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General Psychiatry V. INSOMNIA A. Normal Sleep Patterns and Neurochemistry/Physiology of Sleep 1. About one-third of a life is spent in sleep. Optimal sleep duration for most adults to maintain good health is 7–9 hours per 24-hour period. Variation exists among individuals and according to age....

General Psychiatry V. INSOMNIA A. Normal Sleep Patterns and Neurochemistry/Physiology of Sleep 1. About one-third of a life is spent in sleep. Optimal sleep duration for most adults to maintain good health is 7–9 hours per 24-hour period. Variation exists among individuals and according to age. 2. Adverse outcomes, including increased mortality, are associated with both short sleep duration (6 hours or less per 24-hour period) and long sleep duration (more than 9–10 hours per 24-hour period). 3. The body’s circadian rhythm is controlled by both internal and external factors. It sets the sleep-wake cycle at 24.2 hours, which is modified by sensory input (e.g., darkness to signal sleep and brightness to signal wakefulness). The suprachiasmatic nucleus (SCN) is the main control center for sleep, and the retinal ganglion cells send direct signals to the SCN to provide information about light. 4. The neural networks regulating sleep-wake cycles are located in the brain stem, basal forebrain, and hypothalamus, with projections to the cortex and thalamus. 5. The reticular activating system maintains wakefulness, and when activity here declines, sleep occurs. 6. Several neurotransmitters are involved in the sleep-wake cycle. Norepinephrine, acetylcholine, histamine, orexin, and serotonin promote wakefulness. g-Aminobutyric acid (GABA), adenosine, and melatonin promote sleep. 7. Sleep is divided into two categories: rapid eye movement (REM) and non-REM (see Table 13). They can be characterized by measurements with simultaneous electroencephalograms, electro-oculograms, and electromyograms. These are used to measure sleep latency (time to sleep onset), number of awakenings, number of stage shifts during the night, and latency to REM. These recordings are called polysomnography. Polysomnography is not a routine part of diagnosing insomnia. Table 13. American Academy of Sleep Medicine Sleep Stages State Non-REM stage N1 N2 Characteristics Purpose Rest and rejuvenation Relaxed wakefulness; purpose is to initiate sleep Muscle atonia, low-voltage brain waves; alpha wave activity; low-voltage EEG with sleep spindles and K-complexes N3 Slow-wave (delta) activity; deep sleep; restorative sleep REM sleep Low-voltage, mixed-frequency EEG; low muscle tone; REMs; autonomic fluctuations in heart rate and perspiration; and dreaming reported in 80%–90% of subjects EEG = electroencephalogram; REM = rapid eye movement. Unknown 8. Sleep architecture is cyclic and dynamic. Passing from wakefulness to stage 4 non-REM sleep takes about 45 minutes in young adults. REM usually occurs within 90 minutes of falling asleep; at first, REM lasts 5–7 minutes, but it becomes progressively longer through the night. The sleep cycle (nonREM stages 1–4 and REM), which lasts about 70–120 minutes, is repeated four to six times a night. 9. Sleep patterns change with age. Older adult patients experience less delta sleep, REM sleep, and total sleep time. They have more nocturnal awakenings and more total wake time at night. The incidence of insomnia may be as high as 40%. B. Sleep Disorders 1.  The DSM-5-TR recognizes 10 sleep-wake disorders or disorder groups. Among the most common are insomnia disorder, hypersomnia disorder, narcolepsy, breathing-related sleep disorders (including sleep apnea), and parasomnias (including non-REM sleep arousal disorders such as sleepwalking type or nightmare disorders, and restless legs syndrome). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-451 General Psychiatry 2. Insomnia occurs in 35%–50% of the adult population. Risk factors include increasing age, female sex, comorbid disorders (medical, psychiatric, sleep, and SUD), shift work, and possibly unemployment and lower socioeconomic status. The course is often chronic, with persistence of one to several years in 50%–85% of people. 3. Insomnia has a reciprocal relationship with other psychiatric diagnoses. Many patients with insomnia have comorbid anxiety disorders, mood disorders (including depression and bipolar disorder), psychotic disorders (schizophrenia and schizoaffective disorder), dementia, attention deficit disorder, and personality disorders. Insomnia can also be a symptom of psychiatric disorders such as anxiety, depression, and bipolar disorder and can exacerbate or precipitate episodes. 