief of discomfort associated with acute musculoskeletal conditions for patients over the age of 16. Carisoprodol is a centrally acting skeletal muscle relaxant and it is thought to block interneuronal activity by activating GABA-A receptors in the descending reticular formation and spinal cord.¹⁹ This drug is actually a prodrug that is metabolized the active drug, meprobamate which is an older antianxiety agent previously used to treat muscle spasms.²⁰

Starting Dose

The typical dosing for carisoprodol is 350 mg four times a day.

Metabolism, Side Effects, and Adverse Drug Reactions

The common side effects of carisoprodol are drowsiness, and it can cause psychological and physical dependence. This means that withdrawal symptoms can occur with discontinuation. Moreover, use of this drug in combination with benzodiazepines, barbiturates, codeine, or other muscle relaxants is known to induce respiratory depression. Meprobamate is a Schedule III controlled substance with a potential for drug dependence and carisoprodol is not a controlled substance, although it has been reported to exhibit similar dependence tendency.²¹ A case report that described four cases of carisoprodol intoxication was published in 2005.²² All four cases fulfilled three different sets of criteria for the diagnosis of serotonin syndrome. These findings indicate that an increased serotonin level in the central nervous system could explain some of the symptoms and signs of carisoprodol intoxication. This may have implications for the clinical evaluation and treatment of such intoxications. Since few laboratories routinely screen for carisoprodol it is important to keep this drug in mind when encountering intoxications displaying serotonergic symptoms.

Efficacy for Musculoskeletal Pain Associated Spasm

A 2004 review article concluded that there is fair evidence that cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are effective compared with placebo in patients with musculoskeletal conditions (primarily acute back or neck pain). In contrast there is very limited or inconsistent data regarding the effectiveness of metaxalone, methocarbamol, chlorzoxazone, baclofen, or dantrolene compared with placebo in patients with musculoskeletal conditions.²³

7.2.B Cyclobenzaprine

Description, Mechanism of Action, and Primary Indications

Cyclobenzaprine is FDA approved for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Cyclobenzaprine’s chemical structure, dosing, and side-effect profile are very similar to other tricyclic antidepressants (TCAs), even though it is not classified as such.²⁴ Like the TCAs it has a strong anticholinergic effects and long elimination half-life (12–24 hours). Its site of action is thought to be in the brainstem level of the central nervous system rather than the spinal cord level. Cyclobenzaprine is an antagonist at one or more of the serotonin 5-HT2 receptor subtypes and thus it reduces muscle tone via its antagonism of 5-HT2C receptors.

Starting Dose

Typical dosing is to start with 5 or 10 mg at bedtime and increase dose by 10 mg every 3–7 days and switch to a three-times-a-day dosing schedule.

Metabolism, Side Effects, and Adverse Drug Reactions

The major side effects of cyclobenzaprine are its anticho­linergic effects (drowsiness, urinary retention, dry mouth). It is advisable to avoid using this drug in the elderly or in patients with arrhythmias, a heart block, heart failure, or recent myocardial infarction. This drug has been known to raise intraocular pressure, so avoid it in glaucoma patients also.

