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    May.13.2024

    Opioid Use Disorder

    Synopsis

    Key Points

    • Opioid use disorder is a pattern of opioid use that is problematic and leads to significant distress or impairment
      • Chronic, relapsing, complex disease that affects brain function and behavior
    • Signs and symptoms reflect compulsive, prolonged self-administration of opioids for no legitimate medical purpose or, if a medical condition requiring opioid treatment is present, opioids are used in doses greatly exceeding amount needed r1
    • Primarily diagnosed on the basis of patient history and comprehensive assessment, including physical examination
      • Comprehensive patient assessment is imperative and includes concomitant medical conditions, past and current substance use, addiction treatment history, psychiatric history, social and environmental factors, addictive behaviors, and family history for substance use and addiction
    • Diagnosis, outlined in DSM-5-TR, is based on occurrence of at least 2 of 11 specific criteria related to opioid use over 1-year period; specified as mild, moderate, or severe according to number of symptoms present r1
      • Criteria reflect impaired control, social impairment, risky use, tolerance, and withdrawal
    • Treatment settings, interventions, and services needed vary based on type of drug used and individual patient characteristics (eg, severity, response to treatments, interventions required, comorbidities, complication risks) r2
      • Can be treated effectively with medication (eg, methadone, buprenorphine, naltrexone)
      • Encourage psychosocial services
      • Monitoring, continuing care, and maintenance pharmacotherapy for extended time frames are recommended to help maintain abstinence because relapse is common
    • Complications include social impairment (family, work relations), depression, constipation, infectious diseases (especially from injected drug use), sexual dysfunction, and hyperalgesia
    • Stable long-term remission is possible with appropriate treatment, although prevalence is low (less than 30% after 10-30 years of observation) r3
    • Opioid use is associated with increased mortality; mortality rate of people with opioid use disorder is approximately 6 to 20 times greater than that of general population r3

    Urgent Action

    • Identify and treat or appropriately refer any urgent or emergent medical or psychiatric problems, including drug-related impairment or overdose

    Pitfalls

    • Tolerance and withdrawal are not considered in diagnosis of patients who are taking opioids under appropriate medical supervision only (eg, significant injury requiring prolonged opioid administration for pain control) r1
    • Urine drug tests can provide information about recent drug use but do not identify substance use disorders or physical dependence
    • Owing to relapsing nature of opioid use disorder, be vigilant for evidence of relapse or drug seeking in patients with history of this disease r4
    • Patients are at increased risk of overdose/potential death owing to decreased opioid tolerance if patient discontinues agonist (methadone or buprenorphine) or antagonist (naloxone) therapy and resumes opioid use r5

    Terminology

    Clinical Clarification

    • Opioid use disorder is a pattern of opioid use that is problematic and leads to significant distress or impairment
      • Term opioid use disorder has replaced terms opioid abuse and opioid dependence in diagnostic lexicon r1
      • Defined as occurrence of at least 2 of 11 specific criteria related to opioid use over a 1-year time period r1
    • Chronic, relapsing medical condition associated with compulsive drug-seeking behavior, physical dependence, and tolerance
    • Associated with increased morbidity and death
      • Opioids accounted for over 71,000 overdose deaths in 2021, with increases across age groups, racial/ethnic groups, urbanization levels, and multiple states, according to CDC r6
      • US Department of Health and Human Services declared the opioid crisis a nationwide public health emergency in 2017 r7

    Classification

    • Based on severity of diagnostic criteria symptoms: r1
      • Mild: presence of 2 to 3 symptoms
      • Moderate: presence of 4 to 5 symptoms
      • Severe: presence of 6 or more symptoms
    • Based on time frame of opioid misuse: r1
      • Opioid use disorder (no modifier): currently meets or has met opioid use disorder criteria within the past 3 months
      • Opioid use disorder in early remission: not currently meeting opioid use disorder criteria but met criteria between 3 and 12 months ago
      • Opioid use disorder in sustained remission: has not met opioid use disorder criteria for more than 1 year (includes patients taking medication for opioid use disorder)

    Diagnosis

    Clinical Presentation

    History

    • Signs and symptoms reflect compulsive, prolonged self-administration of opioids for no legitimate medical purpose or, if a medical condition requiring opioid treatment is present, opioids are used in doses greatly exceeding the amount needed r1
    • Comprehensive medical assessment is imperative
      • Obtaining information from other sources such as family members (with appropriate patient consent) can also provide important information about drug use
      • Pay particular attention to the following: r5r8
        • Concomitant medical conditions including infectious diseases (eg, hepatitis, HIV, tuberculosis, infections related to injection use) and acute trauma
        • Evaluation of past and current alcohol and substance use; opioid use often co-occurs with other substance use disorders
          • For opioids, include type and amount used recently, route of administration, last use, and problems resulting from drug use
          • Review prescription drug monitoring program, if available; data may identify patients receiving opioid prescriptions from multiple sources r5
            • Electronic databases that track controlled substance prescriptions within a state allow health care authorities to obtain timely information regarding prescribing and patient behaviors r9
            • Sharing between states can be facilitated in most cases r10
            • Do not capture data from patients using drugs prescribed for others
            • State laws vary regarding prescription drug monitoring programs; clinicians should be familiar with associated legal requirements
          • Concomitant use of alcohol, sedatives, hypnotics, or anxiolytics with opioids can lead to respiratory depression
        • Addiction treatment history
          • Includes previous pharmacotherapy and assessment of withdrawal potential
        • Psychiatric history to evaluate for possible co-occurring psychiatric disorders
          • Complete assessment of mental health status and possible psychiatric disorders
        • Social and environmental factors
          • Can identify facilitators and barriers to addiction treatment, specifically pharmacotherapy and best environment for treatment
        • Addictive behaviors (eg, gambling, video games, exercise)
        • Family history of substance use and addiction treatment, addictive behavior, or psychiatric illness
          • Family history of opioid use disorder or other substance use disorders is common
    • Symptoms of opioid use disorder can be grouped into 4 general categories: r1r11
      • Impaired control c1c2c3c4c5c6c7
        • Taking opioids in larger amounts or over longer period than intended
        • Persistent desire or unsuccessful attempts to stop or reduce use
        • Spending significant time obtaining, using, or recovering from use of opioids
        • Craving opioids
      • Social impairment c8
        • Failure to fulfill home, work, or school obligations because of repeated opioid use c9c10c11c12
        • Continued opioid use despite experiencing social or interpersonal problems c13
        • Giving up or reducing important social, recreational, or occupational activities c14c15c16
      • Risky use
        • Recurrent opioid use in hazardous situations (eg, driving) c17c18
        • Continued opioid use despite knowledge of physical or psychological problems related to use
        • Use of illegal drugs, especially when unknown contents such as diluents (eg, talc) or addition of unknown drugs (eg, fentanyl) may be present c19
      • Pharmacologic criteria
        • Tolerance: needing increased amounts of opioids to achieve same effect c20
          • Typically develops fairly rapidly for analgesic, respiratory-depressant, and euphoria-producing properties; relatively little tolerance occurs to constipation or pupillary constriction r11
        • Physical dependence: physiologic state of adaptation to a substance, without which symptoms and signs of withdrawal occur r12c21
        • These pharmacologic criteria are not considered to be met for those taking opioids solely under appropriate medical supervision r1
        • Presence of these criteria reflects physiologic changes and does not alone indicate opioid use disorder
    • Associated features of opioid use disorder r4
      • History of drug-related crime may be present (eg, possession or distribution of controlled substances, larceny, robbery, forgery, receiving stolen goods) c22
      • Social difficulties related to drug use may occur at all socioeconomic levels; includes divorce or other marital difficulties, irregular employment, unemployment c23c24c25c26
      • Health professionals and those with ready access to legal opioids may have a pattern that involves problems with professional hospital staff, state licensing boards, or other administrative authorities, and is also reflective of illegal activities c27
      • High-risk sexual behavior and history of sexually transmitted infections is frequently present, particularly in younger patients r13c28
      • Medical complications of opioids include constipation, hypogonadism in males, and amenorrhea and osteoporosis in females c29
    • Symptoms of opioid withdrawal may be identified and are a consideration in treatment options c30d1
      • May be spontaneous (discontinuation or abrupt reduction of opioid dose) or precipitated (administration of opioid agonist [eg, naloxone, naltrexone] or partial agonist [eg, buprenorphine])
        • Precipitated withdrawal occurs faster and may be much more severe, occasionally requiring hospitalization c31
      • Onset of withdrawal after opioid discontinuation varies with half-life of particular opioid r13
        • Short-acting opioids (eg, morphine, heroin, fentanyl): symptoms appear within 12 hours of last dose, peak at 24 to 48 hours, and ease after 3 to 5 days r5
        • Longer-acting opioids (eg, methadone, oxycodone extended release): symptoms may take 30 hours to appear after last dose; may last up to 10 days r5
          • Symptoms may be milder than those after equivalent doses of short-acting opioids
      • Initial symptoms include anxiety, restlessness, agitation, and drug craving c32c33c34c35
      • Symptoms of progressive withdrawal include muscle/joint aches, abdominal cramping, nausea, loose stools, and insomnia c36c37c38c39c40c41

