Cyclobenzaprine ER (Amrix)

Cyclobenzaprine is a centrally acting skeletal muscle relaxant. It does not act on the muscle itself but in the brainstem, where it damps the tonic activity of the motor pathways that keep a cramped muscle under constant tension. Chemically it is a tricyclic: a single double bond separates it from the antidepressant amitriptyline. That ancestry explains almost everything you notice about the drug, from the drowsiness and the dry mouth to the interactions.

ER stands for extended release. The classic immediate-release tablet is taken three times a day at 5 to 10mg because the duration of action of a single dose is put at four to six hours. The extended-release form spreads the drug over the day, so one dose is enough. The plasma level shows one flat peak rather than three spikes. Those spikes are exactly what daytime drowsiness follows.

In research, cyclobenzaprine turns up mainly for acute, painful muscle spasm of the back and neck, as a short-course agent over two to three weeks. It is not meant for spasticity caused by disease of the brain or spinal cord and, on the evidence, does not work there. Cyclobenzaprine ER comes as 15mg extended-release tablets, ten per blister.

This information is for research and educational purposes only. No medical advice.

The site of action lies above the spinal cord. Cyclobenzaprine reduces the firing of gamma and alpha motor neurons, the nerve cells that set muscle tone, without touching the muscle fibre or the neuromuscular junction. Animal work points to blockade of 5-HT2 receptors in the spinal cord as the main route, the same path by which amitriptyline and cyproheptadine damp spinal reflexes. On top of that come the usual tricyclic side stages: histamine H1 blockade (sedating), muscarinic blockade (dry mouth, constipation) and weak inhibition of noradrenaline reuptake.

Only about a third to a half of a swallowed dose reaches the bloodstream; the rest is lost on the first pass through the liver. Metabolism runs through CYP3A4 and CYP1A2, with a smaller share through CYP2D6. The half-life is given as about 18 hours for the immediate-release form and about 32 hours for extended release, because the slow release overlays elimination. Accumulation follows suit: roughly fourfold with 10mg immediate release three times daily, about 2.5-fold with 30mg extended release once daily by steady state. In older adults exposure after an extended-release dose runs about 40 percent higher and the half-life stretches to around 50 hours; with even mild liver impairment, levels double.

For the extended-release form, Darwish and Hellriegel (Expert Opin Drug Metab Toxicol 2010) summarised the first four pharmacokinetic studies: 30mg extended release once daily and 10mg immediate release three times daily deliver the same total exposure, but the extended-release form shows a single peak at about six to eight hours instead of three spikes and holds the level over 24 hours. Steady state is reached by day seven. At 30mg the exposure is about twice that of 15mg. Two things push the level higher still: food and older age.

This is not a matter of taste but of dose and daily profile. The immediate-release form can be dosed finely: 5mg three times daily is as effective in trials as 10mg and sedates less, while 2.5mg is already too little. The extended-release form cannot do that, because a 15mg extended-release tablet must not be split; cut it and the delayed release is gone and the day starts with a spike.

What the extended-release form offers instead is the smoother curve. In the registration trials, daytime drowsiness was reported less often on extended release than on 10mg three times daily, with comparable effect. If you want a daily dose around 15mg and prefer the drowsiness to fall at night, extended release is the right tool. If you want to dose very low or intervene only at specific points in the day, you need the immediate-release form.

One note on consistency: because food increases absorption (peak level up about 35 percent, total exposure about 20 percent), the extended-release tablet belongs either always with a meal or always on an empty stomach. Alternating gives you two different levels from the same tablet.

Browning and colleagues (Arch Intern Med 2001) pooled the placebo-controlled trials of cyclobenzaprine for back pain in a meta-analysis. Patients on cyclobenzaprine were almost five times as likely to report improvement by day 14 as those on placebo. Just under three people had to take it for one to benefit. Effect sizes for pain, spasm, tenderness, range of motion and daily activities were only 0.38 to 0.58, which is modest. The benefit was largest in the first four days. The price: more adverse effects, drowsiness above all.

Borenstein and Korn (Clin Ther 2003) tested in two trials with 1,405 patients whether less would do. 5mg three times daily matched the classic 10mg and sedated less, while 2.5mg fell behind. Relief set in after three to four doses and was also present in those who reported no drowsiness, so it was not simply a by-product of sedation. This is why 5mg rather than 10mg is now the entry dose of the immediate-release form.

Malanga and colleagues (Curr Med Res Opin 2009) are the registration trials of the extended-release form: two identically designed, randomised, double-blind trials in 504 patients with muscle spasm from acute neck or back pain, treated for 14 days with 15mg extended release, 30mg extended release, 10mg immediate release three times daily or placebo. At day four patients rated extended release as significantly more helpful than placebo, 30mg in the first study and 15mg in the second, with 30mg additionally improving pain relief and mobility. The physicians' global assessment, however, did not differ between groups. The trials were not powered to compare extended and immediate release against each other. Read honestly: effective, but no breakthrough. The main advantage is less daytime drowsiness.

Friedman and colleagues (JAMA 2015) are the counterpoint. In a New York emergency department, 323 patients with acute, uncomplicated low back pain all received naproxen plus either placebo, cyclobenzaprine 5mg or oxycodone/acetaminophen. After one week, function had improved almost identically in all three groups; adding cyclobenzaprine was worth 0.3 points on a 24-point scale, which is nothing. If you are already taking an analgesic such as naproxen, do not expect much added benefit from cyclobenzaprine on top. The trials that show an effect mostly tested cyclobenzaprine alone against placebo.

• Drowsiness: the most common report in every trial, dose-dependent and strongest in the first days. Less frequent on extended release than on 10mg three times daily, but not gone. Driving and machinery only once you know the next-day effect. Alcohol, benzodiazepines, opioids and other depressants add up.
• Anticholinergic: dry mouth (the second most common report), blurred vision, constipation, urinary retention, fast pulse. With narrow-angle glaucoma, an enlarged prostate or existing urinary retention this is not a side note but an exclusion.
• Serotonin syndrome: documented in combination with SSRIs, SNRIs, other tricyclics, tramadol, meperidine, bupropion or verapamil. Agitation, tremor, muscle twitching, sweating, fever and a racing heart are the signs. Stop immediately if suspected.
• MAO inhibitors: an absolute contraindication. At least 14 days apart in either direction, otherwise hypertensive crisis, seizures and serotonin syndrome are on the table.
• Heart: as with all tricyclics, arrhythmias, conduction disturbances, heart failure and the first weeks after a heart attack are exclusions, as is hyperthyroidism. In overdose cyclobenzaprine shows the tricyclic picture of arrhythmias and seizures.
• Older adults: about 40 percent higher exposure and a half-life stretched to around 50 hours, plus sedation and anticholinergic effects, add up to falls and confusion. The extended-release form is not recommended here.
• Liver: up to twice the levels even with mild impairment. Extended release not recommended.
• Other: dizziness, fatigue, headache, nausea, digestive upset. Rarely raised liver enzymes and skin reactions.

Cyclobenzaprine is not on the WADA prohibited list. It is not classed as a drug of dependence and, unlike carisoprodol, falls outside controlled-substance law in most countries, although misuse for its sedation has been described in isolated cases. It is not a drug for continuous use in any case: the documented benefit ends after two to three weeks.

Keep the tablets in their blister, dry, at room temperature and away from light. Not in the bathroom or kitchen, since moisture attacks the extended-release coating. Keep out of reach of children; tricyclics are dangerous for children even in small amounts.