General Psychiatry: Opioid Withdrawal & Treatment PDF

General Psychiatry Table 18. Timeline of Physical Signs of Opioid Withdrawal (Cont’d) Stage (after last use) Fully developed withdrawal Short-acting opioids: 24–72 hr Long-acting opioids: 72–96 hr Grade Physical Signs/Symptoms 3 Anorexia or nausea Extreme restlessness Fever Hypertension Tachyca...

General Psychiatry Table 18. Timeline of Physical Signs of Opioid Withdrawal (Cont’d) Stage (after last use) Fully developed withdrawal Short-acting opioids: 24–72 hr Long-acting opioids: 72–96 hr Grade Physical Signs/Symptoms 3 Anorexia or nausea Extreme restlessness Fever Hypertension Tachycardia Tachypnea Dehydration Diarrhea, vomiting, or both Fetal position Hyperglycemia Hypotension 4 Total duration: S  hort-acting opioids: 7–10 days Long-acting opioids: ≥ 14 days Adapted from: Substance Abuse and Mental Health Services Administration (SAMHSA). Medications for Opioid Use Disorder for Healthcare and Addiction Professionals, Policymakers, Patients, and Families TIP 63. Rockville, MD: U.S. Department of Health and Human Services, 2021. Available at https://www.ncbi.nlm.nih.gov/books/NBK574910/pdf/Bookshelf_NBK574910.pdf. b. Several scales can be used to monitor the severity of opioid withdrawal symptoms. One of the most commonly used is the Clinical Opiate Withdrawal Scale (COWS). It consists of 11 items that are scored from 0 (asymptomatic) to 4 or 5 (severely symptomatic). The maximum score is 48. A score of 5–12 is considered mild, whereas a score of greater than 36 is severe. c. First-line treatment for severe withdrawal is buprenorphine or methadone (see Methadone and Buprenorphine sections in the text that follows for details). d. Lofexidine (Lucemyra) is FDA approved for the treatment of opioid withdrawal. Although less effective than methadone or buprenorphine for withdrawal symptoms, it is appropriate for use when neither methadone nor buprenorphine is available for use. It is an α2-adrenergic agonist that reduces the release of norepinephrine and reduces sympathetic tone. It has higher selectivity for the α2A-receptor and is thus thought to be less antihypertensive than clonidine. Lofexidine is intended to treat symptoms of opioid withdrawal, and not for long-term therapy to reduce the risk of relapses. It can prolong the QTc interval and thus should be avoided or administered with caution in patients receiving methadone. Clonidine is used off-label because of the similar mechanism of action and cheaper price. 4. Medications for OUD: Pharmacologic therapies for maintenance treatment of OUD include methadone, naltrexone, and buprenorphine with or without naloxone. a. Medication is integral, but not mandatory, to recovery for many people with OUD. Medications used to treat OUD are superior to placebo or no medication for reducing illicit use, maintaining treatment retention, and reducing opioid overdose death. OUD medication allows time for the individual to make necessary life changes that correlate with long-term remission and recovery. Although it should be considered for all patients with OUD, the strongest consideration should be made for patients with moderate to severe OUD. b. Pharmacologic treatment of OUD should be integrated with outpatient and/or residential treatment and facilitated between transitions of care, whether inpatient to outpatient, or from emergency department visit to outpatient follow-up. Patients can benefit from psychotherapy and individualized social supports. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-463 General Psychiatry 5. Methadone (Dolophine) (C-II) a. Has the most extensive evidence base supporting treatment of OUD. It is the most studied and most widely used medication for severe OUD. The World Health Organization considers it an essential medication. b. Full agonist with an affinity for the opioid mu-opioid receptor c. Black boxed warnings i. Fatal respiratory depression: Methadone has a long half-life and is highly lipophilic and may be released slowly from tissue once it accumulates there. For this reason, respiratory depression can occur after the analgesic effects peak; thus, overdose is a risk, particularly during initiation, conversion from another opioid agonist, or a dose increase. There is also an increased risk of respiratory depression when combined with benzodiazepines or other CNS depressants. ii. Prolonged QTc interval and torsades de pointes can occur. The risk is dose related and more common with daily doses greater than 200 mg, though it has been reported with lower doses used to treat OUD. Appropriate monitoring is indicated. Screen for risk factors for a