Sleep or Wake: developments in the management of insomnia

Insomnia is a sleep-wake disorder characterized by difficulty in achieving or maintaining sleep, or early morning awakening for ≥3 nights per week for ≥3 months accompanied with daytime impairment.¹ A study in 2011 found insomnia disorder affected 13.4% of Canadians, although the proportion of Canadians that experienced at least one symptom of insomnia was closer to 30-40%.² The changes and pressures associated with the pandemic have only further exacerbated the prevalence of sleep disturbances experienced by Canadians.³
Data from 2020 shows a significantly higher incidence of insomnia in populations affected by COVID-19, with healthcare workers especially susceptible.^3,4

Management of Insomnia

First-line therapy for insomnia is cognitive behavioral therapy (CBT-i), which can produce sustained improvements compared to benzodiazepine receptor agonists (BZRA) which include benzodiazepines and z-drug hypnotics.^5,6 CBT-i identifies and restructures thoughts and behaviours to promote relaxation and healthy sleeping habits.⁷ For CBT-i resources and free tools, visit www.mysleepwell.ca.

 

Medications to treat insomnia have traditionally focused on inducing sedation.

Although effective in achieving sleep in the short term, pharmacists are well aware of the risks associated with sedatives such as BZRAs, especially in elderly patients. These medications also rapidly lose efficacy (building tolerance in as little as 4 weeks) and are frequently associated with worsened insomnia symptoms and withdrawal upon discontinuation.^6,8

Low dose (3-6mg) tricyclic antidepressant Doxepin is also indicated for insomnia, although its efficacy is for sleep maintenance and early morning awakening, as opposed to sleep initiation.¹⁰ Other off-label therapies for insomnia include atypical antipsychotics and antidepressants, which are used for their sedating side effects. These modalities may be appropriate for patients with additional comorbidities such as depression, anxiety, and behavioural disturbances.⁹

Recent developments in insomnia therapy have taken a new approach; re-evaluating the physiology behind sleep disorders. Regulated sleep requires a balance of GABA pathways (which promote sedation) and orexin pathways (which promote wakefulness).¹¹ Traditional insomnia medications act to enhance signalling in GABA pathways and commonly lead to over-sedation and related side effects. Studies show that inhibiting the orexin pathway is also effective for insomnia. By dampening the excessive signals of wakefulness that are characteristic of insomnia, orexin antagonists are effective for achieving and maintaining sleep. Additionally, orexin antagonists are associated with a lower risk of side effects such as falls, daytime sedation, and driving impairment, which are common concerns with traditional sedatives.^12-15 Patients accustomed to adverse effects from sedative hypnotics (e.g. next-morning grogginess) should therefore be reassured that a lack of these side effects when starting an orexin antagonist does not mean the medication is not working.

An example of a new medication targeting the orexin pathway is Lemborexant (Dayvigo®). Demonstrating no tolerance and low abuse potential, Lemborexant can be prescribed for long-term management of insomnia.^12,13,15 Lemborexant is also appropriate for use in older adults and is proven to be well tolerated and effective in studies of up to one year of use, with no evidence of withdrawal symptoms post-discontinuation.^12-15

Deprescribing BZRA for Insomnia

Even with safe and effective choices for insomnia, inappropriate BZRA use remains a significant issue. BZRAs should only be used in the short term (prescribed 1-2 weeks) for insomnia.^6,8 Pharmacists are well-positioned to educate patients about the risks associated with BZRAs and review the alternatives. Refills (especially requests for early refills) and new prescriptions with dose escalations are opportunities to identify patients that would benefit from pharmacist intervention. Pharmacy dispensing software can also be used to filter and identify patients on continuous BZRA therapy.

It is important to develop a clear discontinuation strategy for every patient inappropriately taking a BZRA for insomnia disorder. Tapering slowly is safer and more effective; reduce the dose gradually (e.g. by 25% every 2 weeks).^6,16 Withdrawal symptoms generally emerge when doses are reduced to 25% of baseline.^6,16,17 Hold dose for 1-2 weeks if symptoms (restlessness, irritability, GI symptoms, anxiety, insomnia) are bothersome, then resume taper at a slower rate.⁶

Additional pharmacist tools and algorithms are available at www.deprescribing.org

Although the end of COVID-19 may be in sight, its repercussions will continue to affect Canadians for years to come. Pharmacists, especially now, have an important role in the management of insomnia. Pharmacists are well poised to address and prevent BZRA dependence before it occurs by educating patients about safer and more effective alternatives. Pharmacists can leverage online resources and tools to promote BZRA deprescribing, which may also be covered by private insurance (e.g. Green Shield Canada offers a deprescribing program for which pharmacists can submit 1 initial assessment and up to 4 follow-ups).¹⁸ In the current state of the world, stress and uncertainty have made insomnia especially pervasive; pharmacists must continue to support their patients and their pharmacy teams in the quest for a good night’s sleep.

