History

• Signs and symptoms reflect compulsive, prolonged self-administration of opioids for no legitimate medical purpose or, if a medical condition is present requiring opioid treatment, opioids are used in doses greatly exceeding amount needed ^r1
• A 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 ^r4
  • Particular attention should be paid to the following: ^r6r9r10
    • Concomitant medical conditions including infectious diseases (eg, hepatitis, HIV, tuberculosis), acute trauma, and pregnancy
    • 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 ^r6
        • Electronic databases that track controlled substance prescriptions within a state allow health care authorities to obtain timely information regarding prescribing and patient behaviors ^r11
        • Sharing between states can be facilitated in most cases ^r12
        • Do not capture data from patients receiving prescription drugs written for others
        • State laws vary regarding prescription drug monitoring programs; clinicians should be familiar with associated legal requirements ^r6
      • Concomitant use of alcohol and 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
      • Assessment of mental health status and possible psychiatric disorders should be completed
    • Social and environmental factors
      • Can identify facilitators and barriers to addiction treatment, specifically pharmacotherapy and best environment for treatment
    • Addictive behaviors (eg, gambling, 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 ^r1r13
  • Impaired control
    • 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 ^c1
    • Failure to fulfill home, work, or school obligations as a result of repeated opioid use
    • Continued opioid use despite experiencing social or interpersonal problems
    • Giving up or reducing important social, recreational, or occupational activities
  • Risky use
    • Recurrent opioid use in hazardous situations (eg, driving)
    • 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
  • Pharmacologic criteria
    • Tolerance: needing increased amounts of opioids to achieve same effect
      • Tolerance typically develops fairly rapidly for analgesic, respiratory-depressant, and euphoria-producing properties; relatively little tolerance occurs to constipation or pupillary constriction ^r13
    • Physical dependence: a physiologic state of adaptation to a substance, without which, symptoms and signs of withdrawal occur ^r14c2
    • Note that these pharmacologic criteria are not considered to be met for those taking opioids solely under appropriate medical supervision ^r1
    • Note that presence of these criteria reflect physiologic changes and do not alone indicate opioid use disorder
• Associated features of opioid use disorder ^r5
  • History of drug-related crime may be present (eg, possession or distribution of controlled substances, larceny, robbery, forgery, receiving stolen goods)
  • Social difficulties related to drug use may occur at all socioeconomic levels; includes divorce or other marital difficulties, irregular employment, unemployment
  • 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
  • High-risk sexual behavior and history of sexually transmitted infections is frequently present, particularly in younger patients ^r15c3
  • Women with opioid use disorder often report amenorrhea, which is secondary to the dopaminergic effects of opioids ^r15c4
• Symptoms of opioid withdrawal may be identified and are a consideration in treatment options ^d1
  • May be spontaneous (discontinuation or abrupt reduction of opioid dose) or precipitated (administration of opioid agonist [eg, naloxone, naltrexone] or partial agonist [eg, buprenorphine]) ^r6
    • Precipitated withdrawal occurs faster and may be much more severe, occasionally requiring hospitalization
  • Onset of withdrawal following opioid discontinuation varies with half-life of particular opioid ^r15
    • Short-acting opioids (eg, morphine, heroin): symptoms may appear within 8 to 12 hours of last dose, peak at 48 to 72 hours, and clear after 7 to 10 days ^r9
    • Longer-acting opioids (eg, methadone): symptoms may take 1 to 3 days to appear after last dose; peak between 3 and 8 days, and do not clear for several weeks ^r9
      • Symptoms may be milder than those following equivalent doses of short-acting opioids
  • Initial symptoms include anxiety, restlessness, agitation, and drug craving ^c5c6c7c8
  • Symptoms of progressive withdrawal include muscle/joint aches, abdominal cramping, nausea, loose stools, and insomnia ^{c9c10c11c12c13c14}

