A common muscle relaxer is one double bond away from an antidepressant
Cyclobenzaprine, long sold as Flexeril, was prescribed more than 13 million times in the United States in 2023. Chemically it is almost identical to the antidepressant amitriptyline, differing by a single double bond in its ring system. How it actually relaxes muscles, nearly half a century after approval, remains unknown.
The drug was approved in the United States in 1977 and is now a cheap generic, ranking 47th among the country's most prescribed medicines in 2023. Oddly, British pharmacies still did not stock it in 2012. It is intended for muscle spasms after sudden musculoskeletal injuries, the tightening the body produces to protect a hurt area, and is typically paired with physical therapy. It does nothing for the spasticity of neurological conditions such as cerebral palsy.
Its benefit is short-lived. Studies find it reduces pain in the first two weeks, peaking within days, with no proven advantage beyond that. In acute lower back pain it performs no better or worse than tizanidine, orphenadrine, carisoprodol or benzodiazepines, though non-benzodiazepine drugs carry less risk of misuse. One trial comparing it with ibuprofen and with the two combined found no difference in pain scores, and all three groups peaked on day seven. It is nonetheless the most thoroughly studied muscle relaxer.
Pharmacologically it behaves like a tricyclic antidepressant, which is what its structure predicts. It blocks the reuptake of serotonin and norepinephrine and antagonises a long list of receptors: several serotonin subtypes, adrenergic receptors, histamine H1 and three of the five muscarinic acetylcholine types. The histamine blocking is thought to explain much of its sedation, and in animal tests it even shows antidepressant-like effects. About 55% of an oral dose reaches the bloodstream, and its half-life is roughly 18 hours.
That broad receptor activity shows up in side effects. Trials report drowsiness in 38% of users, dry mouth in 24% and dizziness in 10%, with the first two rising with dose. It interacts dangerously with MAO inhibitors, and older people are particularly prone to agitation and confusion. An extended-release once-daily version is sold as Amrix.
Source: Cyclobenzaprine