prolonged QTc, and avoid combining with other agents that can prolong the QTc interval. If the QTc exceeds 500 milliseconds, it is recommended to decrease or discontinue the methadone dose, eliminate other risk factors for QTc prolongation (if possible), and consider an alternative medication, such as buprenorphine. d. Metabolized by 3A4; dose should be adjusted for inducers and inhibitors e. Standard of care for pregnancy, though buprenorphine use is increasing. May be beneficial with fewer adverse effects f. According to the Code of Federal Regulations title 32, section 8: Methadone products for the treatment of OUD are only available through federally regulated opioid treatment programs. Methadone is administered as a single liquid daily dose in a supervised outpatient treatment setting. Patients must come to the opioid treatment program to receive their dose. Arrangements can be made for a single take-home dose on days the treatment clinic is closed. Exceptions can be made for inpatient or emergency treatment. These programs must offer other services, including medical, counseling, vocational, and educational. g. Urine drug tests do not routinely screen for methadone. Additional specialized testing is required. 6. Buprenorphine (Subutex, Bunavail, Suboxone, Zubsolv, Sublocade) (C-III; with or without naloxone) a. Use of buprenorphine came about as a result of the Drug Addiction Treatment Act of 2000 (DATA 2000), which allows qualifying physicians to apply for a waiver to treat opioid addiction outside an opioid treatment program using schedule III, IV, and V medications that are FDA approved for this indication. Any prescriber with a DEA number can treat up to 30 patients without completing the required education, but must still register. b. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist of the kappa receptor. The mu-opioid receptor binding affinity is higher than that of full-opioid agonists with a lower intrinsic activity. Thus, buprenorphine will displace morphine, methadone, and other opioid drugs but only gives a fraction of effect that levels out with increasing doses. This ceiling effect may not provide enough craving control if a patient used high doses of opioid. This allows patients enough effect to “feel normal” but minimizes functional impairment. This also makes the drug safer in overdose situations. At high-enough doses, the kappa antagonist properties can precipitate withdrawal. c. The partial mu-agonist activity makes buprenorphine less likely to cause respiratory depression. Lethal overdoses are possible, particularly in opioid-naive patients or individuals who combined it with other CNS depressants such as benzodiazepines or alcohol. d. Adding naloxone reduces abuse potential because naloxone is more rapidly inactivated after oral/ sublingual absorption than after parenteral administration. Thus, if the medication is used as intended (sublingually), the likelihood of withdrawal symptoms is low as opposed to dissolving and injecting it. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-464 General Psychiatry e.  Like with methadone, the World Health Organization considers buprenorphine an essential medication. f.  Dosage forms: i. Short-acting buprenorphine: Sublingual tablets (Subutex) ii. Short-acting buprenorphine/naloxone (4:1 dosing ratios): Buccal film (Bunavail), sublingual film (Suboxone), sublingual tablet (Zubsolv) iii. Long-acting buprenorphine formulations: Implantable subdermal device (Probuphine; discontinued as of October 15, 2020) and ER injection (Sublocade) g. Treatment with buprenorphine involves three phases: induction, stabilization, and maintenance. Buprenorphine/naloxone is preferred for most patients, including those taking short-acting opioids (hydromorphone, oxycodone, heroin). Patients taking long-acting opioids (methadone, long-acting morphine, long-acting oxycodone) should be tapered to methadone 30 mg/day or less or the equivalent and transitioned to buprenorphine first. It is recommended that these patients be changed to the buprenorphine/naloxone combination after no more than 2 days of buprenorphine monotherapy. i. They must also be screened for other SUDs and for appropriateness of buprenorphine therapy. Patients should begin buprenorphine when they have clear signs of opioid withdrawal. In these cases, the opioid receptors are not fully occupied, and buprenorphine is less likely to induce withdrawal. If the patient is transitioning from methadone, it may take 24–48 hours after the last methadone dose for opioid withdrawal symptoms to manifest. ii. Patients should receive concomitant counseling and nonpharmacologic