The term skeletal muscle relaxant is often used to describe a diverse group of medications commonly used in the treatment of back pain ( Table 41.1 ). Medications commonly referred to as skeletal muscle relaxants include carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine. All these agents are labeled by the U.S. Food and Drug Administration (FDA) with an indication for the relief of discomfort associated with an acute, painful, musculoskeletal condition. Oral baclofen and tizanidine are also commonly used to treat acute musculoskeletal conditions and are considered by many clinicians as muscle relaxants, despite the lack of an FDA-approved indication in this regard. Baclofen and tizanidine do have FDA indications for the treatment of spasticity caused by upper motor neuron syndromes including multiple sclerosis, spinal cord disease, or injury. Benzodiazepines, principally diazepam, are also commonly used and indicated for adjunctive relief of skeletal muscle spasm and are often considered in discussions regarding skeletal muscle relaxants.
| Drug | Onset of Action | Duration (Hr) | Side Effects | Important Drug Interactions |
|---|---|---|---|---|
| Carisoprodol | 30 min | 4-6 | Drowsiness, N/V, dizziness, ataxia; withdrawal potential | Additive effects with alcohol and other CNS depressants |
| Chlorzoxazone | ∼1 hr | 3-4 | N/V, headache, drowsiness, dizziness | Additive effects when taken with alcohol or other CNS depressants |
| Cyclobenzaprine | ∼1 hr | 12-24 | Drowsiness, dizziness, dry mouth | Additive effects with barbiturates, alcohol, other CNS depressants; seizures with tramadol and MAOIs; additive effects with TCAs |
| Metaxalone | 1 hr | 4-6 | Dizziness, headache, drowsiness, N/V, rash | Additive effects when taken with alcohol or other CNS depressants |
| Methocarbamol | 30 min (PO) | 4-6 | Dizziness, blurred vision, with drowsiness | Additive effects when taken with alcohol or other CNS depressants |
| Orphenadrine | 1 hr (PO) | 4-6 | Tachycardia, lightheadedness, anxiety | Propoxyphene (confusion, N/V, dry mouth, tremors) |
| Diazepam | 30 min (PO) | Variable, depending on elimination | Sedation, fatigue, hypotension ataxia, respiratory depression | Potentiation of effects when taken with phenothiazines, opioids, barbiturates, MAOIs |
| Baclofen | 3-4 days (PO) 4-6 hr (IT) 30 min (IT) | Variable (PO) | Drowsiness, slurred speech, hypotension, constipation, urinary retention | Antidepressants (short-term memory loss); additive effects with imipramine |
| Tizanidine | 2 weeks | Variable | Drowsiness, dry mouth, dizziness, hypotension, increased spasm, or muscle tone | Additive effects with alcohol and other CNS depressants; reduced clearance with oral contraceptives |
In discussing this broad class of medications, it becomes difficult to cull out the actual intended therapeutic outcomes. These agents are typically prescribed during the initial presentation of acute low back pain problem, often the result of a soft tissue mechanical injury. The injury normally occurs to the muscles, ligaments, or tendons, structures around the lumbar spine. The presentations may include local pain and tenderness, muscle spasm, and limited range of motion. Muscle spasm is often the most difficult to define and is the subject of controversy among some clinicians. Muscle spasm can be described as a vicious pain-spasm-pain cycle that protects compromised tissues and structures. Secondary to these pain impulses, an involuntary reflex muscle contraction at the site of injury can occur, which in turn can lead to local ischemic injury. This can further facilitate the pain-spasm-pain paradigm. Muscle spasm phenomena may be considered a variation of a myofascial pain presentation.
Mechanism of Action
In considering this discussion of muscle spasm pathophysiology, the problem with defining the activity of the skeletal muscle relaxants becomes manifest. The exact mechanism of action for these various agents has not been fully elucidated. It is generally accepted that skeletal muscle relaxants have the ability to depress polysynaptic reflexes within the dorsal horn via a variety of mechanisms ( Box 41.1 ), which in turn may relax skeletal muscle tissue in an indirect manner. In animal studies, these agents exert their muscle-relaxing effects by inhibiting interneuronal activity and blocking polysynaptic neurons in the spinal cord and descending reticular formation in the brain. Interesting to note is that sedating agents also depress polysynaptic reflexes, making it difficult to determine whether skeletal muscle relaxants produce their clinical activity via sedation or a change in the pain-spasm-pain cycle.
