Part 1: Assessment and Diagnosis of Opioid Use Disorder

Diagnosis Recommendations

• (1)
  

  Other clinicians may diagnose opioid use disorder, but confirmation of the diagnosis by the provider with prescribing authority, and who recommends medication use, must be obtained before pharmacotherapy for opioid use disorder commences.

  
  
• (2)
  

  Opioid use disorder is primarily diagnosed on the basis of the history provided by the patient and a comprehensive assessment that includes a physical examination.

  
  
• (3)
  

  Validated clinical scales that measure withdrawal symptoms, for example, the Objective Opioid Withdrawal Scale (OOWS), the Subjective Opioid Withdrawal Scale (SOWS), and the Clinical Opioid Withdrawal Scale (COWS), may be used to assist in the evaluation of patients with opioid use disorder.

  
  
• (4)
  

  Urine drug testing during the comprehensive assessment process, and frequently during treatment, is recommended. The frequency of drug testing is determined by a number of factors including the stability of the patient, the type of treatment, and the treatment setting.

Part 2: Treatment Options

• (1)
  

  The choice of available treatment options for addiction involving opioid use should be a shared decision between clinician and patient.

  
  
• (2)
  

  Clinicians should consider the patient’s preferences, past treatment history, and treatment setting when deciding between the use of methadone, buprenorphine, and naltrexone in the treatment of addiction involving opioid use. The treatment setting described as level 1 treatment in the ASAM Criteria may be a general outpatient location such as a clinician’s practice site. The setting described as level 2 in the ASAM Criteria may be an intensive outpatient treatment or partial hospitalization program housed in a specialty addiction treatment facility, a community mental health center, or another setting. The ASAM Criteria describes level 3 or level 4 treatment, respectively, as a residential addiction treatment facility or hospital.

  
  
• (3)
  

  The venue in which treatment is provided is as important as the specific medication selected. Opioid treatment programs (OTPs) offer daily supervised dosing of methadone, and increasingly of buprenorphine. In accordance with the Federal law (21 CFR §1306.07), office-based opioid treatment (OBOT), which provides medication on a prescribed weekly or monthly basis, is limited to buprenorphine. Naltrexone can be prescribed in any setting by any clinician with the authority to prescribe any medication. Clinicians should consider a patient’s psychosocial situation, co-occurring disorders, and risk of diversion when determining whether OTP or OBOT is most appropriate.

  
  
• (4)
  

  OBOT may not be suitable for patients with active alcohol use disorder or sedative, hypnotic, or anxiolytic use disorder (or who are undergoing treatment for addiction involving the use of alcohol or other sedative drugs, including benzodiazepines or benzodiazepine receptor agonists). It may also be unsuitable for persons who are regularly using alcohol or other sedatives, but do not have addiction or a specific substance use disorder related to that class of drugs. The prescribing of benzodiazepines or other sedative-hypnotics should be used with extreme caution in patients who are prescribed methadone or buprenorphine for the treatment of an opioid use disorder.

  
  
• (5)
  

  Methadone is recommended for patients who may benefit from daily dosing and supervision in an OTP, or for patients for whom buprenorphine for the treatment of opioid use disorder has been used unsuccessfully in an OTP or OBOT setting.

  
  
• (6)
  

  Oral naltrexone for the treatment of opioid use disorder is often adversely affected by poor medication adherence. Clinicians should reserve its use for patients who would be able to comply with special techniques to enhance their adherence, for example, observed dosing. Extended-release injectable naltrexone reduces, but does not eliminate, issues with medication adherence.

Part 3: Treating Opioid Withdrawal

• (1)
  

  Using medications for opioid withdrawal management is recommended over abrupt cessation of opioids. Abrupt cessation of opioids may lead to strong cravings, which can lead to continued use.

  
  
• (2)
  

  Patients should be advised about risk of relapse and other safety concerns from using opioid withdrawal management as standalone treatment for opioid use disorder. Opioid withdrawal management on its own is not a treatment method.

  
  
• (3)
  

  Assessment of a patient undergoing opioid withdrawal management should include a thorough medical history and physical examination, focusing on signs and symptoms associated with opioid withdrawal.

  
  
• (4)
  

  Opioid withdrawal management in cases in which methadone is used to manage withdrawal symptoms must be done in an inpatient setting or in an OTP. For short-acting opioids, tapering schedules that decrease in daily doses of prescribed methadone should begin with doses between 20 and 30 mg per day, and should be completed within 6–10 days.

  
  
• (5)
  

  Opioid withdrawal management in cases in which buprenorphine is used to manage withdrawal symptoms should not be initiated until 12–18 hours after the last dose of a short-acting agonist such as heroin or oxycodone, and 24–48 hours after the last dose of a long-acting agonist such as methadone. A dose of buprenorphine sufficient to suppress withdrawal symptoms is given (this can be 4–16 mg per day) and then the dose is tapered. The duration of the tapering schedule can be as brief as 3–5 days or as long as 30 days or more.

  
  
• (6)
  

  The use of combinations of buprenorphine and low doses of oral naltrexone to manage withdrawal and facilitate the accelerated introduction of extended-release injectable naltrexone has shown promise. More research will be needed before this can be accepted as standard practice.

  
  
• (7)
  

  The Guideline Committee recommends, based on consensus opinion, the inclusion of clonidine as a practice to support opioid withdrawal. Clonidine is not FDA-approved for the treatment of opioid withdrawal, but it has been used extensively off-label for this purpose. Clonidine may be used orally or transdermally at doses of 0.1–0.3 mg every 6–8 hours, with a maximum dose of 1.2 mg daily to assist in the management of opioid withdrawal symptoms. Its hypotensive effects often limit the amount that can be used. Clonidine can be combined with other non-narcotic medications targeting specific opioid withdrawal symptoms such as benzodiazepines for anxiety, loperamide for diarrhea, acetaminophen or nonsteroidal anti-inflammatory medications (NSAIDs) for pain, and ondansetron or other agents for nausea.

  
  
• (8)
  

  Opioid withdrawal management using anesthesia UROD is not recommended due to high risk for adverse events or death. Naltrexone-facilitated opioid withdrawal management can be a safe and effective approach, but should be used only by clinicians experienced with this clinical method, and in cases in which anesthesia or conscious sedation are not being employed.

Part 4: Methadone

• (1)
  

  Methadone is a treatment option recommended for patients who are physiologically dependent on opioids, able to give informed consent, and who have no specific contraindications for agonist treatment when it is prescribed in the context of an appropriate plan that includes psychosocial intervention.

