Sections

Opioid Abuse

Sections Opioid Abuse
Overview
Presentation
- History
- Physical
- Causes
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DDx
Workup
Treatment
Guidelines
Medication
Follow-up
Questions & Answers
References

Treatment

Medical Care

Acute opioid-related disorders that require medical management include opioid intoxication, opioid overdose, and opioid withdrawal. Issues pertaining to treatment of chronic opioid abuse include opioid agonist therapy (OAT), psychotherapy, and treatment of acute pain in patients already on maintenance therapy.

Opioid intoxication

General supportive measures for opioid intoxication are as follows:

Assess patient to clear airway.
Provide support ventilation, if needed.
Assess and support cardiac function.
Provide IV fluids.
Frequently monitor the vital signs and cardiopulmonary status until the patient has cleared opioids from the system.
Give IV naloxone if necessary. Naloxone is a specific opiate antagonist with no agonist or euphoriant properties. When administered intravenously or subcutaneously, it rapidly reverses the respiratory depression and sedation caused by heroin intoxication.

Opioid overdose

Naloxone

Intranasal

In November 2015, intranasal naloxone was approved by the FDA after fast track designation and priority review. It is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. The brand name product (ie, Narcan Nasal Spray) was the first opioid antagonist granted OTC designation in March 2023. The ready-to-use single-dose sprayer delivers a 4-mg dose by intranasal administration. Approval was based on pharmacokinetic studies that compared IM and intranasal dosage forms. The National Institute on Drug Abuse also was crucial to the approval by forming a public-private partnership by designing and conducting the clinical trials required to determine that the intranasal formulation delivered naloxone as quickly and as effectively as an injection.^{[36, 37]} A second OTC product (ie, RiVive) was approved in July 2023 that delivers a 3-mg dose.

A higher concentration intranasal product (ie, Kloxxado) is available by prescription that delivers 8 mg/actuation. Generics that deliver 4 mg/actuation are also prescription.

IM/SC injection

A high-dose (5 mg/0.5 mL; Zimhi) IM/SC injectable solution in a prefilled syringe was approved in October 2021. In pharmacokinetic studies, a single IM dose of 5 mg provided significantly higher peak plasma concentration and AUC compared with a single 2-mg IM injection.^[38]

In 1996, community-based programs began offering naloxone and other opioid overdose prevention services to persons who abuse opioids, their families, and friends, and service providers (eg, homeless shelters). Since their inception, the programs have distributed naloxone to over 53,000 persons who abuse drugs. Naloxone is effective in treating acute overdose and is first-line treatment.^[39]

Because overdoses usually occur in the presence of other people and because medical care is often not sought or is sought too late, at-home naloxone programs have been piloted in several countries. This is a controversial treatment that raises concerns about condoning heroin use, discouraging medical care, and producing side effects that cannot be managed at home. However, the efficacy of these pilot programs should be carefully monitored, as the potential for reducing mortality is high.

Opioid maintenance therapy

Pharmacologic therapy for heroin addiction has focused on ameliorating withdrawal symptoms and reducing cravings. By replacing heroin with legally obtained opioid agonists, many risk factors of the drug-abusing lifestyle can be mitigated.

Methadone maintenance therapy^[40](MMT) has been the standard of care for more than 30 years. However, the recent advent of buprenorphine maintenance therapy (BMT) is changing the landscape of treatment for opioid-dependent patients.^[41]

Methadone, a long-acting synthetic opioid agonist, can be dosed once daily and replaces the necessity for multiple daily heroin doses. As such, it stabilizes the drug-abusing lifestyle, reducing criminal behaviors, and also reducing needle sharing and promiscuous behaviors leading to transmission of HIV and other diseases.

Methadone is a highly regulated Schedule II medication, only available at specialized methadone maintenance clinics. It is estimated that established methadone clinics can accommodate only 15-20% of US heroin addicts.

Methadone clinics often generate controversy in communities fearful of addicts in various stages of recovery. In addition, some patients are unable to travel to clinics, and others will not enter MMT because of fear of stigmatization. Clearly other options would be beneficial for treatment of chronic opioid abuse.

Buprenorphine is a mu-opioid partial agonist that, like methadone, suppresses withdrawal and cravings. However, the property of partial agonism confers a "ceiling effect," at which higher doses of buprenorphine cause no additional effects. This ceiling effect affords a wider margin of safety than methadone, which can be lethal in overdose. The increased safety of buprenorphine has allowed it to become available by prescription as a Schedule III medication.

