Insomnia Medications for Patients in Medication-Assisted Treatment

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In one of my recent blog entries, I talked about some simple measures that can help patients with insomnia, called sleep hygiene. Many times these methods can fix the problem, but other times, patients still can’t sleep well, which interferes with life. In these cases, medications may be of some help.

The “Z” medications
The “Z” group of medications includes zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta). These medications, which are not benzodiazepines, have been touted as being safer and less addictive than older benzodiazepines, like temazepam (Restoril), triazolam (Halcion) or clonazepam (Klonopin). However, the “Z” medications stimulate the same brain receptors as benzodiazepines, and are all Schedule IV controlled substances, just like benzodiazepines. This means they all have roughly the same potential to cause addiction, despite enthusiastic marketing by some drug companies.

I don’t prescribe the “Z” medications for patients on medication-assisted treatment with methadone or buprenorphine because they can cause overdose deaths in these patients. Also, these medications can give many patients with the disease of addiction the same impulse to misuse their medication. I’ve had patients develop problems with misuse and overuse of these medicines.

Trazadone
Many doctors, including me, have prescribed trazadone to help patients get and stay asleep. It’s an antidepressant, but daytime use has been limited due to drowsiness. In an effort to use this side effect for benefit, it’s often prescribed at bedtime to treat insomnia. But a recent study called this practice into question. In this study, trazadone was not found to be effective for methadone maintenance patients with insomnia. Test subjects were monitored with sleep study apparatus, and these subjects had no subjective or objective benefit from trazadone, either in initiating or staying asleep. [1]

Because trazadone can affect the QT interval, just like methadone, it’s possible these two drugs used together will dangerously prolong the QT interval. Also, both can cause sedation, also a concern. In view of this data, I have stopped recommending or prescribing it as an insomnia medication.

Quetiapine (Seroquel)
Quetiapine is in the group of medications known as atypical antipsychotics, and is indicated for the treatment of schizophrenia, the mania of bipolar disorder, and treatment-resistant depression. Because it is a sedating medication, many doctors prescribe it for treatment of insomnia, usually at low doses, around 25 to 100mg at bedtime.

Does it work? Two small studies, designed to see if the drug can help insomnia, showed conflicting results. One study showed significant improvement and the other showed no significant improvement.

Furthermore, this medication is not without side effects. At higher doses, used to treat bipolar disorder and schizophrenia, patients can develop diabetes and hyperlipidemia. But even at low doses, we see weight gain, restless legs, dizziness which can lead to night time falls, and dry mouth. There’s a risk, though likely small, of tardive dyskinesia with this drug. This is a serious movement disorder more commonly seen with the older antipsychotics like thorazine; patients on the atypical antipsychotics can also develop this potentially devastating disorder.

With little evidence to support its use, and potential serious side effects, I no longer initiate a prescription for quetiapine in a patient with insomnia. I do have some patients who’ve been started on this medication before they started seeing me. If they still feel it’s effective and I see no side effects, I’ll continue the medication. I make sure they get yearly lipid profiles done and recommend yearly screens for diabetes, and monitor for weight gain.

At addiction medicine conferences, I’ve heard doctors say that some of their patients misuse quetiapine. Personally, I think that must be unusual, and maybe these are patients in an experimental phase of addiction. I don’t see seasoned addicts using this medication to get high.

Ramelteon (Rozerem)
This medication, approved by the FDA for treatment of insomnia in 2005, isn’t addictive. It works by stimulating melatonin receptors and it helps patients get to sleep somewhat more effectively than placebo, but doesn’t help keep them asleep. Ramelteon doesn’t cause the rebound insomnia commonly seen after use of the “Z” medications, and has few clinically significant drug interactions. Last time I checked, it’s more expensive than many sleep medications, and many insurance companies demand a prior authorization before they’ll pay for it. I’ve had a few patients do well with this medication, so I like to prescribe it.

Melatonin
Once hoped to be the miracle treatment for insomnia, studies show that at best, melatonin is mildly more effective than placebo for the treatment of insomnia. Melatonin isn’t a prescription medication, and is sold by many manufacturers with little quality control. Since it is categorized as a dietary supplement, the FDA does not examine or approve these products. Since 2010, the FDA only requires that dietary supplements be made according to “good manufacturing practices,” and that companies make a consistent product, free of contamination, with accurate labeling. As I see it, that’s not much oversight and people take their chances with dietary supplements of any kind.

Diphenhydramine
More commonly known as Benadryl, many over-the-counter sleep medications contain this sedating anti-histamine. It can cause sedation in patients taking methadone, and should be avoided or used with caution. I’ve seen one methadone overdose death I believed was due to the interaction with methadone and diphenhydramine, though the patient had taken more than one 50mg diphenhydramine pill.