 

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub, 2013.

 

2. Morin, Charles M., Mélanie LeBlanc, Lynda Bélanger, Hans Ivers, Chantal Mérette, and Joseé Savard. "Prevalence of insomnia and its treatment in Canada." The Canadian Journal of Psychiatry 56, no. 9 (2011): 540-548.

 

3. Cénat, Jude Mary, Camille Blais-Rochette, Cyrille Kossigan Kokou-Kpolou, Pari-Gole Noorishad, Joana N. Mukunzi, Sara-Emilie McIntee, Rose Darly Dalexis, Marc-André Goulet, and Patrick Labelle. "Prevalence of symptoms of depression, anxiety, insomnia, posttraumatic stress disorder, and psychological distress among populations affected by the COVID-19 pandemic: A systematic review and meta-analysis." Psychiatry research (2020): 113599.

 

4. Pappa, Sofia, Vasiliki Ntella, Timoleon Giannakas, Vassilis G. Giannakoulis, Eleni Papoutsi, and Paraskevi Katsaounou. "Prevalence of depression, anxiety, and insomnia among healthcare workers during the COVID-19 pandemic: A systematic review and meta-analysis." Brain, behavior, and immunity (2020).

 

5. Mitchell, Matthew D., Philip Gehrman, Michael Perlis, and Craig A. Umscheid. "Comparative effectiveness of cognitive behavioral therapy for insomnia: a systematic review." BMC family practice 13, no. 1 (2012): 1-11.

 

6. Pottie, Kevin, Wade Thompson, Simon Davies, Jean Grenier, Cheryl A. Sadowski, Vivian Welch, Anne Holbrook et al. "Deprescribing benzodiazepine receptor agonists: evidence-based clinical practice guideline." Canadian Family Physician 64, no. 5 (2018): 339-351.

 

7. Edinger, Jack D., and Melanie K. Means. "Cognitive–behavioral therapy for primary insomnia." Clinical psychology review 25, no. 5 (2005): 539-558.

 

8. Vinkers, Christiaan H., and Berend Olivier. "Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABAA receptor modulators?." Advances in pharmacological sciences 2012 (2012).

 

9. Everitt, Hazel, David S. Baldwin, Beth Stuart, Gosia Lipinska, Andrew Mayers, Andrea L. Malizia, Christopher CF Manson, and Sue Wilson. "Antidepressants for insomnia in adults." Cochrane Database of Systematic Reviews 5 (2018).

 

10. Yeung, Wing-Fai, Ka-Fai Chung, Kam-Ping Yung, and Tommy Ho-Yee Ng. "Doxepin for insomnia: a systematic review of randomized placebo-controlled trials." Sleep medicine reviews 19 (2015): 75-83.

 

11. Mieda, Michihiro. "The roles of orexins in sleep/wake regulation." Neuroscience research 118 (2017): 56-65.

 

12. Rosenberg, Russell, Patricia Murphy, Gary Zammit, David Mayleben, Dinesh Kumar, Shobha Dhadda, Gleb Filippov, Antonia LoPresti, and Margaret Moline. "Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial." JAMA network open 2, no. 12 (2019): e1918254-e1918254.

 

13. Kärppä, Mikko, Jane Yardley, Kate Pinner, Gleb Filippov, Gary Zammit, Margaret Moline, Carlos Perdomo, Yuichi Inoue, Kohei Ishikawa, and Naoki Kubota. "Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2." Sleep 43, no. 9 (2020): zsaa123.

 

14. Vermeeren, Annemiek, Stefan Jongen, Patricia Murphy, Margaret Moline, Gleb Filippov, Kate Pinner, Carlos Perdomo et al. "On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers." Sleep 42, no. 4 (2019): zsy260.

 

15. Murphy, Patricia, Dinesh Kumar, Gary Zammit, Russell Rosenberg, and Margaret Moline. "Safety of lemborexant versus placebo and zolpidem: effects on auditory awakening threshold, postural stability, and cognitive performance in healthy older participants in the middle of the night and upon morning awakening." Journal of Clinical Sleep Medicine 16, no. 5 (2020): 765-773.

 

16. Schweizer, Edward, Karl Rickels, W. George Case, and David J. Greenblatt. "Long-term therapeutic use of benzodiazepines: II. Effects of gradual taper." Archives of General Psychiatry 47, no. 10 (1990): 908-915.

 

17. Denis, Cecile, Melina Fatseas, Estelle Lavie, and Marc Auriacombe. "Pharmacological interventions for benzodiazepine mono‐dependence management in outpatient settings." Cochrane Database of Systematic Reviews 3 (2006).

 

18. Green Shield Canada. “Pharmacist deprescribing program.” Provider Connect. Accessed February 22, 2021. https://www.providerconnect.ca/Carriers/GreenShield/DeprescribePDF/en_CA/GSC%20PHC_Deprescribing%20Program_Program%20Guide.pdf