Buprenorphine has been combined with naloxone^[42]in a 4:1 ratio (Suboxone, Zubsolv) or a 6-7:1 ratio (Bunavail) in order to alleviate concerns that the sublingual tablet would be dissolved and injected by addicts. Naloxone is an opioid antagonist that is poorly absorbed sublingually and orally but is well-absorbed intravenously. As a result, an opioid-dependent patient injecting buprenorphine/naloxone will suffer a withdrawal syndrome secondary to naloxone's occupation of mu-opioid receptors.

One study found that a 4-week buprenorphine taper combined with naltrexone maintenance treatment boosted abstinence rates.^{[43, 44]}

A randomized clinical trial found that patients with prescription opioid dependence whose buprenorphine therapy was tapered were less likely to abstain from illicit opioid use during the 14-week study period than were those who received maintenance therapy.^[45]Patients in the taper group reported engaging in a mean of 1.27 days of opioid abuse after the taper, compared with 0.47 days in the maintenance group, and there was a mean of 2.7 consecutive weeks of opioid abstinence in the taper group, compared with 5.2 in the maintenance group.

The FDA approved buprenorphine/naloxone (Zubsolv) sublingual tablets in July 2013 for the maintenance treatment of opioid dependence. The new formulation has high bioavailability, a fast dissolve time, a small tablet size, and a menthol flavor to encourage patient adherence with treatment.^[46] Zubsolv’s indication was expanded to include induction dosing for patients dependent on short-acting opioids (eg, heroin) in August 2015. For patients dependent on long-acting opioids (eg, methadone), buprenorphine monotherapy is recommended for induction.

In June 2014, the FDA approved a buccal form of buprenorphine/naloxone (Bunavail) for opioid dependence maintenance therapy. Approval was based on a phase III, 12-week, clinical trial of 249 patients that were converted to the buccal film from the sublingual tablet (Suboxone). The film was shown to be safe and effective with less constipation than with Suboxone.^[47] Suboxone sublingual tablets have been replaced on the market with a Suboxone sublingual film.

In August 2015, in a randomized double-blinded placebo-controlled clinical trial, 118 participants maintained on buprenorphine were treated with clonidine or placebo for 14 weeks. Those given clonidine maintained initial abstinence for longer periods than the placebo group, suggesting that clonidine could be a useful adjunctive maintenance treatment alongside buprenorphine by decoupling daily-life stress from increases in drug craving.^[48]

Office-based treatment of opioid addiction is now possible with BMT.^[49]Physicians wishing to prescribe buprenorphine must meet several criteria, including requirements outlined in the Drug Abuse Treatment Act of 2000. However, physicians who do not meet these criteria can take an 8-hour training course to become certified to prescribe buprenorphine. Currently, physicians are limited to 30 buprenorphine patients for 1 year, and may apply for a waiver after the first year for 100 patients. In 2016, this limit was raised to 275 patients for providers who held a 100-patient waiver for 1 year and held additional credentialing or practiced in a qualified practice setting.^[50]

In 2016, the FDA approved the first buprenorphine implant (Probuphine) for opioid dependence. The implant, which is comprised of four, one-inch-long rods that are implanted under the skin on the inside of the upper arm, provides a constant, low-level dose of buprenorphine for six months. Each rod contains approximately 80 mg of the drug for a total of 320 mg implanted at once. The implant is designed for use in patients who are already stable on a low dose of the drug. Because it must be inserted and removed surgically, only health care providers who have completed the training and become certified through a restricted program called the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program should insert and remove the implants.^[51]

Persons with opioid dependence often experience difficulty following current existing pharmacologic treatments designed to reduce or eliminate opioid use. Ling et al studied the efficacy of buprenorphine implants over a 6-month period in patients with opioid dependence. Initial induction with sublingual buprenorphine-naloxone tablets preceded implant placement. Less opioid use was observed (as assessed by urine samples) in patients using the buprenorphine implants compared with placebo implants.^[52]

In 2017, the FDA approved a once-monthly SC injection (Sublocade) for opioid use disorder (OUD). When injected, it forms a solid mass upon contact with body fluids from the Atrigel delivery mechanism. The drug must be administered in a healthcare setting to avoid inadvertent IV administration that could result in death. It is indicated for treatment of moderate-to-severe OUD in adults who have initiated treatment with a transmucosal buprenorphine-containing product and have been on a stable dose of transmucosal buprenorphine treatment for ≥7 days.^[53]

Historically, l-alpha-acetylmethadol (LAAM) has also been used for opioid-dependence maintenance pharmacotherapy. However, LAAM is associated with prolonged QT interval, and several cases of cardiac arrhythmia and death have been reported. Therefore, LAAM was recently removed from the market in the European Union and was given a black box label by the FDA.