    Physical examination

    • Patients with opioid use disorder often present with no physical signs; may present with signs of opioid intoxication or withdrawal or signs of IV drug use c42c43c44c45c46
      • Intoxication d2
        • Sedation, often with periodic loss of consciousness or brief sleep (head nodding) c47
        • Decreased respiratory rate (rate of 12 or lower consistent with opioid intoxicationr14); may be accompanied by bradycardia, hypotension, and hypothermia c48
        • Constricted pupils (pupil diameter less than 2 mm with decreased reactivity; may not be present if other drugs used concurrently)r15c49c50
        • Drooping eyelids c51
        • Scratching (to relieve itching caused by histamine release) c52
      • Acute withdrawal
        • Mydriasis (dilated pupils) c53
        • Diaphoresis c54
        • Vomiting and diarrhea c55
        • Tachycardia and hypertension c56c57
        • Piloerection (gooseflesh) c58
        • Rhinorrhea and lacrimation c59c60
        • Yawning c61
        • Observed restlessness c62
    • People who inject drugs may have the following:
      • Recent injection site marks (small red, inflamed puncture wounds with slight bruising surrounding the marks) c63c64
        • Old injection sites show pigmentation change and atrophied skin
      • Thrombosed veins c65
      • Skin abscesses or cellulitis c66c67

    Causes and Risk Factors

    Causes

    • Most opioids bind as agonists to µ-receptor and typically produce effects commonly associated with opioids (eg, miosis, respiratory depression, analgesia, euphoria, drowsiness) r11c68
      • Classes of opioids r16
        • Naturally derived (from opium): morphine, opium, codeine, and thebaine
        • Semisynthetic: buprenorphine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, oxymorphone, levorphanol, and heroin
        • Synthetic: fentanyl, methadone, and tramadol
      • Highly addictive and can cause rapid progression to physiologic tolerance and withdrawal
    • Addiction is a complex disease that affects brain function and behavior
      • Involves alteration of brain structure and function; affects multiple brain circuits, including those involved in reward and motivation, learning and memory, and inhibitory control over behavior c69
        • Effects of prolonged drug exposure compromise the ability to choose; drug seeking and use become compulsive, bypassing a person's self-control or willpower c70c71
      • These alterations remain after drug use has stopped
        • May explain why patients with opioid use disorder remain at risk for relapse even after long periods of abstinence despite potentially adverse consequences
    • Exact process of opioid addiction has not been clearly defined; contributing factors include the reinforcing properties and availability of opioids, social and environmental factors, genetic vulnerability, personality, and existing psychiatric disorders c72c73c74c75c76c77
      • Opioids all have highly reinforcing pharmacologic properties r13
        • Positive reinforcement c78
          • Intrinsic property of opioids is activation of dopamine receptors, a final common pathway of reward (eg, euphoria, analgesia)
          • Drives early stages of opioid use disorder to achieve positive effects of drug
        • Negative reinforcement c79
          • Produced by opioid withdrawal after physiologic dependence has occurred
            • Opioid withdrawal activates region of brain (locus coeruleus) resulting in increased systemic sympathetic tone and high-intensity cravings r13
            • Increased sympathetic tone leads to some characteristic features of withdrawal (eg, chills, diarrhea, nausea, cramps, anxiety)
          • Later stages of opioid use to avoid negative effects of abstinence
      • Substance use disorder and dependence are heritable disorders c80
        • Approximately 40% to 60% of susceptibility to substance use disorders is associated with genetic factors r17
      • Environmental and social factors are believed to affect such factors as drug availability and likelihood of initial use r13c81c82
        • Exposure to opioid drug class, both for medical and nonmedical use
        • Use of or permissive attitudes toward opioids by peers, family members, or role models
        • Ease of access to opioids, both prescription and illicit (eg, heroin)
          • Use in family and/or friends
          • Physician opioid prescribing patterns may be a factor in opioid use disorder and overdose r18
      • Individual temperaments (eg, impulsivity, novelty seeking) have propensity to develop a substance use disorder r1c83c84
      • Psychiatric diseases commonly co-occurring with opioid addiction include: c85
        • Other substance use disorders r19
          • Strong associations exist between alcohol and cocaine use and subsequent development of an opioid use disorder r19c86
        • Depression c87
        • Anxiety c88
        • Conduct disorder in childhood and adolescence c89c90
    • Progression of use often follows trend to maximize drug bioavailability and effect; limited access to prescription opioids may also influence progression to IV use r13
      • Use may start with oral prescription opioids, which can lead to inhaled prescription opioids, inhaled heroin, and ultimately to injection of heroin or fentanyl (most potent and bioavailable method)
        • Inhalation may involve smoking (heating heroin in foil and inhaling smoke) or nasal snorting (heroin or fentanyl)

    Risk factors and/or associations

    Age
    • Can begin at any age but more commonly observed in late teens or early 20s r1c91
      • Young adults (aged 18-25 years) have highest prevalence of both prescription opioid and heroin use r13
      • Use of opioids at earlier age associated with higher likelihood of development of severe use disorder, increased clinical severity, and worse consequences r13
    Sex
    • Males are more likely to use most types of illicit drugs (eg, heroin, misuse of prescription drugs) r20c92c93
      • Both sexes are equally likely to develop a substance use disorder
    • Gender differences are variable regarding opioid use severity, craving, medical conditions, and associated social and functional impairment r21c94
      • In general, females progress from use to physiologic dependence more quickly than males r21c95
      • Females have greater likelihood of psychiatric comorbidity (eg, anxiety, depression), medical problems, employment problems, and family/social impairment r21c96
      • Females may be more susceptible to craving and relapse r20c97
    Genetics r17
    • Characterized by genetic heterogeneity, much of which remains unknown c98
    • Can raise individual risk of addiction to a specific type of drug
      • Genetically determined differences noted in drug metabolism, response to drug administration, and temperamental factors (eg, impulsivity, novelty seeking)
    • Variations in μ-receptor (OPRM1) gene have been studied, but association with rates of opioid dependence is not clearly established r13c99
    Ethnicity/race
    • White people represent majority of persons with opioid use disorder r22c100
    Other risk factors/associations
    • Chronic pain conditions (eg, spinal pain, joint pain, general chronic pain, osteoarthritis, migraines) c101
      • Common in people with opioid use disorder and often present before first diagnosis of opioid use disorder r23
      • Long-term opioid therapy is commonly prescribed as treatment for severe chronic pain; opioid treatment for chronic noncancer pain remains controversial owing to its questionable efficacy and association with opioid misuse and use disorders in some people r23
    • Misuse of prescription opioids is a risk factor for heroin/fentanyl use c102
      • 80% of people who use illicit opioids report misuse of prescription opioids in the past r24

