Released in 1977, cyclobenzaprine (Flexeril) remains the #1 most prescribed muscle relaxant. It is not a controlled substance. Half-life is 18 hours, and it is generally dosed TID. Flexeril is modestly effective for acute lower back pain with muscle spasm, although efficacy begins to decrease after about 4 days. It is not intended for long-term use because it is not effective for muscle spasms beyond 2–3 weeks. It is not useful for spasticity due to neurologic conditions such as cerebral palsy.
Flexeril is not used for the treatment of depression, but it has the structure of a tricyclic antidepressant (TCA) by structure. It differs from amitriptyline (Elavil) by just one double bond. Flexeril causes similar side effects as TCAs but is much less dangerous in overdose. Of 209 cyclobenzaprine overdose cases, there were no deaths, and the QT interval was not prolonged (Bebarta et al, 2011).
Flexeril reduces spasticity through central action, possibly at the brainstem level. It is a 5-HT2 antagonist that reduces muscle tone by decreasing activity of descending serotonergic neurons. Amitriptyline (Elavil) and cyproheptadine (Periactin) have been shown to do this also (Honda et al, 2003).
Dynamic interactions are similar to those of TCAs.
Cyclobenzaprine can theoretically contribute to serotonin syndrome when combined with other serotonergics and is contraindicated with monoamine oxidase inhibitors (MAOIs). However, the risk is very low.
Kinetic interactions with cyclobenzaprine differ from interactions with TCAs. Cyclobenzaprine is a 1A2 substrate (tree) while all TCA antidepressants are 2D6 substrates (beach balls).
Incidence of drowsiness with cyclobenzaprine is 38%. As with some TCAs, cyclobenzaprine can be used as a sleep medication due to its effects on 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors. Flexeril causes anticholinergic side effects, but less so than carisoprodol (Soma) or tizanidine (Zanaflex). None of these spasmolytics should be taken by elderly individuals.
When taken orally, first-pass metabolism in the liver converts much of the dose to norcyclobenzaprine, which is more responsible for the persistent grogginess of the drug. Tonix Pharmaceuticals was testing sublingual cyclobenzaprine for military-related PTSD at 2.8 mg and 5.6 mg strengths, but the trial was halted in Phase III (2018) due to inadequate separation from placebo.
Although it only works short-term as a muscle relaxant, some patients take cyclobenzaprine long-term for insomnia.
Dosing: For muscle spasms the recommended dose is 5–10 mg TID for up to 3 weeks. When used off-label for fibromyalgia, start 10 mg HS, with a maximum of 40 mg total daily dose divided BID–TID.