Opioid use disorder and medication-assisted treatment

• Opioid use disorder (OUD) is a chronic condition in which a person continues to use opioids despite harm, with impaired control, priority given to use, and often tolerance and withdrawal.
• The three medications that treat it are methadone (a full agonist), buprenorphine (a partial agonist, usually combined with naloxone), and naltrexone (an antagonist).
• Medication, together with psychosocial support, is the most effective treatment; abrupt withdrawal alone usually ends in relapse.
• Naloxone is the antidote for overdose; everyone who might witness an overdose should have access to it and know how to use it.
• In pregnancy, untreated opioid use is dangerous, and methadone or buprenorphine are used with careful follow-up.

By the end of this page you should be able to:

1. Define opioid use disorder using modern diagnostic criteria and separate it from simple tolerance or dependence.
2. Explain how opioids produce dependence, tolerance and withdrawal at receptor level.
3. Choose and dose methadone, buprenorphine/naloxone and oral naltrexone, and monitor each.
4. Recognise and treat opioid overdose with nasal naloxone.
5. Describe pregnancy-specific management and neonatal opioid withdrawal.
6. Outline harm-reduction and overdose-prevention strategies in clinic and community.

The diagnostic systems differ. DSM-5 combines everything into one substance use disorder, diagnosed when at least 2 of 11 criteria occur within 12 months, with severity from mild (2 to 3 criteria) through moderate (4 to 5) to severe (6 or more).^[10] ICD-11 keeps a separate diagnosis of substance dependence, requiring at least 2 of 3 central features: impaired control; use taking precedence over other interests, responsibilities or health; and physiological features shown by tolerance, withdrawal, or use to prevent withdrawal, over 12 months or continuous use for at least 3 months.^[10] Neither system requires a specific opioid or a particular dose.

Opioids here include heroin, fentanyl, morphine, oxycodone, codeine, tramadol and others. Some people develop dependence on opioids that were first prescribed for pain. That is still OUD when the criteria are met; pain that needs an opioid and OUD can coexist, and both are treated.

Medication-assisted treatment (MAT) is an older term. Current sources increasingly use medication for opioid use disorder (MOUD): treatment that includes an opioid agonist or antagonist alongside psychosocial care.^[1]

The three approved medications are not interchangeable in every situation:

• Methadone is a full mu-opioid receptor agonist with a long and variable half-life. It is dispensed through certified opioid treatment programmes.
• Buprenorphine is a partial mu-opioid receptor agonist with a ceiling effect on respiratory depression. It is usually combined with naloxone in a sublingual or buccal film or tablet, so that injection produces withdrawal rather than euphoria.
• Naltrexone is a pure opioid antagonist with no agonist effects. It blocks opioid reward and is used after detoxification.

OUD occurs in all world regions. Opioid agonist maintenance is the approach with the strongest evidence base for opioid dependence.^[4] The 2009 WHO guidelines identify opioid agonist maintenance combined with psychosocial assistance as the most effective treatment and the backbone of treatment systems.^[4] This page deliberately avoids unsourced prevalence figures; local surveillance and the annual United Nations and WHO drug reports are the place to look for numbers.

Dependence is not a moral failing or simple weakness. Repeated opioid exposure produces neuroadaptation in the reward and stress systems, so that use continues partly to avoid withdrawal. Risk factors include:

• Exposure to opioids (prescribed long-term, or illicit).
• Previous substance use disorder, including alcohol.
• Mental health conditions such as depression and post-traumatic stress.
• Chronic pain, insomnia and unemployment.
• Social adversity, trauma and imprisonment.
• Family history of substance use disorder.

No single profile predicts OUD at the individual level, so screening is warranted in primary care, emergency and psychiatric settings.

Opioids act mainly at mu-opioid receptors. Acute effects are analgesia, euphoria, sedation and respiratory depression. With repeated use:

• Tolerance develops: larger doses are needed for the same effect.
• Physical dependence develops: the body adapts to the presence of the drug, and removing it produces a withdrawal syndrome.
• Reward salience shifts so that cues, craving and relief of dysphoria drive use rather than pleasure.

Methadone and buprenorphine work by occupying mu-opioid receptors steadily, which suppresses withdrawal and reduces craving and the reward from illicit opioids. Naltrexone works by blocking the receptor, so that taking an opioid produces no euphoria.