  
  
• (2)
  

  The recommended initial dose for methadone ranges from 10 to 30 mg, with reassessment in 3–4 hours, and a second dose not to exceed 10 mg on the first day if withdrawal symptoms are persisting.

  
  
• (3)
  

  The usual daily dosage of methadone ranges from 60 to 120 mg. Some patients may respond to lower doses and some patients may need higher doses. Dosage increases in 5- to 10-mg increments applied no more frequently than every 7 days (depending on clinical response) are necessary to avoid over sedation, toxicity, or even iatrogenic overdose deaths.

  
  
• (4)
  

  The administration of methadone should be monitored because unsupervised administration can lead to misuse and diversion. OTP regulations require monitored medication administration until the patient’s clinical response and behavior demonstrates that the prescribing of nonmonitored doses is appropriate.

  
  
• (5)
  

  Psychosocial treatment, although sometimes minimally needed, should be implemented in conjunction with the use of methadone in the treatment of opioid use disorder.

  
  
• (6)
  

  Methadone should be reinstituted immediately if relapse occurs, or when an assessment determines that the risk of relapse is high for patients who previously received methadone in the treatment of opioid use disorder, but who are no longer prescribed such treatment.

  
  
• (7)
  

  Strategies directed at relapse prevention are an important part of comprehensive addiction treatment and should be included in any plan of care for a patient receiving active opioid treatment or ongoing monitoring of the status of their addictive disease.

  
  
• (8)
  

  Switching from methadone to another medication for the treatment of opioid use disorder may be appropriate if the patient experiences intolerable side effects or is not successful in attaining or maintaining treatment goals through the use of methadone.

  
  
• (9)
  

  Patients switching from methadone to buprenorphine in the treatment of opioid use disorder should be on low doses of methadone before switching medications. Patients on low doses of methadone (30–40 mg per day or less) generally tolerate transition to buprenorphine with minimal discomfort, whereas patients on higher doses of methadone may experience significant discomfort in switching medications.

  
  
• (10)
  

  Patients switching from methadone to oral naltrexone or extended-release injectable naltrexone must be completely withdrawn from methadone and other opioids before they can receive naltrexone. The only exception would apply when an experienced clinician receives consent from the patient to embark on a plan of naltrexone-facilitated opioid withdrawal management.

  
  
• (11)
  

  Patients who discontinue agonist therapy with methadone or buprenorphine and then resume opioid use should be made aware of the risks associated with opioid overdose, and especially the increased risk of death.

Part 5: Buprenorphine

• (1)
  

  Opioid-dependent patients should wait until they are experiencing mild to moderate opioid withdrawal before taking the first dose of buprenorphine to reduce the risk of precipitated withdrawal. Generally, buprenorphine initiation should occur at least 6–12 hours after the last use of heroin or other short-acting opioids, or 24–72 hours after their last use of long-acting opioids such as methadone.

  
  
• (2)
  

  Induction of buprenorphine should start with a dose of 2–4 mg. Dosages may be increased in increments of 2–4 mg.

  
  
• (3)
  

  Clinicians should observe patients in their offices during induction. Emerging research, however, suggests that many patients need “not” be observed and that home buprenorphine induction may be considered. Home-based induction is recommended only if the patient or prescribing physician is experienced with the use of buprenorphine. This is based on the consensus opinion of the Guideline Committee.

  
  
• (4)
  

  Buprenorphine doses after induction and titration should be, on average, at least 8 mg per day. However, if patients are continuing to use opioids, consideration should be given to increasing the dose by 4–8 mg (daily doses of 12–16 mg or higher). The FDA approves dosing to a limit of 24 mg per day, and there is limited evidence regarding the relative efficacy of higher doses. In addition, the use of higher doses may increase the risk of diversion.

  
  
• (5)
  

  Psychosocial treatment should be implemented in conjunction with the use of buprenorphine in the treatment of opioid use disorder.

  
  
• (6)
  

  Clinicians should take steps to reduce the chance of buprenorphine diversion. Recommended strategies include frequent office visits (weekly in early treatment), urine drug testing, including testing for buprenorphine and metabolites, and recall visits for pill counts.

  
  
• (7)
  

  Patients should be tested frequently for buprenorphine, other substances, and prescription medications. Accessing Prescription Drug Monitoring Program (PDMP) data may be useful for monitoring.

  
  
• (8)
  

  Patients should be seen frequently at the beginning of their treatment. Weekly visits (at least) are recommended until patients are determined to be stable. There is no recommended time limit for treatment.

  
  
• (9)
  

  Buprenorphine taper and discontinuation is a slow process and close monitoring is recommended. Buprenorphine tapering is generally accomplished over several months. Patients should be encouraged to remain in treatment for ongoing monitoring past the point of discontinuation.

  
  
• (10)
  

  When considering a switch from buprenorphine to naltrexone, 7–14 days should elapse between the last dose of buprenorphine and the start of naltrexone to ensure that the patient is not physically dependent on opioids before starting naltrexone.

  
  
• (11)
  

  When considering a switch from buprenorphine to methadone, there is no required time delay because the addition of a full mu-opioid agonist to a partial agonist does not typically result in any type of adverse reaction.

  
  
• (12)
  

  Patients who discontinue agonist therapy and resume opioid use should be made aware of the risks associated with an opioid overdose, and especially the increased risk of death.

Part 6: Naltrexone

• (1)
  

  Naltrexone is a recommended treatment in preventing relapse in opioid use disorder. Oral formula naltrexone may be considered for patients in whom adherence can be supervised or enforced. Extended-release injectable naltrexone may be more suitable for patients who have issues with adherence.

  
  
• (2)
  

  Oral naltrexone should be taken daily in 50-mg doses, or three times weekly in two 100-mg doses followed by one 150-mg dose.

  
  
• (3)
  

  Extended-release injectable naltrexone should be administered every 4 weeks by deep IM injection in the gluteal muscle at a set dosage of 380 mg per injection.

  
  
• (4)
  

  Psychosocial treatment is recommended in conjunction with treatment with naltrexone. The efficacy of naltrexone use in conjunction with psychosocial treatment has been established, whereas the efficacy of extended release injectable naltrexone without psychosocial treatment “has not” been established.

  
  
• (5)
  

  There is no recommended length of treatment with oral naltrexone or extended-release injectable naltrexone. Duration depends on clinical judgment and the patient’s individual circumstances. Because there is no physical dependence associated with naltrexone, it can be stopped abruptly without withdrawal symptoms.