Otherwise, the medication is mildly to moderately effect at helping people get to sleep. Don’t take more than 50mg, because higher doses can have a reverse effect, and interfere with sleep.

Hydroxyzine (Vistaril) is another potentially sedating anti-histamine that is felt by some doctors to be safer than diphenhydramine, but I can’t find any data to support that view.

Other medications
Clonidine
I occasionally prescribe clonidine if I think my patient is having a degree of opioid withdrawal as the cause of insomnia. I’m talking about patients who wish to taper, not patients on maintenance. If a patient on maintenance has insomnia from withdrawal, it’s best to increase the dose of the maintenance medication.

Clonidine can help insomnia from withdrawal. Because this is a blood pressure medication, it can drop night-time blood pressure when taken for sleep. This can cause a patient to fall if they get up during the night. I caution patients that if they must get up at night, stand beside their bed for a few minutes to make sure they don’t feel dizzy. I usually prescribe a .1mg pill and have them take only one pill.

Gabapentin (Neurontin)
This anti-seizure medication is used for a little bit of everything, so why not insomnia? Officially, gabapentin is approved by the FDA for treating seizures and for the pain of post-herpetic neuralgia (that’s the pain that stays after a shingles outbreak). But doctors use gabapentin for fibromyalgia, insomnia, migraine headaches, bipolar disorder, and probably other conditions. According to Medscape’s drug interaction checker, gabapentin has no interaction with methadone or buprenorphine, but Epocrates’ drug interaction checker says use with caution with these medications due to possible daytime sedation.

Muscle relaxers
Some patients take these medications at bedtime for their sedating effect, but I don’t think there’s any evidence these medications are particularly effective.

Placebo
I include placebo as a reminder that about thirty percent of people will get benefit from a pill containing no medication. Our minds are powerful. (Parenthetically, I’m highly susceptible to suggestion. As a young adult, I got “drunk” on cider that I was told contained alcohol. I felt intoxicated, to the point of losing my balance and getting dizzy. But my friend had played a trick and there was no alcohol in this cider.) It’s difficult to know if a pill or potion for sleep works because it’s effective, or if it works because of the placebo effect. If you’ve found a medication that works, keep taking it, so long as it’s not doing any harm.

A recent study showed that adults who use sleeping pills are more than three times more likely to die prematurely compared to matched controls who didn’t use sleeping pills.

This relatively large study looked at the medical records of over 10,000 patients who were prescribed hypnotics for sleep, and compared their outcomes to over 23,000 matched control patients, similar except the controls weren’t taking sleeping pills. The sleeping pills, also called “hypnotics” were associated with significant increases in mortality and significant increases in cancer incidence. [2]

The patients’ average age was 54, and they were followed for an average of 2.5 years. All were members of a large U.S. healthcare system in Pennsylvania. The data from the two groups were adjusted for age, gender, smoking status, prior cancer diagnoses, body mass index, ethnicity, and alcohol use.

Patients in the group taking prescribed hypnotics most frequently, defined as more than 132 doses per year, had over five times increased risk of dying than patients not taking hypnotics. Even the group of patients taking hypnotics relatively infrequently (up to 18 doses per year) had a three times higher risk of death. These differences were statistically significant. The medications in the study included all of the “Z” medications, as well as temazepam (Restoril), barbiturates, and the sedating antihistamines, such as diphenhydramine (Benadryl).

The author of this study estimated that hypnotic medications are associated with 320,000 to 507,000 deaths in the U.S. over the year 2010.

This study raises some important questions, since hypnotic drugs are the most commonly prescribed drugs in the U.S., with an estimated 6 to 10% of the population being prescribed these medications.
Sleep medicine doctors say that correlation doesn’t mean causation, and we shouldn’t jump to conclusions. One sleep specialist pointed out that the study didn’t control for psychiatric illness, which could be a significant factor. Additionally, patients who are prescribed sleeping medications may be sicker overall, in ways the study didn’t control, and therefore a generally less healthy group. This could distort study findings.

Other scientists say that sleeping pills could make sleep apnea worse, and cause deaths in that way. Obesity increases the risk of sleep apnea, and with more adults becoming obese, perhaps sleeping pills make apnea worse and these people die in their sleep. Other scientists say sleeping pills slow reflexes, and perhaps patients taking these medications are more likely to be involved in car accidents and other accidents, increasing their death rates.

As for my patients, many of whom are prescribed methadone or buprenorphine, the risk of drug interaction and overdose with the hypnotics usually outweighs all of the benefits, and I recommend that patients do not mix these two types of medications.

As a final bit of advice, I want to remind readers that other physical and mental health conditions can cause insomnia. It’s a good idea to see a primary care doctor to screen for these conditions, which can include sleep apnea, asthma, gastroesophagel reflux, hyperthyroidism, bipolar disorder, depression, and anxiety disorders. Sometimes patients need sleep studies to assess for sleep disorders.