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 ^c15c16c17c18
  • Intoxication ^d2
    • Sedation, often with periodic loss of consciousness or brief sleep (head nodding) ^c19
    • Decreased respiratory rate (rate of 12 or lower consistent with opioid intoxication^r16); may be accompanied by bradycardia, hypotension, and hypothermia ^c20
    • Constricted pupils (pupil diameter less than 2 mm with decreased reactivity; may not be present if other drugs used concurrently)^r17c21c22
    • Drooping eyelids ^c23
    • Scratching (to relieve itching caused by histamine release) ^c24
  • Acute withdrawal
    • Mydriasis (dilated pupils) ^c25
    • Diaphoresis ^c26
    • Vomiting and diarrhea ^c27
    • Tachycardia and hypertension ^c28c29
    • Piloerection (gooseflesh) ^c30
    • Rhinorrhea and lacrimation ^c31c32
    • Yawning ^c33
    • Observed restlessness ^c34
  • May be fentanyl patches on the skin or evidence of their use ^r18
• Injection drug users may have:
  • Recent injection site marks (small red, inflamed puncture wounds with slight bruising surrounding the marks) ^c35c36
    • Old injection sites show pigmentation change and atrophied skin
  • Thrombosed veins ^c37
  • Skin abscesses or cellulitis ^c38c39

Causes

• Most opioids bind as agonists to the µ-receptor and typically produce the effects commonly associated with opioids (eg, miosis, respiratory depression, analgesia, euphoria, drowsiness) ^r13c40
  • Classes of opioids ^r19
    • Naturally derived (from opium): morphine, opium, codeine, and thebaine
    • Semisynthetic: buprenorphine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, oxymorphone, levorphanol, and heroin
    • Synthetic: fentanyl, methadone, meperidine, 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 ^r20
    • Effects of prolonged drug exposure compromise the ability to choose; drug seeking and use become compulsive, bypassing individual's self-control or willpower ^r9
  • 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 ^r20
• 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
  • Opioids all have highly reinforcing pharmacologic properties ^r15
    • Positive reinforcement
      • Intrinsic property of opioids is the 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 the drug
    • Negative reinforcement
      • Produced by opioid withdrawal, after physiologic dependence has occurred
        • Opioid withdrawal activates region of brain (locus caeruleus) resulting in increased systemic sympathetic tone and high intensity cravings ^r15
        • 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 ^c41
    • Approximately 40% to 60% of susceptibility to substance use disorders is associated with genetic factors ^r21
  • Environmental and social factors are believed to affect such factors as drug availability and likelihood of initial use ^r15
    • 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, dependence, and overdose ^r22
  • Individual temperaments (eg, impulsivity, novelty seeking) have propensity to develop a substance use disorder ^r1
  • Psychiatric diseases commonly co-occurring with opioid addiction include:
    • Other substance use disorders ^r23
      • Strong associations exist between alcohol and cocaine abuse and subsequent development of an opioid use disorder ^r23
    • Depression
    • Anxiety
    • Posttraumatic stress disorder
    • Conduct disorder in childhood and adolescence
• Progression of use often follows trend to maximize drug bioavailability and effect; limited access to prescription opioids may also influence progression to IV use ^r15
  • Use may start with oral prescription opioids, which can lead to inhaled prescription opioids, to inhaled heroin, and ultimately to injection of heroin (most potent and bioavailable method)
    • Inhalation may involve smoking (heating heroin in foil and inhaling smoke) or nasal snorting (of powdered heroin)

