• Opioid use disorder (OUD) is defined as a cluster of cognitive, behavioral, and physiologic symptoms in which the individual continues use of opiates despite significant opiate-induced problems. Opiate use disorder is a chronic, relapsing disorder characterized by repeated self-administration that usually results in opiate tolerance, withdrawal, and compulsive drug use. Tolerance is the need to increase dose to achieve the same effect. Dependence may occur with or without the physiologic symptoms of tolerance and withdrawal.
• There are four stages of addiction:
  1. Stage I, acute drug effects: Rewarding effects of drug result from neurobiologic changes in response to the acute drug use. Duration varies from hours to days.
  2. Stage II, transformation to addiction: Associated with changes in neuronal function that accumulate with repeated administration and diminish over days or weeks after discontinuation of drug use.
  3. Stage III, relapse after extended periods of abstinence: Precipitated by an incubation of cue-induced craving (people, places, and things as triggers) and priming (relapse precipitated by drug exposure).
  4. Stage IV, end-stage addiction: Vulnerability to relapse endures for years and results from prolonged changes at the cellular level.
• Pseudoaddiction: Undertreatment of pain resulting in “opiate-seeking” behaviors such as “doctor shopping” and multiple emergency department visits. These behaviors disappear with adequate treatment of pain.

Opioid dependence

OUD

Opiate addiction

Opiate abuse

Narcotic addiction

Narcotic abuse

Substance use disorder

• Physical examination is often noncontributory.
• Small-sized pupils may be the only observable sign of use because only mild tolerance develops for miosis. Acute effects of opioid agonists are summarized in Box 2.
• Scars or tracks from chronic IV use may be visible over the veins of the arms, hands, ankles, neck, and breasts.
• Inflamed nasal mucosa or respiratory wheezing may be apparent in patients who are snorting heroin or OxyContin.
• Patients in withdrawal may have more dramatic findings such as tachycardia, hypertension, fever, piloerection (goose flesh), mydriasis, lacrimation, central nervous system (CNS) arousal, irritability, and repeated yawning. Box 3 summarizes symptoms and signs of opioid withdrawal. In patients with sympathetic overactivity and panic attacks, use of CNS stimulants (Box 4), such as amphetamines or cocaine, should also be ruled out.
• Although gastrointestinal symptoms of nausea, vomiting, and abdominal pain are common in opioid withdrawal, other causes such as gastroenteritis, pancreatitis, peptic ulcer disease, and intestinal obstruction need to be ruled out.
• The history may provide relevant information in making the diagnosis. Significant findings may include:
  1. A long history of opioid self-administration, typically by the IV or intranasal route but sometimes through smoking as well.
  2. Polysubstance use. Intoxication by drugs other than narcotics (e.g., benzodiazepines, barbiturates) should be ruled out in unconscious patients.
  3. A high incidence of non-opioid-related psychiatric disorders (>80%).
  4. History of problems at work, school, or relationships associated with drug use.
  5. History of legal problems associated with drug use, such as arrest for possession, robbery, or prostitution.
  6. History of interpersonal violence (as perpetrator or victim).
  7. History of physical problems such as skin infections, phlebitis, endocarditis, or liver diseases attributable to acetaminophen toxicity (Vicodin/Percocet) or viral hepatitis. Hepatitis C is the most prevalent blood-borne pathogen. It is present in approximately 90% of opiate-dependent people and is often spread by sharing IV drug paraphernalia or snorting devices. There is also a higher incidence of HIV infection.

• Opioid use disorder is a biopsychosocial disorder. Pharmacologic, social, genetic, and psychodynamic factors interact to influence abusive behaviors. Pharmacologic factors are especially prominent in opiate addiction because these drugs are strong reinforcing agents due to their euphoric effects and their ability to reduce anxiety and increase self-esteem and the patient’s subjective feelings of improved ability to cope with daily challenges.

• Psychiatric disorders (e.g., anxiety, depression, bipolar disorder).
• Acute medical illness (e.g., hypoglycemia, seizure disorder, sepsis, renal or hepatic insufficiency) may mimic opiate withdrawal symptoms.

