Chapter outline

Skeletal Muscle Relaxants

The group of drugs known as skeletal muscle relaxants are a heterogeneous group of drugs that are not chemically related (Chou, Peterson, Helfand, 2004) but are grouped together under this classification because they have been approved by the United States Food and Drug Administration (FDA) for treatment of musculoskeletal conditions or spasticity (Chou, Huffman, American Pain Society [APS], et al., 2007). Two groups must be distinguished. The first are drugs used to treat spasticity from upper motor neuron syndromes, such as multiple sclerosis, spinal cord injury, and poststroke syndrome. These drugs include tizanidine [Zanaflex], baclofen [Lioresal], and dantrolene [Dantrium]. The second group consists of drugs used to treat muscular pain or spasms from peripheral musculoskeletal conditions, such as myofascial pain syndrome and mechanical low back or neck pain. This group includes drugs that are antihistamines, such as orphenadrine (Norflex); tricyclic compounds structurally similar to the tricyclic antidepressants, such as cyclobenzaprine (Flexeril); and other types of drugs, such as carisoprodol (Soma), chlorzoxazone (Parafon Forte DSC), methocarbamol (Robaxin), and metaxalone (Skelaxin). Midazolam (Versed) is used primarily for procedural sedation (see Chapter 27).

The musculoskeletal relaxants are administered primarily by the oral route. Because they are chemically unrelated, there are differences in efficacy among the various drugs, but comparative research is lacking (Chou, Peterson, Helfand, 2004). See Table 25-1 for examples of skeletal muscle relaxants, Chapter 23 for a more detailed discussion of baclofen, Chapter 22 for tizanidine, and Chapter 31 for antihistamines. The reader is also referred to extensive reviews of the many skeletal muscle relaxants used for spasticity and musculo- skeletal pain (Chou, Huffman, APS, et al., 2007; Chou, Peterson, Helfand, 2004).

When clinicians use the term muscle relaxant, they most often are referring to the heterogeneous drugs that are frequently used to treat acute musculoskeletal conditions. Ironically, there is little high-quality evidence that these drugs actually relax skeletal muscle. Although they do inhibit myogenic reflexes in animal models, the relationship between this action and analgesia is not known. The common muscle relaxant drugs can relieve musculoskeletal pain, but these effects may not be specific and do not depend on relaxation of skeletal muscle.

Evidence that the muscle relaxants used to treat common musculoskeletal pain are analgesic derives from studies of variable quality. Poor methodologic designs, insensitive assessment methods, and small numbers of patients are responsible for the inability to demonstrate high efficacy with muscle relaxants (Chou, Peterson, Helfand, 2004; See, Ginzburg, 2008). A Cochrane Collaboration Review concluded that muscle relaxants provide effective symptomatic relief of acute and persistent low back pain on the short term, but with a high incidence of drowsiness, dizziness, and other adverse effects (van Tulder, Touray, Furlan, et al., 2003). A later review of guidelines for the treatment of low back pain concluded that muscle relaxants offer fair relief of acute back pain, but did not recommend them for long-term use (Chou, Huffman, APS, et al., 2007). The review also noted that tizanidine (which, as discussed in Chapter 22, is an alpha₂-adrenergic agonist and a multipurpose analgesic) has evidence of efficacy in low back pain. In contrast, little evidence was found to support the effectiveness of baclofen and dantrolene, the other two drugs approved for spasticity. This review provides diagnostic steps and a decision-making algorithm that help to guide appropriate treatment of acute and persistent low back pain.

In a systematic review of 101 clinical trials focused on the common muscle relaxants used for musculoskeletal pain, none of the studies was rated of good quality, and there was little evidence of rigorous assessments of adverse effects (Chou, Peterson, Helfand, 2004). This review also confirmed that there is fair evidence that tizanidine, baclofen, and dantrolene are efficacious for spasticity and that tizanidine and baclofen are equi-effective. While the overall rate of adverse effects between tizanidine and baclofen is similar, tizanidine seems to be associated with more dry mouth and baclofen with more muscle weakness. The researchers also noted that there is insufficient evidence for the relative efficacy or safety of several muscle relaxants for musculoskeletal conditions.

Orphenadrine is combined with aspirin and caffeine and marketed as an analgesic and muscle relaxant. This drug is derived from diphenhydramine (Benadryl) and acts on multiple targets, including histamine and NMDA receptors, the norepinephrine reuptake system, and voltage-gated sodium channels (see Section I) (Desaphy, Dipalma, De Bellis, et al., 2009). Although these actions have implications for analgesia, further research is needed to more clearly define orphenadrine’s role in pain management. Significant adverse effects, such as anticholinergic effects and the potential for seizures and arrhythmias, limit its use.

Cyclobenzaprine has been shown to be more favorable than placebo for fibromyalgia and musculoskeletal disorders (Kroenke, Krebs, Bair, 2009). A meta-analysis of five randomized, placebo-controlled trials of cyclobenzaprine in patients with fibromyalgia revealed that reports of overall improvement and moderate reductions in symptoms, especially sleep disturbances, were three times greater with cyclobenzaprine treatment compared with placebo (Tofferi, Jackson, O’Malley, 2004). A meta-analysis concluded that cyclobenzaprine is efficacious for the treatment of acute back pain, but its effects may be short-lived, with the greatest response occurring within 4 days and slowly diminishing with continued therapy (Browning, Jackson, O’Malley, 2001).

Although the results from clinical studies seem to support the short-term use of skeletal muscle relaxants in clinical practice for various indications, there are no efficacy data from comparator trials to favor one agent over another (Chou, Huffman, APS, et al., 2007). Studies have demonstrated that the analgesic effects of muscle relaxants are superior to those produced by aspirin or acetaminophen, but there have been no controlled trials or investigations that have directly compared the efficacy and adverse effect profiles of these drugs with NSAIDs or opioids. These drugs have no antiinflammatory properties, and it is possible that the combination of a muscle relaxant and an NSAID may provide better analgesia than either drug alone (McCleane, 2009b). Given the limited data available, it may be most appropriate to view the common muscle relaxants as add-on therapy for acute musculoskeletal pain, complementing acetaminophen, NSAIDs, or opioids (Chou, Huffman, APS, et al., 2007).

The muscle relaxant drugs are generally well-tolerated but have sedative effects that may be additive to other centrally-acting drugs, including opioids. Muscle relaxants are not recommended in older adults as this age group has increased sensitivity to the anticholinergic and sedating effects of the drugs, and the muscle relaxant effect may contribute to falls (see Section IV Table 13-4 on p. 336).

Anecdotally, some patients report differences among drugs in analgesic efficacy or sedative adverse effects, and it is reasonable to switch to an alternative drug if treatment is initially ineffective. Although the dose-response relationships of the muscle relaxant drugs have not been systematically explored, dose-dependent effects probably exist, and the use of a low initial dose followed by gradual dose escalation can be recommended as a means to identify the most salutary balance between analgesia and adverse effects. Experience with these drugs is too limited to pursue dose escalation beyond the usual recommended range. A report of severe withdrawal syndrome in a patient who abruptly stopped taking carisoprodol after long-term use has led to the recommendation to gradually taper doses before discontinuing treatment (Reeves, Beddingfield, Mack, 2004). This is probably good advice for all of the skeletal muscle relaxants. (See cyclobenzaprine patient medication information, Form V-5 on pp. 765-766, at the end of Section V.)