Risk factors and/or associations

Primary diagnostic tools

• Opioid use disorder is primarily diagnosed based on patient history and comprehensive assessment, including a physical examination ^r9c48
  • Diagnose opioid use disorder when patient meets at least 2 out of 11 of the revised diagnostic criteria (DSM-5) ^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
      • Opioids are often taken in larger amounts or over a longer period than was 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 opioid's effects
      • Craving, or a 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 the effects of opioids
      • Important social, occupational, or recreational activities are given up or reduced 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:
        • A need for markedly increased amounts of opioids to achieve intoxication or desired effect
        • A markedly diminished effect with continued use of the same amount of an opioid
        • Note: 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
        • Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms
        • Note: 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 have been met for at least 3 months but for less than 12 months (with exception that "craving, or a 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 have been met at any time during a period of 12 months or longer (with exception that "craving, or a strong desire or urge to use opioids" may be met)
    • Specify if: ^r1
      • On maintenance therapy: additional specifier used if individual is taking prescribed agonist medication (ie, methadone or buprenorphine) and none of the criteria for opioid use disorder have been met for that class of medication (except tolerance to, or withdrawal from, the agonist)
        • Also applies to those individuals being maintained on a partial agonist/antagonist, or a full antagonist (ie, oral or depot naltrexone)
      • In a controlled environment: additional specifier used if individual is in an environment where access to opioids is restricted (eg, closely supervised and substance-free jails, therapeutic units, and 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
  • Comparing old terminology, the term opioid dependence most closely compares to the threshold for moderate use disorder^r6
• Various withdrawal scales are available to assist in identifying and quantifying severity of opioid withdrawal symptoms, including: ^r6d1
  • COWS (Clinical Opioid Withdrawal Scale): uses both signs and symptoms (objective and subjective) ^r29c49
• Initial laboratory work-up includes CBC, liver function, hepatitis C, and HIV testing; test women of childbearing age for pregnancy ^r9c50c51c52
  • Consider testing for sexually transmitted infections including syphilis and tuberculosis; test for hepatitis A and B if appropriate ^{r6c53c54c55c56}
  • Hepatitis serology is recommended ^r6
• Urine drug testing during the comprehensive assessment process is recommended ^r6
  • 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 ^r30
    • Results should be used in combination with patient history, psychosocial assessment, and physical examination
  • Can provide information about recent drug use, however: ^r4r6
    • Positive drug test is not diagnostic of physical dependence, opioid use disorder, or its severity
    • Negative urine test does not rule out opioid use, disorder, or physical dependence
  • Many tests available, with variable reliability and validity ^r6
    • Interpretation requires thorough knowledge of methodology and reliability
  • Other sample matrices are available (eg, blood, saliva); use individualized according to patient's needs ^r30
  • Be aware of potential mandatory reporting requirements ^r31
  • Be aware of limitations of various testing matrices

Laboratory

• Urine drug testing ^r4r19c57
  • Understand limitations of tests used, including detection limits and what substances can be detected
  • Used clinically to identify drug use, misuse, diversion, or a suspected substance use disorder or relapse ^r4
  • 2 types:
    • Urine drug screen ^r19
      • 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 the test result
        • Standard drug screening panels screen for amphetamines, cocaine, marijuana, opiates, phencyclidine, and often benzodiazepines
          • Screens for opioids metabolized to morphine (eg, codeine, morphine), but not other opioids like oxycodone, hydrocodone, buprenorphine, and methadone
          • Intended for workplace drug testing; substances targeted and their associated cutoff levels are not appropriate in clinical care of patients with addiction ^r30
        • Other commercial immunoassays available include semisynthetic opioids (eg, buprenorphine, hydrocodone, oxycodone) and synthetic opioids (eg, meperidine, methadone, fentanyl)
          • If heroin use is suspected, test for 6-monoacetylmorphine, a metabolite specific only to heroin; however, 6-MAM has an extremely short half-life and is detected in urine for only up to 8 hours after heroin use ^r19
            • Heroin is rapidly converted to 6-monoacetylmorphine and subsequently to morphine
        • Base drug testing panels on the patient’s drug of choice, prescribed medications, and drugs common within patient’s geographic location and peer group ^r30
      • May also detect substances with similar characteristics (cross reactivity) leading to false-positive test results
        • Nonopioids with potential for false-positive test results for opiates include quinolones, rifampin, poppy seeds, and dextromethorphan, especially at low cutoff thresholds ^r19
      • 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 if confirmatory testing is warranted
    • Confirmatory testing of positive drug screen results ^r19
      • Methods include gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry
        • 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 what 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 the results ^r4r30
        • Can help inform decisions with major clinical or nonclinical patient implications (eg, treatment transition, changes in medication therapies, changes in legal status) ^r30
        • A definitive test should be done if patient disputes findings of presumptive test ^r30
    • 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 ^r19
        • Results lower than established cutoff value are reported as negative; does not indicate the substance is not present, rather that concentration did not meet the 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, such as when testing for medication adherence ^r19
    • Detection times ^r19
      • 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 (morphine): 48 hours
        • Morphine: 48 to 72 hours
        • Oxycodone and hydromorphone: 2 to 4 days
        • Methadone: 3 days
• CBC and liver function test results may show infection or other medical conditions and liver dysfunction ^r6c58c59
  • Abnormal results may require further evaluation
  • Baseline testing may be required before initiation of pharmacotherapy