    Diagnostic Procedures

    Primary diagnostic tools

    • Opioid use disorder is primarily diagnosed by patient history and comprehensive assessment, including a physical examination r5c103
      • Diagnose opioid use disorder when patient meets at least 2 of 11 revised diagnostic criteria (DSM-5-TR) r1
        • Problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least 2 of the following, occurring within a 12-month period: r1
          • Often taking opioids in larger amounts or over a longer period than intended
          • Persistent desire or unsuccessful efforts to cut down or control opioid use
          • Significant time spent in activities necessary to obtain, use, or recover from opioids' effects
          • Craving or strong desire or urge to use opioids
          • Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or home
          • Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by effects of opioids
          • Giving up or reducing important social, occupational, or recreational activities because of opioid use
          • Recurrent opioid use in situations in which it is physically hazardous
          • Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance
          • Tolerance, defined by either:
            • Need for markedly increased amounts of opioids to achieve intoxication or desired effect
            • Markedly diminished effect with continued use of the same amount of an opioid
            • This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision
          • Withdrawal, as manifested by either: r1
            • Characteristic opioid withdrawal syndrome d1
            • Taking opioids (or a closely related substance) to relieve or avoid withdrawal symptoms
            • This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision
        • Specify if:
          • In early remission: after full criteria for opioid use disorder were previously met, none of the criteria for opioid use disorder has been met for at least 3 months but for less than 12 months (with exception that "craving or strong desire or urge to use opioids" may be met)
          • In sustained remission: after full criteria for opioid use disorder were previously met, none of the criteria for opioid use disorder has been met at any time during a period of 12 months or longer (with exception that "craving or strong desire or urge to use opioids" may be met)
        • Specify if: r1
          • On maintenance therapy: additional specifier used if person is taking prescribed medication (ie, methadone or buprenorphine) and none of the criteria for opioid use disorder has been met for that class of medication (except tolerance to, or withdrawal from, the agonist)
            • Also applies to those persons being maintained on a partial agonist/antagonist or a full antagonist (ie, oral or depot naltrexone)
          • In a controlled environment: additional specifier used if person is in an environment where access to opioids is restricted (eg, closely supervised and substance-free jails, therapeutic units, locked hospital units)
        • Specify current severity level:
          • Mild: presence of 2 to 3 symptoms
          • Moderate: presence of 4 to 5 symptoms
          • Severe: presence of 6 or more symptoms
    • Various withdrawal scales can assist in identifying and quantifying severity of opioid withdrawal symptoms, including: d1
      • COWS (Clinical Opioid Withdrawal Scale): uses both signs and symptoms (objective and subjective) r25c104
    • Initial laboratory workup may include CBC, liver function, hepatitis B and C serology, tuberculosis, and HIV testing; test female patients of childbearing age for pregnancy r5r26c105c106c107
      • Consider testing for sexually transmitted infections including syphilis r5c108c109c110c111
    • Urine drug testing during comprehensive assessment process is recommended; however, buprenorphine may be initiated via telemedicine without urine drug testing c112
      • Objective means to verify patient-reported history of use, to show discrepancy between self-reported drug use and substances detected, and to help determine proper treatment r27
        • Use results in combination with patient history, psychosocial assessment, and physical examination
      • Can provide information about recent drug use; however: r5
        • Positive drug test result is not diagnostic of physical dependence, opioid use disorder, or its severity
        • Negative urine test result does not rule out opioid use, disorder, or physical dependence
      • Many tests are available, with variable reliability and validity
        • Interpretation requires thorough knowledge of methodology and reliability
      • Other sample matrices are available (eg, blood, saliva); use individualized according to patient's needs r27
      • Be aware of potential mandatory reporting requirements r28
      • Be aware of limitations of various testing matrices

    Laboratory

    • Urine drug testing r16c113
      • Understand limitations of tests used, including detection limits and which substances can be detected
      • Used clinically to identify drug use, misuse, diversion, or a suspected substance use disorder or relapse
      • 2 types:
        • Urine drug screen r16c114
          • Qualitative test performed at point of care (eg, office setting) or by laboratory; provides relatively rapid results
          • Consists of immunoassays that use antibodies to detect drug or drug-class metabolites in urine; interpreted by visual analysis of test result
            • Standard drug screening panels screen for amphetamines, cocaine, marijuana, opioids, phencyclidine, and often benzodiazepines
              • Screens for opioids metabolized to morphine (eg, codeine, morphine) but not other opioids like oxycodone, fentanyl, hydrocodone, buprenorphine, and methadone; order specific tests to detect these drugs
              • Intended for workplace drug testing; substances targeted and their associated cutoff levels are not appropriate in clinical care of patients with addiction r27
            • Other commercial immunoassays available include semisynthetic opioids (eg, buprenorphine, hydrocodone, oxycodone) and synthetic opioids (eg, methadone, fentanyl)
            • Base drug testing panels on patient's drug of choice, prescribed medications, and drugs common within patient's geographic location and peer group r27
          • May also detect substances with similar characteristics (cross reactivity) leading to false-positive test results
            • Nonopioids with potential for false-positive test results for opioids include quinolones, rifampin, poppy seeds, and dextromethorphan, especially at low cutoff thresholds r16
          • Use as screening test; results are presumptive and prone to false-positive and false-negative outcomes
            • Incorrect interpretation can lead to legal consequences, unemployment, and unnecessary medications
          • Apply clinical judgment, patient history, and other collaborative information to determine whether confirmatory testing is warranted
        • Confirmatory testing of positive drug screen results r16
          • Methods include gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry c115c116
            • Able to identify specific molecular structures and quantify amount of drug or substance present
            • Requires highly trained personnel and is time consuming
            • Requires understanding of which substances can be detected
          • Generally, positive immunoassay results only require definitive testing when they conflict with patient's account of drug use or to detect specific substances not identified, quantify levels present, or refine accuracy of results r27
            • Can help inform decisions with major clinical or nonclinical patient implications (eg, treatment transition, changes in medication therapies, changes in legal status) r27
            • Perform definitive test if patient disputes findings of presumptive test r27
        • Confirmatory testing of negative point of care drug screen results
          • Not done on all negative point of care urine test results but done randomly on some
          • Methods include gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry
            • May show substances not tested for on point of care testing that inform decisions with major clinical or nonclinical patient implications
      • Interpretation
        • Cutoff levels
          • Specify concentrations required to produce positive results for immunoassays and confirmation testing; established to help minimize false-positive results, especially in workplace drug testing r16
            • Results lower than established cutoff value are reported as negative; does not indicate substance is not present, rather that concentration did not meet cutoff level
          • Be aware of cutoff levels used when interpreting urine drug testing in clinical decision making; use of lower cutoff values may be indicated (eg, when testing for medication adherence) r16
        • Detection times r16
          • Vary with drug characteristics (eg, half-life, dosing intervals and strength, metabolites, drug interactions) and patient factors (eg, body mass, urine concentration and pH, renal or liver impairment)
          • Approximate drug detection time in urine
            • Codeine and heroin: 48 hours
            • Morphine: 48 to 72 hours
            • Oxycodone and hydromorphone: 2 to 4 days
            • Methadone and fentanyl: 3 days
    • CBC and liver function test results may suggest infection or other medical conditions and liver dysfunction r5c117c118
      • Abnormal results may require further evaluation

    Procedures

    c119

    Differential Diagnosis

    Most common

    • Other substance intoxication r1d3
      • Alcohol and sedative-hypnotic intoxication can clinically resemble opioid intoxication c120c121
      • May be differentiated by absence of pupillary constriction
      • Diagnosis aided by lack of response to naloxone challenge
        • If coingestion exists, naloxone will not reverse all sedative effects. Fentanyl may require higher doses of naloxone
    • Clinically appropriate use of opioid medications c122
      • People may take opioid medications as physician prescribed for legitimate medical indications for long periods of time
      • May develop physiologic signs and symptoms of tolerance and withdrawal also observed in patients with opioid use disorder
        • However, does not result in symptoms of impaired control, social impairment, and risky use
      • Differentiated by applying diagnostic criteria for opioid use disorder
    • Other substance use disorders (ie, alcohol, sedative, hypnotic, or anxiolytic use disorders) c123c124c125d4
      • May co-occur with opioid use disorder
      • Signs and symptoms may clinically resemble opioid use disorder
      • Similarly associated with impaired control, social impairment, risky use, and pharmacologic criteria of tolerance and withdrawal
      • Differentiated based on thorough history, psychosocial assessment, and physical examination; drug testing can add objective evidence to corroborate information but is not diagnostic

    Treatment

    Goals

    • General treatment goals
      • Stop/decrease illicit drug use
      • Prevent or reduce frequency and intensity of relapses
      • Sustain periods of remission
      • Optimize level of functioning during periods of remission
        • Reestablish relationships with family and friends
        • Gain or maintain employment
    • Goals of pharmacotherapy
      • Suppress opioid withdrawal (eg, with methadone or buprenorphine) or prevent relapse after detoxification (eg, with naltrexone)
      • Block effects of illicit opioids
      • Reduce craving; stop or reduce illicit opioid use
      • Promote/facilitate patient engagement in activities related to recovery, including psychosocial therapies

    Disposition

    Admission criteria

    American Society of Addiction Medicine provides criteria for service planning and placement r29

    • Some cases of mild opioid use disorder can be managed by primary care with medication and, if necessary, referral for outpatient counseling
    • For moderate and severe opioid use disorder, a specialist in addiction medicine can best determine most appropriate American Society of Addiction Medicine criteria to assign

    Inpatient/medically supervised residential treatment may be indicated for patients with severe withdrawal symptoms, need for significant psychosocial support, or management of medical comorbidities d1

    • American Society of Addiction Medicine provides criteria for levels of care for withdrawal management for adults r30
    • For pregnant patients, some obstetricians begin opioid agonist therapy in inpatient setting; not always necessary or available, but allows close monitoring of medication response r28
    • Patients with significant co-occurring substance use disorders, especially severe alcohol or sedative, hypnotic, or anxiolytic use, may require higher level of care; withdrawal may result in seizures, hallucinosis, or delirium
    • Patients with severe or unstable psychiatric symptoms may require hospitalization
    • Patients with significant medical comorbidities may benefit from admission
    Criteria for ICU admission
    • Rarely, precipitated withdrawal from administration of naloxone may be severe enough to warrant admission