treatment support during treatment. Part of the DATA 2000 waiver requires that physicians be able to refer the patient to appropriate supportive services. Counseling should consider all psychosocial factors. iii. Induction phase: Find the lowest buprenorphine dose that minimizes cravings for opioids but prevents withdrawal symptoms. Induction can occur in an inpatient setting, an outpatient office setting, or at home. Office induction is preferred for several reasons, including ensuring the patient knows how to take the medication, improving the therapeutic alliance, verifying the presence of opioid withdrawal symptoms and the absence of precipitated withdrawal symptoms, ensuring the lack of sedation 1–2 hours after taking the medication, and using the time between doses for patient self-monitoring. The patient is given a 2- to 4-mg dose of buprenorphine or the 2/0.5-4/1 mg dose of buprenorphine/naloxone. If withdrawal symptoms are not relieved or return before the 2-hour period, a repeat dose is given, up to a total dose of 8 mg or 8/2 mg on day 1. The dose established during the induction phase depends on the presence of withdrawal symptoms on subsequent days, to a maximum of 32/8 mg/day. Clinically significant differences are not usually seen with doses greater than 24 mg/day of buprenorphine. iv. Stabilization phase: Reached when the patient is without withdrawal symptoms, is not experiencing adverse effects of buprenorphine/naloxone, and no longer has uncontrollable symptoms of craving. Toxicology screens can be used to verify the patient is not using opioids. Patients should be seen weekly until stable. Doses can be adjusted in 2/0.5 to 4/1 increments. Most patients are maintained on 16/4 to 24/6 mg/day. v. Maintenance phase: Once the lowest dose needed to maintain abstinence is reached, buprenorphine/naloxone therapy can be maintained indefinitely. Nonpharmacologic modalities should continue during this time. vi. Discontinuation: This should be considered only if the patient is psychologically and medically stable, can maintain a drug-free lifestyle, and no longer feels the drug is necessary to remain abstinent. The medication should be tapered slowly to avoid withdrawal symptoms. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-465 General Psychiatry h. The ER subcutaneous injection can be used after induction and adjustment to 8–24 mg daily using a transmucosal formulation of buprenorphine. The dosing is 300 mg monthly for the first 2 months, followed by the usual maintenance dose of 100 mg monthly. If patients have suboptimal clinical response to the 100-mg dose, it can be increased to a maximum of 300 mg. The injected liquid forms a solid mass upon contact with body fluids. For this reason, it carries a black boxed warning for risk of serious harm (including occlusion, local tissue damage, and thromboembolic events, including pulmonary emboli) or death with intravenous administration. Health care facilities and pharmacies that order and dispense it must be certified through the Sublocade REMS program. As part of this program, the subcutaneous liquid product can only be dispensed to a health care provider for administration by a health care provider. It cannot be dispensed directly to a patient. Buprenorphine is metabolized by 3A4. Use caution with other medications that either induce or inhibit 3A4. 7. Naltrexone (ReVia, Vivitrol) a. Either the daily tablet or the ER injectable can be used, but the ER injectable is usually preferred because of better adherence. b. The ER injectable is part of a REMS education program. Patients must be counseled on the following points: i. Risk of increased opioid sensitivity and opioid overdose ii. Risk of severe reactions at the injection site iii. Risk of liver injury, including liver damage or hepatitis iv. Therapeutic effects of opioid medications taken for pain, cough and cold, or diarrhea may not be felt by the patient. c. Unlike methadone and buprenorphine, prescription and administration of naltrexone are not restricted by practice setting or prescriber. d. The patient must be completely off opioids for 7–10 days before naltrexone is administered (14 days if taking methadone or buprenorphine). e. If initiated before release from a controlled environment in which the patient has undergone opioid withdrawal, it can help prevent a return to opioid use. Because naltrexone does not provide opioid agonism, it may not be effective in patients experiencing severe cravings. This presents a risk because the patient may try to overcome the antagonism of naltrexone with high-dose opioids, which can lead to overdose and respiratory depression. J. Nicotine Dependence 1. Nicotine use is the main cause of preventable morbidity and mortality. 