Most common

• Other substance intoxication ^r1d3
  • Alcohol and sedative-hypnotic intoxication can clinically resemble opioid intoxication ^c60c61
  • 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 of the sedative effects
• Clinically appropriate use of opioid medications ^c62
  • 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) ^c63c64c65d4
  • 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

Admission criteria

In some cases of mild opioid use disorder, management can be by primary care with medication and referral for intensive outpatient treatment ^r32

For moderate and severe opioid use disorder, determination of the most appropriate American Society of Addiction Medicine criteria to assign is best performed by a specialist in addiction medicine ^r32

American Society of Addiction Medicine provides criteria for service planning and placement ^r32

Inpatient/medically supervised residential treatment may be indicated for withdrawal management in 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 ^r33
• For pregnant women, some obstetricians initiate opioid agonist therapy in inpatient setting; not always necessary or available, but allows close monitoring of medication response ^r31
• 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 ^r6
• Patients with severe or unstable psychiatric symptoms may require hospitalization ^r6
• Patients with significant medical comorbidities may benefit from 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 ^r9
• Consider referring women of childbearing age to gynecologist to discuss contraception
  • Fertility increases as treatment becomes effective

Drug therapy

• For opioid agonist pharmacotherapy (medication-assisted treatment)
  • Buprenorphine ^c66
    • For the prevention of undue symptoms of opiate agonist withdrawal during induction of opiate agonist dependence treatment
      • Buprenorphine Hydrochloride Sublingual tablet; Adults: Administer first dose when early signs of opioid withdrawal appear and at least 4 hours after the last used short-acting opioid or 24 hours after last used long-acting opioid. Rapidly titrate dose, in 2 mg to 4 mg increments, until clinical effect is achieved. Use as part of a complete treatment program. Initiate treatment with supervised administration. Single-agent buprenorphine is preferred over buprenorphine; naloxone for induction. Physicians must meet and maintain the requirements of the Drug Addiction Treatment Act in order to provide medication-assisted treatment (MAT) to opioid-dependent patients.
        • Dose up to 12 mg for induction, but 16 mg/day is common maintenance dose
  • Buprenorphine/naloxone ^c67
    • For induction treatment in patients dependent on heroin or other short-acting opioid products who are in opioid withdrawal
      • Sublingual film (ie, Suboxone)
        • Buprenorphine Hydrochloride, Naloxone Hydrochloride Oral dissolving film; Adults and Adolescents 16 years and older: ONLY the sublingual route should be used during induction therapy due to higher systemic exposure of naloxone during buccal administration and an increased risk of precipitating withdrawal; the buccal or sublingual route may be used during maintenance therapy. DAY 1 DOSING: First induction dose buprenorphine; naloxone 2 mg/0.5 mg or 4 mg/1 mg SL film; may titrate in 2 or 4 mg increments of buprenorphine, at approximately 2-hour increments, under supervision, up to a total dose of buprenorphine\; naloxone 8 mg/2 mg SL film. DAY 2 DOSING: A single daily dose of buprenorphine; naloxone up to 16 mg/4 mg SL film is recommended. DAY 3 DOSING AND BEYOND: Progressively adjust dose in increments or decrements of 2 mg/0.5 mg or 4 mg/1 mg to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms. An adequate maintenance dose should be attained as quickly as possible. To avoid precipitating withdrawal, only initiate the first induction dose when objective signs of moderate withdrawal appear and not less than 6 hours after the patient last used an opioid. Not indicated for induction in patients dependent on methadone or long-acting opioids because these patients may be more susceptible to precipitated and prolonged withdrawal during induction than patients on short-acting agents. Prior to induction therapy, consider the type of opioid dependence (i.e., short- or long-acting opioids), the time since last opioid use, and the severity of opioid dependence. Physicians must meet and maintain the requirements of the Drug Addiction Treatment Act in order to provide medication-assisted treatment (MAT) to opioid-dependent patients.
