Pharmacology: Insomnia PDF

PHARMACOLOGY: INSOMNIA Dr. Adam Gratton NMT200 MSc ND November 6, 2023 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of drugs to treat insomnia with and without comorbidity a. Benzodiazepines - Temazepam b. B...

PHARMACOLOGY: INSOMNIA Dr. Adam Gratton NMT200 MSc ND November 6, 2023 LECTURE COMPETENCIES 1. Compare and contrast the mechanisms of action, indications, and adverse effects of drugs to treat insomnia with and without comorbidity a. Benzodiazepines - Temazepam b. Benzodiazepine receptor agonists (Z-drugs) - Zopiclone c. Dual orexin receptor antagonists - Lemborexant d. Tricyclic antidepressants - Doxepin 2. Discuss drugs often used off-label for comorbid insomnia 3. Discuss pharmacotherapeutic options for children 4. Discuss pharmacotherapeutic options for the elderly 5. Discuss pharmacotherapeutic options for use during pregnancy and breastfeeding 6. Prescribe appropriate medications for people with insomnia based on patient history INTRODUCTION Insomnia is defined as dissatisfaction with sleep quality or quantity plus one or more of: Difficulty falling asleep (sleep onset) Difficulty staying asleep (sleep maintenance) Early morning awakening without being able to return to sleep GOALS OF THERAPY Improve daytime function Reduce daytime impairment (e.g., dysphoria, fatigue, decreased alertness) Promote subjectively sound and restorative sleep when external (e.g., stress, noise, jet lag) or internal (e.g., pain, anxiety) factors disrupt natural sleep (i.e., making sleep more resilient) Potentiate the effectiveness of behavioural interventions for chronic insomnia MEDICATIONS CONTRIBUTING TO INSOMNIA Antidepressants Decongestants and antihistamines Stimulants Analgesics Antihypertensives Herbal supplements Sedatives Substances of abuse INSOMNIA WITH COMORBIDITY Many people have insomnia and another diagnosis that directly contributes to it: Musculoskeletal conditions (rheumatoid arthritis, fibromyalgia, restless leg syndrome, etc.) Psychiatric disorders (Anxiety, substance-use disorders, etc.) Respiratory disorders (COPD, asthma, etc.) GI disorders (GERD) Chronic pain INSOMNIA WITH COMORBIDITY Most (up to 75%) of people with insomnia have comorbidity Many of the medications with Health Canada approval for insomnia were studied in people without comorbidity Has led to variable prescribing behaviours GENERAL PRINCIPLES Use the lowest effective dose for the shortest duration Follow up frequently (3 – 6 weeks) Dispense limited supply ( 30 – 60 days) For those with comorbid insomnia, ensure the underlying condition is adequately treated DEFINITIONS Sedative – A drug that reduces excitement and calms the patient. Also called anxiolytics. They do not induce sleep. Hypnotic – A drug that results in drowsiness that promotes sleep. BENZODIAZEPINES GABA-A receptor agonists Allow for enhanced chloride ion movement through GABA receptors when the drug is bound Enhances the effect of GABA channels and therefore enhances inhibition BENZODIAZEPINES All have sedative and hypnotic properties but differ significantly in potency and pharmacokinetics Should only be considered for short-term acute or intermittent use Long-term use should only be considered in severe or comorbid insomnia where other treatments have failed BENZODIAZEPINES Do not use multiple benzodiazepines (for example, using one for insomnia and another for anxiety) Do not combine with alcohol or any other CNS depressants BENZODIAZEPINES Flurazepam and nitrazepam are not recommended due to their long half-lives Triazolam is not recommended because it has a higher risk of abuse, dependence, and rebound insomnia Temazepam is considered the most suitable of those that carry Health Canada indication ADVERSE EFFECTS Dose-dependent ataxia, dizziness; dependence/withdrawal symptoms, impaired memory, risk of abuse May cause dose-dependent, next-day impairment of activities requiring alertness, including driving a car, despite the patient feeling fully awake Use only when there is a period of at least 7–8 hours before planned awakening. Advise patients to wait ≥12 hours before driving or operating machinery BENZODIAZEPINES Have been studied for use up to 24 weeks Rebound insomnia commonly occurs with discontinuation Deprescribing/gradual tapering over months may help BENZODIAZEPINE RECEPTOR AGONISTS (Z-DRUGS) Allosteric modulators of GABA-A receptors The presence of GABA does not facilitate action Similar mechanism to benzodiazepines where enhanced inhibition is caused via GABA-A receptors Z-DRUGS Are generally the preferred drug class for treating people with insomnia Similar effect on sleep compared to benzodiazepines Fewer adverse effects Less muscle relaxant effects Do not worsen sleep apnea Does not accumulate; may cause less rebound on withdrawal Z-DRUGS Zopiclone Most common Z-drug prescribed in Canada ADVERSE EFFECTS Bitter/metallic taste, dry mouth, dizziness and somnolence Complex sleep behaviours such as night eating and somnambulism with no recollection of such activities ADVERSE EFFECTS May cause dose-dependent, next-day impairment of activities requiring alertness, including driving a car, despite the patient feeling fully awake Use only when there is a period of at least 7–8 hours before planned awakening Advise patients to wait ≥12 hours before driving or operating machinery ADVERSE EFFECTS Do not combine with alcohol or other CNS depressants Increased risk of complex sleep behaviours in combination with other CNS-active drugs DUAL OREXIN