Precision medicine and sleep medications

Many people have trouble sleeping from time to time. For people living with anxiety, depression, PTSD or chronic pain, insomnia is a major problem that can make other symptoms worse. Sleep medications can help in the short term, but they also carry risks, such as next-day drowsiness, falls and dependence. Your genes and your other medications affect how your body handles many of them. This article explains how insomnia is treated, how common sleep medications compare and how pharmacogenetic testing can help you and your doctor choose more safely.

What affects sleep?

Many things can disrupt sleep, including stress, anxiety and depression, pain, shift work, screen use and bright light late in the evening, caffeine, alcohol and nicotine, and conditions such as sleep apnea and restless legs. Some medications also affect sleep, including some antidepressants, stimulants, steroids and decongestants. If you snore loudly, stop breathing during sleep or feel very sleepy during the day, ask your doctor about a sleep apnea assessment, because sleeping pills can make sleep apnea worse.

What is the first treatment for insomnia?

For chronic insomnia, guidelines recommend cognitive behavioural therapy for insomnia (CBT-I) as the first treatment for all adults. CBT-I helps you change the habits and thoughts that keep you awake. It includes keeping a regular sleep schedule, using the bed only for sleep, limiting time in bed, and learning to manage worry about sleep. Its benefits last longer than those of sleeping pills, and it has no medication side effects. CBT-I is available in person, in groups and through online programs.

Simple habits also help: keep a regular wake-up time, get daylight in the morning, avoid caffeine after noon, limit alcohol, and keep screens out of the bedroom.

When are sleep medications used?

If CBT-I and good sleep habits are not enough, your doctor may suggest a medication, usually for a short time and at the lowest effective dose. The table below lists sleep medications commonly used in Canada, the genes and enzymes that process them, and key cautions.

Medication (brand)	Type	Genes and enzymes	Key cautions
zopiclone (Imovane)	"Z-drug"	CYP3A4, CYP2C8	Next-day drowsiness, bitter taste. Rare complex sleep behaviours.
zolpidem (Sublinox)	"Z-drug"	CYP3A4, with CYP2C9 and CYP1A2	Lower dose for women. Rare complex sleep behaviours.
lemborexant (Dayvigo)	Orexin blocker	CYP3A4	Next-day drowsiness. Avoid with strong CYP3A4 blockers.
daridorexant (Quviviq)	Orexin blocker	CYP3A4	Next-day drowsiness. Avoid with strong CYP3A4 blockers.
doxepin, low dose (Silenor)	Antihistamine effect	CYP2D6, CYP2C19	Helps with staying asleep. Do not combine with MAO inhibitors.
trazodone (Desyrel)	Antidepressant, used off-label	CYP3A4	Dizziness, falls. Rare prolonged erection.
temazepam (Restoril), lorazepam (Ativan)	Benzodiazepine	UGT enzymes	Dependence, falls, memory problems.
triazolam (Halcion), alprazolam (Xanax)	Benzodiazepine	CYP3A4	Dependence, falls. Strong CYP3A4 blockers raise levels.
diazepam (Valium)	Benzodiazepine	CYP2C19, CYP3A4	Very long-acting. Higher levels in CYP2C19 poor metabolizers.
melatonin	Supplement (over the counter)	CYP1A2	Modest effect. Fluvoxamine raises levels. Smoking lowers them.
diphenhydramine (Nytol, Sleep-Eze)	Antihistamine (over the counter)	CYP2D6	Confusion, constipation, next-day drowsiness. Avoid in older adults.

This table lists common examples. It is not a complete list of medications or cautions.

What are orexin blockers, such as lemborexant and daridorexant?

Orexin is a brain chemical that keeps you awake. Lemborexant (Dayvigo) and daridorexant (Quviviq) block orexin, which helps you fall asleep and stay asleep without acting on the same brain receptors as benzodiazepines and Z-drugs. Suvorexant (Belsomra) works the same way. In clinical trials:

• Lemborexant improved how quickly people fell asleep and how long they stayed asleep, and the benefit lasted over six months.
• Daridorexant at 50 mg reduced time awake during the night and also improved daytime sleepiness and functioning over three months.

Orexin blockers appear to carry a lower risk of dependence than benzodiazepines, but they can still cause next-day drowsiness. All three are broken down mainly by CYP3A4. Strong CYP3A4 blockers, such as ketoconazole, itraconazole, clarithromycin and some HIV medications, can raise their levels a lot, so labels advise avoiding these combinations or using a lower dose. Grapefruit juice can also raise levels. Drugs that speed up CYP3A4, such as carbamazepine, rifampin and St. John's wort, can make them less effective. People with narcolepsy should not take orexin blockers.

What are the risks of Z-drugs and benzodiazepines?