  
  
• (6)
  

  Switching from naltrexone to methadone or buprenorphine should be planned, considered, and monitored. Switching from an antagonist such as naltrexone to a full agonist (methadone) or a partial agonist (buprenorphine) is generally less complicated than switching from a full or partial agonist to an antagonist because there is no physical dependence associated with antagonist treatment and thus no possibility of precipitated withdrawal. Patients being switched from naltrexone to buprenorphine or methadone will not have physical dependence on opioids and thus the initial doses of methadone or buprenorphine used should be low. Patients should not be switched until a significant amount of the naltrexone is no longer in their system, about 1 day for oral naltrexone or 30 days for extended-release injectable naltrexone.

  
  
• (7)
  

  Patients who discontinue antagonist therapy and resume opioid use should be made aware of the increased risks associated with an opioid overdose, and especially the increased risk of death.

Part 7: Psychosocial Treatment in Conjunction With Medications for the Treatment of Opioid Use Disorder

• (1)
  

  Psychosocial treatment is recommended in conjunction with any pharmacological treatment of opioid use disorder. At a minimum, psychosocial treatment should include the following: psychosocial needs assessment, supportive counseling, links to existing family supports, and referrals to community services.

  
  
• (2)
  

  Treatment planning should include collaboration with qualified behavioral healthcare providers to determine the optimal type and intensity of psychosocial treatment and for renegotiation of the treatment plan for circumstances in which patients do not adhere to recommended plans for, or referrals to, psychosocial treatment.

  
  
• (3)
  

  Psychosocial treatment is generally recommended for patients who are receiving opioid agonist treatment (methadone or buprenorphine).

  
  
• (4)
  

  Psychosocial treatment is recommended in the treatment of pregnant women with opioid use disorder.

  
  
• (5)
  

  Counseling and testing for HIV should be provided in accordance with state law. Tests for hepatitis B and C and liver function are also suggested. Hepatitis A and B vaccination is recommended for those whose hepatitis serology is negative.

  
  
• (6)
  

  Urine drug testing may be used to detect or confirm suspected opioid and other drug use with informed consent from the mother, realizing that there may be adverse legal and social consequences of her use. State laws differ on reporting substance use during pregnancy. Laws that penalize women for use and for obtaining treatment serve to prevent women from obtaining prenatal care and worsen outcomes.

  
  
• (7)
  

  Pregnant women who are physically dependent on opioids should receive treatment using methadone or buprenorphine monoproduct rather than withdrawal management or abstinence.

  
  
• (8)
  

  Care for pregnant women with opioid use disorder should be comanaged by an obstetrician and an addiction specialist physician. Release of information forms need to be completed to ensure communication among healthcare providers.

  
  
• (9)
  

  Treatment with methadone should be initiated as early as possible during pregnancy.

  
  
• (10)
  

  Hospitalization during initiation of methadone and treatment with buprenorphine may be advisable due to the potential for adverse events, especially in the third trimester.

  
  
• (11)
  

  In an inpatient setting, methadone should be initiated at a dose range of 20–30 mg. Incremental doses of 5–10 mg are given every 3–6 hours, as needed, to treat withdrawal symptoms.

  
  
• (12)
  

  After induction, clinicians should increase the methadone dose in 5- to 10-mg increments per week. The goal is to maintain the lowest dose that controls withdrawal symptoms and minimizes the desire to use additional opioids.

  
  
• (13)
  

  Twice daily dosing is more effective and has fewer side effects than single dosing but may not be practical because methadone is typically dispensed in an outpatient clinic.

  
  
• (14)
  

  Clinicians should be aware that the pharmacokinetics of methadone are affected by pregnancy. With advancing gestational age, plasma levels of methadone progressively decrease and clearance increases. Increased or split doses may be needed as pregnancy progresses. After child birth, doses may need to be adjusted.

  
  
• (15)
  

  Buprenorphine monoproduct is a reasonable and recommended alternative to methadone for pregnant women. Whereas there is evidence of safety, there is insufficient evidence to recommend the combination buprenorphine/naloxone formulation.

  
  
• (16)
  

  If a woman becomes pregnant while she is receiving naltrexone, it is appropriate to discontinue the medication if the patient and doctor agree that the risk of relapse is low. If the patient is highly concerned about relapse and wishes to continue naltrexone, she should be informed about the risks of staying on naltrexone and provide her consent for ongoing treatment. If the patient wishes to discontinue naltrexone, but then reports relapse to opioid use, it may be appropriate to consider treatment with methadone or treatment with buprenorphine.

  
  
• (17)
  

  Naloxone is not recommended for use in pregnant women with opioid use disorder except in situations of life-threatening overdose.

  
  
• (18)
  

  Mothers receiving methadone and buprenorphine monoproduct for the treatment of opioid use disorders should be encouraged to breastfeed.

Part 9: Special Populations: Individuals With Pain

• (1)
  

  For all patients with pain, it is important that the correct diagnosis be made and that a target suitable for treatment is identified.

  
  
• (2)
  

  If pharmacological treatment is considered, non-narcotic medications such as acetaminophen and NSAIDs should be tried first.

  
  
• (3)
  

  Opioid agonists (methadone or buprenorphine) should be considered for patients with active opioid use disorder who are not under treatment.

  
  
• (4)
  

  Pharmacotherapy in conjunction with psychosocial treatment should be considered for patients with pain who have opioid use disorder.

  
  
• (5)
  

  Patients on methadone for the treatment of opioid use disorder will require doses of opioids in addition to their regular daily dose of methadone to manage acute pain.

  
  
• (6)
  

  Patients on methadone for the treatment of opioid use disorder and who are admitted for surgery may require additional short-acting opioid pain relievers. The dose of pain relievers prescribed may be higher due to tolerance.

  
  
• (7)
  

  Temporarily increasing buprenorphine dosing may be effective for mild acute pain.

  
  
• (8)
  

  For severe acute pain, discontinuing buprenorphine and commencing on a high-potency opioid (such as fentanyl) is advisable. Patients should be monitored closely and additional interventions such as regional anesthesia should also be considered.

  
  
• (9)
  

  The decision to discontinue buprenorphine before an elective surgery should be made in consultation with the attending surgeon and anesthesiologist. If it is decided that buprenorphine should be discontinued before surgery, this should occur 24–36 hours in advance of surgery and restarted postoperatively when the need for full opioid agonist analgesia has passed.