ANTAGONISTS Orexin/receptor pathways play vital regulatory roles in many physiologic processes (feeding behaviour, sleep-wake rhythm, reward and addiction, energy balance) Neuropeptides produced in the lateral hypothalamus that promote arousal/wakefulness by stimulating orexin-1 and -2 receptors DUAL OREXIN ANTAGONISTS Lemborexant Competitive dual orexin antagonists normalize sleep- wake function by reducing wakefulness and unwanted transitions between wake and sleep Indicated for sleep-onset and sleep maintenance insomnia LEMBOREXANT No evidence of withdrawal symptoms or rebound insomnia Evidence suggests efficacy with use up to 12 months Minimal next-day impairment Minimal abuse potential ADVERSE EFFECTS Somnolence Less commonly: sleep paralysis, hypnagogic/hypnopompic hallucinations, cataplexy-like symptoms Complex sleep behaviours such as night eating and somnambulism with no recollection of such activities ADVERSE EFFECTS May cause dose-dependent, next-day impairment of activities requiring alertness, including driving a car, despite the patient feeling fully awake Use only when there is a period of at least 7–8 hours before planned awakening Limited effects on driving impairment after 9 hours ADVERSE EFFECTS Do not combine with other CNS depressants Contraindicated in narcolepsy TRICYCLIC ANTIDEPRESSANTS Doxepin Selective histamine H1 receptor antagonist at very low dosages H1 receptors are found in high density in regions of the brain associated with arousal and waking Agonists promote wakefulness; antagonists promote sleep DOXEPIN Indicated by Health Canada for sleep-maintenance difficulties Trials support use up to 3 months May improve sleep maintenance better than GABA-A agonists Not associated with rebound insomnia, dependence, or next-day impairment Recommended treatment for the elderly ADVERSE EFFECTS At dosages used here the typical adverse effects of tricyclic antidepressants are not seen (until the dose reaches 10 mg or more) Somnolence, sedation, nausea. Not recommended in combination with alcohol or other CNS depressants Should not be taken within 3 h of a meal to minimize drowsiness the next day OFF-LABEL AGENTS There are many drugs that can cause sedation that are used off-label The goal is to use a drug that treats an underlying comorbidity but also promotes sleep There is generally a lack of evidence supporting this practice OFF-LABEL AGENTS Insomnia associated with centralized pain (fibromyalgia, etc.) - Anticonvulsants (like gabapentin) Insomnia associated with allergic conditions (eczema, allergies, etc.) - Antihistamines Insomnia with mood disorder - Sedating antidepressants INSOMNIA AND CHILDREN Non-pharmacologic therapy is recommended as first-line There is little evidence to guide the use of medications for insomnia in pediatric populations Although often used, over-the-counter antihistamine use is not recommended due to the risk of rapid tolerance, next-day sedation, cognitive impairment, and paradoxical reaction Drugs should target the comorbidity INSOMNIA AND THE ELDERLY Elderly are prone to polypharmacy and potential drug interactions Always want to limit the use of medications that cause sedation, reduced cognitive impairment, ataxia, etc., due to the increased risk of falls Low-dose doxepin for sleep-maintenance Lemborexant has demonstrated a favourable safety and efficacy profile in the elderly up to 6 months of use INSOMNIA AND PREGNANCY Disrupted sleep is a very common complaint during pregnancy Sleep apnea and restless legs are known to worsen during pregnancy Little research on the effects of insomnia during pregnancy and no controlled studies of any intervention in this population INSOMNIA AND PREGNANCY Like with all sensitive populations, non-pharmacologic options are first-line If insomnia is severe or disabling, pharmacologic intervention may be warranted provided a careful consideration of the risk-benefit ratio to both the patient and the developing fetus INSOMNIA AND PREGNANCY Zopiclone does not appear to be teratogenic and may be a reasonable choice if clinically justified Benzodiazepines should be avoided, particularly in the first trimester, due to an increased risk of oral cleft; they may also cause neonatal withdrawal symptoms when used closer to term CASE #1 72-year-old patient with a chief concern of fatigue Sleep history reveals the patient takes about 1 – 2 hours to fall asleep, wakes 1 – 2 times per night to urinate Currently medicated for hypertension and dyslipidemia Amlodipine 5 mg PO daily Atorvastatin 20 mg PO daily Hydrochlorothiazide 12.5 mg PO daily CASE #1 CONSIDERATIONS Elderly patient Type of insomnia? Adverse effects of existing medications? Drug interactions? What would be the best drug option? CASE #2 47-year-old patient with alcohol-use disorder and a chief concern of daytime sleepiness Recently finished an outpatient recovery program and has been sober for 5 months and denies the use of any other substance Sleep history reveals it takes the patient 2 hours or more to fall asleep. Wakes 4 -5 times throughout the night. Wakes earlier than desired and cannot fall back asleep No medications Currently taking a B complex daily CASE #2 CONSIDERATIONS Underlying diagnosis? Type of insomnia? Alcohol use? What would be the best drug option? SAMPLE QUESTION A patient complains of a bitter taste in their mouth and dizziness following a recent prescription to help them sleep. Which of the following was most likely prescribed? A. Doxepin B. Lemborexant C. Temazepam D. Zopiclone