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Skeletal muscle relaxants are prescribed for either spasticity management or musculoskeletal conditions. This category includes baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, and tizanidine. However, only baclofen, dantrolene, and tizanidine are specifically approved for spasticity treatment. These three drugs work through different mechanisms: baclofen modulates GABAB_B receptors at both pre- and post-synaptic sites, tizanidine acts as a centrally acting α2_2-adrenergic receptor agonist, and dantrolene inhibits muscle contraction by reducing calcium release from the sarcoplasmic reticulum.
Other medications, such as benzodiazepines, have also been used for spasticity management, though they are not officially approved for this purpose. Diazepam was the first to be considered effective for spasticity, acting through GABAA_A receptor modulation. Additionally, clonidine, gabapentin, and botulinum toxin have been used off-label for spasticity treatment.
For musculoskeletal disorders, several skeletal muscle relaxants—including carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine—are approved but not indicated for spasticity. These drugs vary in composition and action: cyclobenzaprine is structurally similar to tricyclic antidepressants, carisoprodol metabolizes into meprobamate, methocarbamol shares similarities with mephenesin, chlorzoxazone is a benzoxazolone derivative, and orphenadrine is related to diphenhydramine. Their exact mechanisms remain unclear but may be partly linked to sedative effects.
Among 52 clinical trials analyzing skeletal muscle relaxants for musculoskeletal conditions, 12 involved direct comparisons between two relaxants. These included head-to-head comparisons such as tizanidine vs. chlorzoxazone, cyclobenzaprine vs. methocarbamol, and cyclobenzaprine vs. carisoprodol. Additionally, nine trials compared skeletal muscle relaxants to diazepam, with five focused on cyclobenzaprine, and others on carisoprodol, chlorzoxazone, and tizanidine. No head-to-head studies assessed orphenadrine, metaxalone, dantrolene, or baclofen for musculoskeletal conditions. Some trials were excluded due to non-equivalent analgesic comparisons or the inclusion of medications not approved in the U.S.
Overall, limited comparative data exist on the efficacy of skeletal muscle relaxants for musculoskeletal conditions. Most research has focused on acute neck and lower back pain, assessing drugs such as carisoprodol, cyclobenzaprine, metaxalone, orphenadrine, tizanidine, and diazepam. While one trial found carisoprodol superior to diazepam and another reported chlorzoxazone’s superiority over diazepam for certain outcomes, no other robust head-to-head comparisons exist. Additionally, these studies used unvalidated methods to measure treatment effects, making definitive conclusions difficult.
None of the 12 head-to-head trials were considered high-quality, as all had at least two significant methodological flaws (see Evidence Table 5). While most were rated as fair, one trial comparing cyclobenzaprine and diazepam was classified as poor due to multiple issues, including incomplete data reporting—results were provided for only 52 of the 105 participants, with no explanation for the missing data.
Among the fair-quality studies, the most reliable trial compared carisoprodol and diazepam. However, it lacked details on allocation concealment and used unvalidated methods to assess outcomes. The study found carisoprodol to be significantly better than diazepam in reducing stiffness, tension, and discomfort, though the differences were measured using an unvalidated 1-5 scale, with an average advantage of 0.5 points. No notable differences were found in terms of pain reduction, activity limitations, or sleep disturbances.
Other trials used various methods to evaluate treatment effects, including different pain rating scales (ranging from 4 to 9 points and visual analog scales), tenderness assessments, and functional status measures. However, most of these scales lacked validation, and reporting methods were inconsistent. Functional status was either not assessed or measured using unstandardized tools.
The trials investigated different medication doses, including cyclobenzaprine (10-20 mg three times daily), tizanidine (2-8 mg three times daily), chlorzoxazone (500 mg three times daily to 750 mg four times daily), carisoprodol (350 mg four times daily), and diazepam (5-10 mg three times daily). No clear evidence emerged suggesting that one muscle relaxant was significantly more effective than another.
In a trial comparing tizanidine and chlorzoxazone for back pain, no significant differences were observed in terms of muscle pain, tension, tenderness, or activity levels. However, more patients rated their overall experience as “excellent” with tizanidine (57%) compared to chlorzoxazone (23%). When combining “good” and “excellent” ratings, the results were more comparable (79% vs. 69%).
A study comparing cyclobenzaprine and methocarbamol in patients with localized muscle spasms found no significant differences in the percentage of patients reporting mild or no muscle spasms, restricted movement, or limitations in daily activities. However, a slightly higher proportion of those taking cyclobenzaprine reported mild or no local pain compared to methocarbamol (48% vs. 40%, p=0.05), but this was only significant when patients with mild baseline pain were excluded from the analysis.
Similarly, a trial comparing cyclobenzaprine and carisoprodol in patients with acute back pain and spasms showed no significant differences in pain levels, muscle stiffness, activity or sleep impairment, tension, or relief scores when compared to baseline.
Regarding the potential for abuse, one study examined carisoprodol’s risk in 40 patients who had been taking the drug for over three months. Since carisoprodol metabolizes into meprobamate, a federally controlled substance, it is suspected to have a higher potential for abuse. The study used an unvalidated six-item questionnaire and found that 20% of patients with no history of substance abuse and 65% of those with a history of substance abuse answered affirmatively to at least one question, suggesting a possible risk of misuse.
No other observational studies were found assessing the rates of abuse or addiction related to carisoprodol or other skeletal muscle relaxants in patients with musculoskeletal conditions. Most documented cases of abuse or addiction stem from case reports, with nearly all involving carisoprodol. Additionally, two case reports described abuse of orphenadrine. (http://www.adult-dentistry.com)
An autopsy study from Jefferson County, Alabama, found carisoprodol present in 24 out of 8,162 cases, though it was never the sole drug detected or the direct cause of death. Reports also indicate carisoprodol misuse in combination with oxycodone, tramadol, alcohol, benzodiazepines, or cocaine. Furthermore, a French report from 1997 identified meprobamate as the most frequently cited drug in fatal pharmaceutical overdoses, accounting for 19 cases (15.3%).