Off-Label Prescribing for Insomnia: What to Expect

Several drugs approved for insomnia are in the doghouse these days, and physicians are doing a fair amount of off-label prescribing. What medications should we expect to be prescribed in lieu of zolpidem (Ambien) and temazepam (Restoril)?

Using a “translational approach,” McGill University researchers have reviewed a host of medications with sedative properties and found the evidence base for some is stronger than for others. Here are the drugs they’ve found are most likely to work.

Insomnia treated with sleeping pill substituteSeveral drugs approved for insomnia are in the doghouse these days, and physicians are doing a fair amount of off-label prescribing. What medications should we expect to be prescribed in lieu of zolpidem (Ambien) and temazepam (Restoril)?

Using a “translational approach,” McGill University researchers have reviewed a host of medications with sedative properties and found the evidence base for some is stronger than for others. Here are the drugs they’ve found are most likely to work.

Why Not Stick With the Tried and True?

Z-drugs such as zolpidem and benzodiazepines such as temazepam may be fine for short-term or occasional use. But lots of people who take these sleeping pills go on to become chronic users.

This can cause problems. People who take a Z-drug or a benzodiazepine nightly for months and years often experience adverse effects: a decrease in deep (or slow-wave) sleep and/or cognitive and motor impairments the next day. Some develop drug dependency.

The Off-Label Prescribing Dilemma

So where’s the next generation of sleeping pills in line to replace the ones we’re using now? A few new drugs are in the pipeline, but none I’m aware of are going up for FDA approval soon. As often happens, we’ve got to fall back on drugs already approved to treat other health problems. It’s perfectly legal for doctors to prescribe such drugs off label as treatment for insomnia.

The problem lies in knowing which other drug(s) to choose. Medications approved for insomnia have demonstrated their efficacy in at least two randomized clinical trials (RCTs) conducted on people with insomnia (and no other related condition). Compared with placebo, they’ve been found to significantly improve sleep. Medications approved for other health conditions—such as depression, anxiety, or neuropathic pain—may have known sedative properties. But in many cases they haven’t been tested for efficacy on people with simple insomnia.

A Translational Approach

In an in-depth review paper published this month in Pharmacological Reviews, the McGill University researchers propose instead using a translational approach to evaluate these drugs for efficacy in treating insomnia. This involves integrating what basic scientific research has shown about a drug’s pharmacology and mechanism of action with clinical data and current medical practice.

Using this approach, the researchers went on to identify medications most likely to serve as effective alternatives for Z-drugs and benzodiazepines. Here they are:

Drugs That Act on the Melatonin System

1. Prolonged-release melatonin (PRM): FDA-approved dietary supplement sold over the counter in the United States; sold as a prescription drug (2 mg/day) in Europe. “Good evidence,” based on 4 RCTs, that PRM is effective for insomnia disorder in adults over age 55 (particularly in reducing time to sleep onset). There’s no evidence that PRM is effective for younger adults with insomnia. (Caveat: The quality control of dietary supplements sold in the United States is not nearly as reliable as the control of prescription medications. Your physician may be able to steer you toward a reliable brand.)

2. Ramelteon (Rozerem): FDA-approved drug for treatment of sleep onset insomnia. “Strong evidence,” based on 2 meta-analyses, that the drug reduces subjective time it takes to fall asleep but no evidence that it helps people sleep longer.

3. Agomelatine (Melitor): Not available in the United States but approved for treatment of major depressive disorder in Canada and Europe. “Good evidence,” based on 1 review and 2 RCTs, that this drug reduces sleep latency in people with depression. Unlikely to improve sleep in people with simple insomnia.

A Drug That Acts on the Orexin System

4. Suvorexant (Belsomra): FDA-approved drug for treatment of insomnia disorder. “Strong evidence,” based on 2 systematic reviews, that the drug reduces insomnia symptoms at doses of 15 mg and higher. It purportedly increases total subjective sleep time and decreases subjective time to sleep onset. (Caveat: Because this drug is a relative newcomer, less is known about its real-world effectiveness and actual side effects. For more information, read my earlier post about Belsomra and take a look at the reader comments.)

Sedating Antidepressants

5. Low-dose doxepin (Silenor): FDA-approved drug for treatment of sleep maintenance insomnia that acts on the histamine system. “Strong evidence,” based on 1 systematic review, that this drug enhances sleep maintenance by reducing nighttime wake-ups. It has not been found to cut down on time to sleep onset.

6. Trazodone: FDA-approved drug for treatment of depression. At low doses, commonly prescribed off label for treatment of insomnia. It acts on the histamine, serotonin, and catecholamine systems. “Good evidence,” based on 2 RCTs, that trazodone reduces insomnia symptoms in people who are taking selective serotonin reuptake inhibitors (SSRIs) to manage depression. This is the only conclusion drawn by the McGill researchers about trazodone. It does not account for the drug’s great popularity with physician prescribers, who for decades have been prescribing trazodone for insomnia rather than Z-drugs and benzodiazepines.