    Recommendations for specialist referral

    • While patients can be treated by primary care providers, patients with moderate to severe opioid use disorder are often referred to an addiction specialist physician who holds subspecialty board certification in addiction medicine or addiction psychiatry
      • State laws vary regarding specific referral requirements (eg, if going over specific daily doses of buprenorphine)
    • Refer to behavioral health care provider to determine optimal type and intensity of psychosocial treatment

    Treatment Options

    Patients often have concomitant medical or psychiatric conditions requiring immediate attention

    • Treat or appropriately refer any urgent or emergent medical or psychiatric problems, including drug-related impairment or overdose r5
      • Resuscitate volume-depleted patients with IV crystalloid fluids; monitor electrolytes
      • Support respiration with bag valve mask (or intubation) if necessary
      • Administer naloxone for opioid overdose r31

    Withdrawal management d1

    • Involves medically supervised, controlled tapering with treatment medication (ie, methadone or buprenorphine) to replace illicit opioid dosing r32
      • Recommended over abrupt cessation of opioids because this may lead to strong cravings and/or acute withdrawal syndrome and increased risk for relapse, overdose, and overdose death r5
    • Methadone and buprenorphine are the preferred treatments r5r26
      • α-2 adrenergic agonists (eg, lofexidine, clonidine) are safe and effective for management of some opioid withdrawal symptoms but less effective in reducing symptoms of withdrawal compared to methadone and buprenorphine
    • Not to be used as sole treatment for opioid use disorder owing to increased risk of relapse and associated safety concerns r5
      • Follow with ongoing maintenance medication and psychosocial treatment according to patient's needs

    Treatment of opioid use disorder

    • Pharmacotherapy (medications for opioid use disorder), in conjunction with psychosocial interventions, is the cornerstone of treatment
      • Use of medications, combined with counseling and other behavioral therapies, is effective in helping patients stabilize their lives and reduce substance use r2
      • Consider patient preference, past treatment, and treatment setting when determining medication
      • Recommended for patients with opioid use disorder who are able to give informed consent and who have no specific contraindication to medication chosen, including adolescents and young adultsr33r5
      • FDA-approved pharmacotherapy for treatment of opioid use disorder includes: r34
        • Methadone
          • Full opioid agonist; long acting (24-30 hours) r5
            • Occupies μ-receptors, relieving withdrawal symptoms and reducing or eliminating cravings for opioids
            • Taken orally; reaches brain slowly and dampens euphoric effects
          • Can only be dispensed through federal- and state-approved opioid treatment programs; initially requires daily supervised dosing to help prevent misuse and diversion r5
            • Regulations require monitored administration of methadone until patient's clinical response and behavior show that unmonitored prescribed dosing is appropriate
          • Recommended for patients who may need daily doses and supervision or who are unsuccessful with buprenorphine treatment
          • Some studies show patients are slightly more likely to remain in treatment with methadone compared to buprenorphine r35
          • Has substantial QT-prolonging effects; can increase risk of ventricular arrhythmia (torsades de pointes), especially at higher doses r36
            • Other adverse effects include constipation, sweating, insomnia, and decreased libido/sexual performance r32
        • Buprenorphine (with or without naloxone, an opioid antagonist)
          • Partial opioid agonists r5
            • Relieve drug cravings without euphoria or dangerous adverse effects of other opioids
              • Maximal effect is less than that of full opioids; reaches ceiling where additional doses do not increase effect
              • Safer than full agonists, as respiratory depression is limited by ceiling effect
            • High affinity for μ-receptor; displaces full agonists (eg, morphine, methadone) and reduces their effects
              • Can cause precipitated withdrawal if insufficient time has passed since last opioid dose
              • Full agonists cannot displace buprenorphine
          • Initiated when patients are in mild to moderate withdrawal to reduce risk of precipitated withdrawal r5
            • Generally at least 6 to 12 hours after last use of heroin/short-acting opioids or 24 to 72 hours after last use of long-acting opioids (eg, methadone, fentanyl)
            • COWS score of at least 11 to 12 (mild to moderate withdrawal) is indicative of sufficient level of withdrawal to start treatment (induction) with buprenorphine
            • Once objective signs of withdrawal are confirmed, administer a dose of buprenorphine sufficient to suppress withdrawal symptoms r5
          • Available forms include buprenorphine sublingual tablets and extended-release injection and buprenorphine-naloxone sublingual film and tablets or buccal film r5
            • Combined buprenorphine-naloxone
              • Preferred over buprenorphine monotherapy in most patients (except if allergic or in pregnant or lactating patients)
              • Less likely to be misused or diverted; oral naloxone has poor bioavailability but becomes bioeffective if taken by IV and can precipitate withdrawal r13
          • Generally well tolerated; adverse effects can include headache, anxiety, sweating, constipation, oral mucosal irritation, and sleep disturbance r5
          • Discontinuation and tapering is a slow process (indefinite duration) and should be closely monitored; typically takes several months
          • Ongoing maintenance treatment with buprenorphine is more effective in maintaining abstinence from opioids than tapering or discontinuation of buprenorphine therapy r37
        • Naltrexone and extended-release naltrexone
          • Opioid antagonists; long acting; naltrexone (24-30 hours) and extended release (up to 30 days)
            • Block physiologic and subjective effects of exogenous opioids; produce no opioidlike effect and no physiologic dependence r38
          • Indicated for prevention of opioid relapse after detoxification
            • Cannot be initiated until patients are fully detoxified without risking precipitated withdrawal
            • In general, requires about 6 days for short-acting opioids and 7 to 10 days for long-acting opioids (eg, methadone, buprenorphine) after last use r5
            • Naloxone challenge (administration of short-acting naloxone or low-dose oral naltrexone followed by observation for signs or symptoms of withdrawal) can be used to determine patient is no longer physically opioid dependent
          • Can be prescribed in any setting by any clinician; requires no special regulations for facilities or prescribers
          • Consider for patients with mild opioid use disorder who have occupations not permitting opioid agonist treatment or when medication administration cannot be supervised r34
            • Oral formula may be useful when adherence can be supervised or patient is highly motivated; extended-release injectable form may be preferred when issues with adherence are present r5
          • Outcomes are often adversely affected by poor medication compliance r5
            • Patients must remain abstinent from opioids for 7 to 10 days before initiation of extended-release naltrexone; therefore, this treatment can be difficult to initiate, resulting in increased risk of relapse r38
            • Once initiated, extended-release naltrexone and buprenorphine with or without naloxone have been shown to be equally effective r38
          • Adverse effects may include headache, insomnia, decreased energy/sedation, anxiety, nausea/vomiting, abdominal cramping/pain, cold symptoms, and joint/muscle pain
      • Other medications 
        • Heroin maintenance programs are controversial and are not commonly available; however, programs in Europe and Canada that provided injectable- medical-grade heroin to patients with chronic opioid (heroin) use disorder who were refractory to standard opioid use treatment achieved greater retention in treatment as compared with methadone maintenance treatment r39
    • Treatment settings, interventions, and services needed vary by type of drug used and individual patient characteristics (eg, severity of episode, response to treatments, interventions required, comorbidities, complication risks) r2
      • Effective treatment addresses patient's multiple needs, not just their drug use disorder r40
        • Includes associated medical, psychological, social, vocational, and legal problems; should also be appropriate to the person's age, sex, gender, ethnicity, and culture
      • Should be a shared decision that accommodates patient preference r36
        • Consider patient's openness to and understanding of pharmacologic treatment, preferred treatment setting, past treatment experiences, and potential efficacy and safety of treatments
    • Treatment needs to be readily available; longer delays between first contact, initial screening, and treatment result in fewer patients actually entering treatment r2r32
      • Treatment ideally should be voluntary, but coercive treatment sometimes can be effective r40
        • Enticements from family, work, or criminal justice system can increase treatment entry, retention, and potential success
      • Emergency/inpatient settings
        • To allow initiation of treatment of opioid use disorder as soon as possible, patients may be started on pharmacotherapy in emergency department and inpatient settings by providers without additional Drug Enforcement Administration waiver under certain conditions
          • Federal guideline on emergency narcotic addiction treatment (Title 21 Code of Federal Regulations Part 1306.07 [b]) allows practitioners not specifically registered as narcotic treatment providers to administer (but not prescribe) narcotic drugs to relieve acute withdrawal symptoms while arranging for referral for treatment r41
            • May not be carried out for more than 3 days (also referred to as the 72-hour rule); may not be renewed or extended
        • Provider may administer (but not prescribe) buprenorphine or methadone without a waiver as an induction or bridge medication for up to 3 consecutive days while arranging for referral for treatment r18
        • Provide plan for prompt follow-up in outpatient clinic or addiction treatment facility to continue initiation of medication for opioid use disorder, stabilization, and long-term maintenance r18
        • Inpatient induction of medication for opioid use disorder is associated with a higher likelihood of short-term adherence to treatment after discharge r42
    • Different treatment programs/settings provide variety of intensity of clinical and environmental support services r5
      • Offer various settings, staffing, support systems, therapies, assessments, documentation, and treatment plans
      • Determine level of care based on priority dimensions, diagnoses, and dose and intensity required r30
        • American Society of Addiction Medicine established 6 dimensions of multidimensional assessment: r30
          • Acute intoxication or withdrawal potential: past and current experiences of substance use and withdrawal
          • Biomedical conditions and complications: health history and current physical condition
          • Emotional, behavioral, or cognitive conditions and complications: thoughts, emotions, and mental health issues
          • Readiness for treatment
          • Relapse, continued use, or continued problem potential
          • Recovery/living environment: a person's recovery or living situation and surrounding people, places, and things
      • Settings include:
        • General outpatient location (eg, clinician's office or practice site)
          • Provide regularly scheduled sessions, usually fewer than 9 contact hours per week for adults r30
          • When determining whether opioid treatment program or office-based opioid treatment is preferable, consider each person's psychosocial situation, co-occurring disorders, and chance for treatment retention versus risks of diversion
          • Information for locating physicians authorized to treat opioid use disorder or opioid treatment programs can be found on Substance Abuse and Mental Health Services Administration's website r43
        • Intensive outpatient program or partial hospitalization program
          • Typically located in specialty addiction treatment facility, community mental health center, or similar setting
          • Intensive outpatient programs typically provide 9 to 19 hours of structured programming per week for adults r30
          • Partial hospitalization programs (day treatment) generally provide 20 or more hours of clinically intensive programming per week r30
        • Residential addiction treatment facility or hospital
          • Organized treatment services featuring planned and structured care regimen in 24-hour residential setting r30
    • Opioid treatment programs
      • Federally approved programs certified by Substance Abuse and Mental Health Services Administration in conformance with Title 42 Code of Federal Regulations Part 8 r32
        • Also referred to as methadone clinics; opioid medications administered or dispensed include methadone, a schedule II drug, as well as buprenorphine and naltrexone
        • Can also exist in other settings (eg, residential and hospital settings)
      • Patients with co-occurring alcohol or other substance use disorders (eg, sedatives, hypnotics, anxiolytics) may best be treated in more supervised opioid treatment program setting to reduce risk of adverse events
      • Provide comprehensive, individually tailored program of medication therapy integrated with psychosocial and medical treatment and support services r32
      • While proven to decrease opioid use and related sequelae, capacity of opioid treatment programs has been unable to meet demands of increasing prevalence of opioid use disorder r12
    • Office-based opioid treatment
      • All clinicians with current Drug Enforcement Administration registration, including Schedule III authority, may prescribe buprenorphine for opioid use disorder if permitted by applicable state law r44
      • Various models exist for providing medication for opioid use disorder in primary care settings in the United States. Key components include: r45
        • Pharmacotherapy with buprenorphine or naltrexone
        • Integration of care
        • Psychosocial services, including peer support
        • Education and outreach
      • Advantages over specialized opioid treatment programs include greater accessibility and reduced stigma associated with obtaining treatment r34
      • May not be suitable for patients with active alcohol, sedative, hypnotic, or anxiolytic use disorder or heavy use of these substances
    • Length of treatment
      • No predetermined time frame r5
        • Remaining in treatment for an adequate period is critical r2
          • Individuals progress at various rates; depends on type and degree of patient's problems and needs
          • Optimally determined as collaboration between patient and clinicians
          • Best outcomes occur with longer durations of treatment
        • However, research indicates that generally: r40
          • For residential/outpatient setting, less than 90 days is of limited effectiveness and significantly longer times are recommended
          • For methadone maintenance, 12 months is considered minimum, with some people benefiting from years-long duration