The history is the most important part of the workup. A single-question screening test (“How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?”) should be incorporated in the medical history. Useful screening tools for OUD are the CAGE-AID (Table 1), the DAST-10 (Table 2), and the CRAFFT (Table 3). The CAGE-AID has a sensitivity of 70% and a specificity of 85% when two questions are answered in the affirmative. The DAST-10 can discriminate between current users versus former users. The CRAFFT is a useful screening tool for adolescents. A CRAFFT score of 2 or higher is optimal for identifying any problem (sensitivity 76%, specificity 94%), any disorder (sensitivity 80%, specificity 86%), and drug dependence (sensitivity 92%, specificity 80%).

• Observation of opioid withdrawal is indicative of opioid addiction.
• Observation of purposeful behaviors such as complaints and manipulations directed at getting more drugs and anxiety during withdrawal is suggestive of opioid addiction.
• Screen blood and urine for opioid metabolites.
• Screen for communicable diseases: HIV, hepatitis B and hepatitis C, tuberculosis.
• Screen for endocarditis in patients with newly diagnosed murmurs.

• Urine and serum toxicology screen
• Complete blood count
• Chemistries (alanine aminotransferase, aspartate aminotransferase, serum creatinine): Elevated liver function test (LFT) results may be from viral hepatitis or acetaminophen toxicity
• Hepatitis screen: If hepatitis C antibody positive, follow up with hepatitis C polymerase chain reaction (viral load) even in patients with normal LFTs
• HIV
• PPD

Generally not helpful in routine diagnosis and treatment. Consider echocardiography in patients with heart murmurs and liver sonography or CT scan in patients with elevated LFTs or who are positive for hepatitis C or B (increased risk of hepatocellular carcinoma).

• Brief counseling interventions during a visit with their primary care physician or OB/GYN have proved efficacious in motivating patients for treatment
• Therapeutic communities (residential)
• 12-step or other self-help groups (e.g., Alcoholics Anonymous, Narcotics Anonymous)
• Relapse prevention (counseling)
• Opioid prevention education (Table 4)

• Medical withdrawal (not overdosed). Opioid withdrawal alone is not recommended for treatment of opioid use disorder in most patients because of increased risk of overdose death and infectious disease (e.g., HIV through IV drug use) following detoxification.
• Short- (30 days) or long-term (30 to 180 days) protocols.
• Buprenorphine (opioid partial agonist) or methadone (opioid agonist) is initiated in tapering doses.
• CDC guidelines advise naloxone coprescription to patients with a history of overdose, substance use disorder, and concurrent benzodiazepine use as well as patients using higher doses of opioids (defined as at least 50 mg of morphine [or equivalent]). Every state in the U.S. now has a naloxone access law that allows an individual to obtain naloxone without a personal prescription. Laws also grant civil and criminal immunity to laypersons who administer naloxone.
• Clonidine 0.1 mg bid to tid can be used to minimize autonomic symptoms (sweating) and craving.
• Nonsteroidal antiinflammatory drugs for body and muscle aches.
• The anticholinergic dicyclomine can be used to minimize gastrointestinal hyperactivity.
• Nonbenzodiazepine hypnotics, low-dose atypical antipsychotics (e.g., quetiapine), or low-dose tricyclic antidepressants are effective for promoting adequate sleep.
• Psychosocial supports tailored to patient needs should be offered as an adjunct to medical treatment.

Opioid antagonist treatment:

• Buprenorphine/naloxone is the preferred first-line treatment. Methadone is an alternative in certain populations.
• Naltrexone: Does not stabilize neuronal circuitry like partial or full opioid agonists and generally results in poor outcomes, much like Antabuse for alcohol.
• Opioid partial agonist therapy: Buprenorphine (Suboxone, Bunavail).
• Opioid agonist therapy: Methadone.
• NOTE: Buprenorphine and methadone are both metabolized by the cytochrome P-450 3a4 and 2d6 I isoenzyme pathways. Prescribers should be aware of multiple possible drug interactions. Methadone and buprenorphine produce similar improvements during opioid withdrawal, although buprenorphine is associated with less sedation and respiratory depression. To avoid precipitating more intense withdrawal, buprenorphine should be initiated 12 to 18 h after the last administration of opioids in patients who misuse shorter-acting opioids (48 h in patients who are receiving long-acting drugs such as methadone), with initial doses of 4 to 8 mg.²