2. Smoking cessation reduces the risk of several adverse health effects, including reproductive health outcomes, cardiovascular diseases, chronic obstructive pulmonary disease (COPD), and cancer. It is also beneficial to those with preexisting cardiovascular disease and COPD. 3. According to the CDC, 12.5% of adults smoked cigarettes in 2020. Rates of nicotine use have greatly declined over the past decade, and there are now more former smokers than current smokers. 4. Smoking cessation counseling is not consistently offered and tends to be directed to patients with tobacco-related conditions. Interventions lasting as few as 3 minutes can make a difference. Patient counseling can help encourage patients who are unwilling to quit to reconsider quitting and act on it in the future. 5. As of January 2015, the Joint Commission requires inpatient psychiatric services to screen for tobacco use (TOB-1), offer or provide treatment for tobacco dependence (TOB-2), and provide or offer treatment for tobacco dependence at discharge (TOB-3). 6. On average, seven attempts are necessary for a patient to quit successfully. 7. Willingness to quit should be assessed by the five A’s: ask about tobacco use, advise to quit, assess willingness to attempt to quit, assist in quit attempt, and arrange for follow-up. 8. Motivational interviewing can help identify barriers to change and help the patient overcome them. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-466 General Psychiatry 9. The five R’s can increase motivation to quit: relevance, risks, rewards, roadblocks, and repetition. 10. Quit lines such as 1-800-QUIT-NOW can facilitate attempts. 11. Seven pharmacologic agents (five nicotine and two non-nicotine) are available to help. They should be used with nonpharmacologic modalities to increase the success of quitting. 12. A usual pack contains 20 cigarettes. 13. Nicotine replacement therapy: All forms are equally efficacious. Patients should be advised to stop smoking completely before initiating. Nicotine replacement therapy is available in the following forms: a. Patch: For patients who smoke more than 10 cigarettes/day, start with 21 mg/day for 6 weeks (4 weeks if Habitrol), then 14 mg/day for 2 weeks, then 7 mg/day for 2 weeks. For those who smoke 10 cigarettes/day or less, start with 14 mg/day for 6 weeks, then 7 mg/day for 2 weeks. Patches may be used for longer periods, if needed, to improve success. The patch should be changed when awakening every day. If the patch causes sleep disturbances, including disturbing or vivid dreams, it can be removed at bedtime. Rotate sites. b. Gum: The gum should be chewed until a “peppery” or flavored taste develops; it should then be “parked” between the cheek and gum to facilitate buccal absorption. The gum should be chewed and parked for 30 minutes or until the flavor is gone. The maximum amount of gum to use is 24 pieces in 24 hours. At least 9 pieces of gum should be used daily to increase the chances of quitting. Patients who smoke their first cigarette within 30 minutes of waking should use the 4-mg strength. Otherwise, the 2-mg dose is used. One piece of gum should be used every 1–2 hours for the first 6 weeks of therapy, followed by 1 piece every 2–4 hours for weeks 7–9, then 1 piece every 4–6 hours for weeks 10–12. Acidic beverages (e.g., coffee, juices, and soft drinks) interfere with buccal absorption and should be avoided at least 15 minutes before using the gum. Adverse effects include soreness, dyspepsia, hiccups, and jaw ache. These are usually mild and can be corrected with changes in chewing technique. c. Lozenge: Patients who smoke their first cigarette within 30 minutes of waking should use the 4-mg strength. Otherwise, the 2-mg dose is used. The lozenge should be dissolved in the mouth rather than chewed or swallowed. The frequency of use and tapering are the same as for the gum. Adverse effects are also similar. At least 9 lozenges should be used at the beginning to increase chances of quitting. Only 1 lozenge should be used at one time. No more than 5 lozenges within 6 hours, maximum 20 lozenges/24 hours d. Inhaler: Available by prescription only in the United States. Each cartridge delivers 4 mg of nicotine over 80 inhalations. The recommended dosing is 6–16 cartridges/day. Results are best if the contents of the cartridges are continuously puffed over about 20 minutes. Recommended treatment length is 3 months, with reduction in frequency during the last 6–12 weeks. As with the gum and lozenges, patients should not drink acidic