      • Sublingual tablet (ie, Zubsolv)
        • Buprenorphine Hydrochloride, Naloxone Hydrochloride Sublingual tablet; Adults and Adolescents 16 years and older: Consider type of opioid dependence (i.e., short- or long-acting opioids). Not indicated for induction in patients dependent on long-acting opioids. For short-acting opioid dependence, initiate 1st induction dose only when signs of withdrawal appear and not less than 6 hours after last used opioid. Induction dosing is as follows: DAY 1 DOSING: Initial dose is 1.4 mg/0.36 mg SL. During the remainder of Day 1, may administer 1 to 2 SL tablets of buprenorphine; naloxone 1.4 mg/0.36 mg SL at 1.5 to 2 hour intervals up to a total of 5.7 mg/1.4 mg. Some patients may tolerate up to 3 tablets (1.4 mg/0.36 mg per tablet) as a single, second SL dose. DAY 2 DOSING: A single daily dose of up to 11.4 mg/2.9 mg SL is recommended. Base dosage on clinical need to control acute withdrawal symptoms and administer under supervision. DAY 3 DOSING AND BEYOND: Maintenance target dose is 11.4 mg/2.9 mg SL as a single daily dose. See maintenance treatment section. Physicians must meet and maintain the requirements of the Drug Addiction Treatment Act in order to provide medication-assisted treatment (MAT) to opioid-dependent patients.
  • Methadone ^c68
    • NOTE: For the treatment of narcotic addiction in detoxification programs, methadone may be dispensed only by pharmacies and clinics approved by the FDA and state authorities according to treatment requirements stipulated in the federal methadone regulations. However, in a hospital setting, a physician or authorized hospital staff personnel may administer or dispense narcotic drugs to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction
    • For the treatment of opiate agonist withdrawal during detoxification treatment
      • Methadone Hydrochloride Oral solution; Adults, including pregnant women: 20 to 30 mg PO initially unless low opioid tolerance is expected; use a lower initial dose for these patients. May give an additional 5 to 10 mg 2 to 4 hours after initial dose if withdrawal symptoms have not been suppressed or if symptoms reappear. Max total dose on day 1: 40 mg. Base subsequent days dosing on withdrawal control at the time of expected peak methadone activity (2 to 4 hours after dosing). May take up to 5 days to achieve steady-state dose. Prior to achieving steady state, adequate total daily doses may not hold patients for a full 24 hours. Continue stabilizing dose for 2 to 3 days.
      • Patients need to show withdrawal symptoms but no signs of sedation or intoxication. Deaths caused by the cumulative effects of methadone have occurred in early treatment
    • 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 ^r48
• For relapse prevention
  • Naltrexone ^c69
    • Oral tablet
      • Naltrexone Hydrochloride Oral tablet; Adults: 25 mg PO with food initially. If no withdrawal signs occur, give 50 mg PO once daily thereafter. NOTE: Naltrexone should be used as part of a comprehensive treatment plan that includes psychosocial support and medication compliance techniques. Patients must be opioid-free for a minimum of 7—10 days before starting naltrexone to avoid precipitation of opioid withdrawal.
    • Intramuscular injection
      • Naltrexone Suspension for injection, Extended Release; Adults: 380 mg IM by gluteal injection every 4 weeks or once monthly.
• For opioid overdose
  • Naloxone ^c70
    • Effective dose is empiric ^r34
      • 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, or subcutaneously every 2 to 3 minutes as needed up to a total dose of 10 mg.