Efficacy for Musculoskeletal Pain Associated Spasm

A small randomized trial on jaw-pain patients found that cyclobenzaprine was superior to clonazepam or placebo.²⁵ A 2003 study described two short (8-day duration) randomized placebo-controlled clinical trials that involved 1400 patients with acute musculoskeletal pain.²⁶ The results of this study suggested that the 5- and 10-mg doses of cyclobenzaprine were superior to the 2.5-mg dose and that this drug has at best a mild-to-moderate effect on symptoms, and both somnolence and dry mouth were reported. A much earlier study²⁷ examined the relative efficacy of cyclobenzaprine compared with and combined with diflunisal (an NSAID) for acute low back pain. This 10-day study reported that the combined-drug protocol was better than a single-drug protocol for acute pain. The same result, namely, that combined therapy was better than single therapy, was seen in another study, which combined and compared cyclobenzaprine and naproxen. A recent prospective, randomized, open-label, multicenter, community-based study compared cyclobenzaprine used alone or in combination with 1200 mg/day or 2400 mg/day of ibuprofen in adults with acute neck or back pain with muscle spasm.²⁸ The exact dosing was cyclobenzaprine (5 mg three times a day [t.i.d.]; given for 7 days) or ibuprofen (400 mg t.i.d. or 800 mg t.i.d.; given for 7 days). There were 867 subjects who gave post-treatment data; they were between the ages of 18 and 65 years and all had cervical or thoracolumbar pain and spasm for at least 14 days. The subjects were randomly assigned to one of three treatment groups and effect of treatment was measured at 3 and 7 days of therapy. Outcomes were primarily patient-rated scales assessing spasm, pain, global change, medication helpfulness, and disability. The authors reported that all three treatment groups demonstrated significant improvements from baseline for these outcomes, all three groups found the treatments tolerable, and adverse events (fatigue, somnolence, dizziness, sedation, and nausea) were equally distributed among the groups. Finally, a 2004 systematic review that examined efficacy and safety of cyclobenzaprine for fibromyalgia found five randomized controlled clinical trials that were of sufficient quality to include in the review on cyclobenzaprine.²⁹ The authors concluded that patients on cyclobenzaprine were more likely to report themselves to be improved versus the placebo group, but no remarkable improvement in fatigue or tender points were noted for these patients.

7.2.C Metaxalone

Description, Mechanism of Action, and Primary Indications

Metaxalone was approved by the FDA for treating acute musculoskeletal conditions in adults and in children over the age of 12 years. The advantage of this drug over other skeletal muscle relaxants include reduced sedation, diminished abuse potential, and limited accumulation of the drug because of its short elimination half-life. The mechanism of action for metaxalone is unknown in humans, but its effect is presumed to be due to general depression of the central nervous system.

Starting Dose

Dosing for this drug is 800 mg three times a day or four times a day.

Metabolism, Side Effects, and Adverse Drug Reactions

Common side effects of metaxalone include drowsiness, dizziness, headache, and irritability. It should not be used in patients with renal or hepatic failure or with a history of anemia, hemolytic, or other blood dyscrasias. The authors of this study examined Intercontinental Marketing Services data from January 2003 through January 2004 to determine which skeletal muscle relaxants were being utilized. They reported that carisoprodol, cyclobenzaprine, and metaxalone were the most commonly prescribed drugs for musculoskeletal pain. Based on this, they searched the literature on these drugs to find randomized controlled trials on metaxalone. This study concluded this drug was helpful for musculoskeletal pain but has some noticeable side effects (drowsiness, dizziness, headache, and nervousness) and some rare adverse events (leukopenia or hemolytic anemia and a potential for an elevation in liver function tests). Finally, paradoxical muscle cramps may also occur.

Efficacy for Musculoskeletal Pain Associated Spasm

Data for metaxalone is limited; its efficacy has been evaluated on low back pain patients.³⁰

7.2.D Chlorzoxazone

Description, Mechanism of Action, and Primary Indications

Chlorzoxazone works primarily in the spinal cord and in the subcortical areas of the brain.³¹ Its main action is to inhibit multisynaptic reflex arcs. It has no direct action on the contractile mechanism of striated muscle, motor endplate, or nerve.

Starting Dose

This drug is indicated for relaxing stiff, sore muscles and its typical adult dose is 250 mg to up to 750 mg three times a day.

Metabolism, Side Effects, and Adverse Drug Reactions

The main side effects of chlorzoxazone are dizziness, drowsiness, rare cases of hepatotoxicity, gastrointestinal irritation, and rare cases of gastrointestinal bleeding. There is a risk of respiratory depression if used with benzodiazepines, barbiturates, codeine or its derivatives, or other muscle relaxants.

Efficacy for Musculoskeletal Pain Associated Spasm

The quality studies on the use of this medication for musculoskeletal pain are few. See the comments in Section 7.2.A about the efficacy of carisoprodol for musculoskeletal pain, as chlorzoxazone is also discussed.

