NMT200 final - pharm

Pharmacology: Insomnia

• Insomnia is defined as dissatisfaction with sleep quality or quantity, plus one or more of the following: difficulty falling asleep (sleep onset), difficulty staying asleep (sleep maintenance), or early morning awakening without being able to return to sleep.
• Lecture competencies include comparing and contrasting the mechanisms of action, indications, and adverse effects of drugs to treat insomnia; discussing drugs often used off-label for comorbid insomnia; discussing pharmacotherapeutic options for children, the elderly, during pregnancy and breastfeeding; and prescribing appropriate medications based on patient history.
• Therapy goals include improving daytime function, reducing daytime impairment (e.g., dysphoria, fatigue), promoting subjectively sound and restorative sleep, and potentiating the effectiveness of behavioral interventions for chronic insomnia.
• Medications that can contribute to insomnia include antidepressants, stimulants, antihypertensives, sedatives, decongestants, antihistamines, analgesics, herbal supplements, and substances of abuse.
• Many people with insomnia also have other conditions, called comorbidities. These may include musculoskeletal conditions (e.g., rheumatoid arthritis, fibromyalgia, restless leg syndrome), psychiatric disorders, respiratory disorders (e.g., COPD, asthma), gastrointestinal disorders (e.g., GERD), and chronic pain. 75% of people with insomnia have comorbidities. Some medications used to treat insomnia were studied in people with no comorbidities, leading to variable prescribing behavior.

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.
• Enhance the effect of GABA channels, therefore enhancing inhibition.
• Have sedative and hypnotic properties, but differ significantly in potency and pharmacokinetics.
• Should be considered only for short-term acute or intermittent use.
• Long-term use should be considered only in severe or comorbid insomnia where other treatments have failed.
• Do not use multiple benzodiazepines.
• Do not combine with alcohol or other CNS depressants.
• Specific examples, dosages, and half-lives are listed on slide 15 (see below).

Benzodiazepine Receptor Agonists (Z-drugs)

• Allosteric modulators of GABA-A receptors.
• The presence of GABA does not facilitate action.
• Similar mechanism to benzodiazepines; enhanced inhibition is via GABA-A receptors.
• Generally the preferred drug class for treating insomnia.
• Similar effect on sleep compared to benzodiazepines.
• Fewer adverse effects.
• Less muscle relaxant effects.
• Do not worsen sleep apnea.
• Do not accumulate; may cause less rebound on withdrawal.
• Zopiclone is the most common Z-drug prescribed in Canada.

Adverse Effects (General)

• 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.
• Specific adverse effects for benzodiazepines, Z-drugs, and Doxepin are listed throughout the presentation.

Adverse Effects (Benzodiazepines)

• Have been studied for use up to 24 weeks.
• Rebound insomnia commonly occurs with discontinuation.
• Deprescribing/gradual tapering over months may help.

Adverse Effects (Zopiclone)

• Bitter/metallic taste, dry mouth, dizziness, and somnolence.
• Complex sleep behaviors (night eating, somnambulism) may occur with no recollection.
• May cause next-day impairment of activities requiring alertness— use only when there is a period of at least 7-8 hours before planned awakening. Avoid in combination with other CNS depressants to reduce risk of complex sleep behaviors.

Dual Orexin Antagonists

• Orexin/receptor pathways play vital regulatory roles in many physiologic processes (feeding behavior, sleep-wake rhythm, reward and addiction, energy balance).
• Neuropeptides in the lateral hypothalamus promote arousal/wakefulness by stimulating orexin-1 and -2 receptors.

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.
• No evidence of withdrawal symptoms or rebound insomnia.
• Evidence suggests efficacy with use up to 12 months.
• Minimal next-day impairment.
• Minimal abuse potential.

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.
• 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.

Off-Label Agents

• There are many drugs that 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.
• Examples include anticonvulsants (e.g., gabapentin), antihistamines, and sedating antidepressants.

Insomnia and the Elderly/Children/Pregnancy

• Elderly: Prone to polypharmacy, interactions. Prefer to limit use of medications that cause sedation to minimize risk of falls. Low-dose doxepin is a good option for sleep maintenance; Lemborexant has a good safety and efficacy profile.
• Children: Non-pharmacological therapy is recommended as first-line. Limited evidence to guide use of medications. Avoid OTC antihistamines, as they can cause next-day sedation, cognitive impairment, and paradoxical reactions.
• Pregnancy: Disrupted sleep is common. Sleep apnea and restless legs are known to worsen during pregnancy. Little research about effects, and no controlled studies about interventions. Use non-pharmacological methods as a first-line. If insomnia is severe, consider potential risks and benefits to both the patient and fetus before pharmacological intervention; zopiclone might be a reasonable option, and benzodiazepines should be avoided early in pregnancy to reduce risk of oral cleft and neonatal withdrawal symptoms.

Case Studies (page 41 and 43)

• Case Study 1: 72-year-old patient with fatigue. Sleep history reveals that it takes the patient 1-2 hours to fall asleep and they wake 1-2 times per night to urinate. Current medications include Amlodipine 5 mg PO daily, Atorvastatin 20 mg PO daily, and Hydrochlorothiazide 12.5 mg PO daily.
• Case Study 2: 47-year-old patient with an alcohol use disorder and daytime sleepiness. The patient recently completed an outpatient recovery program and is sober for 5 months. Sleep history reveals that it takes them 2 or more hours to fall asleep. They wake 4-5 times during the night and wake earlier than desired, unable to fall back asleep. The patient is taking a B-complex daily.

Case Study Considerations, including sample questions (page 42 and 44)

• Case Study 1 Considerations: Is the patient elderly? What type of insomnia? What are the adverse effects of the current medications? Are there any drug interactions? What would be the best drug option?
• Case Study 2 Considerations: What is the underlying diagnosis? What type of insomnia? What about their recent alcohol use? What is the best drug option?

Sample Question (page 45)

A patient complains of a bitter taste in their mouth and dizziness following a recent prescription. Which of the following was most likely prescribed? A. Doxepin B. Lemborexant C. Temazepam D. Zopiclone

Specific Benzodiazepine Examples, Dosages, and Half-Lives (Slide 15)

• (This section is included here from the provided text; list specific examples and dosages as they appear in slide 15)*