CNS Depressants
Antihistamine: orphenadrine
Sedatives: carisoprodol, chlorzoxazone, metaxalone, methocarbamol
TCA-like: cyclobenzaprine
Central α 2 Agonists
Tizanidine
GABA Agonists
Baclofen, benzodiazepines
CNS, central nervous system; GABA, gamma-aminobutyric acid; TCA, tricyclic antidepressant.
Indications for Use
Despite the common use of skeletal muscle relaxants, relatively little data exist to elucidate their role in the treatment of back pain, especially chronic back pain. None of the agents discussed in this chapter have an indication for use in the setting of chronic back pain. In one survey of skeletal muscle relaxant use in the United States, muscle relaxants, although indicated for short-term treatment, are most often prescribed on a long-term basis. In general, skeletal muscle relaxants, excluding baclofen and tizanidine, maintain FDA labeling as adjuncts for treatment of short-term acute low back pain (LBP) and are commonly used to treat muscle spasms and associated pain for periods of 1 to 3 weeks. This time frame coincides with how long many patients may expect it will take to recover from an initial acute low back insult. In this context, it may be difficult to discern the role of these agents, other than the palliative analgesic quality that they may provide for patients. Skeletal muscle relaxant selection depends on an evaluation of adverse effects, contraindications, patient tolerability, and clinical experience. This discussion will also include a brief review of the clinical use of botulinum toxin as a treatment for musculoskeletal pain.
Indications for Use
Despite the common use of skeletal muscle relaxants, relatively little data exist to elucidate their role in the treatment of back pain, especially chronic back pain. None of the agents discussed in this chapter have an indication for use in the setting of chronic back pain. In one survey of skeletal muscle relaxant use in the United States, muscle relaxants, although indicated for short-term treatment, are most often prescribed on a long-term basis. In general, skeletal muscle relaxants, excluding baclofen and tizanidine, maintain FDA labeling as adjuncts for treatment of short-term acute low back pain (LBP) and are commonly used to treat muscle spasms and associated pain for periods of 1 to 3 weeks. This time frame coincides with how long many patients may expect it will take to recover from an initial acute low back insult. In this context, it may be difficult to discern the role of these agents, other than the palliative analgesic quality that they may provide for patients. Skeletal muscle relaxant selection depends on an evaluation of adverse effects, contraindications, patient tolerability, and clinical experience. This discussion will also include a brief review of the clinical use of botulinum toxin as a treatment for musculoskeletal pain.
Specific Drugs
Carisoprodol (Soma)
Carisoprodol is available as a 250-mg or 350-mg tablet and in combination with aspirin (soma compound) and with aspirin and codeine (soma compound with codeine). Carisoprodol dosing should not exceed four doses in a 24-hour period ( Table 41.2 ). Similar to other muscle relaxants, carisoprodol has additive sedative effects when taken with alcohol or other central nervous system (CNS) depressants.
| Muscle Relaxants | |
|---|---|
| Agent | Dosage |
| Baclofen | 5-10 mg PO tid |
| Carisoprodol ∗ | 250 mg PO qid |
| Chlorzoxazone | 250-750 mg PO qid |
| Cyclobenzaprine | 5-10 mg PO tid |
| Diazepam ∗ | 2-10 mg PO qid |
| Metaxalone | 800 mg PO qid |
| Methocarbamol | 750-1500 mg PO qid |
| Orphenadrine | 100 mg PO bid |
| Tizanidine | 4-8 mg PO qid |
Carisoprodol is converted in the liver to meprobamate (Miltown), an intravenous (IV) controlled substance. Meprobamate is well known to produce phenomena that result in physical and psychological dependence. Substance abuse is problematic with carisoprodol, probably as a consequence of meprobamate formation. Several states within the United States have begun listing carisoprodol as a controlled substance in their state formularies. However, carisoprodol is not considered a controlled substance at the federal level. Because of the dependence potential, carisoprodol use should be avoided. It should also be cautiously tapered as opposed to immediately discontinued following long-term use.
Chlorzoxazone (Paraflex, Parafon Forte DSC)
Chlorzoxazone is available as 250- and 500-mg tablets, taken up to four times daily. It has been suggested that chlorzoxazone may be less effective than the other skeletal muscle relaxants. It does not have any significant drug-drug interactions, but it does have a significant adverse effect profile that includes a rare idiosyncratic hepatocellular reaction. The role of this agent is unclear, considering the potential lack of efficacy and significant toxicity profile.