  
  
• (10)
  

  Patients on naltrexone will not respond to opioid analgesics in the usual manner. Therefore, it is recommended that mild pain be treated with NSAIDs, and moderate to severe pain be treated with ketorolac on a short-term basis.

  
  
• (11)
  

  Oral naltrexone should be discontinued 72 hours before surgery and extended-release injectable naltrexone should be discontinued 30 days before an anticipated surgery.

Part 10: Special Populations: Adolescents

• (1)
  

  Clinicians should consider treating adolescents who have opioid use disorder using the full range of treatment options, including pharmacotherapy.

  
  
• (2)
  

  Opioid agonists (methadone and buprenorphine) and antagonists (naltrexone) may be considered for treatment of opioid use disorder in adolescents. Age is a consideration in treatment, and Federal laws and US FDA approvals need to be considered for patients under age 18.

  
  
• (3)
  

  Psychosocial treatment is recommended in the treatment of adolescents with opioid use disorder.

  
  
• (4)
  

  Concurrent practices to reduce infection (e.g., sexual risk reduction interventions) are recommended as components of comprehensive treatment for the prevention of sexually transmitted infections and blood-borne viruses.

  
  
• (5)
  

  Adolescents may benefit from treatment in specialized treatment facilities that provide multidimensional services.

Part 11: Special Populations: Individuals With Co-occurring Psychiatric Disorders

• (1)
  

  A comprehensive assessment including determination of mental health status should evaluate whether the patient is stable. Patients with suicidal or homicidal ideation should be referred immediately for treatment and possibly hospitalization.

  
  
• (2)
  

  Management of patients at risk for suicide should include reducing immediate risk; managing underlying factors associated with suicidal intent; and monitoring and follow-up.

  
  
• (3)
  

  All patients with psychiatric disorders should be asked about suicidal ideation and behavior. Patients with a history of suicidal ideation or attempts should have opioid use disorder, and psychiatric medication use, monitored.

  
  
• (4)
  

  Assessment for psychiatric disorder should occur at the onset of agonist or antagonist treatment. Reassessment using a detailed mental status examination should occur after stabilization with methadone, buprenorphine, or naltrexone.

  
  
• (5)
  

  Pharmacotherapy in conjunction with psychosocial treatment should be considered for patients with opioid use disorder and a co-occurring psychiatric disorder.

  
  
• (6)
  

  Clinicians should be aware of potential interactions between medications used to treat co-occurring psychiatric conditions and opioid use disorder.

  
  
• (7)
  

  Assertive community treatment should be considered for patients with co-occurring schizophrenia and opioid use disorder who have a recent history of, or are at risk of, repeated hospitalization or homelessness.

Part 12: Special Populations: Individuals in the Criminal Justice System

• (1)
  

  Pharmacotherapy for the continued treatment of opioid use disorders, or the initiation of pharmacotherapy, has been shown to be effective and is recommended for prisoners and parolees regardless of the length of their sentenced term.

  
  
• (2)
  

  Individuals with opioid use disorder who are within the criminal justice system should be treated with some type of pharmacotherapy in addition to psychosocial treatment.

  
  
• (3)
  

  Opioid agonists (methadone and buprenorphine) and antagonists (naltrexone) may be considered for treatment. There is insufficient evidence to recommend any one treatment as superior to another for prisoners or parolees.

  
  
• (4)
  

  Pharmacotherapy should be initiated a minimum of 30 days before release from prison.

Part 13: Naloxone for the Treatment of Opioid Overdose

• (1)
  

  Naloxone should be given in case of opioid overdose.

  
  
• (2)
  

  Naloxone can and should be administered to pregnant women in cases of overdose to save the mother’s life.

  
  
• (3)
  

  The Guideline Committee, based on consensus opinion, recommends that patients who are being treated for opioid use disorder and their family members/significant others be given prescriptions for naloxone. Patients and family members/significant others should be trained in the use of naloxone in overdose.

  
  
• (4)
  

  The Guideline Committee, based on consensus opinion, recommends that first responders such as emergency medical services personnel, police officers, and firefighters be trained in and authorized to administer naloxone.

Epidemiology

According to the 2013 National Survey on Drug Use and Health (NSDUH), ¹⁴⁶ 4.5 million individuals were current nonmedical users of prescription opioids (past month) and 1.9 million individuals met DSM-IV criteria for abuse or dependence of prescription opioids. In addition, the NSDUH reported that 289,000 people were current (past month) users of heroin and 517,000 met DSM IV criteria for abuse or dependence in 2013. The rate of prescription opioid use for nonmedical purposes was 1.7% in persons 12 years and older. However, the rate of prescription opioid use among youth aged 12–17 declined from 3.2% in 2002 and 2003 to 1.7% in 2013.

It is important to note that nonmedical use of prescription opioids has been shown to be associated with the initiation of heroin use. In a study pooling data from the NSDUH from 2002 to 2012, the incidence of heroin use was 19 times greater among individuals who reported prior nonmedical use of prescription opioids compared to individuals who did not report prior nonmedical prescription opioid use. ¹¹⁷

Mortality and Morbidity

Opioid use is associated with increased mortality. The leading causes of death in people using opioids for nonmedical purposes are overdose and trauma. ⁵⁰ The number of unintentional overdose deaths from prescription opioids has more than quadrupled since 1999. ¹²⁷

Opioid use increases the risk of exposure to HIV, viral hepatitis, and other infectious agents through contact with infected blood or body fluids (e.g., semen) that results from sharing syringes and injection paraphernalia, or through unprotected sexual contact. Similarly, it increases the risk of contracting infectious diseases such as HIV/AIDS and hepatitis because people under the influence of drugs may engage in risky behaviors that can expose them to these diseases. ⁵⁰

It is notable that injection drug use (IDU) is the highest-risk behavior for acquiring hepatitis C virus (HCV) infection and continues to drive this epidemic. Of the 17,000 new HCV infections in the United States in 2010, more than half (53%) involved IDU. In 2010, hepatitis B virus (HBV) infection rates were estimated to be 20% higher among people who engaged in IDU in the United States. ¹²³

Included and Excluded Medications

The medications covered in this guideline include the following:

• (1)
  

  Methadone (Part 4)

  
  
• (2)
  

  Buprenorphine (Part 5)

  
  
• (3)
  

  Naltrexone in oral and extended-release injectable formulations (Part 6)

  
  
• (4)
  

  Naloxone (Part 13)

All of these medications act directly upon the opioid receptors, particularly the mu-subtype. Methadone is a mu-receptor agonist; buprenorphine is a partial mu-receptor agonist; and naltrexone is an antagonist. Naloxone is a fast-acting antagonist used to reverse opioid overdose, a condition that may be life-threatening. Because of the differing actions of these medications at the receptor level, they can have very different clinical effects during treatment.