4. Insomnia causes significant morbidity, including impaired driving and occupational accident risk. 5. Insomnia disorder (DSM-5-TR) a. Dissatisfaction with sleep quantity or quality, associated with one or more of the following symptoms: i. Difficulty initiating sleep (also called onset or initial insomnia) ii. Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings (also called sleep maintenance or middle insomnia) iii. Early morning awakening with an inability to return to sleep (also called late insomnia) b. The sleep disturbance causes clinical significant distress or impairment in one or more important areas of function in life. c. The sleep difficulty occurs at least 3 nights of the week. d. The sleep difficulty is present for at least 3 months. e. Occurs despite the opportunity for adequate sleep f. The insomnia is not better explained by another sleep-wake disorder or comorbid mental or physical condition and is not attributable to the effects of a substance. g. Evaluation of insomnia should include an assessment of medical and psychiatric status. Medical causes are many and include disorders of the heart and lungs, disorders of the musculoskeletal system, diabetes, thyroid disease, and therapy with medications that can interfere with sleep. A detailed sleep history should be obtained that should include an evaluation of nighttime sleep, daytime functioning, sleep-wake rhythms, the sleeping environment, beliefs about sleep, and development of the sleep problem. 6. Parameters used to monitor sleep a. Sleep onset latency (SOL) or time to sleep onset (TTSO): Time that it takes to transition from wakefulness to sleep b. Total sleep time (TST): Total sleep period (time in bed) minus the time spent awake c. Wake time after sleep onset (WASO): Time spent awake after initial sleep onset until awakening d. Sleep efficiency: Ratio of TST divided by the time spent in bed; reported as a percentage 7. Treatment goals a. Primary i. Improved sleep quality and time ii. Improved insomnia-related daytime impairments b. Other goals: i. SOL less than 30 minutes ii. WASO less than 30 minutes iii. Decreased frequency of awakenings iv. TST greater than 6 hours v. Sleep efficiency greater than 80%–85% vi. Formation of positive and clear association between the bed and sleeping vii. Improvement in sleep-related psychological distress ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-452 General Psychiatry 8. Nonpharmacologic management of insomnia a. CBT for insomnia (CBT-I) is considered the gold standard of therapy and is first line in many insomnia guidelines. CBT-I combines cognitive therapy with behavioral treatments, such as stimulus control and sleep restrictions, with or without relaxation therapy. For insomnia, the cognitive therapy portions work with the patient to identify maladaptive behaviors and cognitions that contribute to the patient’s insomnia, bring the associated cognitive distortions to the patient’s attention, and work with the patient to structure the thoughts into more sleep-compatible forms. CBT-I requires a trained professional and thus may not be available to all patients. b. Stimulus control is designed to extinguish the negative associations between the bed and undesired outcomes. The objective is to form a positive relationship between the bed and sleep and to foster a stable sleep-wake schedule. It involves the following: i. Go to bed only when sleepy. ii. Maintain a regular sleep schedule. iii. Avoid naps. iv. Use the bed only for sleep or sexual activity. v. If unable to fall asleep (or back to sleep) within 20 minutes (perceived, not by watching the clock), get out of bed, engage in a relaxing activity until drowsy, and then return to bed; repeat as necessary c. For all types of insomnia, patients can be instructed about good sleep hygiene in conjunction with stimulus control. These principles include: i. Maintain regular bedtimes and awakenings. ii. Sleep long enough to avoid feeling tired, but no more. iii. Optimize the bedroom conditions (e.g., light, temperature, removal of animals, minimize noise or use white noise). iv. Exercise regularly early in the day, but avoid vigorous exercise in the evening. v. Develop a bedtime ritual (at least 30 minutes) that allows you to unwind. vi. Have a light snack or beverage before bed, if hungry, but avoid heavy meals or spicy food. vii. Avoid stimulants such as caffeine and nicotine throughout the day, but particularly in the afternoons and evenings. viii. Avoid alcohol because it can lead to “fragmented” sleep. xi. Cover the clock or phone to minimize the risk of focusing on it throughout the night. x. Disconnect electronics and avoid light-emitting devices (e.g., television, phones, tablets, and computers) for at least 5–10 minutes before bed. xi. Ensure adequate exposure to natural light during the day. C. Pharmacotherapy of Insomnia 1. Pharmacotherapy works best for insomnia when it is part of an overall plan to deal with the causes and is used for well-defined periods. Initial treatment for 2–4 weeks may be appropriate, with a reevaluation of the continued need for treatment. Some patients with chronic insomnia may be appropriate candidates for longer therapy durations, though evidence for long-term use of medications is sparse. Little empiric evidence exists to guide treatment. If hypnotic medications are used long term, regular follow-ups should be scheduled at least every 6 months to monitor use. If a hypnotic is used long term, it should be tapered, not discontinued abruptly. Guidance for deprescribing hypnotics can be found at https://deprescribing.org/. 