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Skeletal Muscle Relaxants


Key Points

  • There are three broad classes of muscle relaxants: antispasmodic, antispasticity, and combination agents.

  • Muscle relaxants may treat muscle spasticity in two manners. First, they can modify the stretch reflex arc, either by reducing the excitatory signals or by augmenting the inhibitory interneurons. This decreases activation of the alpha motor neuron. Second, they can disrupt the excitation-contraction coupling that produces muscle contraction.

  • Cyclobenzaprine is a centrally acting skeletal muscle relaxant that is structurally related to tricyclic anti-depressants; it acts primarily at the level of the brainstem.

  • As a GABA B agonist, baclofen causes hyperpolarization and thus decreases the release of excitatory neurotransmitters in the brain and spinal cord. It causes less sedation than benzodiazepines and may reduce pain by decreasing substance P release.

  • Skeletal muscle relaxants have been shown to be more effective than placebo for patients with acute LBP with respect to outcomes, such as short term pain relief, global efficacy, and improvement of physical outcomes.

  • Botulinum toxin not only inhibits the release of acetylcholine from cholinergic nerve terminals but has also been found to inhibit the release of glutamate, substance P, and calcitonin gene-related peptide, as well as inhibiting the expression of the transient receptor potential vanilloid type 1 (TRPV1) and P2X 3 receptors in the DRG ganglion. These effects contribute to its analgesic properties.

  • Botulinum toxin type A (onabotulinumtoxinA) injections are found to be effective for head and neck myofascial pain, temporomandibular joint disorders, cervical dystonia, and chronic LBP.

  • Carisoprodol is converted in the liver to meprobamate, an intravenous controlled substance. Meprobamate is well known to produce phenomena that result in physical and psychological dependence.

The term skeletal muscle relaxant can be confusing for patients and clinicians alike as there are different classes of skeletal muscle relaxants. Specifically, antispasticity, antispasmodic classes of skeletal muscle relaxants exist, and some medications overlap in both of these categories. ( Table 55.1 ). – The use of such agents with or without nonsteroidal anti-inflammatory drugs (NSAIDs) can be considered for acute low back pain. Medications commonly referred to as skeletal muscle relaxants include carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine. These agents are labeled by the United States Food and Drug Administration (FDA) with an indication for the relief of discomfort associated with an acute, painful, musculoskeletal condition. Baclofen and tizanidine have FDA indications for the treatment of spasticity caused by upper motor neuron syndromes, including multiple sclerosis and spinal cord disease or injury. Benzodiazepines, principally diazepam, are also used and indicated for adjunctive relief of skeletal muscle spasms and are often considered in discussions regarding skeletal muscle relaxants.

TABLE55.1
Skeletal Muscle Relaxant Profiles
Drug Onset of Action Duration (h) Dosing (can be taken as needed or standing) Side Effects Important Drug Interactions
Dantrolene
Antispacticity agent		 >7 days (PO) Variable (PO) peak plasma concentration in 6 h 25–100 mg PO four times daily Muscle weakness, phlebitis, respiratory failure, gastrointestinal failure Chronic therapy can cause hepatic dysfunction. Ace-Inhibitors, paralytics, i.e. Vecuronium
Baclofen
Antispasticity agent		 Three to four days (PO)
4–6 h (IT)
30 min (IT)		 Variable (PO) 5–10 mg PO three times daily Drowsiness, slurred speech, hypotension, constipation, urinary retention Anti-depressants (short-term memory loss); additive effects with imipramine
Carisoprodol
Antispasmodic		 30 min 4–6 250–350 mg PO three times daily Drowsiness, dizziness, headache CYP2C19 inhibitors and inducers
Chlorzoxazone
Antispasmodic agent		 ∼1 h 3–4 250–750 mg PO four times daily N/V, headache, drowsiness, dizziness Additive effects when taken with alcohol or other CNS depressants
Cyclobenzaprine
Antispasmodic agent		 ∼1 h 12–24 5–10 mg PO three times daily Drowsiness, dizziness, dry mouth Additive effects with barbiturates, alcohol, other CNS depressants; seizures with tramadol and MAOIs; additive effects with TCAs
Metaxalone
Antispasmodic agent		 1 h 4–6 800 mg PO four times daily Dizziness, headache, drowsiness, N/V, rash Additive effects when taken with alcohol or other CNS depressants
Methocarbamol
Antispasmodic		 30 min (PO) 4–6 750–1500 mg PO four times daily Dizziness, blurred vision, with drowsiness Additive effects when taken with alcohol or other CNS depressants
Orphenadrine
Antispasmodic		 1 h (PO) 4–6 100 mg PO twice daily Tachycardia, lightheadedness, anxiety Propoxyphene (confusion, N/V, dry mouth, tremors)
Diazepam
Antispasmodic and antispasticity agent		 30 min (PO) Variable, depending on elimination 2–10 mg PO four times daily Sedation, fatigue, hypotension ataxia, respiratory depression Potentiation of effects when taken with phenothiazines, opioids, barbiturates, MAOIs
Tizanidine
Antispasmodic and antispasticity agent		 Two weeks Variable 2–8 mg PO four times daily Drowsiness, dry mouth, dizziness, hypotension, increased spasm, or muscle tone Additive effects with alcohol and other CNS depressants; reduced clearance with oral contraceptives
CNS , Central nervous system; IT , intrathecal; MAOIs , monoamine oxidase inhibitors; N/V , nausea and vomiting; TCA , tricyclic anti-depressant.