Other medications show promise for the treatment of opioid use disorder; however, there is insufficient evidence at this writing to make a full analysis of their effectiveness. For example, whereas not FDA-approved for opioid withdrawal syndrome in the United States, it is recognized that clonidine, an alpha-2 adrenergic agonist, has been in use in clinical settings for 25 years. Lofexidine (known as BritLofex, Britannia Pharmaceuticals) is approved for treating opioid withdrawal use in the United Kingdom. Because of their long history of off-label use in the United States, clonidine and buprenorphine are described for opioid withdrawal syndrome in this Practice Guideline. Again, there are other off-label medications for withdrawal management in the treatment of opioid use disorder (e.g., tramadol) that have been excluded from this guideline because there is insufficient evidence to make a full analysis of their effectiveness or consensus recommendations for their use at this time.

The ASAM recognizes that withdrawal management and withdrawal management medications could be potential topics for future guideline development. ASAM will regularly review its published guidelines to determine when partial or full updates are needed. The emergence of newly approved medications and new research will be considered as part of this process. It is also recognized that ASAM may develop guidelines or consensus documents on topics addressed in this Practice Guideline (e.g., urine drug testing). If that occurs before any update to this Practice Guideline, it is to be assumed that the recommendations in the latter documents will take precedence until this Practice Guideline is updated.

Review of Existing Clinical Guidelines

All existing clinical guidelines that addressed the use of medications and psychosocial treatments in the treatment of opioid use disorders including special populations (e.g., pregnant women, individuals with pain, and adolescents), and that were published during the period from January 2000 to April 2014, were identified and reviewed. In total, 49 guidelines were identified and 34 were ultimately included in the analysis. See “Appendix I” for a list of the guidelines that were reviewed. The included guidelines offered evidence-based recommendations for the treatment of opioid use disorder using methadone, buprenorphine, naltrexone, and/or naloxone.

The majority of existing clinical guidelines are based on systematic reviews of the literature including appropriateness criteria used in the RAM. Therefore, the aim of this exercise was not to re-review all of the research literature, but to identify within the existing clinical guidelines how they addressed common questions or considerations that clinicians are likely to raise in the course of deciding whether and how to use medications as part of the treatment of individuals with opioid use disorder.

Analysis of Clinical Guidelines

On the basis of the previously reviewed existing clinical guidelines, an analytic table was created and populated to display the identified key components. This table served as the foundation for development of hypothetical statements. The hypothetical statements were sentences describing recommendations derived from the analysis of the clinical guidelines.

Preparation of Literature Review on Psychosocial Interventions

A review of the literature on the efficacy of psychosocial treatment delivered in conjunction with medications for the treatment of opioid use disorder was conducted. This review was partially supported by funding from the National Institute on Drug Abuse (NIDA). Articles were identified for inclusion in the review through searches conducted in two bibliographic databases (e.g., PsycINFO and PubMed) using predefined search terms and established selection criteria. Titles and abstracts were reviewed for inclusion by two members of the research team.

To increase the overall relevance of the review, the search was limited to articles in the 6-year period from 2008 to the present. In the event that the article reflected a secondary analysis of data from a relevant study, the original study was included in the literature review. In addition, findings from three prominent systematic reviews (i.e., 2007 review on psychosocial interventions in pharmacotherapy of opioid dependence prepared for the Technical Development Group for the World Health Organization, “Guidelines for Psychosocially Assisted Pharmacotherapy of Opioid Dependence,” and two 2011 Cochrane reviews examining psychosocial and pharmacological treatments for opioid withdrawal management and psychosocial interventions combined with agonist treatment) were summarized. ^4,5,55

The literature search yielded 938 articles. The titles and abstracts were reviewed to determine if the study met the inclusion/exclusion criteria, and those that did not ( n = 787) were removed. The remaining 151 articles were then reviewed for inclusion, and 27 articles were ultimately retained for use in the literature review, as the others did not meet the predetermined inclusion/exclusion criteria. These articles, along with the relevant systematic reviews of the literature, are described in the literature review in the next section.

RAND/UCLA Appropriateness Method

The first step in the RAM is to develop a set of hypothetical statements, which were derived from the guideline analysis and literature review described in the previous section, for appropriateness rating.

The analysis and literature review generated a list of 245 hypothetical statements that reflected recommended medical or psychosocial treatment. Each member of the Guideline Committee reviewed the guideline analysis and literature review, and privately rated 245 hypothetical clinical statements on a nine-point scale of “appropriateness.” In the context of this Practice Guideline, the meaning of appropriateness was defined as:

A statement, procedure or treatment is considered to be appropriate if the expected health benefit (e.g., increased life expectancy, relief of pain, reduction in anxiety, improved functional capacity) exceeds the expected negative consequences (e.g., mortality, morbidity, anxiety, pain) by a sufficiently wide margin that the procedure is worth doing, exclusive of cost.

An appropriateness score of 1 meant that the statement was “highly inappropriate.” An appropriateness rating of 9 meant that the statement was “highly appropriate.” These appropriateness statements were meant to identify a lack of consensus in existing guidelines and research literature.

Guideline Committee Meeting

Upon completion and collection of the individual Guideline Committee member ratings, 201 of the 245 hypothetical statements were identified as meeting the criteria for consensus. The remaining 44 statements had divergent ratings. On September 15, 2014, the Guideline Committee met in Washington, District of Columbia, to discuss the hypothetical clinical statements. At this meeting, the committee came to consensus on the hypothetical statements. After the meeting, the information gathered was used to revise several of the statements; and the Guideline Committee was asked to re-rate the revised statements.

Literature Review

A supplementary literature review was also conducted to identify relevant studies that might resolve statements that had resulted in divergent ratings during the Guideline Committee meeting. Information relating to the vast majority of these divergent ratings was subsequently found within the existing guideline data set, and consequently included in the first draft of the Practice Guideline.

For the topics and questions for which answers were not found in the existing guideline data set, a full literature review was conducted. The topics and questions for which no further clarification was found in the literature were considered “gaps” that require additional research before inclusion in this guideline. These gaps in the literature were: urine drug testing; patients using marijuana; the safety of delivering injectable naltrexone doses to patients with high metabolism every 3 weeks; and the safety of adding full agonists to treatment with buprenorphine for pain management.