Several Cochrane Database Systematic Reviews about the efficacy of opioid agonist therapy have been published in recent years. While all of these reviews stress the need for larger, multicenter, randomized clinical trials of longer duration, some conclusions can be drawn from existing data.

A review of Cochrane reviews found that high-dose MMT (60-109 mg/d) is more effective in retaining patients in treatment than low-dose MMT (1-59 mg/d). Moreover, methadone at flexible doses was more effective in retaining patients in treatment (RR, 1.23) than buprenorphine. A second systematic review of databases found that low-dose methadone (20 mg/d) was less effective than buprenorphine (2-8 mg/d) and that high-dose methadone (>50-65 mg/d) was more effective than buprenorphine (2-8 mg/d).

Another Cochrane review found that oral substitution treatment was associated with significant reductions in heroin injection and needle sharing, as well as a decrease in patients with multiple sexual partners and a reduction in exchanges of sex for drugs or money.^[54]Importantly, these changes were correlated with reductions in cases of HIV infection.

Although pain is common among opioid-dependent patients, pharmacologic approaches are limited. Tsui et al found that treatment with escitalopram, a selective serotonin reuptake inhibitor, was associated with clinically meaningful reductions in pain severity and pain interference during the initial 3 months of treatment.^[55]

Preventing opioid dependence relapse

A randomized, placebo-controlled trial suggested that an injectable, sustained-release form of naltrexone (Depotrex) increased retention of patients in treatment for opioid abuse.^[56]Further studies are necessary to evaluate the efficacy of this treatment modality.

FDA approval of extended-release IM naltrexone for the prevention of relapse to opioid dependence was based on data from a 6-month, multicenter, randomized, phase 3 study, which met its primary efficacy endpoint and all secondary efficacy endpoints. Once monthly treatment with extended-release IM naltrexone showed statistically significant higher rates of opioid-free urine screens compared with placebo (P< .0002).

A study of 150 opioid-dependent individuals examined the efficacy of two methods of outpatient opioid detoxification for induction to extended-release naltrexone – .naltrexone-assisted detoxification and a buprenorphine taper. The trial demonstrated that naltrexone-assisted detoxification increased the likelihood of a successful transition to extended-release injection naltrexone (XR-naltrexone) by almost threefold compared with those given a buprenorphine taper. Study findings support the development of a detoxification regimen of ascending doses of oral naltrexone for transitioning opioid-dependent patients seeking induction onto XR-naltrexone for the prevention of relapse.^[57]

In a double-blind, placebo-controlled, randomized, 24-week trial, 250 patients with opiate dependence were given monthly injections of an extended-release formulation of 380 mg of naltrexone or placebo.^[58]The study found substantial benefit in the actively treated group, with abstinence rates of 90% compared with 35%. Other measures confirmed this benefit, with a median retention of 168 days in the naltrexone group compared with 96 days in the placebo group, and reduced craving in the naltrexone group. Given the poor therapeutic efficacy of oral naltrexone in most opioid-dependent populations, this intramuscular formulation may be a valuable addition to the methods of treating opioid dependence if its value is verified in subsequent studies over longer therapeutic time periods in diverse groups of patients.

The use of naltrexone was shown to be effective in fostering sobriety in heroin- and amphetamine-dependent outpatients in a 10-week randomized, double-blind, placebo-controlled trial. Naltrexone implants resulted in higher retention in the study (52% of patients with naltrexone implants versus 28% in the control group), decreased heroin and amphetamine use (drug-free urine samples were 38% for the naltrexone group versus 16% placebo), and improved clinical conditions for the patients.^[59]

A long-acting buprenorphine subdermal implant (Probuphine) was approved by the FDA in May 2016 for use in opioid tolerant patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (ie, doses ≤8 mg/day of Subutex or Suboxone sublingual tablet equivalent or generic equivalent). Four implants (80 mg/implant of buprenorphine HCl) are inserted in the upper arm for 6 months of treatment and removed by the end of the sixth month. In addition to improved adherence, other benefits of buprenorphine implant include a reduced risk of diversion, abuse, misuse, and accidental exposure.