In discussing this broad class of skeletal muscle relaxants 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. The injury normally occurs to the muscles, ligaments, or tendons, structures around the lumbar spine. The presentations may include local pain and tenderness, muscle spasms, 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. However, it is generally accepted that skeletal muscle relaxants can depress polysynaptic reflexes within the dorsal horn via various mechanisms ( Box 55.1 ), which may relax the 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.

• BOX 55.1
Classification of Agents by Proposed Mechanism of Action

Drug Mechanism of action Site of action
Baclofen Similar to GABA acts on the presynaptic GABA a site, decreasing synaptic transmission to the spinal cord Centrally acting- spinal cord
Dantrolene Prevents the release of calcium from the sarcoplasmic reticulum in skeletal muscle cells Peripherally acting
Carisoprodol Causes altered neuronal output at the reticular formation and spinal cord Centrally acting - spinal cord and brain
Chlorzoxazone Acts on the spinal cord and subcortical regions to inhibit reflex arcs involved in causing and maintaining muscle spasm Centrally acting- spinal cord and brain
Cyclobenzaprine α 2 agonists at descending noradrenergic neurons on the supraspinal area of the brain stem, seratonergic antagonism at 5HT 2 receptor Centrally acting - brainstem
Metalaxone CNS depressant Centrally acting
Methocarbamol CNS depressant Centrally acting
Orphenadrine Central atropine like structure alleviates muscle spasm Centrally acting
Diazepam Benzodiazepine increases GABA mediated presynaptic inhibition at spinal and supraspinal sites Centrally acting - spinal cord and brain
Tizanidine α 2 adrenergic agonist, presynaptic inhibition of motor neurons Centrally acting
Botulinum Toxin Neurotoxin- blocks the release of acetylcholine at the neuromuscular junction, causing muscle paralysis Centrally and peripherally acting

Indications for Use

Despite the common use of skeletal muscle relaxants, relatively little data exist to elucidate their role in the treatment of chronic low 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 one to three weeks as most patients with acute or subacute low back pain improve with time. 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. Therefore 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 By Class

Antispasmodic Agents

Carisoprodol (Soma)

Carisoprodol is a Schedule IV substance and 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 h period ( Table 55.1 ). In addition, it should not be prescribed for longer than three weeks. , Similar to other muscle relaxants, carisoprodol has additive sedative effects when taken with alcohol or other central nervous system (CNS) depressants. Its most common side effects are drowsiness, dizziness, and headache.

Carisoprodol is converted in the liver to meprobamate, a substance with a long half-life of 10 h. , Meprobamate is well known to produce phenomena that result in physical and psychological dependence. – After oral ingestion, carisoprodol has a quick onset of action with time to maximum plasma concentration being 1.5 to 1.7 h. Within the United States since 2012, carisoprodol has been listed as a Schedule IV controlled substance by the Controlled Substance Act. Because of the risk of physical and psychological dependence potential, carisoprodol use should be avoided. It should also be cautiously tapered as opposed to immediately discontinued following long-term use.

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