Zopiclone and zolpidem help people fall asleep but can cause next-day drowsiness and slower reactions, even when you feel awake. Do not drive the morning after taking them until you know how they affect you. Women clear zolpidem more slowly than men, so they are prescribed a lower dose. Rarely, Z-drugs cause complex sleep behaviours, such as sleepwalking, eating or even driving while not fully awake, which can lead to serious injuries. In 2019, the US Food and Drug Administration added its strongest warning about this to these medications. Stop the medication and contact your doctor if this happens.

Benzodiazepines can cause dependence, memory problems and falls, and stopping them suddenly after regular use can cause withdrawal. They should be used only for a short time. If you have taken one for a while, your doctor can help you reduce it slowly.

Avoid combining sleep medications with alcohol, opioids or other sedatives, which can cause dangerous drowsiness and slowed breathing.

Which sleep medications should older adults avoid?

Older adults are more sensitive to sleep medications and more likely to fall, become confused or have memory problems. The American Geriatrics Society Beers Criteria and Choosing Wisely Canada recommend that older adults avoid benzodiazepines and Z-drugs as a first choice for insomnia, and avoid sleep aids containing diphenhydramine or other older antihistamines. CBT-I works well at any age and is the preferred first step. Low-dose antipsychotics such as quetiapine are not recommended for sleep because of their side effects.

How do genes and other medications affect sleep medications?

If your body clears a sleep medication too slowly, you may feel groggy the next day, which raises the risk of falls and accidents. If it clears it too quickly, the medication may not work.

• CYP3A4 processes zopiclone, zolpidem, the orexin blockers, trazodone, triazolam and alprazolam. Drug interactions through CYP3A4 are common and often matter more than genes.
• CYP2C19 processes diazepam. Poor metabolizers clear it more slowly and can have much higher levels.
• CYP2D6 and CYP2C19 process doxepin and many antidepressants that can affect sleep.
• CYP1A2 processes melatonin. Smoking speeds up CYP1A2 and lowers melatonin levels, while fluvoxamine strongly blocks it and can raise melatonin levels many times over.

Can antidepressants affect sleep?

Yes. Some antidepressants, such as SSRIs and bupropion, can cause trouble sleeping or vivid dreams, which is why they are often taken in the morning. Others, such as mirtazapine and trazodone, cause drowsiness and are sometimes chosen for people with poor sleep. Higher-than-expected blood levels, which can happen with CYP2D6 or CYP2C19 variants, make these effects stronger. If a new antidepressant affects your sleep, talk to your prescriber about the timing, dose or a different medication.

How can a pharmacogenetic test help?

A Pillcheck test reports CYP3A4, CYP2C19, CYP2D6, CYP1A2, CYP2C9 and other genes that affect sleep medications, antidepressants, anxiety medications and pain relievers. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. A Pillcheck pharmacist reviews your results together with all your medications, checks for interactions and recommends options to discuss with your doctor.

Summary

• CBT for insomnia is the recommended first treatment for chronic insomnia.
• Sleep medications are best used for a short time, at the lowest effective dose.
• Lemborexant and daridorexant are newer orexin blockers with a lower risk of dependence, but they can still cause next-day drowsiness.
• Z-drugs and benzodiazepines can cause next-day impairment, falls and, rarely, complex sleep behaviours. Older adults should avoid them and diphenhydramine as a first choice.
• CYP3A4, CYP2C19, CYP2D6 and CYP1A2, along with drug interactions, affect how your body handles many sleep medications.

Frequently asked questions

What is the safest sleep medication?

No sleep medication is risk-free. The best choice depends on your age, health, other medications and the type of sleep problem. CBT for insomnia is safer and works longer than any sleeping pill.

Are lemborexant and daridorexant addictive?

They appear to have a lower risk of dependence than benzodiazepines and Z-drugs, but they can still cause drowsiness the next day. Use them only as prescribed.

Is melatonin safe?

Melatonin is generally well tolerated, but its effect on insomnia is modest. Check with your pharmacist if you take fluvoxamine, which can raise melatonin levels a lot, or blood thinners.

Can I drive after taking a sleeping pill?

Not until you know how it affects you. Many sleep medications can impair driving the next morning, even if you feel awake.

References

Qaseem A, Kansagara D, Forciea MA, et al. Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;165(2):125-133.

Kärppä M, Yardley J, Pinner K, et al. 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. 2020;43(9):zsaa123.

Mignot E, Mayleben D, Fietze I, et al. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022;21(2):125-139.

By the 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081.

US Food and Drug Administration. FDA adds Boxed Warning for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. Drug Safety Communication. April 30, 2019.

Dean L. Diazepam Therapy and CYP2C19 Genotype. In: Medical Genetics Summaries. National Center for Biotechnology Information (US); 2016.

Choosing Wisely Canada. Recommendations on sedative-hypnotics for insomnia in older adults.