    Relapses (resumption of use)

    • Recovery from substance use disorder often requires multiple episodes of treatment r2
    • Involvement of peer recovery coaches can be effective
    • Relapses to substance use can occur and treatment should be reinstated or adjusted r2
    • Inform patients of increased risk of overdose/potential death owing to decreased opioid tolerance if patient discontinues agonist (methadone or buprenorphine) or antagonist (naltrexone) therapy and resumes opioid use r5

    Prescribe or supply naloxone rescue kit with counseling on proper use to patients with opioid use disorder and their family members r5r18

    Drug therapy

    • Opioid agonist pharmacotherapy
      • Buprenorphine c126
        • Sublingual tablet
          • Buprenorphine Hydrochloride Sublingual tablet; Adults: 2 to 4 mg SL as needed to achieve clinical effectiveness as rapidly as possible, then titrate dose by 2 to 4 mg to a level that holds the person in treatment and suppresses opioid withdrawal signs and symptoms. Target maintenance dose: 16 mg SL once daily. Usual dose range: 4 to 24 mg/day. Max: 32 mg/day.
      • Buprenorphine-naloxone c127c128
        • Sublingual film
          • Buprenorphine Hydrochloride, Naloxone Hydrochloride Oral dissolving film; Adults: 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone SL once, initially; may titrate dose by 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone every 2 hours up to 8 mg/2 mg buprenorphine/naloxone on day 1 based on the control of acute withdrawal symptoms, then 16 mg/4 mg buprenorphine/naloxone SL once daily starting on day 2. Titrate dose by 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the person in treatment and suppresses opioid withdrawal signs and symptoms. Target maintenance dose: 16 mg/4 mg buprenorphine/naloxone SL once daily. Usual dose range: 4 mg/1 mg/day to 24 mg/6 mg/day buprenorphine/naloxone. Max: 24 mg/6 mg/day buprenorphine/naloxone.
        • Sublingual tablet
          • Buprenorphine Hydrochloride, Naloxone Hydrochloride Sublingual tablet; Adults: 1.4 mg/0.36 mg buprenorphine/naloxone SL once, initially, then 1.4 mg/0.36 mg or 2.8 mg/0.72 mg buprenorphine/naloxone every 1.5 to 2 hours up to 5.7 mg/1.4 mg buprenorphine/naloxone on day 1, then up to 11.4 mg/2.9 mg buprenorphine/naloxone SL once daily starting on day 2. Those with recent exposure to buprenorphine may tolerate up to 4.2 mg/1.08 mg buprenorphine/naloxone as a single, second dose on day 1. Titrate dose by 2.9 mg/0.71 mg buprenorphine/naloxone or less to a level that holds the person in treatment and suppresses opioid withdrawal signs and symptoms. Target maintenance dose: 11.4 mg/2.9 mg buprenorphine/naloxone SL once daily. Usual dose range: 2.9 mg/0.71 mg/day to 17.2 mg/4.2 mg/day buprenorphine/naloxone. Max: 17.2 mg/4.2 mg/day buprenorphine/naloxone.
        • Buccal film
          • Buprenorphine Hydrochloride, Naloxone Hydrochloride Oral dissolving film; Adults: 2.1 mg/0.3 mg buprenorphine/naloxone buccally every 2 hours as needed up to 4.2 mg/0.7 mg buprenorphine/naloxone on day 1 based on the control of acute withdrawal symptoms, then up to 8.4 mg/1.4 mg buprenorphine/naloxone buccally once daily starting on day 2. Titrate dose by 2.1 mg/0.3 mg buprenorphine/naloxone to a level that holds the person in treatment and suppresses opioid withdrawal signs and symptoms. Target maintenance dose: 8.4 mg/1.4 mg buprenorphine/naloxone buccally once daily. Usual dose range: 2.1 mg/0.3 mg/day to 12.6 mg/2.1 mg/day buprenorphine/naloxone. Max: 12.6 mg/2.1 mg/day buprenorphine/naloxone.
      • Methadone c129c130
        • For the treatment of opioid use disorder, methadone may be dispensed only by entities approved by FDA and state authorities according to treatment requirements stipulated in federal methadone regulations. However, in a hospital setting, a physician or authorized hospital staff personnel may administer or dispense opioids to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction.
        • Patients need to show withdrawal symptoms but no signs of sedation or intoxication
        • Methadone Hydrochloride Oral tablet; Adults: 20 to 30 mg PO once, initially; may administer an additional 5 to 10 mg after 2 to 4 hours if withdrawal symptoms have not been suppressed or if symptoms reappear, up to 40 mg/day on day 1. Use lower initial doses for persons whose tolerance is expected to be low at treatment entry. Adjust the dose over the first week of treatment based on control of withdrawal symptoms at 2 to 4 hours after dosing. Subsequently, titrate dose to a level that prevents opioid withdrawal symptoms for 24 hours, reduces drug hunger or craving, and blocks or attenuates the euphoric effects of self-administered opioids, ensuring tolerance to sedative effects. Usual dose range: 80 to 120 mg/day. During medically supervised withdrawal from methadone treatment, decrease dose by 10% every 10 to 14 days.
        • Monitor patients with a QTc interval of 451 to 499 milliseconds more frequently and discuss the potential risks versus benefits of treatment; patients with a QTc interval of 500 milliseconds or greater should receive intervention to lower cardiac risk either by discontinuing or lowering the methadone dose or by eliminating contributing factors r46
    • Maintenance therapy to prevent relapse
      • Naltrexone c131
        • Oral tablet
          • Naltrexone Hydrochloride Oral tablet; Adults: 25 mg PO once daily, initially. Increase the dose to 50 mg PO once daily if no withdrawal signs occur.
        • Intramuscular injection
          • Naltrexone Suspension for injection, Extended Release; Adults: 380 mg IM every 4 weeks or once monthly.
    • Opioid overdose
      • Naloxone c132
        • Effective dose is empiric r31
          • Goal is to reverse respiratory depression while avoiding precipitous withdrawal
          • Has short half-life; patient should be observed for 4 to 6 hours after respiratory rate has improved
        • Naloxone Hydrochloride Solution for injection; Adults: 0.4 to 2 mg IV/IM/subcutaneously every 2 to 3 minutes as needed up to a total dose of 10 mg.