Nondrug and supportive care

• Psychosocial interventions
  • Recommended in conjunction with any pharmacologic treatment of opioid use disorder ^r9
    • Minimum recommended requirements include psychosocial needs assessment, supportive counseling, links to existing family supports, and referrals to community services ^r9
  • 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 which may trigger relapse ^r6r20
  • 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 ^r49
    • Variety of formats available, including: ^r6r49
      • Cognitive-behavioral therapy ^c71
        • Learning to recognize and stop negative patterns of thinking and behaving
      • Contingency management
        • Providing incentives to encourage/reinforce positive behaviors
      • Individual, group, and couples counseling ^c72
        • Includes behavioral therapy, commonly for substance use disorder treatment ^r20c73
          • Behavioral therapies vary in focus
            • May include addressing a 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 ^r20
          • Participation in group therapy and other peer-support programs during and following treatment can help maintain abstinence
      • Mutual help programs
        • Includes 12-step programs such as Narcotics Anonymous, Alcoholics Anonymous, and Methadone Anonymous ^c74
          • Other groups include Self-Management and Recovery Therapy, Women for Sobriety, and Secular Organization for Sobriety groups, among many others
        • Not considered a form of treatment on their own, but may provide positive reinforcement and motivation and social support from other members during and after active treatment ^r36
      • Motivational interviewing ^c75
        • Building motivation/commitment to engaging in treatment and recovery process
      • Social skills training ^c76
      • Family therapy
  • Relapse-prevention strategies are an important part of an addiction-treatment plan; opioid use disorder is a chronic, relapsing disease ^r9
    • 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 ^r10
  • Psychiatric treatment may be needed to manage psychiatric comorbidities that complicate addictive disorder or act as trigger ^r2
• Education/harm reduction ^c77c78
  • Provide targeted risk-reduction counseling for infectious diseases (eg, HIV/AIDS, HBV, HCV, tuberculosis) and link patients to treatment if necessary ^r2
  • Offer contraceptive counseling to age-appropriate women in treatment for substance use disorder to minimize risk of unplanned pregnancy ^r31
    • Unplanned pregnancy rates are about 80% in women with substance use disorders ^r31
  • Safe injection information to help reduce hazards of injection and can include:
    • Self-administering small test dose to test potency before administering entire dose of drug of unknown potency ^r50
    • Proper skin cleaning before injection ^r50
    • Using clean/new needles and avoiding reuse of needles or sharing needles ^r50
      • Refer to syringe exchange program if available ^r51
  • Medication interactions ^r41
    • Concurrent use of alcohol, benzodiazepines, or gabapentin with buprenorphine can increase risk of sedation, respiratory depression, and death
    • Naltrexone should not be used concurrently with opioids
• Offer HAV and HBV vaccination, if appropriate ^r9c79c80

Comorbidities

• Viral (eg, HIV, HCV) and bacterial infections ^r1c81c82
  • Most common with opioid injection
• Other substance use disorders (eg, tobacco, alcohol, cannabis, benzodiazepines, stimulants) ^{r1c83c84c85c86c87c88}
  • 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: ^r1r6
  • Depression ^c89
    • May be opioid-induced or exacerbate pre-existing primary depressive disorder
  • Anxiety ^c90
  • Post-traumatic stress disorder ^c91
  • Personality disorders ^c92
  • Conduct disorder in childhood or adolescence ^r1c93c94