Opioid withdrawal begins within hours for short-acting opioids and can be delayed by a day or two for long-acting ones. Symptoms include lacrimation, rhinorrhoea, sneezing, yawning, excessive sweating, goose-flesh, fever alternating with flushing, restlessness, irritability, weakness, anxiety, depressed mood, dilated pupils, tremor, tachycardia, abdominal cramps, body aches, involuntary twitching, anorexia, nausea, vomiting, diarrhoea, intestinal spasm and weight loss.^[6] With methadone or buprenorphine withdrawal can be more prolonged and less intense than with heroin.

Patients rarely volunteer the diagnosis. A useful approach is to ask about amount, frequency, route, last use, previous withdrawals, overdoses and treatment, and to screen for co-occurring depression, anxiety and suicidal thoughts. Physical clues include track marks, chronic nasal inflammation in people who snort opioids, constricted pupils acutely (dilated in withdrawal), and signs of infection. Overlap with chronic pain, anxiety and insomnia is common.

Acute intoxication presents with drowsiness, small pupils, slurred speech, slow breathing and a low respiratory rate. Withdrawal is miserable but not usually life-threatening in adults; the dangers are aspiration, dehydration and relapse.

Baseline assessment before starting medication:

• History of use, overdose, periods of abstinence and previous treatment.
• Mental health screen, including suicide risk.
• Physical examination for anaemia, infection (endocarditis, soft-tissue infection), liver disease and pregnancy.
• Blood-borne virus testing for hepatitis B, hepatitis C and HIV, with vaccination where indicated.
• Liver and renal function, and full blood count.
• Urine drug screening where available, interpreted with care (it records exposure, not diagnosis).
• Electrocardiogram where methadone is contemplated, because methadone prolongs the QT interval.

Urine drug testing is an adjunct to clinical assessment, not a substitute for it.

Use DSM-5 or ICD-11 as above. Severity guides intensity of treatment rather than which drug: people with severe OUD, previous overdose or injection use often need the higher end of agonist doses and closer supervision.

The goal is not always abstinence on day one. Goals include reducing overdose risk, stabilising health, retaining in treatment, and supporting recovery.^[10] WHO recommends opioid agonist maintenance combined with psychosocial assistance as the most effective treatment and the backbone of systems.^[4] NICE recommends methadone or buprenorphine as options for maintenance, and naltrexone for detoxified people who are highly motivated to remain abstinent.^[2][3]

Psychosocial support is not optional. Cognitive behavioural approaches, motivational interviewing, contingency management, peer support and 12-step facilitation all have evidence. Medication without support is less effective; support without medication is usually insufficient for opioid dependence.

NICE states that if both methadone and buprenorphine are equally suitable, methadone should be prescribed as the first choice.^[2] WHO similarly recommends methadone generally over buprenorphine for maintenance, while both are recommended for withdrawal.^[4] In practice, choice also depends on:

• Patient preference and previous experience.
• Risk of diversion or misuse.
• Presence of liver disease (buprenorphine/naloxone is not recommended in severe hepatic impairment).^[7]
• Pregnancy (see below).
• Ability to attend observed dosing (both methadone and buprenorphine need initial supervision).^[2][7]
• Availability and licensing in the country.

Methadone is a full mu-opioid agonist. It is dispensed only through certified opioid treatment programmes,^[6] and take-home doses increase as stability is demonstrated.

Dosing (from the product label): An initial single dose of 20 to 30 mg suppresses withdrawal; the initial dose should not exceed 30 mg. The total on day one should not ordinarily exceed 40 mg. For short-term detoxification, titrate to about 40 mg daily in divided doses, then reduce. Maintenance stability is most commonly achieved at 80 to 120 mg per day.^[6] Dose reductions during withdrawal should generally be under 10% of the maintenance dose, spaced 10 to 14 days apart.^[6]

NICE requires daily supervised administration for at least the first 3 months.^[2]

Safety points:

• Respiratory depression is the main risk at induction, especially after a break in use or with benzodiazepines or alcohol. Do not dose if the patient is sedated.
• Methadone prolongs the QT interval; risk rises with doses above 200 mg per day, though cases occur at maintenance doses too.^[6]
• Methadone interacts with cytochrome P450 enzymes; adding an inhibitor or stopping an inducer can precipitate overdose.^[6]
• Naloxone access should be offered to every patient starting or renewing methadone, because relapse or induction can cause overdose.^[6]

Buprenorphine is a partial agonist with a ceiling on respiratory depression. The combination film or tablet includes naloxone in a 4:1 ratio. Sublingual or buccal administration delivers buprenorphine and very little naloxone; if dissolved and injected, the naloxone can precipitate withdrawal.