2. Agents that can depress respiration should be avoided in patients with respiratory disorders, a history of SUD, or obstructive sleep apnea. 3. In the past, barbiturates were used as hypnotics. They are no longer indicated because of the risk of respiratory depression, with no respiratory depression ceiling. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-453 General Psychiatry 4. Benzodiazepines a. In general, they are safe, effective, and well tolerated by most patients, but they are not considered first line. Although all members of this class can be used as sedatives, only five are FDA approved and marketed as such. These five are primarily used as sedative-hypnotics because they are rapidly absorbed and produce CNS actions more quickly than most anxiety agents. Table 14 lists the sedative-hypnotic benzodiazepines. They are primarily differentiated by their onset of action, metabolism, and half-life in the body. According to their half-life, they are classified as short acting (half-life less than 6 hours), intermediate acting (half-life 6–24 hours), and long acting (half-life more than 24 hours). These are important parameters when selecting therapy. For instance, someone with problems falling asleep would probably benefit from an agent with a quick onset but short duration of action. Someone with problems maintaining sleep in the middle of the night might respond better to a drug with a longer half-life. Table 14. Benzodiazepines for Insomnia Drug (trade) Triazolam (Halcion) Temazepam (Restoril) Estazolam (Prosom) Flurazepam (Dalmane) Quazepam (Doral) b. Usual Dose (mg) 0.125–0.25 15–30 1–2 15–30 7.5–15 Half-Life (hr) 2–6 8–20 8–24 48–120 48–120 Duration Short Intermediate Intermediate Long Long Benzodiazepines are usually well tolerated. However, several problems still exist. i. Tolerance: Tolerance can develop, particularly when the drugs are used consistently for long periods. These drugs are not indicated for chronic use; however, newer evidence is emerging that they may be effective for longer periods than originally thought. Most are effective for 2–4 weeks and, in some cases, longer. An intermittent pattern of use can reduce the development of tolerance. In addition, most people without a history of SUD do not escalate their doses. ii. Residual daytime sedation: This is a common concern of patients using these drugs and is especially likely with agents having a long half-life. Dose is also an important factor; always use the lowest effective dose. iii. Rebound insomnia: This can occur when the drug is discontinued abruptly. Insomnia is usually worse than at baseline and usually lasts for 1–2 days; tapering the drug may minimize its effect. Rebound insomnia is most common after the use of short- and intermediate-acting agents. iv. Anterograde amnesia: All benzodiazepines appear to impair the acquisition and encoding of new information. They may also impair memory storage and recall. Incidence may be dose-dependent. v. Special populations: Be careful when using benzodiazepines in older adult patients because benzodiazepines can cause memory problems, increase the risk of falls, and accumulate (agents with a long half-life). If a benzodiazepine is used in this population, temazepam is preferred because of its phase II metabolism. Idiosyncratic reactions can occur in older adult and pediatric populations with benzodiazepine use. vi. Withdrawal: Physical dependence will occur if these agents are used for more than 2–4 weeks. Symptoms of withdrawal include worsening insomnia, anxiety, muscle twitches, photophobia, tinnitus, auditory and visual hypersensitivity, and seizures. Minimize by gradually tapering the drug at discontinuation. Guidelines for deprescribing benzodiazepine and benzodiazepine receptor agonists in patients with insomnia are available (Can Fam Physician 2018;64:339; see also https://deprescribing.org/), which recommend a slow taper. