Sleeping Medications & Women’s Health

Edited by Mirabella Chan



It’s no surprise that the past year has been exhausting for many people. With the winter months having less hours of sunlight, and everyone being cooped up at home, you may be getting more questions about sleeping medications. While it’s perfectly normal to experience temporary trouble sleeping during stressful times, there are also plenty of medications that can affect sleep. As such, pharmacists can make many meaningful interventions in this area.



Review: Which medications can affect sleep?

  • Stimulants

  • Antidepressants

  • Corticosteroids

  • Smoking cessation agents

  • Hormone replacement therapy and oral contraceptives

  • Many more – always check the monograph!


It can be difficult to differentiate the cause of acute sleep disturbances, especially when there are comorbid conditions present. For example, depression has a well-established association with insomnia. However, antidepressant medication can also affect one’s sleep. In situations like these, a thorough patient history and temporal associations of symptoms may guide a clinician’s judgment. A diary, app, or other means of tracking sleeping patterns can be an invaluable resource.


Patients who present to the pharmacy with chronic sleep disturbance (3+ nights per week for 3+ months) where you do not suspect a substance-related etiology, should be referred to a sleep specialist for further assessment. Additionally, patients who present with physical symptoms keeping them from sleeping (ex. pain, shortness of breath, overactive bladder) should be referred to their family physician.



Do men and women have different risk factors for sleep disturbances?


Sex and gender differences in sleep health are not well understood. While a number of new studies have identified both biological and psychosocial factors that may explain differences in prevalence and etiology of sleep disorders, there is still a substantial knowledge gap.


What we do know, is that certain life experiences like menstruation, pregnancy and menopause, can have profound impacts on quality and quantity of sleep. Animal models suggest that estrogen plays a more significant role in modulating sleep than progesterone, but additional research is needed to understand the role these hormones play in human sleep behaviour. Temporary sleep disturbance in menopause due to vasomotor symptoms like hot flashes suggest a potential role for HRT in this population, though studies are inconclusive. If psychosocial factors are the suspected cause, there is high-quality evidence that this patient group responds well to Cognitive Behavioural Therapy.


Note that safety data for many OTC and prescription sleeping medications in pregnancy and breastfeeding is lacking, so nonpharmacological treatments should always be tried first.


What over-the-counter options are there?


Natural Health Products


Melatonin is a very popular supplement that comes in a variety of formulations. 2-3 mg HS is the usual starting dose, which can be titrated up to 10 mg HS as needed. For patients who prefer a natural health product, melatonin has the best safety data. Some product monographs suggest that patients with hypertension and those on warfarin should be closely monitored when initiating therapy.


There are a wide variety of herbal products on the market containing chamomile, valerian, L-tryptophan and other agents. While these products may be acceptable in non-pregnant or lactating individuals, we do not have robust efficacy or safety data on these agents.


First-generation Antihistamines


Diphenhydramine and doxylamine succinate are found in many nighttime or PM products. While drowsiness is a known side effect of this class of medication, so are the less-desirable anticholinergic effects. These products can cause dry mouth, urinary retention, and confusion, and thus should be used with caution in elderly patients. Ensure that patients are not using unnecessary combination products (ex. using Tylenol PM for sleep, without accompanying pain or fever). Watch for interactions with CYP2D6 substrates (antidepressants, codeine, antiarrhythmics). Patients should be advised that there is contradicting evidence for efficacy of these agents, and the risks generally outweigh the benefits.


What prescription options are there?


Benzodiazepine Receptor Agonists (“Z drugs”):

  • Zopiclone – starting dose is 3.75 mg HS, titrated up to 7 mg HS as needed

o Most cost-effective option in this class

o May cause taste changes

  • Zolpidem – starting dose is 5 mg HS, titrated up to 10 mg HS as needed.

o Females metabolize zolpidem 50% slower than males, and thus should not take more than 5 mg QHS unless advised by a sleep specialist

o Food may delay onset of action

o Zolpidem is a controlled substance in Canada

  • Eszopiclone (Lunesta) – starting dose 1 g HS, titrated up to 3 g HS as needed

o Recently approved by Health Canada.

o May cause taste changes

o High-fat meal may delay onset of action

o May be efficacious in perimenopausal / postmenopausal women with hot flashes


Note that all Z drugs are on the Beer’s Criteria list of medications that should be used with caution in the elderly. All Z drugs are approved for short-term treatment, though there is no set definition of short-term. Onset of action is ~ 30 minutes, with an average duration of effect ~8 hours. However, patients should be advised not to operate a vehicle or heavy machinery for 12 hours after each dose. Alcohol should be avoided. Watch for interactions with CYP3A4 inhibitors and CNS depressants.


Using Z drugs in pregnancy is controversial, due to risk of pre-term delivery and low birth weight infants. If nonpharmacological measures fail and a hypnotic agent is indicated, smaller studies have suggested zopiclone may be safe. There is a lack of data on excretion of Z drugs in breastmilk.