Efficacy of noninferiority was assessed for buprenorphine implant in clinically-stable patients on maintenance treatment by comparing the implant with daily doses of buprenorphine/naloxone SL of 8 mg or less. Results of primary and secondary endpoint analyses showed buprenorphine implant met the criteria for noninferiority with a 95% CI of (0.009, 0.167).^[60]

Treatment with catechol-O -methyltransferase (COMT) inhibitors may improve adherence to buprenorphine maintenance treatment for opioid addiction.^[61]In a study of 253 opiate-dependent patients who had failed to comply with initial buprenorphine maintenance treatment, 186 (73.5%) remained abstinent for longer than 6 months when they received the COMT inhibitor entacapone (200-1000 mg/day) in addition to buprenorphine. Another 61 patients (24.1%) remained abstinent for 12- to 24 months and 41 (16.2%) remained abstinent for 24- to 30 months. Forty-one (16.2%) patients were able to achieve abstinence using long-acting naltrexone.^[61]This is the first study of its kind to demonstrate COMT-inhibitors' anticraving effects.

Stress has been associated with impaired decision making and increased risk for relapse, even after long periods of abstinence. In a double-blind, placebo-controlled, randomized protocol, the negative effects of stress on performance were prevented by the beta-adrenoceptor antagonist propranolol as early as after 30 days and as late as 24 months after abstinence began, suggesting a potential role for beta-blockers in decreasing the risk for relapse.^[62]

Because decision-making deficits are common, individuals with more prominent deficits may particularly benefit from treatment in a residential setting.^[63]

Opiate withdrawal

Opiate withdrawal is generally considered less likely to produce severe morbidity or mortality compared with barbiturates and benzodiazepines. Safe withdrawal from opioids is termed detoxification and can be performed as outpatient or inpatient therapy, depending upon presence of comorbid medical and psychiatric problems, availability of social support, and polydrug abuse.

Lofexidine (Lucemyra) is an oral centrally-acting alpha2 agonist approved by the FDA in May 2018 for mitigation of opioid withdrawal symptoms in adults. Approval was supported by 2 randomized, double-blind, placebo-controlled clinical trials, an open-label study, and clinical pharmacology studies with concomitant administration of either methadone, buprenorphine, or naltrexone. Data show that compared to placebo, participants treated with lofexidine experienced less severe withdrawal symptoms and were significantly more likely to complete a 7-day opioid discontinuation treatment.^{[64, 65]}

In 2017, the FDA approved the first device designed to reduce the symptoms of opioid withdrawal. The NSS-2 Bridge device is placed behind the patient's ear and emits electrical pulses to stimulate branches of certain cranial nerves. The device can be used for up to 5 days during the acute phase of opioid withdrawal. Approval was based on a single-arm study of 73 patients undergoing physical withdrawal from opioids. Within 30 minutes of using the device, all patients showed a reduction in Clinical Opiate Withdrawal Scale (COWS) score of almost 31%. The device is available by prescription only.^[66]

The FDA approved another wearable device for the treatment of opioid withdrawal symptoms in 2018. The device is an auricular neurostimulator that emits electrical pulses to ear-fitted needles, much like the first device approved. Continuous treatment from the wearable device can be provided for up to 5 days, but there have been reports of reductions in symptoms of opioid withdrawal within 30 to 60 minutes after treatment starts, according to the manufacturer.^[67]

Methadone, buprenorphine, and alpha-2 agonists, such as clonidine and lofexidine, are commonly used pharmacologic methods of detoxification. The use of methadone and buprenorphine is based on the principle of cross-tolerance in which one opioid is replaced with another and then slowly withdrawn. Alpha-2 agonists appear to be most effective in suppressing autonomically mediated signs and symptoms of abstinence,^[68]but they are less effective for subjective symptoms.

Two Cochrane reviews compared the efficacy of alpha-2 adrenergic agonists to methadone or buprenorphine for management of withdrawal.^{[69, 70]}Patients experienced decreased side effects and stayed in treatment longer using tapered methadone compared to the alpha-2 agonists, clonidine or lofexidine.

Buprenorphine was associated with fewer adverse effects than clonidine, and patients were more likely to complete withdrawal with buprenorphine compared with clonidine. Moreover, a second multicenter randomized trial demonstrated that buprenorphine-naloxone was more effective than clonidine for opioid detoxification. Buprenorphine was equally effective as methadone for withdrawal completion, but withdrawal symptoms appeared to resolve more quickly with buprenorphine.