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-454 General Psychiatry D. Nonbenzodiazepine Receptor Agonists (Z-drugs) 1. Eszopiclone (Lunesta): This nonbenzodiazepine is a GABA A agonist whose half-life is 6 hours; thus, morning effects can result if it is taken late in the night. Eszopiclone can be used for chronic insomnia. The FDA reduced the starting dose to 1 mg to minimize next-day impairment. Patients should be counseled to use caution when driving or performing activities that require alertness, particularly with the 2- to 3-mg doses. Eszopiclone should be taken immediately before bed and when the patient will be in bed for at least 7–8 hours. Eszopiclone can cause a metallic taste in the mouth. 2. Zaleplon (Sonata): This is a nonbenzodiazepine with a pharmacology similar to zolpidem (see the text that follows) and a very short half-life. For patients with sleep maintenance problems, it may not last as long. However, zaleplon has a shorter half-life (about 1 hour) and may cause fewer problems in the morning, especially if given late. Zaleplon shortens onset to sleep but does not prolong sleep time or number of awakenings. Zaleplon is indicated only for short-term treatment of insomnia and has been used in trials for up to 5 weeks. 3. Zolpidem (Ambien): This nonbenzodiazepine sedative-hypnotic modulates the GABAA receptor complex. a. Compared with benzodiazepines, zolpidem lacks anticonvulsant action, muscle-relaxant properties, and respiratory depressant effect; it also has a lower risk of tolerance and withdrawal. Zolpidem should still be avoided in obstructive sleep apnea. Zolpidem is a good choice for patients in whom benzodiazepines should be avoided. b. Zolpidem is available as an IR tablet, CR tablet (Ambien CR), sublingual tablet (Edluar, Intermezzo), and sublingual spray (Zolpimist). The pharmacokinetics and indications vary depending on the dosing form. The sublingual spray has a shorter onset of action, but that of the sublingual tablet is similar to both the IR and the CR tablets. c. Indications vary by dosage form. All are indicated to decrease sleep latency. The CR tablets are indicated to improve sleep maintenance and can be used for longer-term therapy. The sublingual tablet formulation Intermezzo, but not Edluar, is indicated as an “as-needed” treatment for patients who have difficulty falling back to sleep as long as 4 hours or more remain. d. The FDA has reduced the dosing recommendations to limit next-day impairment. Dosing differs on the basis of the patient’s sex and degree of debility. For women, the nightly dose is 5 mg (IR) or 6.25 mg (CR). For men, it is 5–10 mg (IR) or 6.25–12.5 mg (CR). Patients with debility and older adult patients should receive 5 mg (IR) or 6.25 mg (CR). Patients should be maintained on the lowest dose needed to benefit. 4. Patients should be warned about the potential risk of engaging in complex behaviors while asleep when taking sedative-hypnotics. Such behaviors may include driving, eating, having sex, or talking on the telephone while asleep (with amnesia for the event). Other cautions include anaphylaxis and decreased respiratory drive. Table 15. Nonbenzodiazepines for Insomnia Drug Daridorexant (Quviviq) Doxepin (Silenor) Eszopiclone (Lunesta) Half-Life (hr) Administration (minutes before sleep) 8 30 Doxepin: 15.3 Nordoxepin: 31 6 30 Immediately Indications Sleep Onset X Sleep Maintenance X DEA Scheduling Chronic Therapy C-IV X X X Not controlled X C-IV ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-455 General Psychiatry Table 15. Nonbenzodiazepines for Insomnia (Cont’d) Drug Half-Life (hr) Lemborexant (Dayvigo) Ramelteon (Rozerem) Suvorexant (Belsomra) Zaleplon (Sonata) Zolpidem (Ambien) Administration (minutes before sleep) Indications Sleep Onset X 17–19 Immediately (dose-dependent) 1–2.6 30 X 12 30 X 1 Immediately X 1.4–6.5 Immediately X Sleep Maintenance X DEA Scheduling Chronic Therapy C-IV X X Not controlled C-IV C-IV X (CR only) X (CR only) C-IV DEA = Drug Enforcement Administration. E. Orexin (OX1 and OX2) Receptor Antagonists 1. The neuropeptide orexin promotes wakefulness. By blocking the OX1R and OX2R receptors, daridorexant (Quviviq), lemborexant (Dayvigo), and suvorexant (Belsomra) decrease sleep latency and promote sleep maintenance. Orexin receptor antagonists are contraindicated in patients with concomitant narcolepsy. 2. Lemborexant should be taken with at least 7 hours of remaining sleep. It is metabolized by 3A4, and use should be avoided in patients taking either inducers or inhibitors of 3A4. Time to onset may be delayed if taken with food. 3. Suvorexant should be taken within 30 minutes of bedtime and with at least 7 hours of sleep time. Suvorexant is metabolized by 3A4, and the dose must be decreased in patients taking concomitant 3A4 inhibitors. F. Miscellaneous Agents 1. Doxepin (Silenor) is a TCA indicated for impaired sleep maintenance. Doses used are lower than for depression. Chances for morning effects are high because of the long half-life of both doxepin and its active metabolite, nordoxepin. 