7.2.E Methocarbamol

Description, Mechanism of Action, and Primary Indications

Methocarbamol acts centrally and does not directly relax tense skeletal muscles in humans. Although the exact mechanism of action is not fully understood, it is thought to be due to methocarbamol’s sedative properties. Methocarbamol is a carbamate derivative of guaifenesin.³²

Starting Dose

The typical dosing for this drug is 1500 mg four times a day for the first 2–3 days, then 750 mg four times a day.

Metabolism, Side Effects, and Adverse Drug Reactions

Side effects include discoloration of the patient’s urine (brown-to-black or green) and impaired mental status. Most of the precautions for methocarbamol are associated with its parenteral form, which is generally used to treat tetanus.

Efficacy for Musculoskeletal Pain Associated Spasm

In a small but well-designed study (double blind, placebo controlled, crossover) the effects of methocarbamol versus placebo were described using 14 subjects.³³ Psychomotor and cognitive performance was described before and at 5.5 hours after drug administration. The results showed that methocarbamol produced significant increases in sedation but only minor impairment of psychomotor and cognitive performance.

7.2.F Orphenadrine

Description, Mechanism of Action, and Primary Indications

Orphenadrine citrate is indicated as an adjunct to physical therapy treatment and for the relief of acute pain seen with musculoskeletal conditions. Orphenadrine is thought to be a noncompetitive antagonist at N-methyl-D-aspartate (NMDA) receptor complexes and it is an antagonist at histamine H1 receptors. Orphenadrine may also act as an antagonist at M1, M2, M3, and M4 muscarinic acetylcholine receptors. This drug has a mechanism of action that is similar to antihistamines,^34,35 The structure of orphenadrine is similar to that of diphenhydramine, but orphenadrine possesses greater anticholinergic effects. The effects of orphenadrine are presumed to be due to its analgesic and anticholinergic properties.

Starting Dose

The typical dosing for this drug is 100 mg two or three times a day.

Metabolism, Side Effects, and Adverse Drug Reactions

As mentioned orphenadrine has anticholinergic activity (which is responsible for some side effects such as dry mouth). The main side effects are also anticholinergic in nature (drowsiness, urinary retention, dry mouth). Like cyclobenzaprine, avoid using this drug in the elderly and avoid using it for any patient with glaucoma or gastrointestinal disturbances.

Efficacy for Musculoskeletal Pain Associated Spasm

A clinical trial evaluated intravenous administration of 60 mg of orphenadrine citrate compared with a placebo for the treatment of spastic hypertonia in 11 patients with spinal cord injuries.³⁶ The Ashworth Spasticity Scale was used to compare the effects, and the authors report that orphenadrine was found to be statistically superior to placebo.

7.2.G Miscellaneous Other Drugs Used for Spasticity

Multiple other drugs have been used for management of spasticity, including gabapentin^37,38 and clonidine. Both are being used off-label and neither has a systematic random-assignment controlled trial to document its efficacy for spasticity against a placebo medication. Nevertheless, case reports do suggest they may have value in the management of spasticity. Gabapentin is an anticonvulsant drug that is FDA approved for epilepsy and for neuropathic pain. Patients may require higher doses of gabapentin (2700–3200 mg/day), and its safety at this level over long periods in spasticity is unknown; thus, caution is advised. The second drug in this miscellaneous category is clonidine, which is an alpha-2-adrenergic agonist; its mechanism of action is similar to tizanidine and, like gabapentin, there are no double-blind, placebo-controlled studies to show its efficacy in spasticity. It is suggested for use as an alternative when other medications are ineffective.³⁹

7.3 Antispasticity Drugs

There are four drugs and one drug class discussed in this section (baclofen, tiagabine, dantrolene, and tizanidine and the benzodiazepines); while some can be used for muscle spasm due to musculoskeletal conditions, these drugs are really used mostly to treat spasticity due to neurological disorders such as spinal cord injury, brain trauma, and multiple sclerosis. There has been one very well done systematic Cochrane-style review of the literature that examined both the efficacy and likelihood of adverse events occurring with baclofen, dantrolene, and tizanidine when used for long-term spasticity due to spinal cord injury.⁴⁰