Creation and Revision of Guideline Outline

All the identified appropriate/uncertain hypothetical statements and supporting research were incorporated into an outline defining each specific section to be included in the final Practice Guideline. The draft outline, review of existing guidelines, and literature review were all sent to the Guideline Committee members for review and discussion during two web teleconferences and through private communication. Two teleconferences were held to ensure full participation from members of the Guideline Committee.

Committee Review and Rating

The Guideline Committee then re-rated the 211 “appropriate” hypothetical statements for necessity. When rating for necessity, the Guideline Committee members were asked to adhere to the following guidance:

A statement was considered necessary when all the following criteria were met:

• (1)
  

  It would be considered improper care not to provide this service.

  
  
• (2)
  

  Reasonable chance exists that this procedure and/or service will benefit the patient. (A procedure could be appropriate if it had a low likelihood of benefit, but few risks; however, such procedures would not be necessary.)

  
  
• (3)
  

  The benefit to the patient is of significance and certainty. (A procedure could be appropriate if it had a minor but almost certain benefit, but it would not be necessary.)

Necessity is a more stringent criterion than appropriateness. If a procedure is necessary, this means that the expected benefits outweigh the expected harms (i.e., it is appropriate), and that they do so by such a margin that the physician must recommend the service. Of course, patients may decline to follow their physician’s recommendations. ⁶⁴

Of the 211 rated statements, 184 hypothetical statements met the criteria for being both appropriate and necessary, and were incorporated in the guideline.

Final Draft Outline

The final draft outline highlighted hypothetical statements that had been determined to rise to the level of necessity.

Draft and Review

A first draft of the Practice Guideline was created using the Guideline Committee’s recommendations resulting from supporting evidence and the appropriateness and necessity ratings discussed above. The first draft of the Practice Guideline was sent to the Guideline Committee for review and electronic comment. During a subsequent teleconference in January 2015, the Guideline Committee discussed the comments received via first review. Revisions were made to the draft, which went again through subsequent reviews by the Guideline Committee and the ASAM Quality Council throughout February and March 2015.

External Review

The ASAM sought input from ASAM members—patients and caregiver groups, stakeholders including experts from criminal justice system, government agencies, other professional societies, and hospitals and health systems. ASAM also made the document and a qualitative review guide available to ASAM members and the general public for a one week period of review and comment. The final draft Practice Guideline was submitted to the ASAM Board of Directors in April 2015.

Exhibit 1: Methodology

Assessment and History Considerations Specific to Females

Use of contraception and determination of pregnancy are factors in choosing treatment options for women with opioid use disorder. Contraception and reproductive health are topics of discussion within the assessment process of female patients who are considering opioid use disorder treatment. Clinicians and female patients should keep in mind that fertility increases as treatment becomes effective. Case management plans may need to include referral to gynecological services for female patients. An in-depth discussion of the treatment of opioid use disorder in pregnant women is described later in “Part 8: Special Populations: Pregnant Women.”

Laboratory Tests

Initial lab testing should include hepatitis C and HIV testing. Hepatitis serology and vaccination are recommended. Hepatitis A and B testing and vaccination should be offered when appropriate. As above, women of childbearing potential and age should be tested for pregnancy. Tuberculosis testing and testing for sexually transmitted infections, including syphilis, may be considered.

A complete blood count and liver function study should be conducted to screen for liver dysfunction, infection, and other medical conditions. Abnormal results may require further investigation.

Assessment for Mental Health Status and Psychiatric Disorder

Patients being evaluated for opioid use disorder, and/or for possible medication use in the treatment of opioid use disorder, should undergo an evaluation of possible co-occurring psychiatric disorders. During the assessment process and physical examination, it is important for the clinician to assess for mental health status consistent with the ASAM Standards.

In the ASAM Standards, I.1 indicates that the physician “assures that an initial comprehensive, multicomponent assessment is performed for each patient, either by performing it her/himself or by assuring it is conducted in full or in part by another qualified professional within the system in which she/he is working.” A thorough medical and psychiatric history and family history is indicated as a component of this same standard. Patients who are determined as exhibiting urgent or emergent psychiatric conditions, or who are psychiatrically unstable and represent a danger to themselves or others, should be referred to the appropriate level of care for their safety and the safety of others. Further specialty evaluation may be warranted depending on severity of indicators for psychiatric instability. Indicators of psychiatric instability or disorder include acute suicidal or homicidal ideation, acute psychosis, and delirium.

Assessment for Alcohol and Substance Use and Treatment History

A careful evaluation of current and past use of alcohol and drugs, including nonmedical use of prescription medications, is required to diagnose opioid use disorder. Because opioid use disorder may co-occur with other use disorders, the evaluator should assess frequency and quantity of use.

Completing a history of opioid drug use with a patient who has been identified as using opioids should focus on the following:

• (1)
  

  type and amount of opioid(s) used recently;

  
  
• (2)
  

  route of administration;

  
  
• (3)
  

  last use;

  
  
• (4)
  

  treatment history; and

  
  
• (5)
  

  problems resulting from drug use.

The amount of drug being consumed will impact the likelihood and severity of withdrawal symptoms when the drug is stopped, so it is useful to obtain an estimate of the amount used (each time and number of times per day).

Prescription Drug Monitoring Programs (PDMPs) offer information about prescription opioid use. They can serve as important resources for clinicians’ use in completing full patient clinical assessments of opiate and other controlled substance use history, and it is recommended that they be utilized. It is recognized, as detailed in “Exhibit 2: Prescription Drug Monitoring Programs,” that there is variation across states in terms of the level of operation of these programs, the extent of their data sharing across states, and state requirements for their use before prescribing controlled substances.

In addition, a history of outpatient and inpatient treatment for alcohol and other substance use disorders should be collected. Clinicians should ask for information about the type and duration of treatment and outcomes.

Assessment for Co-Occurring Alcohol and Substance Use

Opioid use disorder often co-occurs with alcohol and other substance use disorders. Therefore, evaluation of co-occurring alcohol and substance use is recommended.

Clinicians should assess signs and symptoms of alcohol or sedative, hypnotic, or anxiolytic intoxication or withdrawal. Alcohol or sedative, hypnotic, or anxiolytic withdrawal may result in seizures, hallucinosis, or delirium, and may represent a medical emergency. Likewise, concomitant use of alcohol and sedatives, hypnotics, or anxiolytics with opioids may contribute to respiratory depression. Patients with significant co-occurring substance use disorders, especially severe alcohol or sedative, hypnotic, or anxiolytic use, may require a higher level of care.