2. Ramelteon (Rozerem): Melatonin agonist (no activity at the GABA or benzodiazepine receptor). Duration is 2–5 hours. To date, there is no evidence that this melatonin agonist is associated with dependence or tolerance, and it can be used long term for chronic insomnia. Ramelteon is primarily metabolized by 1A2, but inducers and inhibitors of 2C9 and 3A4 can also affect it. Ramelteon should be avoided in patients with severe sleep apnea. Melatonin, the molecule on which ramelteon is based, is available OTC as a dietary supplement. It is used off-label to treat jet lag and sleep onset insomnia. 3. Taking any of the agents listed in Table 15 with food can delay onset of effects, thus prolonging the time to onset of sleep and increasing the risk of hangover effects in longer-acting agents. Doxepin should be separated from meals by 3 hours. 4. Over-the-counter medications: These are most often antihistamines (doxylamine or diphenhydramine) that are both sedating and anticholinergic. They are possibly effective, but not as effective as benzodiazepines. Regular use is not recommended. In fact, some data suggest that they do not maintain efficacy beyond a few days. They are associated with a higher incidence of daytime sedation than short- or intermediate-acting benzodiazepines. Diphenhydramine has been popular when benzodiazepines were ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-456 General Psychiatry contraindicated. However, caution should be used in older adult patients because an anticholinergic action can cause delirium or worsen dementia or other medical conditions. In addition, diphenhydramine should not be administered with the cholinesterase inhibitors used for Alzheimer disease. 5. Other: In some situations, antidepressants such as trazodone can be used as sedative-hypnotics. These can be effective, and often, the dose required is lower than for depression. However, efficacy has not been fully established through clinical trials. Trazodone has been popular for managing insomnia caused by SSRI antidepressants (see discussion in Depression section). Trazodone is also popular by itself as a sleep agent because the potential for dependence is low. However, trazodone is associated with considerable adverse effects, and the data for long-term use are scant. G. Guideline-Based Treatment (Chronic Insomnia) 1. American Academy of Sleep Medicine (J Clin Sleep Med 2017;13:307-49) a. Initial (sleep onset) insomnia: Zaleplon, triazolam, ramelteon b. Middle (sleep maintenance) insomnia: Suvorexant, doxepin c. Sleep onset and maintenance insomnia: Eszopiclone, zolpidem, temazepam d. Recommends against: Trazodone, tiagabine, diphenhydramine, melatonin, tryptophan, valerian e. Inadequate data for other agents 2. American College of Physicians (Ann Intern Med 2016;165:125-33) a. General population: Eszopiclone, zolpidem, suvorexant, doxepin b. Older adults: Eszopiclone, zolpidem, ramelteon, doxepin 3. VA/DoD (available at https://www.healthquality.va.gov/guidelines/CD/insomnia/index.asp) a. Recommended: Doxepin, nonbenzodiazepine receptor agonist b. Insufficient evidence: Ramelteon, suvorexant c. Recommend against: Antipsychotics, benzodiazepines, chamomile, diphenhydramine, kava kava, melatonin, trazodone, valerian Patient Cases Questions 20–22 pertain to the following case. A 50-year-old patient with a 25-year history of alcohol dependence was found unconscious after a drinking binge. The patient was first admitted to the medical unit for alcohol withdrawal symptoms before being transferred to the substance dependence unit. The last drink was 6 hours ago, and fluids have been initiated. The patient has had three alcohol withdrawal seizures in the past and an episode of delirium tremens. Significant hepatitis is also present, and liver function tests show AST 275 U/L and ALT 130 U/L. Additional laboratory test values include albumin 4.2 g/ dL, alkaline phosphatase 152 IU/L, and g-glutamyl transferase 470 units/L. 20. Which symptom are you most likely to observe in the medical unit in this patient on admission? A. Alcohol craving. B. Delirium tremens. C. Increased heart rate. D. Seizures. 21. Which agent is best for this patient’s alcohol withdrawal symptoms? A. Chlordiazepoxide. B. Clonazepam. C. Diazepam. D. Lorazepam. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-457 General Psychiatry Patient Cases (Cont’d) 22. Which medication is best for this patient’s alcohol dependence? A. Acamprosate. B. Diazepam. C. Disulfiram. D. Naltrexone. 