Special populations

• Pregnant women
  • Rise of opioid use in pregnancy has increased parallel to the epidemic in the general population ^r31
    • Pregnant women with opioid use disorder are more likely to seek prenatal care late in pregnancy, miss appointments, and experience poor weight gain ^r9
  • Complications of untreated opioid use disorder specific to pregnancy include: miscarriage, preterm labor and delivery, intrauterine growth restriction, and neonatal abstinence syndrome ^r52
    • 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 women taking opioid agonist therapies ^r31r53
      • Characterized by disturbances in newborn's gastrointestinal, autonomic, and central nervous systems (eg, irritability, high-pitched cry, tremors, poor feeding, regurgitation, loose stools, sweating, yawning, sneezing) ^r53
      • The term NOWS (neonatal opioid withdrawal syndrome) is sometimes used to reflect associated constellation of symptoms ^r52
      • Dosage of methadone or buprenorphine does not have consistent effect on incidence and severity of neonatal abstinence syndrome ^r52
  • Universal SBIRT (screening, brief intervention, and referral to treatment) is essential in early obstetric care to improve maternal and infant outcomes ^r31r54
    • Validated screening tools include: 4Ps, NIDA (National Institute on Drug Abuse) Quick Screen, and CRAFFT (for women aged 26 years or younger) ^r55
    • Providers should be aware of state laws surrounding substance use screening and reporting ^r56r57
      • Policies that dissuade women from seeking prenatal care are contrary to the welfare of the mother and fetus ^r56
  • Some elements of prenatal care may require modification (eg, increased testing for sexually transmitted diseases, additional ultrasonography examinations) based on patient's particular clinical needs ^r31
  • Care should be comanaged by an obstetrician and an addiction medicine specialist physician ^r9
    • 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 ^r58
  • Treatment with opioid agonist pharmacotherapy (medication-assisted treatment) is recommended for pregnant women with opioid use disorder, in addition to counseling and behavioral therapy ^r31
    • Medications include methadone and buprenorphine; benefits and disadvantages exist for both and choice should be individualized^r52
      • Methadone ^r31
        • Associated with higher retention rate ^r52
        • 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 ^r9
      • Buprenorphine
        • Buprenorphine monotherapy is currently recommended in pregnancy ^r31r52
          • Use of buprenorphine/naloxone combination therapy appears to have no maternal, fetal, or neonatal adverse effects and may be additional option during pregnancy; however, the FDA only recommends monotherapy in pregnancy ^r52
        • 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 stays^r60r59
        • Typically requires fewer dosing adjustments during pregnancy than methadone ^r9
      • Hospitalization during initiation of methadone or buprenorphine may be advisable, especially in third trimester ^r9
    • Data on safety and efficacy of naltrexone in pregnancy are limited ^r31r52
  • Infants born to women using opioids during pregnancy should be monitored in hospital for neonatal abstinence syndrome by a pediatric care provider, typically for 4 to 7 days^r52r31
    • Opioids are recommended as first line drug for newborns with neonatal abstinence syndrome ^r53
  • Encourage breastfeeding for mothers who are stable on opioid agonists, are not using illicit drugs, and have no other contraindications (eg, HIV infection) ^r31
    • 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 ^r9r31
    • Not recommended for use in pregnant women as it may precipitate preterm labor or fetal distress, however risk of maternal death from overdose outweighs fetal risks ^r6
  • Vaccination for HAV and HBV are recommended if serology is negative ^r9
• Adolescents
  • During adolescence (about age 12 into early 20s), neurodevelopmental molding and maturation confer greater vulnerability to addictions; in addition, risk-taking behaviors are generally more prevalent ^r61
    • Age at first substance use is inversely correlated with the lifetime incidence of developing a substance use disorder
  • Progression of use from oral opioids to injection of heroin is more prominent in adolescents than adult opioid users; accelerates faster with earlier age of first opioid use ^r15
    • Tolerance to opioids happens rapidly in adolescents; heroin'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) ^r15
  • Treatment in specialized facilities providing multidimensional services may be beneficial for adolescents ^r9
    • Many unique medical, legal, and ethical dilemmas may complicate treatment
  • Full range of treatment options (including methadone, buprenorphine, and naltrexone) can be considered in treatment of opioid use disorder in adolescents; most efficacy studies have been conducted on adults ^r9
    • Methadone is not easily available for patients under age 18 years ^r15
    • Buprenorphine is FDA approved for adolescents aged 16 years and older ^r9
    • Naltrexone may be considered for young adults aged 18 years or older ^r6
• Individuals with co-occurring psychiatric disorders
  • Common among individuals with opioid use disorder ^r6
    • 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
  • Patients with psychiatric disorders should be asked about suicidal ideation and behavior ^r6
    • Management of patients with suicide risk includes immediate risk reduction, managing underlying factors associated with suicidal intent, and careful monitoring and follow-up
  • Pharmacotherapy in conjunction with psychosocial treatment should be considered for patients with opioid use disorder and a co-occurring psychiatric disorder ^r6
    • Providers should have knowledge of potential interactions between medications used to treat opioid use disorder and co-occurring psychiatric disorders
    • Reassessment using a detailed mental status examination should be obtained after stabilization with methadone, buprenorphine, or naltrexone
• Individuals with pain
  • Acute and chronic pain are common among patients with opioid use disorder ^r6
  • Accurate diagnosis of cause of pain is important so choice of suitable treatment can be made ^r6
    • Nonpharmacologic treatments may be effective (eg, physical therapy)
    • Pharmacologic treatments to consider include: ^r6
      • 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 ^r6
    • Patients with untreated and active opioid use disorder ^r6
      • Both methadone and buprenorphine have analgesic effects and may be considered; transition to opioid agonist treatment can help comanage both pain and opioid use disorder
    • Patients in treatment for opioid use disorder with opioid agonists ^r6
      • Patients on methadone with severe, acute pain will 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 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 (eg, fentanyl) 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) ^r6
      • 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
• Individuals in criminal justice system
  • Substantial proportion of people in the criminal justice system (eg, prisons, jails, drug courts, probation, parole) have opioid use disorder and associated problems ^r6
    • Screening for opioid use disorder and consideration for initiation or continuation of medication for opioid use disorder is recommended ^r6
  • Pharmacotherapy (methadone, buprenorphine, or naltrexone), in addition to psychosocial treatment, may be considered ^r6
    • Insufficient evidence to recommend any one treatment superior for prisoners or parolees
    • Pharmacotherapy should be initiated 30 days before release from prison and aftercare established in advance ^r6
      • Discharge from prison is often associated with opioid overdose and death