Cyclobenzaprine (Flexeril)
Cyclobenzaprine is available as 5- and 10-mg tablets, with recommended dosing of up to three times daily. Cyclobenzaprine is more structurally and pharmacologically related to the tricyclic antidepressants than to the CNS depressant skeletal muscle relaxants. As with other skeletal muscle relaxants, cyclobenzaprine does not have activity directly on muscle tissue, with animal data suggesting that this agent acts primarily in the brainstem. The net result of this action is a reduction in tonic somatic motor activity. Although no human evidence exists to support this mechanism, the newer 5-mg dose has yielded similar clinical efficacy with less sedation than the more sedating 10-mg dose. In the future, this may prove to be an important distinction with the CNS depressant agents. In an open-label study of patients with acute neck or low back pain associated with muscle spasm who were randomized to be treated for 7 days with cyclobenzaprine 5 mg PO three times daily alone or cyclobenzaprine 5 mg PO three times daily in combination with ibuprofen, at doses of 400 mg PO three times daily or 800 mg three times daily, no significant treatment differences were found among these groups.
Because of the structural relationship to tricyclic antidepressants (TCAs), clinicians must be cognizant of the anticholinergic side effects, such as dry mouth, urinary retention, dizziness, hypotension, and constipation, seen with cyclobenzaprine. Use of cyclobenzaprine is contraindicated in the setting of arrhythmias, congestive heart failure, hyperthyroidism, acute glaucoma, narrow angle glaucoma, or during the acute recovery phase of a myocardial infarction. One report suggested that coadministration with pro-serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs) may predispose patients to life-threatening serotonin syndrome.
Cyclobenzaprine labeling suggests that concomitant use with tramadol may place patients at higher risk for developing seizures. Attendant use of cyclobenzaprine with monoamine oxidase inhibitors or use within 14 days after their discontinuation is contraindicated. It can also enhance the effects of agents with CNS depressant activity. Older adults appear to have a higher risk for CNS-related adverse reactions, such as hallucinations and confusion, when using cyclobenzaprine. Withdrawal symptoms have been noted with the discontinuation of chronic cyclobenzaprine use. Use of a medication taper may be warranted for chronic-use patients.
Metaxalone (Skelaxin)
Metaxalone is available as a 400- and 800-mg tablet and has a recommended maximal dose of 800 mg three or four times daily. Metaxalone does not have any significant drug-drug interactions and appears to have a fairly benign side effect profile, although fatalities attributed to the use of metaxalone have been reported. Hemolytic anemia, leukopenia, and impaired liver function have been seen with the use of metaxalone, but they are uncommon. Metaxalone is contraindicated in patients who have severe renal or hepatic impairment. It is known to cause an elevation in the cephalin flocculation test, necessitating serial liver function assessments. Metaxalone can also produce a false-positive result for Benedict’s test. In this scenario, alternatives to urine glucose testing may be necessary. Although FDA approved since the 1980s, there are few published placebo-controlled studies comparing metaxalone with placebo for the treatment of musculoskeletal pain.
Methocarbamol (Robaxin, Robaxisal)
Methocarbamol is available in oral and parenteral forms for IV or intramuscular use. However, many complications have arisen with the injectable form, including pain, sloughing of the skin, and thrombophlebitis. The injectable form should be used cautiously in patients with known latex hypersensitivity. The oral dosage form of the medication is marketed as a 500- and 750-mg tablet, with a recommended daily dosage range of 4000 to 4500 mg as three or four divided doses daily. For difficult situations, the dose for the first 24 to 48 hours can be up to 6 to 8 g/day. Methocarbamol is also combined with aspirin and marketed as Robaxisal. Similar to metaxalone, although FDA approved in the 1980s, there are few published placebo-controlled studies comparing methocarbamol with placebo for the treatment of musculoskeletal pain.
Orphenadrine Citrate (Norflex, Norgesic, Norgesic Forte)
Orphenadrine is a direct descendant of diphenhydramine and thus exhibits antihistaminic and anticholinergic properties. Like methocarbamol, orphenadrine is available in a parenteral dosage formulation. There have been reports of severe adverse reactions with parenteral use (e.g., anaphylactoid reaction), making this formulation difficult to use. Orphenadrine is available as a 100-mg tablet (Norflex) and in combination with aspirin (Norgesic) and caffeine (Norgesic Forte).