1. Stein et al, “Trazadone for sleep disturbance during methadone maintenance: a double-blind, placebo-controlled trial,” Drug and Alcohol Depend., 2012, Jan 1;120(1-3):65-73
2. BMJ Open 2012;2:e000850 doi:10.1136/bmjopen-2012-000850

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15 responses to this post.

  1. Posted by Alan Wartenberg on April 12, 2014 at 1:33 am

    A very nice review. One thing I would stress is the issue of proper sleep hygiene, preparing for bed in a proper way, not eating, watching TV or engaging in actitivites like to energize in the hour or so before preparing to sleep. Second is the avoidance of large amounts of caffeine and other energizing substances (like Sudafed), which really is the problem more often than we thing – we don’t sleep well at night, use 5 cups of coffee to stay awake, can’t sleep the next night, use 7 cups of coffee to stay awake, sleep even worse the next night etc. Lastly, I have had good luck with patients using chamomile tea and other herbal sleep remedies. In true chronic insomnia, cognitive behavioral therapy, a form of psychotherapy, has been proven to be effective.

    Reply

  2. I use most of the agents U mention. Do not write and Z’s. Additionally, I have found Amitriptyline to be useful for sleep induction.

    Reply

  3. Posted by Benjamin Keith Phelps on April 12, 2014 at 1:49 am

    This has been the bane of my existence on MMT. I got hooked on Lunesta to the point I got arrested for passing scripts for it; benzos help, but have the same risk of misuse for me, though I have only misused Xanax intentionally in the past b/c it has a fast onset of action. But there is NOTHING ELSE that seems to help with this problem for me! I’m NOT willing to risk TD with Seroquel, plus it weighs me down really bad – like I’m trying to walk through molasses. Antihistamines do NOTHING for me, except potentially cause me restless leg syndrome & paradoxical effects, rather than sedation. I will make one comment about your article, though, Dr Burson. While I understand that daytime sedation is not wanted with sleep aids, I’ve always kinda thought sedation is what you’re HOPING for with a sleep aid… You (& other articles/drug interaction pamphlets) mention sedation as a potential SIDE-EFFECT of sleep aids. I don’t quite get it?? The problem with most effective sleep aids is that we addicts will tend to take them & then fight the actual effect of the medicine that would normally put people to sleep. We often will stay awake & enjoy the feeling they create instead, eventually increasing the dose to try to feel it even more. Of course, I speak from my own experience, & those of others I know… Not for every addict. I always find it really odd that there would be any talk of overdose from Benadryl & methadone, unless the patient was not tolerant to methadone’s effects yet, b/c Benadryl is virtually useless for me when on opioids – I’ve tried to take it for allergies, & not only does it not help with those, but it does NOT make me drowsy AT ALL on opioids. It does when I’m NOT on them, but not when I am. And God forbid anybody give me any antihistamine or tri-cyclics for sleep when I’m in withdrawal – OMG, they make withdrawal EXPONENTIALLY worse for me. I can’t speak for anyone else on that matter. I cannot take Phenergan, Benadryl, nor Vistaril while in w/drawals, nor Elavil, Remeron, or any other tri/tetra-cyclic antidepressant b/c they are potent antihistamines also. I thought I’d go insane when I was given those in withdrawal while in jail before I knew better. The last time I went through w/d’s abruptly, I threw them in the trash can when they tried to give them to me. I’ll suffer w/o anything before I’ll take an antihistamine while in withdrawal! Other patients, be aware of this!

    Reply

  4. Posted by nspunx4 on April 12, 2014 at 1:54 am

    Seroquel can also cause qt prolonging effects.

    Reply

  5. Posted by William Taylor, MD on April 14, 2014 at 5:28 pm

    Thanks for a comprehensive review. One additional possibility is Valerian root, although all the usual caveats about herbal preparations and lack of proven safety and efficacy apply.

    Reply

  6. Posted by Annette on April 20, 2014 at 6:51 pm

    My daughter is using Remeron with no bad effects….so far.