In summary, data to date suggest that buprenorphine and methadone are more effective than alpha-2 agonists, such as clonidine, for opioid detoxification, with buprenorphine associated with a shorter duration of withdrawal symptoms. However, all of these medications are effective, and the choice may depend in part on availability.

Kunoe et al described use of an investigational naltrexone implant in 56 abstinence-oriented patients who completed inpatient treatment for opioid dependence compared with patients who received usual care instead of the implant. The implant group had an average 45 days less heroin use and 60 days less opioid use than the usual care group over a 6-month period (P < 0.05). The naltrexone implant significantly reduced opioid use compared with usual care.^[71]

Hulse et al compared daily oral naltrexone with a sustained-release naltrexone implant in 70 patients with DSM-IV heroin dependence. Study participants were randomized to receive either daily oral naltrexone (50 mg/d, plus placebo implants) or naltrexone implant (2.3 g, plus placebo tablets). More patients in the oral group had naltrexone serum concentrations less than 2 mg/mL at month 1 (P< 0.001) and month 2 (P< 0.01) compared with the implant group. Return to regular heroin use was observed more in the oral group by 6 months (P =0.003) and at an earlier stage (median 115 d vs 158 d) compared with the implant group. The authors concluded that naltrexone implant is effective in reducing relapse to regular heroin use compared with oral naltrexone.^[72]

Psychotherapies and support groups: Detoxification alone, without ongoing treatment, is not adequate to manage patients.^[73]

Patients in methadone programs often benefit from cognitive behavioral, supportive, or analytical-oriented psychotherapies if they are added to standard drug counseling.

Cognitive behavior psychotherapy primarily focuses on the patient's thoughts and behaviors. Cognitive behavior–based models are widely used in drug rehabilitation programs. Cognitive behavior theories were aimed at substance abuse beginning in the mid-1980s. The techniques used help patients acquire specific skills for resisting substance use and teach coping skills to reduce problems related to drug use. Two major cognitive behavior theories of substance abuse are the following:

Relapse prevention: Based on the work of Marlatt and Gordon, important relapse prevention concepts and techniques include identification and avoidance of high-risk situations, understanding the chain of decisions leading to drug use, and changing one's lifestyle.
Cognitive therapy of substance abuse: Developed by Beck and colleagues, cognitive therapy of substance abuse is based on the concept that drug abusers engage in complex behaviors and thought processes, such as positive and negative drug-related beliefs and spontaneous flashes related to drug use before giving in to the actual drug use

Dynamic psychotherapy is based on the concept that all symptoms arise from underlying unconscious psychological conflicts. The major goal of this therapy is to help the patient become aware of these conflicts and develop more adaptive coping mechanisms and healthier methods of resolving intrapsychic conflict.

Group therapy is argued to be especially effective because it can target the social stigma attached to having lost the ability to control one's self with regard to the use of a substance. The presence of other group members who acknowledge having similar problems can provide support and be therapeutic in developing alternative methods of maintaining abstinence.

Aversion therapy involves pairing aversive stimuli to cognitive images of opioid use and conversely conjuring images of socially appropriate behaviors such as employment, education, and nondrug behavior.

Narcotics Anonymous (NA): In 1947, NA was formed in Lexington, Ky. NA is based on principles similar to those of Alcoholics Anonymous (AA), including progression through 12 steps of recovery. Some patients have difficulty engaging in the AA-NA approach to recovery; however, these programs do help some people and can provide much needed support for those attempting abstinence.

Although psychosocial therapy is likely to be beneficial in the treatment of opiate withdrawal, the specific type of psychosocial therapy may not be important. A Cochrane review assessed 11 studies involving 1592 patients and explored the effectiveness of any psychosocial intervention combined with any pharmacological intervention versus any pharmacological intervention alone for opioid detoxification treatment. Five different psychosocial interventions (including behavioral, counseling, and family therapies) were added to treatment with either methadone or buprenorphine. The addition of the psychosocial intervention (regardless of the specific psychosocial approach) to the pharmacological treatment significantly reduced dropouts, use of opioids during treatment, use of opioids during follow up, and clinical absences during treatment.^[74]

Pain management

A recent systematic review found that patients with chronic pain (noncancer) who had comorbid substance use disorders are more likely to be prescribed opioids and higher doses of opioid medications compared with patients who do not have a history of substance use disorders despite similar pain outcomes.^[75]