23. A 34-year-old wants to stop using oxycodone. They have been buying it off the street and are using 160 mg daily. The patient has no interest in methadone maintenance but wants to enroll in an outpatient program. The last oxycodone dose was 24 hours ago. The patient is having some anxiety and muscle aches. Treatment will start in the clinic. Which is best to initiate in this patient? A. Buprenorphine 2 mg. B. Buprenorphine 4 mg. C. Buprenorphine/naloxone 2/1. D. Buprenorphine/naloxone 4/1. VI. SUBSTANCE USE DISORDER A. DSM-5-TR Criteria 1.  The DSM-5-TR recognizes a range of SUDs. Pharmacologic therapy is available for alcohol, opioid, and tobacco use disorders. 2. General criteria for SUD: A pattern of use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: a. More of the substance is taken or the substance is taken longer than intended b. There is persistent desire or unsuccessful efforts to cut back or control use c. Much time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects d. Craving, or a strong desire or urge to use e. Recurrent use resulting in a failure to fulfill major obligations, such as at work, school, or home f. Continued use despite persistent or recurrent social or interpersonal problems caused by or exacerbated by the substance g. Because of substance use, the individual gives up or reduces important social, occupational, or recreational activities h. Recurrent use in situations in which it is physically hazardous i. Continued use despite knowledge of having a continued physical or psychological problem that is caused or exacerbated by use of the substance j. Tolerance, as evidenced by a need for more of the substance for the desired effect k. Withdrawal symptoms after a decrease in or discontinuation of use B. Screening for SUD 1. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), all health care providers should screen for alcohol, tobacco, and other substance misuse (including opioids). Many validated tools exist for this purpose. A good review can be found in SAMHSA at https://store.samhsa. gov/product/TIP-63-Medications-for-Opioid-Use-Disorder-Full-Document/PEP20-02-01-006. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-458 General Psychiatry 2. Screening, brief intervention, and referral to treatment (SBIRT) model a. SBIRT is an evidence-based and universal approach to screening for SUD that is endorsed by SAMHSA. More information can be found at https://www.samhsa.gov/sbirt/about. b. SBIRT steps: i. Screening: Quickly assesses the severity of substance use and identifies the appropriate level of treatment ii. Brief intervention: Focuses on increasing insight and awareness regarding substance use and motivation toward behavior change iii. Referral to treatment: Those identified as needing more extensive treatment are provided with the appropriate access to specialty care. C. SUDs are often comorbid with other psychiatric diagnoses. D. Withdrawal from use of most substances of abuse is not life threatening, but can be distinctly uncomfortable. The exceptions to this are withdrawal from alcohol, benzodiazepines, and barbiturates, which are life threatening and should be undertaken with medical supervision. E. Goal: Remission of the disorder, leading toward lasting recovery F. SUD is a treatable chronic illness. G. Treatment of SUD should be patient centered and use shared decision-making, motivational interviewing, and harm reduction strategies, as appropriate. H. Alcohol 1. CAGE questionnaire (for screening for alcohol use disorder) a. Questions: i. Have you ever felt you should Cut down on your drinking? ii.  Have people Annoyed you by criticizing your drinking? iii. Have you ever felt bad or Guilty about your drinking? iv. Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (Eye-Opener)? b. Scoring: 0 for each “no,” 1 for each “yes.” A score of 2 or more is a positive screen for problematic drinking. A score of 1 or more suggests the need for follow-up. 2.  Acute withdrawal a. Characteristic symptoms occur after alcohol discontinuation. The symptoms that develop, how quickly they develop, and the degree of severity depend on the level of alcohol use and a person’s characteristics. Not all patients develop delirium tremens, nor do all develop seizures. These symptoms are difficult to predict, so detoxification should always be supervised. A history of alcohol withdrawal complications suggests that inpatient detoxification is indicated. b. Table 16 lists the stages of acute alcohol withdrawal. Not everyone progresses through all stages. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-459 AL GRAWANY General Psychiatry Table 16. Stages of Acute Alcohol Withdrawal Stage Onset (after last drink or decrease in intake) 1 6–12 hr 2 12–24 hr 3 4 24–48 hr 48–72 hr (peaks at 3–5 days) Symptoms Minor withdrawal symptoms: Agitation, anorexia, anxiety, diaphoresis, headaches, insomnia, nausea/vomiting, tachycardia, tremors Alcohol hallucinosis: Hallucinations – usually visual, but can be auditory or tactile (usually resolve within 48 hr) Withdrawal seizures (generalized tonic-clonic) Delirium tremens (alcohol withdrawal delirium): Agitation, diaphoresis, disorientation, hallucinations (usually visual), hyperpyrexia, hypertension, tremor c. Delirium tremens, which can be life threatening, should be considered a potential medical emergency and treated promptly. d. The seizures that occur are often difficult to control. Status epilepticus can develop; thus, it is important to ensure these patients have intravenous access before onset. 3. Treatment of acute alcohol withdrawal a. The degree of symptoms and the resulting treatment level should be individualized, and an accurate history regarding amount, duration, and past withdrawal symptoms, including seizures and delirium tremens, should guide treatment. i. Because of cross-tolerance at the GABA A receptors, benzodiazepines are considered first-line treatment for alcohol withdrawal symptoms, including delirium tremens and seizures. ii. Chlordiazepoxide, clorazepate, diazepam, and oxazepam carry FDA indications for treating alcohol withdrawal, but other benzodiazepines are used off-label. Long-half-life benzodiazepines such as chlordiazepoxide and diazepam minimize the potential for breakthrough symptoms and allow for more self-taper between doses but may also lead to overmedication, particularly in older adult patients or patients with liver disease. Lorazepam or oxazepam is preferred in these patients. Lorazepam’s shorter half-life allows for tighter control of dosing with minimal risk of oversedation. iii. Several dosing regimens are used (Table 17). Symptom-driven treatment using the Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) is the gold standard. The CIWA-Ar consists of seven items and has a score range of 0–67. The higher the score, the more severe the symptoms. The patient’s CIWA-Ar score is determined routinely. Patients are typically treated if the score is greater than 8–10 (depending on facility protocol). This protocol is efficacious and results in lower total benzodiazepine use. iv. Scheduled dosing: For severe alcohol withdrawal, including in patients with a history of withdrawal seizures or delirium tremens, fixed-dose benzodiazepine therapy is used for 2–3 days, regardless of symptoms, with supplementation according to the CIWA-Ar score. The benzodiazepine can then be tapered for 3–4 days until symptoms have abated. The drawback of using scheduled dosing is the risk of overmedication. It is not appropriate for mild-moderate withdrawal, nor is this method commonly used for outpatient treatment. v. Loading-dose (front loaded) protocol: Chlordiazepoxide is given at a dose of 25–100 mg every 1–2 hours until the withdrawal symptoms are alleviated (or CIWA-Ar is less than 10). Most patients will need two or three doses, especially those with a history of seizures during withdrawal, in which case three doses should be used. The half-life of chlordiazepoxide is long, and most patients will not need subsequent doses in this protocol once symptoms are relieved. Of course, patients should be monitored closely. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-460 General Psychiatry Table 17. Benzodiazepines for Acute Alcohol Withdrawal Drug Chlordiazepoxide (Librium) CIWA-Ar Dosing 25–100 mg PO Fixed-Dose Regimen Diazepam (Valium) 5–20 mg PO/IV/ IMa Lorazepam (Ativan) 2–4 mg PO/IV/IM 10 mg every 6 hr × 4; then 5 mg every 6 hr × 8 Oxazepam (Serax) 10–30 mg PO 50 mg every 6–12 hr × 4; then 25 mg every 6 hr × 4; then 25 mg BID; then 25 mg at bedtime 2 mg every 6 hr × 4; then 1 mg every 6 hr × 8 30 mg every 6 hr × 4; then 15 mg every 6 hr × 4 Comments Long acting; decrease dose for liver disease Decrease dose for liver disease Preferred medication, particularly for older adults and those with liver disease; no active metabolites Short-acting; preferred in older adults and those with liver disease IM administration of diazepam is unreliable. BID = twice daily; IM = intramuscular(ly); IV = intravenous(ly); PO = oral(ly). a b. Nutritional considerations i. Thiamine: Should be given to all patients to prevent Wernicke-Korsakoff syndrome. Because thiamine has poor oral bioavailability, it is administered intramuscularly/intravenously to replete thiamine in severe cases: 100–250 mg intramuscularly/intravenously daily for 3–5 days, followed by 100 mg by mouth three times daily for 1 week, and then 100 mg daily thereafter. Always give the first dose before glucose because thiamine is a cofactor for the metabolism of glucose. ii. Magnesium: Assess by serum chemistry; if low, give an intravenous supplement. iii. Electrolytes: Assess by serum chemistry, and add to intravenous solutions as indicated (e.g., potassium). iv. Vitamins: Patients are usually undernourished; a multivitamin and/or folic acid may be indicated. v. Fluid therapy: The patient may initially be overhydrated, but usually, fluid deficit will follow; replace fluids, usually with intravenous 5% dextrose solution with half-normal saline plus other electrolytes (e.g., potassium, phosphate). c. Other agents: Antiseizure medications: as adjuncts to benzodiazepines in uncontrolled seizures. They should not be used as monotherapy for alcohol withdrawal seizures. Carbamazepine, gabapentin, and valproic acid have all been used. Of note, gabapentin does not decrease benzodiazepine requirements as assessed by CIWA-Ar in clinical studies. 