    Nondrug and supportive care

    Psychosocial interventions

    • Recommended, but not required, in conjunction with any pharmacologic treatment of opioid use disorder r5
      • At minimum may include psychosocial needs assessment, peer counselor support, supportive counseling, links to existing family supports, and referrals to community services
      • Lack of availability or patient declining psychosocial therapy should not preclude or delay pharmacologic treatment
    • Help engage patient in treatment, provide incentive to remain abstinent, modify attitudes and behavior surrounding drug use, manage cravings, and increase skills to cope with emotional/social challenges and environmental cues that may trigger relapse r40
    • Selecting psychosocial therapy appropriately targeted and individualized to suit patient needs is important
    • Research on optimal interventions to use with medications in opioid addiction is limited r47
      • Variety of formats are available, including: r47
        • Cognitive behavioral therapy c133
          • Learning to recognize and stop negative patterns of thinking and behaving
        • Contingency management c134
          • Providing incentives to encourage/reinforce positive behaviors
        • Individual, group, and couples counseling c135
          • Includes behavioral therapy, commonly for substance use disorder treatment r40c136
            • Behavioral therapies vary in focus
              • May include addressing patient's motivation to change, providing incentives for abstinence, building skills to resist drug use, replacing drug-using activities with constructive and rewarding activities, improving problem-solving skills, and facilitating better interpersonal relationships r40
            • Participation in group therapy and other peer-support programs during and after treatment can help maintain abstinence
            • Regular meetings with peer support/community health worker
        • Mutual help programs
          • Include 12-step programs (eg, Narcotics Anonymous, Alcoholics Anonymous, Methadone Anonymous) c137
            • Other groups include Self-Management and Recovery Therapy, Women for Sobriety, and Secular Organization for Sobriety groups, among many others
          • May provide positive reinforcement and motivation and social support from other members during and after active treatment r32
        • Motivational interviewing c138
          • Building motivation/commitment to engaging in treatment and recovery process
        • Social skills training c139
        • Family therapy c140
    • Relapse prevention strategies are an important part of an addiction-treatment plan; opioid use disorder is a chronic, relapsing disease r5
      • May involve drug counseling and/or other psychosocial treatments; involvement of patient's social network (eg, family, friends, clergy, employers) may provide strong support systems r8
    • Psychiatric treatment may be needed to manage psychiatric comorbidities that complicate addictive disorder or act as trigger r2

    Education/harm reduction c141c142

    • Provide targeted risk-reduction counseling for infectious diseases (eg, HIV/AIDS, hepatitis B, hepatitis C, tuberculosis) and link patients to treatment if necessary r2
    • Offer contraceptive counseling to age-appropriate female patients in treatment for substance use disorder to minimize risk of unplanned pregnancy r28
    • Safe injection information to help reduce hazards of injection can include:
      • Self-administering small test dose to test potency before administering entire dose of drug of unknown potency r48
      • Proper skin cleaning before injection r48
      • Fentanyl test strips
      • Using clean/new needles and avoiding reuse of needles or sharing needles r48
        • Refer to syringe exchange program if available r49
    • Medication interactions r34
      • Concurrent use of alcohol, benzodiazepines, muscle relaxers, pregabalin, or gabapentin with methadone or buprenorphine can increase risk of sedation, respiratory depression, and death
        • However, do not withhold treatment with methadone or buprenorphine due to use of benzodiazepines and other sedative-hypnotics r5
      • Naltrexone should not be used concurrently with opioids

    Offer hepatitis A and hepatitis B vaccination, if appropriate r5c143c144

    Procedures
    c145

    Comorbidities

    • Viral (eg, HIV, hepatitis C) and bacterial infections r1c146c147
      • Most common with use of drugs by injection
    • Other substance use disorders (eg, tobacco, alcohol, cannabis, benzodiazepines, stimulants) r1c148c149c150c151c152c153
      • May be taken to manage symptoms of withdrawal and craving or enhance opioid effects
      • Concomitant use of alcohol, sedatives, hypnotics, or anxiolytics with opioids may contribute to respiratory depression
    • Coexisting psychiatric disorders, including: r1r5
      • Depression c154
        • May be opioid-induced, or opioid use may exacerbate preexisting primary depressive disorder
      • Anxiety c155
      • Posttraumatic stress disorder c156
      • Personality disorders c157
      • Conduct disorder in childhood or adolescence r1c158c159