    Reply

    • Posted by Benjamin Keith Phelps on April 21, 2014 at 6:30 pm

      Oh Annette,
      I WISH a tetra-cyclic antidepressant would help me sleep during MMT. It has virtually NO effect on me whatsoever. Many MMT docs won’t prescribe tri or tetra-cyclic antidepressants b/c believe it or not, as lousy as it is as a recreational thing, there evidently ARE, somewhere in this world, a small sub-group of people who try to take them as a recreational drug. Though I cannot imagine this on ANY level whatsoever, many drug-store tests for recreational drugs that you can buy that are comprehensive (i.e.- not just for 1 drug in particular, but rather ones that search for many abused/misused drugs) actually test for tri-cyclic (& I’d assume tetra-cyclic as well) antidepressant use. I don’t know if there’s cross reaction between something like Elavil/amitriptyline, Sinequan/doxepin, Pamelor/nortriptyline, etc & Remeron/mirtazipine, but they have virtually the same effect on the patient in my experience (cause sleepiness, weight gain for many, etc etc) & they are ALL potent antihistamines, which is something that I DEFINITELY CANNOT take during withdrawal, though I can take any other time. While either actively an addict or in MMT, they have NO effect whatsoever. While in withdrawal, they potentiate & cause a paradoxical reaction that will lead to me acting & behaving like a totally insane man. I’ll pace, & grumble to myself, moan aloud from the pain, & sit/stand/sit/stand (symptoms of akathisia, which I believe describe withdrawal symptoms FAR more accurately than merely calling it “restless leg syndrome”, which minimizes the discomfort caused by it. Watch a YouTube video of someone w/akathisia & you’ll get a MUCH closer pic of what it looks like for someone in w/d’s than you will reading or seeing RLS symptoms! Anyway, this is PURELY ANECDOTAL, & should NOT be construed as medical advice – I am NOT qualified nor otherwise licensed to dispense ANY such advice. I can only speak on experience of numerous times of w/d’s, & haven been given almost every antidepressant, antihistamine, antipsychotic, anticonvulsant, etc over the years in an effort to control addiction – when all along, I merely needed to be maintained on methadone – the drug CREATED, DEVELOPED, LICENSED, INDICATED, & DISPENSED for the treatment of opioid dependence to begin with! Once I got myself on it at a well-run clinic w/a good counselor, doctor, & staff, I got better almost immediately w/VERY FEW bumps in the road, & those were pretty much within the first 4-5 months. As usual, I’ve typed way too much, digressed, etc, but I hope something I can write somewhere along the way helps someone avoid the problems I have endured at various times in my life that were SO needless.

      Reply

  7. Posted by Dr. DiLauro on April 28, 2014 at 6:45 pm

    I am very supprised at your discomfort with melatonin. There are many reputable sources (store brands) and doses up to 10mg seem to be fairly safe and effective if timed right. What I do see is rampant clonidine abuse in our area of Pennsylvania, and even benadryl and phenergan abuse. These drugs are easier to obtain and are inexpensive. I am very wary about recomending them at all anymore.

    Reply

    • Posted by Benjamin Keith Phelps on April 29, 2014 at 2:11 am

      Dr. DiLauro, the sad fact of the matter is that the disease of addiction DOES INDEED lead those of us affected to abuse almost anything that leads to a particularly desired feeling. For many of us, that feeling is one of relaxation or a “tranquilizing effect”, so to speak (as you know, I’m quite sure). Hence, I have found myself misusing many different things at many different times in my addiction. It’s been MANY years ago now, but back in 1998, I did misuse clonidine – it was only a couple of times, but I did so nevertheless. That’s a dangerous thing – playing with your blood pressure! But we do SO MANY stupid & dangerous things in the pursuit of that feeling we’re seeking, & it makes me SO ANGRY at myself for knowing that I can be that way. I have had times where I think NOTHING of benzodiazepines & their use & couldn’t care less about them, even if they’re in my face. Then I’ve had times where I did them & misused them & then had a compulsion to try to go out of my way to find them like crazy. The way it can change up & move from 1 drug class to another that I feel compelled to seek out & take & the fact that this happens to other addicts, as well (while opioids are STILL ALWAYS my drug of choice – but methadone takes care of that completely for me) makes me wonder if any headway will ever REALLY be made in understanding this disease, other than to say EVERY drug is or can be dangerous at some point in time to an addict – & then at other points in time, that very same drug may be totally ignored & not even cared about. There’s just no way to know. I’ve also experienced this with uppers, though to a lesser degree (b/c I’d MUCH rather be relaxed & chilled out than up & anxious & ESPECIALLY paranoid – there’s nothing worse, to me… but I know what it is to have a compulsion to use something that will put me right there in the middle of it!) I just wish I didn’t have this disease. I wish NOBODY had this disease. It just sucks, & that’s about all I can really say about it for sure.

      Reply

  8. Posted by John Mark on May 6, 2014 at 3:19 pm

    In our methadone assisted program we see diphenhydramine frequently being used…It is thought to prolong the QT intercal and can trigger a false positive UDS for BZD.

    Reply

  9. Posted by Terry Ptacek MD on June 3, 2014 at 4:53 am

    The problem is if out patients can’t sleep they just don’t do well, as well as being more likely to use ambien and the other addictive ones. Despite the study you noted, and despite the risk, I do allow Trazodone, Remeron, and Elavil if sleep hygiene or melatonin doesn’t work nor does Rozerem ( or they can’t afford it).We do try sleepytime tea also. No simple answers here.

    Reply

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