Orphenadrine use with propoxyphene (removed from the U.S. market in 2011) may cause confusion, anxiety, and tremors, perhaps because of additive effects. Orphenadrine’s anticholinergic actions have been noted to produce significant adverse effects at high dosages, such as tachycardia, palpitations, urinary retention, and blurred vision. Given its significant anticholinergic profile, orphenadrine use is contraindicated in patients with underlying neuromuscular junction defects such as myasthenia gravis and Lambert Eaton syndrome.
Diazepam (Valium)
This is the most commonly prescribed and referenced benzodiazepine for the treatment of muscle spasms. Diazepam demonstrates hypnotic, anxiolytic, antiepileptic, and antispasmodic properties. With respect to muscle relaxation, gamma-aminobutyric acid (GABA)–mediated presynaptic inhibition at the spinal level is thought to be the main mechanism of action for diazepam. Sedation and abuse potential are the main concerns with this agent; therefore, it should not be used as a first-line muscle relaxant agent. It is important to taper this agent slowly after long-term use to avoid any withdrawal symptoms. Diazepam is available in a wide range of dosages, and each patient should be treated on an individual basis. The recommended dosage range for musculoskeletal pain is 2 to 10 mg four times daily. Coadministration of the benzodiazepine class of medications with opioids, as they are commonly prescribed, can lead to significant morbidity in the form of respiratory depression and mortality from respiratory failure.
Baclofen (Lioresal)
Baclofen is chemically related to GABA and produces its effects by inhibiting monosynaptic and polysynaptic transmission along the spinal cord. This drug is mainly used for spasticity associated with CNS disorders (multiple sclerosis [MS], spinal cord lesions). Studies have shown baclofen to have superior efficacy when compared with diazepam. Baclofen is unique in that it can be administered intrathecally in cases of severe spasticity and for patients who do not tolerate or have failed oral therapy. It has also found a niche in the treatment of trigeminal neuralgia because of a more favorable side effect profile. Baclofen is available in 10- and 20-mg tablets, with a therapeutic range of 40 to 80 mg daily. The medication should be started at 5 mg three times daily and tapered up to a therapeutic level of 5 mg every 3 to 5 days. It should be tapered slowly after long-term use to avoid a withdrawal reaction, rebound phenomena, and potential withdrawal seizures that can occur with sudden cessation. It should be used with caution in older patients and patients with renal impairment.
Tizanidine (Zanaflex)
Tizanidine (Zanaflex) is a short-acting inhibitor of excitatory (presynaptic) motor neurons at the spinal and supraspinal levels, producing agonistic activity at the noradrenergic α 2 receptors. This activity results in the inhibition of neurotransmitter release from spinal interneurons and the concomitant inhibition of facilitatory spinal pathways that enhance muscle movement. Tizanidine is related chemically to clonidine, but it has significantly lower antihypertensive effects. The main adverse effect for most patients is sedation. Currently, tizanidine is FDA approved for the management of increased muscle tone associated with spasticity resulting from CNS disorders, such as multiple sclerosis or spinal cord injury. There are published studies on the use of tizanidine in the setting of back pain or muscle spasm, either alone or in combination with ibuprofen, as well as a report of effective use for myofascial pain. In a multicenter placebo-controlled study evaluating the efficacy and safety of tizanidine for the treatment of low back pain, tizanidine was found to provide more pain relief and less restriction of movement compared with placebo. Drowsiness was the most common side effect, but this adverse effect may actually be desired in patients with nighttime exacerbations of their pain. In a separate study, 105 patients with acute low back pain were given tizanidine 4 mg PO three times daily in conjunction with ibuprofen 400 mg PO three times daily, or ibuprofen 400 mg PO three times daily with placebo. The study results suggested that the tizanidine-ibuprofen combination is more effective for the treatment of moderate or severe acute low back pain than ibuprofen only. Tizanidine is available as 2- and 4-mg tablets; treatment should be instituted with a 4-mg single dose, increasing by 2- to 4-mg increments up to a therapeutic dose. The maximum daily dose should not exceed 36 mg.
Tizanidine should be used with caution in the setting of renal impairment. Tizanidine clearance decreases by 50% in patients with creatinine clearance lower than 25 mL/min. Coadministration with alcohol can increase the area under the curve (AUC) of tizanidine by approximately 20% and increase the maximum concentration (C max ) by approximately 15%. Use with oral contraceptives can decrease the clearance of tizanidine and place patients at higher risk for sedating adverse effects.
