Insomnia Treatment For Patients Diagnosed With Opioid Use Disorders

Aspen Fernando | Mental and Behavior Health Rotation (Zephyr Medical Group)

Case Overview
38Y male with PMH of opioid dependence, elevated blood pressure, and insomnia presents to the clinic
for medication refill/surveillance. Patient has a 15 year history of opioid abuse, and has been on Subutex
8mg SL, twice a day for the past 3 months. Patient has been experiencing symptoms of inadequate sleep
latency and has been using marijuana via smoke to help him fall asleep. He has tried other OTC
medications such as melatonin which makes him groggy, but uses marijuana (smoke) becauses it allows
him to sleep and has no side effects when he wakes up. Patient denies any symptoms of depression and
anxiety at this time. Patient denies any withdrawal symptoms at this time.

PICO Question
Among patients diagnosed with insomnia along with opioid use disorder, is Mirtazapine more effective in
decreasing sleep latency in comparison to Ambien?

Insomnia Background
In the U.S. alone, insomnia, or the ability to initiate or maintain sleep, creates over 5 million health visits
with increasing prevalence in lower socioeconomic status. Insomnia involves dysfunction in a network of
complex interactions between numerous brain centers including the posterior hypothalamic nuclei to
promote sleep. Specifically, in the opioid-using population, chronic opioid use is associated with
interference of several sleep mechanisms increasing the development of insomnia. While there are
glorified insomnia medications to help treat insomnia, there is no evidence on which insomnia medication
is appropriate to prescribe for patients being treated for opioid use disorder.

Study Goals
The primary purpose of the study is to understand the efficacy of mirtazapine, zolpidem, and
mirtazapine-zolpidem on sleep latency and sleep maintenance on patients receiving methadone
maintenance for opioid use disorder. Providers prescribe a variety of sleep aids without any research
backing them in opioid use disorder patients. While Mirtazapine and Trazodone are the most prescribed
sleep aids for insomnia, there are previous studies that Trazodone has no effect on total sleep time in
methadone patients.

Methods
For this randomized, double-blind clinical trial, the researchers used a placebo, Zolpidem CR 12.5mg,
Mirtazapine 30mg, and Zolpidem/Mirtazapine 10mg/30mg in comparing sleep latency and sleep
maintenance. The primary criteria for participants were those who have been on methadone maintenance
treatment for a minimum of 6 months and continue to utilize methadone for their opioid use disorder. In
addition, they must have tested negative in a urine toxicology screen for any substance that may affect
sleep, such as cocaine and amphetamines and have no history of a sleep disorder. Participants were given
three of the active medications or a placebo, where they would take one of the medications for a week and
then take a week off, and then finally start the next medication. Upon going to bed, patients would wear a
wrist actigraph to measure sleep parameters (total minutes awake during sleep period, total minutes asleep
during sleep period, sleep latency) during this trial.
Outcomes/Results
From the 10 participants who participated in this trial, mirtazapine alone had the lowest average total
minutes asleep followed by the mirtazapine-zolpidem combo, placebo, and finally, zolpidem alone. For
total minutes awake during sleep periods, zolpidem alone had the highest value, followed by placebo,
mirtazapine-zolpidem combo, and mirtazapine alone. For sleep latency, mirtazapine alone had the lowest
average followed by the placebo, zolpidem alone, and mirtazapine-zolpidem combo.

Conclusion
From the study, mirtazapine alone was the best drug choice for decreasing sleep latency and wakefulness
after sleep onset and increasing the total number of minutes during the sleep period for patients receiving
methadone treatment. Based on the results, the mirtazapine-zolpidem combo treatment is superior to the
zolpidem alone when it comes to increasing total minutes of sleep during the sleep period and decreasing
the total number of minutes awake during the sleep period. However, the placebo performed very
similarly to the mirtazapine-zolpidem when it came to decreasing the total number of minutes of
wakefulness during the sleep period. The only benefit that zolpidem alone has over the
mirtazapine-zolpidem medication is the ability for zolpidem to decrease sleep latency.

Critical Appraisal
With this randomized double-blind clinical trial, the main limitation is the number of participants they
analyzed (n=10) which creates severe setbacks in how this research is applied in clinic. Also, the study In
addition, sleep period times were self-reported by the participants through a diary which could introduce
errors if the patient needs to be properly documenting the most accurate time the participant goes to bed
and the time participant awakes. Also, some variables were not accounted for such as naps throughout the
day as the effect of zolpidem on day-time function following a poor night’s sleep and how it subsequently
could affect future night’s sleep.

Supplementary Research
What do we know about the pharmacotherapeutic management of insomnia in cannabis withdrawal: A
systematic review

Across 17 publications involving 562 participants, this systematic review analyzed 12 sleep medications
including Mirtazapine and Zolpidem to help manage insomnia caused by cannabis withdrawal. This
systematic review utilized 5 primary databases including PubMed, MEDLINE, Cochrane Review,
Embase, and PsycINFO to include articles where pharmacotherapy was used for sleep disturbance related
to Cannabis withdrawal. Based on their findings, Mirtazapine and Zolpidem have been shown to improve
in increasing sleep hours during their sleep period.

Clinical Application
Based on the publication, the patient could be trialed on Mirtazapine 30mg along with his current Subutex
regimen to help manage his dual diagnosis of insomnia and opioid use disorder. However, close
monitoring of the patient’s response to Mirtazapine is required for the next 2 weeks to manage adverse
side effects of Mirtazapine as well as the efficacy of the treatment.

Answer to the PICO Question

While Mirtazapine is typically prescribed as an atypical antidepressant, Mirtazapine is more effective in
decreasing sleep latency in comparison to Ambien among patients who have a dual diagnosis of
insomnia.

References
Stein MD, Kurth ME, Anderson BJ, Blevins CE. A Pilot Crossover Trial of Sleep Medications for Sleep-disturbed Methadone Maintenance
Patients. J Addict Med. 2020 Mar/Apr;14(2):126-131. doi: 10.1097/ADM.0000000000000531. PMID: 30870203; PMCID: PMC6733669.

Rosen I. Chronic opioid therapy and sleep: An American Academy of Sleep Medicine . Journal of Clinical Sleep Medicine.
https://jcsm.aasm.org/doi/10.5664/jcsm.8062. Published November 15, 2019. Accessed February 10, 2023.

Julie A. Dopheide PD. Insomnia overview: Epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy. AJMC.
https://www.ajmc.com/view/insomnia-overview-epidemiology-pathophysiology-diagnosis-and-monitoring-and-nonpharmacologic-therapy.
Accessed February 1, 2023.