Induction (label):^[7]

• Short-acting opioid (heroin) dependence: first give a dose when objective signs of moderate withdrawal appear, not less than 6 hours after last use. Day 1 induction up to 8 mg/2 mg in divided doses, titrating by 2 mg or 4 mg increments every 2 hours; Day 2 up to 16 mg/4 mg as a single dose. ^[7]
• Long-acting opioid (methadone) dependence: use buprenorphine monotherapy for Days 1 and 2, then switch to the combination product.

Avoid precipitated withdrawal by waiting for clear objective signs of withdrawal before the first dose. Warn patients not to supplement with extra opioids during induction.

Maintenance: generally 4 mg/1 mg to 24 mg/6 mg per day, titrated to clinical response. There is no maximum recommended duration; patients may need treatment indefinitely.^[7] Supervised administration at initiation, with a move to unsupervised administration as stability permits; weekly visits in the first month are typical.^[7]

Only patients who inject long-acting opioids should be induced under specialist care. Naloxone access should also be offered at initiation and renewal.^[7]

Naltrexone is only for patients who are fully detoxified and highly motivated.^[3] It blocks opioid receptors, so that taking an opioid gives no euphoria. It reinforces compliance poorly; it works best when embedded in a compliance-enhancing programme.^[8]

Dosing: oral naltrexone 50 mg blocks the effects of 25 mg intravenous heroin for up to 24 hours; higher doses (100 mg, 150 mg) extend blockade roughly 48 and 72 hours.^[8] A 50 mg tablet is the standard daily dose.

Detoxification requirement: an opioid-free interval of at least 7 to 10 days for short-acting opioids, and patients transitioning from buprenorphine or methadone may be vulnerable to precipitated withdrawal for up to 2 weeks.^[8] Only start when there is no clinical evidence of withdrawal. Patients should carry an opioid overdose reversal agent because tolerance falls during treatment.^[8]

Overdose is the commonest way OUD kills. An estimated 69,000 people die each year from opioid overdose.^[5] Recognise it by:

• Unresponsiveness or severe drowsiness.
• Slow, shallow or absent breathing.
• Pinpoint pupils.
• Cyanosis or grey-blue lips.
• Choking or snoring (gurgling) sounds.

Response:

1. Check breathing and response.
2. Call emergency services.
3. Give naloxone: one 4 mg dose sprayed into a nostril.^[9]
4. Wait 2 to 3 minutes; repeat every 2 to 3 minutes in alternating nostrils if there is no response, and give all available doses.^[9]
5. Support breathing (rescue breaths or recovery position) until help arrives.
6. Stay with the person, because naloxone is shorter-acting than many opioids and sedation can return.^[9]

WHO recommends that people likely to witness an overdose, including people who use opioids and their families and friends, should have access to naloxone and training in its use.^[5] Naloxone has minimal effects in people who have not used opioids, and can be injected or given intranasally.^[5] It is an emergency interim measure, not a replacement for comprehensive care.^[5]

Take-home naloxone programmes are a standard part of harm reduction, and prescribing an overdose reversal agent is recommended when starting or renewing methadone or buprenorphine.^[6][7]

Harm reduction means reducing the risk of death and infection while engaging people in care, even if they are not ready for abstinence.^[10] Practical measures:

• Take-home naloxone and training for the person and their household.
• Avoid using alone; use in the presence of someone who can give naloxone.
• Avoid mixing opioids with alcohol or benzodiazepines, the commonest mixtures in overdose deaths.
• If injecting, use sterile equipment, do not share, and rotate sites to prevent infection and abscess.
• Offer treatment for hepatitis C and HIV, and vaccination for hepatitis B.
• Engage with needle and syringe programmes and outreach services.
• Review driving and operating machinery safety on agonist therapy.

Many people cycle in and out of treatment. Each contact is a chance to reduce risk and to offer medication again.