At-risk populations

• Screening for drug use remains controversial
  • In 2015, the US Preventive Services Task Force concluded that evidence was insufficient to assess the balance of benefits and harms of screening adolescents, adults, and pregnant women for illicit drug use; this topic is currently in update process ^r66
  • However, the Substance Abuse and Mental Health Services Administration recommends SBIRT (substance use screening, brief intervention, and referral to treatment) as part of routine health care ^r61
  • The American College of Obstetricians and Gynecologists recommends universal screening of pregnant women for substance use; maternal and infant outcomes are improved with universal screening, intervention, and treatment referral ^r31
    • Pregnancy provides an opportunity to identify and treat women with substance use disorders
    • Screening should be done, in partnership with the pregnant woman, at the first prenatal visit ^r31c120
    • Screening tools for prenatal substance abuse include: NIDA (National Institute on Drug Abuse) Quick Screen, CRAFFT (for women age 26 or younger), and 4Ps ^r31c121c122
  • American Academy of Pediatrics recommends that pediatricians incorporate universal SBIRT (substance use screening, brief intervention, and referral to treatment) practices into the medical care standards for adolescents ^r61c123
• Providers should educate themselves on state and federal laws surrounding substance use screening and reporting before applying universal screening protocols ^r52
  • 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 ^r2
• SBIRT (screening, brief intervention, and referral to treatment): ^c124
  • An 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) ^r54
    • 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 needed
• Many screening tools are available, for example: ^r22
  • SOAPP-R (Revised Screener and Opioid Assessment for Patients with Pain) ^r67c125
    • Devised as screening tool for chronic pain patients before initiation of opioid therapy; found to correlate well with opioid use disorder in emergency department setting ^r22
  • NIDA (National Institute on Drug Abuse) Quick Screen: ^r2c126
    • First, inquires about patient's (aged 18 or older) drug use during the past year ^r68
    • If patient affirms use of illegal or prescription drugs for nonmedical reasons, begin NIDA (National Institute on Drug Abuse)-Modified ASSIST; determine risk level
  • CRAFFT ^c127
    • Screening tool validated for adolescents aged 12 through 18 years; 2 or more positive responses indicate need for further assessment ^r69
      • 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 ^r31
    • A screening tool for pregnant women; 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 ^r22