As more patients with opioid addiction receive OAT, physicians will encounter OAT patients with acute pain syndromes. Acute pain must be adequately treated in these patients.^[76]

Common misconceptions include the following:

OAT provides analgesia: Maintenance methadone or buprenorphine does not provide sustained analgesia. Although methadone and buprenorphine are potent analgesics, the analgesic properties last only 4-8 hours, while the medications are dosed every 24-48 hours.
Use of opioid analgesia may cause addiction relapse: No evidence indicates that exposure to opioid analgesics during acute pain increases relapse rates. In fact, evidence suggests that the stress of unrelieved pain can trigger relapse.
The combination of OAT and other opioids may cause respiratory depression: This is a theoretical risk that is not supported by clinical or empirical experience. Tolerance to respiratory and CNS depressant effects occurs rapidly and reliably.

Recommendations include the following:

Reassure patients that their addiction histories will not prevent adequate pain management, and discuss plans in a nonjudgmental manner.
Verify methadone and buprenorphine doses with clinics or prescribing physicians, and inform these physicians of any benzodiazepines or opioids given that may be detected on urine drug screening.
Aggressively treat pain with conventional opioid analgesics. Opioid cross-tolerance often necessitates higher opioid analgesic doses at shorter intervals.
Use continuous scheduled dosing orders rather than as-needed orders.
For patients receiving methadone maintenance therapy: Continue methadone maintenance dose and add short-acting opioid analgesics.
For patients receiving buprenorphine maintenance therapy: Pain management with opioids is complicated by the high affinity of buprenorphine for the mu receptor. This affinity may cause buprenorphine to compete with opioid analgesics at mu receptors. As buprenorphine's rate of dissociation from mu receptors is highly variable, naloxone should be available, and consciousness and respiration should be closely monitored.

Several options are possible, and the most effective approach will be determined with increasing clinical experience:

Continue BMT and titrate a short-acting opioid analgesic to effect.
Divide buprenorphine dose to 6-8 hours to take advantage of its short-acting analgesic properties.
Discontinue BMT, implement opioid analgesia, and restart BMT when opioid analgesia is no longer necessary.
In the hospitalized patient, discontinue BMT, initiate MMT, and add short-acting opioids to treat pain. Have naloxone at bedside. Convert back to BMT prior to discharge from hospital.

Guidelines

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David W Dixon, DO Psychiatrist, 2nd Chance Treatment Center, Gilbert, AZ

David W Dixon, DO is a member of the following medical societies: American Medical Association, American Psychiatric Association

Disclosure: Nothing to disclose.

Coauthor(s)

Ryan P Peirson, MD Aerospace Psychiatry Consultant, Aeromedical Consultation Service, Neuropsychiatry Branch (FECN), US Air Force School of Aerospace Medicine; Assistant Professor of Psychiatry, Chief of Forensic Psychiatry, Assistant Training Director, General Psychiatry Residency, Wright State University, Boonshoft School of Medicine

Ryan P Peirson, MD is a member of the following medical societies: Aerospace Medical Association, American Academy of Psychiatry and the Law, American Psychiatric Association, Ohio Psychiatric Physicians Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Glen L Xiong, MD Associate Clinical Professor, Department of Psychiatry and Behavioral Sciences, Department of Internal Medicine, University of California, Davis, School of Medicine; Medical Director, Sacramento County Mental Health Treatment Center

Glen L Xiong, MD is a member of the following medical societies: AMDA - The Society for Post-Acute and Long-Term Care Medicine, American College of Physicians, American Psychiatric Association, Central California Psychiatric Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: SafelyYou, Blue Cross Blue Shield<br/>book co-editor for: Wolter Kluwer, American Psychiatric Publishing Inc.

Additional Contributors

Barry I Liskow, MD Professor of Psychiatry, Vice Chairman, Psychiatry Department, Director, Psychiatric Outpatient Clinic, The University of Kansas Medical Center

Disclosure: Nothing to disclose.

Adrian Preda, MD Professor of Clinical Psychiatry and Human Behavior, University of California, Irvine, School of Medicine

Adrian Preda, MD is a member of the following medical societies: American Association for the Advancement of Science, American Psychiatric Association, International College of Neuropsychopharmacology, International Congress of Schizophrenia Research, Schizophrenia International Research Society, Society of Biological Psychiatry

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous authors Ziaur Rehman, MD, Suzan Khoromi, MD, James E Douglas, MD, Steven A Adelman, MD, and William J Meehan, MD, PhD to the development and writing of this article.

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