4. Medications for alcohol use disorder a. Acamprosate (Campral) and naltrexone (Revia, Vivitrol) are considered first line. b. Naltrexone: This drug can also be used chronically and reduces cravings. If used, it should be combined with CBT. Naltrexone has a precaution listed for hepatocellular injury. Patients should have liver function tests monitored periodically. Naltrexone should be avoided in patients with acute hepatitis or severe hepatic impairment (liver function tests greater than 3 times the upper limit of normal). Additional adverse effects include nausea, diarrhea, injection site reactions, headache, insomnia, and nervousness. The ER injectable suspension (Vivitrol) is available in an intramuscular formulation and is approved for alcohol dependence in patients who can abstain from alcohol in an outpatient setting before treatment initiation. Naltrexone is also available as a daily oral tablet. For further details on use, see the naltrexone entry under Opioid Use Disorder in the text that follows. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-461 General Psychiatry c. Acamprosate (Campral): This drug is a structural analog of GABA that also reduces cravings. Evidence regarding efficacy is more mixed than with naltrexone. Acamprosate is not metabolized by the liver; however, it must be taken three times daily. The dose must be decreased for a CrCl of 30–50 mL/minute/1.73 m 2, and the drug should not be used in patients with a CrCl less than 30 mL/ minute/1.73 m2. It carries a warning for suicidal ideation and should not be used in patients with active suicidal ideation. d. Disulfiram (Antabuse): This drug blocks acetaldehyde dehydrogenase. If alcohol is used with it, acetaldehyde concentrations increase. The person will develop symptoms that include nausea/ vomiting, flushing, and headache, among others. For this reason, it is considered aversion therapy. Adherence is critical, and disulfiram is usually reserved for patients with considerable motivation for adherence. Caution should be exercised in patients with liver disease, particularly if it is severe or the patient has cirrhosis. Disulfiram has been associated with hepatotoxicity, though it is not known whether patients with existing liver disease are at an increased risk. Because of the increase in acetaldehyde concentrations, it should be avoided in patients with severe myocardial disease. It should not be combined with metronidazole because of an increased risk of encephalopathy. Patients should also be counseled to avoid alcohol-containing items, particularly medications and certain mouthwashes, because of the risk of adverse effects. I. Opioid Use Disorder (OUD) 1. Opioid-related overdose deaths, illicit use, and prescription misuse constitute a public health crisis. 2.  Opioid intoxication a. Symptoms include miosis (unless mydriasis occurs secondary to anoxia from overdose), together with one of the following signs beginning after opioid use: drowsiness or coma, slurred speech, or impaired attention or memory. b. Naloxone should be considered for all patients exposed to opioids regardless of the source. An excellent educational source is available at the AAPP American Association of Psychiatric Pharmacists. https://aapp.org/guideline/naloxone. SAMHSA has an Opioid Overdose Prevention Kit available at https://store.samhsa.gov/product/Opioid-Overdose-Prevention-Toolkit/SMA18-4742. Repeat doses of naloxone are potentially necessary, depending on the potency of the opioid used. Naloxone should only be used in unresponsive patients beginning to show, or showing, signs of respiratory distress. 3. Opioid withdrawal a. Not life threatening in the absence of concomitant medical conditions. See Table 18 for details. Table 18. Timeline of Physical Signs of Opioid Withdrawal Stage (after last use) Grade Early withdrawal (symptoms may resemble mild flu) Short-acting opioids: 8–24 hr 1 Long-acting opioids: ≥ 36 hr 2 Physical Signs/Symptoms Diaphoresis Insomnia Lacrimation, rhinorrhea, or both Restlessness Yawning Abdominal pain Arthralgia Mydriasis Muscle twitching Myalgias Piloerection ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-462