An evaluation of past and current substance use should be conducted, and a determination as to whether addiction involving other substances or other behaviors is present. For instance, the regular use of marijuana or cannabinoids, tobacco or electronic nicotine delivery devices, or other drugs should not be a reason to suspend medication use in the treatment of addiction involving opioid use. Concurrent use of other drugs or active engagement in other addictive behaviors should lead to consideration of other treatment plan components for the patient. The presence of co-occurring substance use disorders should provoke a re-evaluation of the level of care that is in place for psychosocial treatment, along with pharmacological therapy. In most cases, co-occurring drug use will not represent a medical emergency. In such cases, patients can be treated for both their opioid use disorder and co-occurring alcohol or substance use disorders. However, ongoing use of other drugs may lead to poorer treatment outcomes. Evidence does demonstrate that individuals who are actively using other substances during opioid use disorder treatment have a poorer prognosis. ^66,99,128

The Guideline Committee cautioned against excluding patients from treatment for their opioid use disorder because they are using marijuana or other psychoactive substances that do not interact with opioids, and that are not prescribed by their physician. Whereas there is a paucity of research examining this topic, evidence demonstrates that patients under treatment have better outcomes than those not retained under treatment. ^82,108

Suspension of opioid use disorder treatment may increase the risk for death from overdose, accidents, or other health problems. However, continued use of marijuana or other psychoactive substances may impede treatment for opioid use disorder; thus, an approach emphasizing cessation of all unprescribed substances is likely to result in the best results. Further research is needed on the outcomes of patients in opioid use disorder treatment who are continuing the nonmedical use of psychoactive substances.

Assessment for Tobacco Use

Tobacco use should be queried, and the benefits of cessation should be promoted routinely with patients presenting for evaluation and treatment of opioid use disorder. Several studies have demonstrated that smoking cessation improves long-term outcomes among individuals receiving treatment for substance use disorders. ^15,129,157

Assessment of Social and Environmental Factors

Clinicians should conduct an assessment of social and environmental factors (as outlined in the ASAM Standards) to identify facilitators and barriers to addiction treatment and specifically to pharmacotherapy. Before a decision is made to initiate a course of pharmacotherapy for the patient with opioid use disorder, the patient should receive a multidimensional assessment in fidelity with the ASAM Criteria: Treatment Criteria for Addictive, Substance-Related, and Co-occurring Conditions (the “ASAM Criteria”). The ASAM Patient Placement Criteria uses six dimensions to create a holistic biopsychosocial assessment of an individual to be used for service planning and treatment. Dimension one is acute intoxication or withdrawal potential. Dimension two is biomedical conditions and conditions. Dimension three is emotional, behavioral, or cognitive conditions or complications. Dimension four is readiness for change. Dimension five is continued use or continued problem potential. Dimension six is recovery/living environment. ¹¹¹

The use of medications for the patient with addiction involving opioid use can be appropriate across all levels of care. Pharmacotherapy is not a “level of care” in addiction treatment, but one component of multidisciplinary treatment. Whereas medication as a standalone intervention has been utilized in North America and internationally, ASAM recommends that the use of medications in the treatment of addiction be part of a broad bio-psycho-social-spiritual intervention appropriate to the patient’s needs and to the resources available in the patient’s community. Addiction should be considered a bio-psycho-social-spiritual illness, for which the use of medication(s) is but only one component of overall treatment.

Exhibit 2: Prescription Drug Monitoring Programs

DSM-5 Criteria for Diagnosis

The diagnosis of opioid use disorder is based on criteria outlined in the DSM-5. The criteria describe a problematic pattern of opioid use leading to clinically significant impairment or distress. There are a total of 11 symptoms and severity is specified as either mild (presence of 2–3 symptoms), moderate (presence of 4–5 symptoms) or severe (presence of 6 or more symptoms) within a 12-month period. Opioid use disorder requires that at least two of the following 11 criteria be met within a 12-month period: (1) taking opioids in larger amounts or over a longer period of time than intended; (2) having a persistent desire or unsuccessful attempts to reduce or control opioid use; (3) spending excess time obtaining, using, or recovering from opioids; (4) craving for opioids; (5) continuing opioid use causing inability to fulfill work, home, or school responsibilities; (6) continuing opioid use despite having persistent social or interpersonal problems; (7) lack of involvement in social, occupational, or recreational activities; (8) using opioids in physically hazardous situations; (9) continuing opioid use in spite of awareness of persistent physical or psychological problems; (10) tolerance, including need for increased amounts of opioids or diminished effect with continued use at the same amount—as long as the patient is not taking opioids under medical supervision; and (11) withdrawal manifested by characteristic opioid withdrawal syndrome or taking opioids to relieve or avoid withdrawal symptoms—as long as the patient is not taking opioids under medical supervision.

More detail about diagnosing opioid use disorder is available in the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition . Arlington, VA, American Psychiatric Association, 2013.

Withdrawal Scales

There are a number of useful opioid withdrawal scales that can assist the clinician in evaluating patients with opioid use disorder by identifying and quantitating the severity of opioid withdrawal symptoms. The Objective Opioid Withdrawal Scale (OOWS), which relies on clinical observation, is useful in measuring and documenting the objectively measurable symptoms of opioid withdrawal. The Subjective Opioid Withdrawal Scale (SOWS) records the patient’s rating of opioid withdrawal on a 16-item scale. ⁷⁴

Finally, the Clinical Opioid Withdrawal Scale (COWS) includes 11 items, and contains signs and symptoms of opioid withdrawal, which are both objective and subjective in nature. ⁷⁴

Urine Drug Testing

Urine drug testing, or other reliable biological tests for the presence of drugs, during the initial evaluation and frequently throughout treatment, is highly recommended. There are a variety of toxicology tests available, some with greater and lesser reliability and validity. The person who is interpreting these labs should be very familiar with the methodology and the reliability. There is little research on the optimal frequency of testing. The recommendations given below are based on the consensus opinion of the Guideline Committee. The frequency of drug testing will be determined by a number of factors, including the stability of the patient, the type of treatment, the treatment setting, and the half-life of drugs in the matrix being tested. Patients will likely require more testing early in treatment or during periods of relapse. Patients participating in office-based treatment with buprenorphine may be tested at each office visit. Patients participating in treatment for opioid use disorder at Opioid Treatment Programs (OTPs) are mandated by the Federal law ³⁰ to receive a minimum of eight drug tests per year, but may be tested more frequently based on clinical need. More detailed information on drug testing is contained in “Drug Testing: A White Paper of the American Society of Addiction Medicine.” ¹⁰

Opioids are detectable in the urine for 1–3 days after use. A negative urine test combined with no history of withdrawal may indicate a lack of physical dependence. However, a negative urine test does not rule out opioid use, disorder, or physical dependence. Urine testing is also helpful to identify use of other psychoactive substances.