Botulinum Toxins (Botox-onabotulinumtoxinA, Dysport-abobotulinumtoxinA, Xeomin-incobotulinumtoxinA and Myobloc-rimabotulinumtoxinB)
Botulinum toxin is a potent neurotoxin produced by the gram-positive anaerobic bacterium Clostridium botulinum . Of the seven known immunologically distinct serotypes of botulinum toxin (A to G), only types A and B have been developed for routine commercial use. Historically, the toxin’s primary mechanism of action has been linked to its ability to inhibit the release of acetylcholine from cholinergic nerve terminals. However, it is now appreciated that these neurotoxins may also inhibit the release of glutamate, substance P, and calcitonin gene-related peptide. These effects may strongly contribute to the analgesic effects of these toxins. Botulinum toxin has been studied in a number of chronic pain conditions associated with painful muscle spasm, including cervicogenic headache, temporomandibular joint disorders, craniocervical dystonia syndromes, chronic myofascial pain, and chronic low back pain.
The potential benefit of the use of botulinum toxin for the treatment of cervicogenic headache associated with “whiplash” injuries has been noted. In 1997, Hobson and Gladish reported that botulinum toxin type A (onabotulinumtoxinA) injections could be effective in reducing cervicogenic headache resulting from cervical whiplash-type injuries. In a randomized, double-blind, placebo-controlled study, Freund and Schwartz found that the botulinum toxin type A–treated patients (onabotulinumtoxinA) demonstrate significant greater improvement from baseline with respect to pain reduction and cervical range of motion. Mixed results have been observed in evaluating the effect of botulinum toxin injection on temporomandibular joint and other orofacial-related pain. In an open-label study completed by Freund and Schwartz, patients with temporomandibular joint dysfunction believed to be related to myofascial dysfunction were treated with a total of 200 units of botulinum toxin A (onabotulinumtoxinA) (masseter and temporalis muscles injected), with most patients experiencing pain reduction as well as improvements in jaw function. Von Lindern and colleagues’ study of patients with chronic facial pain associated with muscular hyperactivity also demonstrated improvement in botulinum toxin type A (onabotulinumtoxinA)–treated patients. However, in a placebo-controlled crossover trial evaluating botulinum toxin type A (onabotulinumtoxinA) in patients with chronic moderate to severe orofacial pain of muscular origin, no statistically significant differences were seen between placebo and active treatment.
There have been several published evaluations of the use of botulinum toxin for the treatment of myofascial pain in the cervicothoracic regions. In a small crossover trial ( N = 6), patients whose cervical myofascial trigger points were injected with botulinum toxin type A (onabotulinumtoxinA) had an average of 30% pain reduction. In a separate study, Wheeler and associates completed a randomized, double-blind, prospective, placebo-controlled study in 33 patients with chronic cervical myofascial pain who were injected with either 50 or 100 units of botulinum toxin type A (onabotulinumtoxinA) or normal saline. No clear benefit was found in the botulinum toxin–treated patients. Porta, in a single-blinded study, evaluated the potential difference between “conventional” lidocaine-methylprednisolone trigger point injections and botulinum toxin type A injections (onabotulinumtoxinA) for myofascial pain treatment and concluded that although each group received benefit, the duration of benefit was longer in the botulinum toxin–treated group.
Botulinum toxin injections have also been studied in the treatment of chronic low back pain. In one study, 31 patients with chronic low back pain were randomized to be treated with 200 units of botulinum toxin A (onabotulinumtoxinA) into five sites (L1-5 or L2-S1, 40 units/site) or placebo injections. Pain and disability were measured at 3 and 8 weeks following injection using the visual analog scale and the Oswestry Low Back Pain and Disability Questionnaire. At 3 and 8 weeks, the pain reduction experienced by the botulinum toxin–treated group was greater than that experienced by the placebo group, and at 8 weeks there was less disability in the botulinum toxin–treated group compared with placebo. A report evaluating the use of botulinum toxin type A (abobotulinumtoxinA) for the relief of upper back myofascial pain syndrome concluded that several secondary parameters, such as physicians’ global assessment and patients’ global assessment, significantly favored abobotulinumtoxinA over placebo at weeks 8 and 12. The precise role of botulinum toxin injection therapy in the management of conditions associated with chronic muscle spasm remains to be determined.
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