beverages or eat within 15 minutes of using the inhaler. Delivery decreases at less than 40°F, so the inhaler should be kept in an inner pocket in cold weather. The most common adverse effects are sore throat, coughing, and rhinitis. Inhalers should be avoided in patients with reactive airway diseases. e. Nasal spray: Available by prescription only. The dose is 0.5 mg delivered to each nostril. One or two doses should be used hourly, up to five doses. The 24-hour maximum is 40 doses. At least eight doses should be used at the start of therapy. Each bottle contains 100 doses. Recommended length of therapy is 3–6 months, with tapering. Risk of dependency is higher than with other forms of nicotine replacement. Inhaling, sniffing, and swallowing can increase the risk of nasal irritation and should thus be avoided when using the spray. Nasal irritation can occur in up to 94% of patients. Although nasal irritation can resolve, many patients may have it as long as 8 weeks into therapy. Nasal spray is not recommended for patients with reactive airway diseases or nasal conditions. f. Nicotine patches can be used with the as-needed dosage forms to increase the chances of quitting. g. Patients with a history of cardiovascular disease can use nicotine replacement therapies. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-467 General Psychiatry h. The treatment of choice in pregnant women is nonpharmacologic. Nicotine is freely transferred to the fetus throughout pregnancy. Use of cigarettes or nicotine gum in the third trimester has been associated with diminished breathing movement in the fetus. The FDA has developed labeling for nicotine replacement products in pregnancy. Although the FDA advises using these products only on the advice of a health care provider, it also states that the products are believed to be safer than smoking. 14. Bupropion SR: Should be initiated 7 days before the quit date. Treatment should last for at least 8 weeks but can be continued for up to 6 months to increase the chances of quitting. Bupropion can also be combined with the nicotine patch, if needed. 15.  Varenicline: A nicotine receptor partial agonist. Varenicline blocks the effects of nicotine from smoking. Varenicline should be started 1 week before the quit day, though patients can choose to quit smoking up to 35 days after starting varenicline. Varenicline should be continued for a total of 12 weeks. If the patient is successful at smoking cessation, varenicline can be continued for another 12 weeks. The black boxed warning about neuropsychiatric symptoms was removed in 2016. A metaanalysis and systematic review showed that the risk of neuropsychiatric symptoms was not significantly different from placebo (BMJ 2015;350:h1109). An FDA advisory warned of a small increase in the risk of cardiovascular events, particularly in patients with preexisting cardiovascular disease. The benefits of smoking cessation must be weighed against the possible risk. Varenicline must be used with caution in patients with a CrCl less than 30 mL/minute/1.73 m2. Combining varenicline with nicotine replacement therapy may increase adverse effects, though varenicline has been used in combination with the nicotine patch. Varenicline can be combined with bupropion. 16. Other agents used include clonidine and nortriptyline. 17. Patients who were unsuccessful in quitting on one form of pharmacologic therapy should be tried on a different method. 18. The American Thoracic Society has released guidelines for initiating pharmacologic treatment in tobacco-dependent adults. The ATS makes five strong recommendations and two conditional recommendations. a. Strong recommendations: For tobacco-dependent adults in whom treatment is being initiated: • Varenicline is recommended over a nicotine patch. • Varenicline is recommended over bupropion. • Varenicline plus a nicotine patch is recommended over varenicline alone. • Varenicline is recommended over electronic cigarettes. • In patients who are not ready to discontinue tobacco use, it is recommended to start varenicline treatment rather than wait until patients are ready to stop. b. Conditional recommendations: • For tobacco-dependent adults with comorbid psychiatric conditions in whom treatment is being initiated, varenicline is recommended over a nicotine patch. • For tobacco-dependent adults, extended-duration (more than 12 weeks) therapy with varenicline is recommended over standard-duration (6–12 weeks) therapy. Acknowledgments ACCP gratefully acknowledges the contributions of previous authors, Drs. William Kehoe and Kelly Lee. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-468