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 substitute

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.

Author: Lois Maharg, The Savvy Insomniac

Lois Maharg has worked with language for many years. She taught ESL, coauthored two textbooks, and then became a reporter, writing about health, education, government, Latino affairs, and food. Her lifelong struggle with insomnia and interest in investigative reporting motivated her to write a book, The Savvy Insomniac: A Personal Journey through Science to Better Sleep. She now freelances as an editor and copy writer at On the Mark Editing.

8 thoughts on “Off-Label Prescribing for Insomnia: What to Expect”

  1. Hi Lois!
    I have written to you before about a few issues, but I have something I have tried recently that I thought would interest you. I live in Chicago, near some top rated hospitals. I went to a newer integrative dr who studied under Dr. Andrew Weil to get advice about my insomnia and restless leg issues. I also was diagnosed with Fibro some 20 years ago, but there have been some conflicting thoughts on this for me, so who knows. Sometimes I think it is all sleep related to be honest. I currently take a low dose of Klonopin (.25 most nights, 200mg. of Neurontin (sometimes 100mg. depending on the night, and .5 of Lexapro).

    With that bit of background, this dr. recommended that I try the Charlotte Web’s CBD oil, one dropper under the tongue every night. This is a very reputable hemp grower (no pesticides) No cannibus. I have had a lot of success with this regimen. I look forward to learning more about how this oil helps with sleep, but for now I am truly amazed.

    I thought you would be interested in hearing about my experience. I want to stress how reputable this Dr. was. Also, I went on vacation recently and usually have terrible travel insomnia, but with the CBD oil I did not need the usual Sonata dose the entire trip.

    I look forward to your thoughts on this. There is a lot written on the internet about this as you probably know.

    Be well,


  2. Thanks for posting. I can attest pregabalin works for insomnia (your results may vary, consult your doctor) and have tried all of the benzodiazepines and Z-drugs. CBD oil is also helpful for sleep and fibromyalgia. One thing you didn’t mention was benedryl or antihistamines, which again can work in the short term but not good for long term use. As with all medications, pregabalin may have side effects such as weight gain.


    1. You’re welcome for the post. It’s always good to get comments from readers who’ve actually tried these medications (although drugs that work for some people with insomnia may not work for others).

      The McGill researchers didn’t review over-the-counter antihistamines as possible substitutes for the Z-drugs and benzodiazepines. These drugs aren’t highly spoken of among sleep doctors, researchers and therapists. Past research has shown they’re not particularly effective at improving sleep and that they have lots of bad side effects: daytime sedation, diminished cognitive function, dry mouth, blurred vision, urinary retention, and constipation.

      But some people I’ve spoken with take them for sleep and are satisfied with the effects. As you point out, though, they’re not good for long-term, nightly use. Thanks for writing in!


  3. Be careful about trazodone. It was given to my father to help him sleep when he was in the hospital, and it caused hallucinations. Once they stopped it, he was fine again.

    Liked by 1 person

  4. I have been taken 100-200mg of Trazadone for over 7 years yes i could sleep for about 4-5 hours a night , but i developed really bad constipation and laxitives would not work except for a new product called Constella but they are like 6-9 dollars a pill. So i tried to stop taking Trazadone but could not sleep without it and in fact i found out you cant stop taking Trazadone ,you have to wean off it slowly and it can take 6-9 months until your head is straight again, I am asking what can i take instead of Trazadone that does not cause constipation or sexual dysfunction?


    1. Hello Paul,

      I’m sorry to hear about your sleep problem and the bad side effects trazodone seems to have caused you. There are other sedating antidepressants, but unfortunately many are known to cause sexual dysfunction. Here’s a blog post on those most widely prescribed:

      A doctor should be able to advise you about a substitute drug if you want to continue going the medical route to improve your sleep. Other drugs mentioned in this blog post might work for you, too, depending on whether the problem is sleep onset insomnia or sleep maintenance insomnia.


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