• Overdose, especially with fentanyl-containing supplies and when tolerance has fallen after abstinence.
• Infective endocarditis, soft-tissue infection, osteomyelitis, hepatitis C and HIV in people who inject.
• Constipation, hypogonadism, sexual dysfunction and sleep-disordered breathing on chronic opioids.
• Hyperalgesia (increased sensitivity to pain) in some long-term users, which complicates analgesia.
• Neonatal opioid withdrawal in infants exposed in utero.
• Psychiatric comorbidity: depression, anxiety, and increased suicide risk, especially early in treatment and after discontinuation.

Retention in treatment improves with agonist medication. NICE-approved regimens of methadone or buprenorphine are provided within programmes of supportive care.^[2] Recovery is possible but is usually a long-term process; many people need maintenance for years, and some indefinitely. Do not push a medically stable patient to taper before they are ready: rapid discontinuation carries a high relapse risk.^[6][7]

• Screen for drug use routinely in primary care and emergency settings, including pregnancy.
• Prescribe opioids cautiously for pain, with review dates and taper plans.
• Review long-term opioid prescriptions and deprescribe where possible.
• Make naloxone widely available in the community and to first responders.
• Reduce stigma so that people seek help early.

Untreated opioid use in pregnancy is associated with preterm birth, growth restriction, infection and stillbirth, and leaves the newborn at risk of withdrawal. Methadone or buprenorphine maintenance is recommended over repeated withdrawal; every prescribing decision is shared among the pregnant person, addiction, obstetric and paediatric teams.

• Methadone: clearance increases during pregnancy, so the dose may need to be increased or the dosing interval shortened.^[6] Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged opioid use in pregnancy, and increases in late pregnancy use.^[6]
• Buprenorphine: NOWS also occurs; the risk must be balanced against the risk of untreated addiction.^[7]
• Naltrexone: is reserved for pregnancy when the expected gain outweighs the possible harm to the baby.^[8]
• Breastfeeding: both methadone and buprenorphine pass into milk in small amounts; monitor the infant for sedation and feeding problems. Naltrexone safety in lactation is not established.

Neonates should be observed for NOWS and managed with scoring systems and, if needed, opioid treatment in a neonatal unit.

• A clinical assessment and supervised first dose of methadone or buprenorphine can be provided even where laboratory testing is limited. The diagnosis is clinical.
• Where methadone is unavailable, buprenorphine with psychosocial support is the next best evidence-based option.
• Where neither is available, medically assisted withdrawal with symptom control, plus harm-reduction measures and urgent referral, is safer than leaving the person untreated.
• Naloxone should be stocked in emergency departments and distributed to carers; intranasal 4 mg devices are easy to use.
• Screening and treatment for blood-borne infections can be batched into the same visit.
• WHO guidelines emphasise voluntary, accessible, equitable treatment within healthcare systems, integrated with care for HIV, hepatitis and tuberculosis.^[4]

• Opioid use disorder is diagnosed by impaired control, priority given to use, and physiological features, not by dose alone.
• Medication plus psychosocial support is the most effective treatment; opioid agonist maintenance is the backbone of treatment systems.
• Methadone and buprenorphine are both recommended for opioid dependence; naltrexone is for detoxified, highly motivated patients.
• NICE recommends methadone as first choice if both agonists are equally suitable, and daily supervised doses for at least the first 3 months. ^[2]
• Methadone is induced at 20-30 mg and maintained commonly at 80-120 mg per day; respiratory depression and QT prolongation are the key risks.
• Buprenorphine is induced up to 8 mg/2 mg on day one and 16 mg/4 mg on day two, with a maximum recommended daily dose of 24 mg/6 mg in trials; there is no maximum recommended duration.
• Naltrexone 50 mg blocks the effects of 25 mg intravenous heroin for up to 24 hours; it requires 7 to 10 opioid-free days, or 2 weeks after methadone or buprenorphine.
• Naloxone 4 mg nasal spray reverses overdose: repeat every 2 to 3 minutes until the person wakes. ^[9]
• WHO recommends that bystanders likely to witness overdose have access to naloxone and training.
• In pregnancy, maintenance with methadone or buprenorphine is preferred to repeated withdrawal, with monitoring for neonatal opioid withdrawal.
• Harm-reduction measures (take-home naloxone, sterile equipment, not using alone) save lives even without abstinence.

• Substance use disorders: approach and treatment (MedGrasp topic, unscheduled link text).
• Suicidality and self-harm (MedGrasp topic).
• Harm reduction and addiction (MedGrasp topic, planned).