• Appropriate patients for buprenorphine office-based treatment:
  1. Patients interested (highly motivated) in treatment
  2. Have no major contraindications (see following)
  3. Can be expected to be reasonably compliant with treatment
  4. Understand the benefits and risks of buprenorphine treatment
  5. Willing to follow safety precautions
• Less likely to be appropriate for office-based treatment:
  1. Have comorbid dependence on benzodiazepines or other CNS depressants (including ethylene alcohol)
  2. Have significant untreated psychiatric comorbidities
  3. Have active or chronic suicidal or homicidal ideation or attempts
  4. Have multiple previous treatments with frequent relapses
  5. Have poor response to previous treatment with buprenorphine
  6. Have significant medical complications (e.g., hepatic insufficiency, bacterial endocarditis, active tuberculosis)
• Methadone maintenance: Narcotic treatment program (clinic setting) indications:
  1. Evidence of opiate addiction >1 yr
  2. Two failed previous treatment attempts
  3. Patients not appropriate for office-based treatment
  4. Eligible without active “use” if prior methadone maintenance patient within previous 2 mo
  5. Pregnancy

• Opioid addiction is a chronic, relapsing disease
• High rate of relapse after “detox”
• Relapse potential after medically supervised withdrawal from methadone:
  1. 90% after 1 yr stable in treatment
  2. 80% after 3 yr stable in treatment
  3. 70% after 5 yr stable in treatment
• Postmarketing surveillance indicates that the diversion and abuse of prescription opioid medications increased between 2002 and 2010 and plateaued or decreased between 2011 and 2013. These findings suggest that the U.S. may be making some progress in controlling the abuse of opioid analgesics.²

Refer to addiction medicine specialist or narcotic treatment program when the neurobiologic disease of opioid addiction is identified.

• Detoxification is contraindicated during pregnancy. Methadone maintenance has been the gold standard for the pregnant opioid-addicted patient regardless of the duration of the addiction or prior treatment attempts. The use of buprenorphine in pregnancy is associated with a lower risk of adverse neonatal outcomes than methadone use; however, the risk of adverse maternal outcomes is similar among persons who receive buprenorphine and those who receive methadone.³
• Breastfeeding is encouraged in mothers on methadone maintenance. The American Academy of Pediatrics statement regarding “Transfer of Drugs and Other Chemicals into Human Milk” has placed methadone into the “usually compatible with breastfeeding” group based on the assumption that maternal urine is monitored to detect use of illicit drugs. The U.S. Department of Health and Human Services also recommends that mothers on methadone be encouraged to breastfeed.
• When a physician identifies a patient as a “drug seeker,” it is imperative that the physician avoid abruptly stopping the opioid prescription because this will often result in the patient’s buying the drugs illegally. These patients should be counseled and referred for treatment.
• Patients on methadone or buprenorphine who have pain resulting from an acute injury will need pain medication in addition to their daily dose of methadone or buprenorphine. They will require higher than usual doses of pain medications because of opioid receptor blockade attributable to their methadone or buprenorphine use.
• Opioid-dependent patients have a lower pain threshold resulting from hyperalgesia caused by the long-term use of opioids.

Education is the hallmark of prevention:

• School drug prevention education programs.
• Educate children about their family medical history, including diseases of addiction.
• Address childhood psychiatric disorders to prevent self-medicating.
• Educate patients on nonopioid analgesics for pain management.

Opioid overdose:

• Naloxone (Narcan) is a competitive mμ-opioid receptor antagonist in the brain and is effective for opioid overdose. It is available for IM/IV and intranasal administration. It begins to reverse respiratory depression, sedation, and hypotension 2 to 5 min after IM administration and 1 to 2 min after IV administration. Treatment of opioid overdose is summarized in Box 5.

• Stigma of addictions and treatment often interferes with good treatment.
• Family needs to be educated so they can support the patient’s efforts.
• Encourage family meeting with addiction specialist, counselor.
• Recommend support groups for family members. Table 5 identifies organizations providing referral information for patients. Recommendations for integrating risk reduction strategies for addressing opioid misuse in the primary care setting are summarized in Table E6.
• Physicians should also offer reliant immunizations to people with OUD, including hepatitis A and B and TDAP and consider referral to syringe service programs.¹

Drug Use Disorder (Patient Information)

Opioid Overdose (Related Key Topic)