Benzodiazepines


Only 4 benzodiazepines have Health Canada-approved indications for insomnia:

  • Flurazepam – 15-30 mg HS

  • Nitrazepam – 5-10 mg HS

  • Temazepam – 15-30 mg HS

  • Triazolam – 0.125-0.25 mg HS

However, other benzodiazepines like clonazepam and oxazepam are often prescribed off-label as sleeping medications. Due to their significant side effect profile, risk of dependence, and potential for rebound insomnia, benzodiazepines should be used with caution. They are also on the Beer’s Criteria list. Alcohol should be avoided. Watch for interactions with CYP3A4/2C19 inhibitors and CNS depressants.


The use of benzodiazepines as hypnotic agents in the absence of a comorbid disorder (ex. anxiety or seizures) is contraindicated during pregnancy. Short-term use may be acceptable in breastfeeding but is generally not recommended. There is a lack of data on the efficacy of benzodiazepines for sleep disturbances in menopause.


Other


Doxepin (Silenor) is a tricyclic antidepressant indicated only for difficulty maintaining sleep, not falling asleep. Standard dosing is 3-6 mg, 30 minutes before bedtime, but not within 3 hours of a meal. There are significant interactions with cimetidine and sertraline. Doxepin is not recommended for use in pregnancy or breastfeeding.


There are a number of other antidepressant and antipsychotic medications commonly prescribed off-label for sleep disturbances (ex. trazodone, mirtazapine, quetiapine). The use of these medications should be limited to those with relevant comorbid conditions. There is limited evidence that the use of short course, cyclical dosing of SSRIs in the luteal phase of the menstrual cycle may improve pre-menstrual sleep disturbances.


Lemborexant (Dayvigo) is the first orexin receptor antagonist approved for use in Canada. Orexins are neuropeptides that promote arousal and wakefulness. Interestingly, some animal models have shown that ovarian hormones modulate orexin activity. Further research is needed to elucidate the role of orexins in female sleep physiology. Standard dosing is 5-10 mg HS, although doses >5 mg are not recommended for elderly patients. Although head-to-head comparison data is lacking, clinical trials have suggested that lemborexant has less rebound insomnia and withdrawal than benzodiazepines or Z drugs. There is very limited data on safety in pregnancy and breastfeeding. Watch for interactions with alcohol, CNS depressants, CYP3A4 inducers or inhibitors.


 

Overall, patients experiencing difficulty sleeping, whether acute or chronic, should be counselled on the importance of nonpharmacological treatments. Proper sleep hygiene measures, like minimizing screen time before bed, or reducing caffeine intake, should be strongly encouraged. Cognitive behavioural therapy has proven efficacy for patients with or without comorbid psychiatric disorders.


Advise patients that prescription options are recommended for short term use only, unless under careful supervision of a physician. For patients who have been using benzodiazepines or BZRAs chronically, detailed deprescribing algorithms are available at https://www.deprescribingnetwork.ca/algorithms.


Understand that there is still an immense gap in knowledge when it comes to sleep disorders in women. Older drugs were historically only tested in male populations, and many agents lack safety data in pregnancy or breastfeeding. Very few studies have directly compared treatment options for use in insomnia secondary to menopause or pre-menstrual syndrome.


Getting a good night’s rest is tremendously important for both mental and physical wellbeing. Regularly checking in with your patients about their sleep health can make a big difference!



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References

  1. Dorsey A, De Lecea L, Jennings KJ. Neurobiological and hormonal mechanisms regulating women’s sleep. Front Neurosci 2020;14: 625397.

  2. e-CPS [Internet]. Ottawa, ON: Canadian Pharmacists Association; Benzodiazepines monograph [May 2015]. http://www.e-therapeutics.ca. (Accessed February 18, 2021).

  3. e-CPS [Internet]. Ottawa, ON: Canadian Pharmacists Association; Silenor monograph [December 2012]. http://www.e-therapeutics.ca. (Accessed February 18, 2021).

  4. Fleming JAE. Insomnia. In: Compendium of Therapeutic Choices. Ottawa, ON: Canadian Pharmacists Association. Updated May 1, 2018. Accessed February 16, 2021.

  5. Mallampalli MP, Carter CL. Exploring Sex and Gender Differences in Sleep Health: A Society for Women's Health Research Report. J Womens Health (Larchmt) 2014;23(7): 533-562.

  6. Nowakowski S, Meers J, Heimbach E. Sleep and Women's Health. Sleep Medicine Research 2013;4(1): 1-22.

  7. Okun ML, Ebert R, Saini B. A review of sleep-promoting medications used in pregnancy. Am J Obstet Gynecol 2015; 212(4):428-41.

  8. TRC Healthcare. Comparison of Insomnia Treatments. [Pharmacist’s Letter website]. May 2020. Available at https://ca-pharmacist-therapeuticresearch-com./PRL/2013/May/Comparison-of-Insomnia-Treatments-5647. (Accessed February 17, 2021).

  9. TRC Healthcare. Melatonin. [Natural Medicines website]. September 9, 2020. Available at: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=940. (Accessed February 16, 2021).

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