Assessment Recommendations

• (1)
  

  First clinical priority should be given to identifying and making appropriate referral for any urgent or emergent medical or psychiatric problem(s), including drug-related impairment or overdose.

  
  
• (2)
  

  Completion of the patient’s medical history should include screening for concomitant medical conditions including infectious diseases (hepatitis, HIV, and TB), acute trauma, and pregnancy.

  
  
• (3)
  

  A physical examination should be completed as a component of the comprehensive assessment process. The prescriber (the clinician authorizing the use of a medication for the treatment of opioid use disorder) may conduct this physical examination him/herself, or, in accordance with the ASAM Standards, ensure that a current physical examination is contained within the patient medical record before a patient is started on a new medication for the treatment of his/her addiction.

  
  
• (4)
  

  Initial laboratory testing should include a complete blood count, liver function tests, and tests for hepatitis C and HIV. Testing for TB and sexually transmitted infections should also be considered. Hepatitis B vaccination should be offered, if appropriate.

  
  
• (5)
  

  The assessment of women presents special considerations regarding their reproductive health. Women of childbearing age should be tested for pregnancy, and all women of childbearing potential and age should be queried regarding methods of contraception, given the increase in fertility that results from effective opioid use disorder treatment.

  
  
• (6)
  

  Patients being evaluated for addiction involving opioid use, and/or for possible medication use in the treatment of opioid use disorder, should undergo (or have completed) an assessment of mental health status and possible psychiatric disorders (as outlined in the ASAM Standards).

  
  
• (7)
  

  Opioid use is often co-occurring with other substance-related disorders. An evaluation of past and current substance use and a determination of the totality of substances that surround the addiction should be conducted.

  
  
• (8)
  

  The use of marijuana, stimulants, or other addictive drugs should not be a reason to suspend opioid use disorder treatment. However, evidence demonstrates that patients who are actively using substances during opioid use disorder treatment have a poorer prognosis. The use of benzodiazepines and other sedative hypnotics may be a reason to suspend agonist treatment because of safety concerns related to respiratory depression.

  
  
• (9)
  

  A tobacco use query and counseling on cessation of tobacco products and electronic nicotine delivery devices should be completed routinely for all patients, including those who present for evaluation and treatment of opioid use disorder.

  
  
• (10)
  

  An assessment of social and environmental factors should be conducted (as outlined in the ASAM Standards to identify facilitators and barriers to addiction treatment, and specifically to pharmacotherapy). Before a decision is made to initiate a course of pharmacotherapy for the patient with opioid use disorder, the patient should receive a multidimensional assessment in fidelity with the ASAM Criteria. Addiction should be considered a bio-psycho-social-spiritual illness, for which the use of medication(s) is but only one component of overall treatment.

Diagnosis Recommendations

• (1)
  

  Other clinicians may diagnose opioid use disorder, but confirmation of the diagnosis by the provider with prescribing authority and who recommends medication use must be obtained before pharmacotherapy for opioid use disorder commences.

  
  
• (2)
  

  Opioid use disorder is primarily diagnosed on the basis of the history provided by the patient and a comprehensive assessment that includes a physical examination.

  
  
• (3)
  

  Validated clinical scales that measure withdrawal symptoms, for example, the OOWS, SOWS, and the COWS, may be used to assist in the evaluation of patients with opioid use disorder.

  
  
• (4)
  

  Urine drug testing during the comprehensive assessment process, and frequently during treatment, is recommended. The frequency of drug testing is determined by a number of factors, including the stability of the patient, the type of treatment, and the treatment setting.

Treatment Setting

In accordance with US Federal laws and regulations derived from the Harrison Act and Congressional exceptions to that 1914 law, the venue in which treatment for opioid use disorder is provided is as important a consideration as is the specific medication selected (methadone vs. buprenorphine vs. naltrexone). ⁷⁵ Federal and state-licensed OTPs offer daily supervised dosing of methadone. OTPs are state and federally regulated to dispense opioid agonist treatment. An increasing number of such highly regulated programs also offer the option of daily supervised dosing of buprenorphine.

In accordance with Federal law 21 CFR §1306.07, office-based opioid treatment (OBOT), which provides authorization of medication via regular outpatient prescriptions filled in a retail pharmacy like any other prescription medication, is available for buprenorphine, but not for methadone. Physicians in private practices, or various other types of private and public sector clinics, can be authorized to prescribe outpatient supplies of the partial opioid agonist buprenorphine. This flexibility to provide OBOT is discussed more in “Part 5: Buprenorphine.” There are no regulations regarding facilities themselves, but rather of the individual physician who prescribes buprenorphine (see “Part 5: Buprenorphine” for physician qualifications associated with OBOT).

Naltrexone can be prescribed in any setting by any clinician with the authority to prescribe any medication. It is not listed among federal or state-controlled substances schedules, and there are no regulations of facilities or prescribers for the use of naltrexone in the treatment of opioid use disorder (such that there are for OTP and OBOT).

It is recommended that the clinician consider a patient’s psychosocial situation, co-occurring disorders, and opportunities for treatment retention versus risks of diversion when determining whether OTP or OBOT is most appropriate.

Pharmacology

Differences in efficacy may also arise from differences in pharmacology; whereas methadone is a full agonist at the mu-opioid receptor and produces higher levels of physiological dependence; buprenorphine is a partial agonist with less physiological dependence. There are few studies comparing the relative efficacy of methadone versus buprenorphine in reducing opioid use. Likewise, evidence supports the efficacy of naltrexone for relapse prevention compared to a placebo control. ^40,93 There is an absence of studies that compare treatment using either oral naltrexone or extended-release injectable naltrexone versus agonist treatment with either methadone or buprenorphine.

Contraindications and Precautions

The following section describes the major indications, contraindications, and precautions for methadone, buprenorphine, and naltrexone. This section is a summary and is not an exhaustive description of medication information. (Refer to Table 3 below for a summary of contraindications and precautions.)