    Special populations

    • Pregnant patients
      • Rise of opioid use in pregnancy has increased parallel to epidemic in general population r28
        • Pregnant people with opioid use disorder are more likely to seek prenatal care late in pregnancy, miss appointments, and experience poor weight gain
      • Complications of untreated opioid use disorder specific to pregnancy include miscarriage, preterm labor and delivery, intrauterine growth restriction, and neonatal abstinence syndrome r50
        • Neonatal abstinence syndrome is an expected and treatable drug withdrawal syndrome experienced by neonates shortly after birth resulting from chronic maternal opioid use during pregnancy; occurs in 30% to 80% of infants born to mothers taking opioid agonist therapies r28r51
          • Characterized by disturbances in neonate's gastrointestinal, autonomic, and central nervous systems (eg, irritability, high-pitched cry, tremors, poor feeding, regurgitation, loose stools, sweating, yawning, sneezing) r51
          • Term neonatal opioid withdrawal syndrome is sometimes used to reflect associated constellation of symptoms r50
          • Dosage of methadone or buprenorphine does not have consistent effect on incidence and severity of neonatal abstinence syndrome r50
      • Universal SBIRT (screening, brief intervention, and referral to treatment) is essential in early obstetric care to improve maternal and infant outcomes r28r52
        • Validated screening tools include 4Ps, NIDA (National Institute on Drug Abuse) Quick Screen, and CRAFFT (for pregnant patients aged 26 years or younger) r53
        • Providers should be aware of state laws surrounding substance use screening and reporting r54
          • Policies that dissuade people from seeking prenatal care are contrary to welfare of mother and fetus r54
      • Some elements of prenatal care may require modification (eg, increased testing for sexually transmitted infections, additional ultrasonography examinations) based on patient's particular clinical needs r28
      • Care should be comanaged by an obstetrician and an addiction medicine specialist physician r5
        • Other specialty consults may be required according to individual patient's needs (eg, anesthesiology, pediatrics, pain management, maternal-fetal medicine, nutrition, behavioral health, social services)
        • By federal law, to coordinate care among health care providers, written patient consent regarding addiction treatment must be obtained r55
      • Treatment with opioid agonist pharmacotherapy is recommended for pregnant patients with opioid use disorder in addition to counseling and behavioral therapy r28
        • Medications include methadone and buprenorphine; benefits and disadvantages exist for both and choice should be individualizedr50
          • Methadone r28
            • Associated with higher retention rate r50
            • Managed by addiction treatment specialists within registered opioid treatment program in communication with obstetric team
            • With advancing gestation, often requires increased or split dosing to maintain adequate levels
          • Buprenorphine
            • Buprenorphine monotherapy is currently recommended in pregnancy r28r50
              • Use of buprenorphine-naloxone combination therapy appears to have no maternal, fetal, or neonatal adverse effects and may be additional option during pregnancy r50
            • Compared to methadone, evidence suggests lower risk of preterm birth, greater birth weight, and larger head circumference with buprenorphine treatment; neonatal abstinence syndrome may be less severe and require shorter hospital staysr57r56
            • Typically requires fewer dosing adjustments during pregnancy than methadone, but dose may need to be increased in third trimester
          • Hospitalization during initiation of methadone or buprenorphine may be advisable, especially in third trimester r5
        • Data on safety and efficacy of naltrexone in pregnancy are limited r28r50
      • Infants born to mothers using opioids during pregnancy should be monitored in hospital for neonatal abstinence syndrome, typically for 4 to 7 daysr50r28
        • Opioids are recommended as a first line drug for neonates with neonatal abstinence syndrome r51
      • Encourage breastfeeding for mothers who are stable on opioid agonists, are not using illicit drugs, and have no other contraindications (eg, HIV infection) r28
        • Associated with less severe neonatal abstinence syndrome, less need for pharmacotherapy, and shorter infant hospital stay
      • Consider providing prescription for naloxone for emergency administration in case of life-threatening opioid overdose r28
        • Not recommended for use in pregnant patients because it may precipitate preterm labor or fetal distress; however, risk of maternal death from overdose outweighs fetal risks
      • Vaccination for hepatitis A and hepatitis B is recommended if serology test result is negative r5
    • Adolescents
      • During adolescence (approximately age 12 to early 20s), neurodevelopmental molding and maturation confer greater vulnerability to addictions; in addition, risk-taking behaviors are generally more prevalent r58
        • Age at first substance use is inversely correlated with lifetime incidence of developing a substance use disorder
      • Progression of use from oral opioids to injection is more prominent in adolescents than in adults who use opioids; accelerates faster with earlier age of first opioid use r13
        • Tolerance to opioids happens rapidly in adolescents; fentanyl's lower cost and higher potency make it appealing as addiction increases
      • Signs of opioid use disorder in younger patients may manifest as failing grades, breaking curfew, and legal involvement
        • Other associated features may include changing peer groups, isolation from family/friends, decreased social and leisure activities, mood changes (eg, depression, irritability, anger), and problematic behaviors (eg, truancy, running away, stealing, lying) r13
      • Treatment in specialized facilities providing multidimensional services may be beneficial for adolescents
        • Many unique medical, legal, and ethical dilemmas may complicate treatment
      • Full range of treatment options (including methadone, buprenorphine, naltrexone) can be considered in treatment of opioid use disorder in adolescents; most efficacy studies have been conducted in adults r5r33r59
        • Methadone is not easily available for patients aged younger than 18 years r13
        • Buprenorphine is FDA-approved for adolescents aged 16 years and older
        • Naltrexone may be considered for young adults aged 18 years and older
    • Patients with co-occurring psychiatric disorders r5
      • Common among people with opioid use disorder
        • Higher prevalence of substance use in those with psychiatric disorders than in general population
        • Evaluation for presence of commonly associated disorders, including depression, anxiety, personality disorders, and posttraumatic stress disorder, should be obtained at onset of treatment
      • Ask patients with psychiatric disorders about suicidal ideation and behavior
        • Management of patients with suicide risk includes immediate risk reduction, managing underlying factors associated with suicidal intent, and careful monitoring and follow-up
      • Consider pharmacotherapy in conjunction with psychosocial treatment for patients with opioid use disorder and a co-occurring psychiatric disorder
        • Providers should have knowledge of potential interactions between medications used to treat opioid use disorder and co-occurring psychiatric disorders
        • Obtain reassessment using a detailed mental status examination after stabilization with methadone, buprenorphine, or naltrexone
    • Patients with pain r5
      • Acute and chronic pain is common among patients with opioid use disorder
      • Accurate diagnosis of cause of pain is important so choice of suitable treatment can be made
        • Nonpharmacologic treatments may be effective (eg, physical therapy)
        • Pharmacologic treatments to consider include:
          • Nonnarcotic medications (eg, NSAIDs, acetaminophen) should be tried initially
          • Adjunctive medications may include anticonvulsants, tricyclic antidepressants, or combined norepinephrine-serotonin reuptake inhibitors
      • Pain management is variable depending on whether patient is in treatment for opioid use disorder
        • Patients with untreated and active opioid use disorder
          • Both methadone and buprenorphine have analgesic effects and may be considered
        • Patients in treatment for opioid use disorder with opioid agonists
          • Patients on methadone with severe, acute pain require doses of opioids in addition to their regular daily dose of methadone
            • Those on methadone with chronic pain should be managed in coordination with a pain specialist
          • Patients on buprenorphine
            • For mild acute pain: may require temporarily increasing buprenorphine dosing
            • For severe acute pain: discontinuing buprenorphine and starting high potency opioid with close monitoring is suggested
            • Buprenorphine is often adequate for chronic pain control in patients with opioid use disorder; consider splitting doses
        • Patients in treatment for opioid use disorder with opioid antagonist (naltrexone)
          • Will not respond to opioid analgesics in usual manner
          • Mild pain may be treated with NSAIDs and more severe pain with short-term ketorolac
          • Emergency pain control options include regional anesthesia, conscious sedation with benzodiazepines or ketamine, and general anesthesia using nonopioids
    • People in the criminal justice system r5
      • Substantial proportion of people in the criminal justice system (eg, prisons, jails, drug courts, probation, parole) have opioid use disorder and associated problems
        • Screening for opioid use disorder and consideration for initiation or continuation of medication for opioid use disorder is recommended
      • Offer pharmacotherapy (methadone, buprenorphine, or naltrexone), in addition to psychosocial treatment; people should not be forced to undergo opioid withdrawal
        • Patients should be stabilized on pharmacotherapy before release from prison and continue treatment after their release with community treatment providers established in advance
          • Discharge from prison is often associated with opioid overdose and death. Prescribe naloxone for emergency treatment of overdose

    Monitoring

    • Drug use during treatment must be monitored continuously because lapses during treatment do occur r40c160
      • May provide incentive to maintain abstinence, as well as early indications of relapse, and allow for individual treatment plan modification
      • Methadone treatment is monitored through certified opioid treatment programs and involves:
        • Frequent testing for alcohol and other relevant substances in monitoring for relapse c161c162c163
        • Testing for methadone to ensure adherence and detect potential diversion
      • Buprenorphine and naltrexone treatment requires frequent monitoring in early treatment r5c164c165
        • Weekly office or telemedicine visits recommended until patients are stable
          • Stable patients can be seen less often
          • Stability can be determined by factors such as:
            • Participation in psychosocial treatment and other recovery-associated activities
            • Good occupational and social functioning
            • Abstinence from illicit drugs
        • Typically involves urine drug testing for buprenorphine/metabolites and other substances; other reliable test for presence of drugs may be used r5c166c167c168
        • Reviewing state prescription drug monitoring program for other prescribed medication may be useful c169
    • Frequency of urine drug testing is determined by various factors including stability of patient, type of treatment, and treatment setting r5
      • More frequent testing may be required in early treatment or during episodes of relapse
      • Monthly testing is common for patients in office-based practice with buprenorphine; federal law mandates at least 8 drug tests per year for patients in opioid treatment programs
      • Periodic definitive/confirmatory testing of negative immunoassay test results for specific drugs or metabolites is warranted
    • Treatment and service plans must be continually assessed and modified as necessary to ensure individual needs are met r2
      • In addition to counseling or psychotherapy, patient may require medication, medical services, family therapy, parenting instruction, vocational rehabilitation, and/or social and legal services
    • Diversion potential exists for both buprenorphine and buprenorphine/naloxone. Strategies to reduce diversion include: r5
      • Frequent office visits
      • Observed dosing
      • Urine drug testing for buprenorphine and metabolites
      • Recall visits for medication counting