More on Trazodone

So I looked at another paper, this one a systematic review of trazodone for insomnia published in Innovations in Clinical Neuroscience in August 2017. From a pool of 45 studies (the inclusion criteria were evidently less stringent for these researchers than for the McGill researchers, who reviewed 16 studies of trazodone), the second team of researchers concluded that trazodone “is a generally safe therapeutic that has been repeatedly validated as an efficacious treatment for insomnia, particularly for patients with comorbid depression,” with some evidence that it decreases sleep latency, increases sleep duration, and improves sleep quality. Side effects, which may show up in people taking doses higher than 100 mg, include daytime sleepiness, headache, and hypotension, increasing the risk of falls.

The evidence base for trazodone’s effectiveness as a drug for people with simple insomnia is sparse yet suggestive of similar benefits, the second research team reports. (Results of a recent 6-week clinical trial comparing 3 active insomnia treatments—behavioral therapy, zolpidem, and trazodone—are not yet available. Stay tuned.)

An Anticonvulsant Drug

7. Pregabalin: FDA-approved drug for treatment of neuropathic pain, seizures, and fibromyalgia. There is “good evidence,” based on 2 review papers, that pregabalin is effective in reducing symptoms of insomnia in generalized anxiety disorder. There is also “good evidence,” based on 1 review, that the drug is effective in reducing symptoms of insomnia in fibromyalgia. But no evidence base for pregabalin as a treatment for simple insomnia exists.

The medical treatment of insomnia has always been problematic, even more so in the past than today. While your physician may be reluctant to keep writing prescriptions for zolpidem, other, possibly safer medications may be available when behavioral treatments for insomnia don’t suffice.

Pregabalin for Insomnia: A Viable Off-Label Option?

Sleeping pills approved by the Food and Drug Administration–Ambien and Lunesta–are getting some negative press these days, and I hear more talk of using off-label medications to treat insomnia. (Off-label meds are drugs approved for the treatment of other disorders.) I’ve blogged about some of these drugs before: trazodone, clonazepam and quetiapine.

Pregabalin is another, which is now being prescribed for people with trouble waking up in the middle of the night.

off-label-drugSleeping pills approved by the Food and Drug Administration–Ambien and Lunesta–are getting some negative press these days, and I hear more talk of using off-label medications to treat insomnia. (Off-label meds are drugs approved for the treatment of other disorders.) I’ve blogged about some of these drugs before: trazodone, clonazepam and quetiapine.

Pregabalin is another. Recently I saw a video interview of Thomas Roth, who directs the Sleep Disorders and Research Center at Henry Ford Hospital in Detroit, following a professional conference early this month. Asked about insomnia treatments, Roth mentioned two drugs for people with sleep maintenance insomnia (trouble waking up in the middle of the night):

  • Low-dose doxepin, a tricyclic antidepressant approved by the FDA for sleep maintenance insomnia under the brand name Silenor in 2010, and
  • Pregabalin, an anticonvulsant approved to treat neuropathic pain, epilepsy, and fibromyalgia in the US and for generalized anxiety disorder (GAD) in Europe and Russia.

Lots of people come to The Savvy Insomniac looking for information about sleeping pills and supplements, and sleep maintenance insomnia is the most common type of insomnia problem. So I decided to investigate pregabalin. Here’s what I found out.

Is Pregabalin Effective for Trouble Sleeping?

There haven’t been any controlled trials of pregabalin as a treatment for insomnia per se. But one main side effect of the drug is drowsiness. In chemical structure, pregabalin is similar to GABA, a neurochemical that tranquilizes the brain at night. (But unlike Ambien, Lunesta, and benzodiazepines such as temazepam and clonazepam, pregabalin does not bind directly to GABA or benzodiazepine receptors.)

Insomnia and anxiety are closely linked, and pregabalin inhibits the release of neurotransmitters associated with anxiety. Reviewers looking at the effects of the drug on people with anxiety and insomnia found that the drug improved subjects’ sleep in seven controlled clinical trials.

But the kind of insomnia most often associated with anxiety is trouble getting to sleep at night. Why might pregabalin be effective for people whose problem is that they can’t stay asleep?

The elimination half-life of pregabalin is about 6 hours. So it’s longer lasting than many sleeping pills on the market today, and certainly longer lasting than over-the-counter melatonin supplements. Reviewers of pregabalin’s effects on sleep disturbance associated with other disorders say, based on data from overnight sleep studies, that pregabalin improves sleep and “primarily affects sleep maintenance.”

Is Pregabalin Safe?

Research on pregabalin used in the treatment of other disorders suggests the drug is relatively safe. The two most common side effects of the drug are drowsiness and dizziness. But few randomized, controlled trials have been conducted to determine its long-term safety, though the drug has been on the market since 2005.

Like most prescription sleeping pills, pregabalin is a controlled substance. But it is classified as a Schedule V drug, considered by the FDA and the Drug Enforcement Administration to have a lower potential for abuse and dependence than benzodiazepines like temazepam and clonazepam and Ambien and Lunesta, which are Schedule IV drugs.

If sleep maintenance is your problem and you’re unable to manage it by other means, pregabalin might be worth checking into with your doctor.

If you’ve already tried pregabalin, what effect did it have on your sleep?