    Complications and Prognosis

    Complications

    • Social/family disruption and lost productivity r60
    • Depression r1c173
      • Common during chronic intoxication or in association with physical or psychosocial stressors related to opioid use c174
    • Insomnia, especially during withdrawal r1c175
    • Overdose c176
    • Injected opioid complications r1r11
      • Hepatitis and HIV infection (hepatitis C can occur in up to 90% of people with opioid use disorder) r1c177c178c179
      • Cellulitis, abscesses from injection directly into subcutaneous tissues (skin popping) c180c181
      • Bacterial endocarditis c182
      • Tuberculosis c183
      • Peripheral edema secondary to sclerosed veins c184
    • Risky behaviors (eg, unprotected sexual contact) can lead to contracting infectious diseases (eg, HIV/AIDS, hepatitis)
    • Sniffing heroin, fentanyl, or cocaine can result in irritation of nasal mucosa, potentially resulting in perforation of nasal septum c185
    • Constipation from slowing of gastrointestinal activity and gut motility r1c186
    • Sexual dysfunction r1
      • Erectile dysfunction in males c187
      • Altered reproductive function and irregular menses in females c188c189
    • Hyperalgesia r61c190
      • Some evidence suggests chronic opioid use may lead to hyperalgesia, a state of nociceptive sensitization caused by opioid exposure
      • A paradoxical response; patient taking opioids for treatment of pain could become more sensitive to certain painful stimuli

    Prognosis

    • Opioid use disorder typically continues over many years once established, though brief periods of abstinence are common r1
      • Patients generally require long-term or repeated episodes of care to achieve sustained abstinence and recovery r40
      • Short-term treatment programs focused on abstinence are associated with high relapse rates r28
        • Longer treatment is associated with a greater likelihood of abstinence r3
    • Stable long-term remission is possible with appropriate treatment and follow-up
      • Maintaining opioid abstinence for at least 5 years substantially increases likelihood of future stable abstinence r3
    • In treated patients, relapse after abstinence is not uncommon r1
      • Factors that contribute to relapse include:
        • Development of conditioned responses to drug-related stimuli (eg, craving on seeing any powdery substance that looks like heroin) r1
        • Comorbid psychiatric disorders and history of abuse (physical or sexual) are associated with persistent opioid use; social/family support and employment facilitate recovery r3
      • Associated with increased risk of accidental overdose from loss of tolerance
    • Acute opioid withdrawal is not typically life-threatening; however: r18
      • Patients with comorbid conditions (eg, type 1 diabetes, congestive heart failure, coronary artery disease, liver failure, epilepsy) have increased risk of death
      • Symptoms of withdrawal may lead to behaviors (eg, crime, foregoing needed medical treatments) that increase risk of morbidity and mortality
    • Mortality r60
      • Opioid use is associated with increased mortality
        • Long term, mortality rate of people addicted to opioids is approximately 6 to 20 times greater than that of the general population r3
      • Treatment of opioid use disorder with methadone or buprenorphine is associated with lower rates of all-cause mortality, suicide, and drug-related mortality r62
      • Leading causes of death in people using opioids for nonmedical purposes are overdose and trauma r60
        • Overdose
          • Opioids accounted for over 71,000 overdose deaths in 2021 with increases across age groups, racial/ethnic groups, urbanization levels, and multiple states, according to CDC r6
            • Drug overdose deaths involving opioids increased from an estimated 70,029 in 2020 to 80,816 in 2021
          • Opioids were involved in approximately 70% of drug overdose deaths during 2018 r63
          • Opioid overdose may be accidental or deliberate (clinically distinct problems)
          • 32% of all opioid overdose deaths involved a prescription opioid r63
          • Fatal overdoses due to synthetic opioids (usually fentanyl) outnumber those due to prescribed opioids r1
          • The age-adjusted rate of drug overdose deaths involving synthetic opioids other than methadone, was relatively stable between 2002 to 2013 (0.4 -1.0 deaths per 100,000 standard population) and then increased significantly through 2022 (22.7 deaths per 100,000 standard population) r64
            • Rate of drug overdose deaths involving heroin, natural and semisynthetic opioids (eg morphine, oxycodone, and hydrocodone), and methadone have remained relatively stable in comparison over the past 2 decades, and decreased between 2021 and 2022
      • Associated with increased risk for completed suicides and suicide attempts r1
      • Mortality rate owing to infection (eg, cellulitis, HIV, hepatitis, endocarditis) up to 1.5% to 2% per year r1

    Screening and Prevention

    Screening

    At-risk populations

    • US Preventive Services Task Force recommends screening by asking questions about unhealthy drug use in adults aged 18 years or older, including pregnant patients; evidence was insufficient to assess balance of benefits and harms of screening adolescents aged 12 to 17 years r65
    • Substance Abuse and Mental Health Services Administration recommends SBIRT (screening, brief intervention, and referral to treatment) as part of routine health care r58
    • American College of Obstetricians and Gynecologists recommends universal screening of pregnant patients for substance use; maternal and infant outcomes are improved with universal screening, intervention, and treatment referral r28
      • Pregnancy provides opportunity to identify and treat people with substance use disorders
      • Screening should be done, in partnership with pregnant patient, at first prenatal visit r28c191
      • Screening tools for prenatal substance abuse include NIDA Quick Screen, CRAFFT (for patients aged 26 or younger), and 4Ps r28c192c193
    • American Academy of Pediatrics recommends that pediatricians incorporate universal SBIRT (screening, brief intervention, and referral to treatment) practices into medical care standards for adolescents r58c194
    • Providers should educate themselves on state and federal laws surrounding substance use screening and reporting before applying universal screening protocols r50
      • Mandatory reporting of substance use may be required in some states

    Screening tests

    • Screening is not a full assessment; patients with problem identified on screening or through discussion with patient require referral for full assessment r2c195
    • SBIRT (screening, brief intervention, and referral to treatment) c196
      • Evidence-based practice used to identify, reduce, and prevent problematic use, abuse, and dependence on alcohol and illicit drugs; useful in any health care setting (eg, emergency departments, primary care centers, office/clinic practices, other community settings) r52
        • Screening: use standardized screening tools to assess patient for risky substance use behaviors
        • Brief Intervention: engage patient in short conversation, providing feedback and advice
        • Referral to Treatment: provide referral for brief therapy or additional treatment if necessary
    • Many screening tools are available, for example: r18
      • SOAPP-R (Revised Screener and Opioid Assessment for Patients with Pain) r66c197
        • Devised as a screening tool for chronic pain patients before initiation of opioid therapy; found to correlate well with opioid use disorder in emergency department setting r18
      • NIDA Quick Screen r2c198
        • First, ask about patient's (aged 18 or older) drug use during the past year r67
        • If patient affirms use of illegal or prescription drugs for nonmedical reasons, begin NIDA-Modified ASSIST (Alcohol, Smoking, and Substance Involvement Screening Test); determine risk level
      • CRAFFT c199
        • Screening tool validated for adolescents aged 12 to 18 years; 2 or more positive responses indicate need for further assessment r68
          • Have you ever ridden in a CAR driven by someone (including yourself) who was high or had been using alcohol or drugs?
          • Do you ever use alcohol or drugs to RELAX, feel better about yourself, or fit in?
          • Do you ever use alcohol or drugs while you are by yourself, or ALONE?
          • Do you ever FORGET things you did while using alcohol or drugs?
          • Do your FAMILY or FRIENDS ever tell you that you should cut down on your drinking or drug use?
          • Have you ever gotten into TROUBLE while you were using alcohol or drugs?
      • 4Ps r28
        • Screening tool for pregnant patients; any affirmative answer should prompt further questions
          • Parents: did any of your parents have a problem with alcohol or other drug use?
          • Partner: does your partner have a problem with alcohol or drug use?
          • Past: in the past, have you had difficulties in your life because of alcohol or other drugs, including prescription medications?
          • Present: in the past month have you drunk any alcohol or used other drugs?
    • In combination with self-reported data, review of state prescription drug monitoring program may provide objective data for consideration; used alone, does not assess risk for opioid use disorder r18

    Prevention

    • Encourage use of nonopioid analgesics to treat pain when appropriate r18r69r70r71c200
      • Physician prescribing may be important driver of opioid abuse, dependence, and overdose
    • Guidelines are available for prescribing opioids for chronic pain (defined as pain for 3 months or longer, excluding cancer, palliative, and end-of-life care) c201
      • CDC guideline provides recommendations for primary care clinicians prescribing opioids for chronic pain (outside active cancer treatment, palliative care, end-of-life care) r72
      • American Society of Interventional Pain Physicians has developed guidelines to improve pain and function in chronic noncancer pain on a long-term basis r73
    • Prescription drug monitoring programs r9r74c202
      • State-level intervention intended to improve opioid prescribing, inform clinical practice, and protect patients at risk
    • Education c203
      • Opioid Overdose Prevention Toolkit is available from Substance Abuse and Mental Health Services Administration r75
        • Provides strategies to health care providers, communities, and local governments for developing practices and policies to help prevent opioid-related overdoses and deaths
      • Provide adolescents with clear and consistent education about abstaining from substance use because this is a critical period r58c204
      • US Preventive Services Task Force finds insufficient evidence to make any recommendation regarding primary care–based behavioral counseling interventions to prevent illicit drug use in children, adolescents, and young adults aged up to 25 years r76
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