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Medications for opioid use disorder

What medications are used for opioid use disorder, how buprenorphine, methadone, and naltrexone compare, and where overdose reversal fits.

Medically reviewed by Shariq Refai, MD, MBA Last reviewed: June 8, 2026

First-line options

Buprenorphine

Buprenorphine is a partial mu-opioid agonist with high receptor affinity. That combination gives it a ceiling on respiratory depression and a strong ability to block other opioids from binding. Available in several formulations:

  • Sublingual tablets or films (Suboxone with naloxone, Subutex without naloxone). Typical maintenance dose is 8 to 24 mg/day, sometimes higher. Split dosing is fine but once-daily works for many patients.
  • Extended-release subcutaneous injection (Sublocade, Brixadi). Sublocade is monthly, Brixadi is weekly or monthly. These options remove daily dosing and reduce diversion concerns.
  • Buccal film (Bunavail, discontinued in some markets).

For office-based buprenorphine, the X-waiver was eliminated by the MAT Act (2023), so any DEA-registered clinician can prescribe. Induction can be done in the office or at home; low-dose or microdosing induction protocols have expanded options for patients on high-dose full agonists.

Precipitated withdrawal is the main clinical concern at induction. If buprenorphine is given while a full opioid agonist is still active at the receptor, buprenorphine's high affinity displaces the full agonist and can precipitate immediate withdrawal. Standard advice is to wait for moderate opioid withdrawal symptoms (COWS score 8 or higher, roughly 12 to 24 hours after short-acting opioid last use, 24 to 48 hours after long-acting) before the first dose. For patients on fentanyl (which distributes into fat and has variable washout), waiting longer or using microdosing protocols is often more successful.

Methadone

Methadone is a full mu-opioid agonist. Given daily at federally regulated opioid treatment programs (OTPs). Not prescribed for OUD in office-based practice in the US, though there's been ongoing regulatory movement to expand access.

Effective for retention and mortality reduction. Typical maintenance doses are 60 to 120 mg/day, sometimes higher. QT prolongation at higher doses is a real concern (particularly above 100 to 120 mg) and warrants ECG monitoring. Drug interactions (CYP2B6, CYP3A4) can shift levels significantly.

Methadone is the option that keeps some patients in treatment when buprenorphine hasn't worked, particularly in patients with prolonged high-dose opioid use, chronic pain, or difficulty tolerating buprenorphine's ceiling effect.

For patients on methadone maintenance, transitioning to buprenorphine is possible but requires a taper of methadone (usually to 30 to 40 mg or lower) before starting, and even then some patients have difficulty tolerating buprenorphine after methadone.

Extended-release naltrexone

Injectable naltrexone (Vivitrol) at 380 mg IM monthly. Full opioid antagonist. Doesn't produce a physical dependence or withdrawal, and doesn't produce mood effects. Blocks the effects of opioids while active.

The challenge with naltrexone is induction. The patient must be fully opioid-free (typically 7 to 10 days for short-acting opioids, 10 to 14 days for long-acting) before the first injection, because giving naltrexone to someone with residual opioid dependence produces severe withdrawal. This makes naltrexone harder to start than buprenorphine, and retention is generally lower.

Naltrexone is a reasonable choice for highly motivated patients, patients transitioning from a controlled setting (prison, residential treatment) where opioid abstinence is confirmed, or patients who want a non-agonist option. Overdose risk after discontinuation is a real concern because tolerance has been lost during the naltrexone period.

Oral naltrexone at 50 mg daily is FDA-approved for OUD but has much lower retention than the injectable formulation because of daily dosing and adherence challenges. Rarely first choice.

For the fuller picture, see the related medication pages below.

Second-line and augmentation

Overdose reversal: naloxone

Naloxone should be co-prescribed for anyone at overdose risk. This includes:

  • All patients starting buprenorphine or methadone maintenance.
  • All patients on chronic opioid therapy for pain.
  • Anyone with a history of overdose or high-dose opioid use.
  • Family members and friends of anyone at risk.

Naloxone is now available OTC as Narcan nasal spray (approved 2023). Prescription options include intramuscular naloxone (Zimhi 5 mg high-dose autoinjector), higher-dose nasal spray (Kloxxado), and multi-dose vials for administration by trained bystanders.

Fentanyl overdoses may require multiple doses of naloxone because of fentanyl's potency and rapid onset. Standing supply of 2 to 4 nasal spray doses per household is reasonable.

Withdrawal management

Lofexidine (Lucemyra) is FDA-approved for management of acute opioid withdrawal symptoms. Alpha-2A agonist. Helps with autonomic withdrawal signs (tachycardia, tremor, anxiety, insomnia). Doesn't cover craving or muscle aches as well. Reasonable for tapering off short courses of opioids or for those refusing agonist maintenance.

Clonidine off-label serves a similar role at lower cost. More sedating and more orthostatic.

Symptomatic management during withdrawal: loperamide for diarrhea (with caution about cardiac effects at high doses), ondansetron for nausea, NSAIDs or acetaminophen for muscle aches, trazodone or hydroxyzine for insomnia.

Behavioral treatment alongside

Medication for OUD is more effective when combined with psychosocial support: counseling, contingency management, cognitive behavioral therapy, 12-step or SMART Recovery involvement. Medication alone is still worthwhile even without therapy, and the "no meds without therapy" position is not evidence-based.

Adjuncts for common comorbidities

OUD frequently coexists with depression, anxiety, PTSD, insomnia, and chronic pain. Treating comorbidities improves OUD outcomes.

When to consider a different approach

Buprenorphine isn't holding

If a patient on buprenorphine is continuing to use opioids and craving remains high, options include increasing the dose (some patients need 24 to 32 mg or higher for stability), switching to methadone (typically requires transfer to OTP), or considering long-acting injectable buprenorphine (Sublocade, Brixadi) to remove daily dosing variability.

Uncontrolled psychiatric comorbidity or ongoing use of other substances (stimulants, alcohol, benzodiazepines) often explains why buprenorphine isn't holding.

Methadone isn't accessible or acceptable

For patients who need agonist maintenance but can't access an OTP or don't want daily dosing there, buprenorphine (especially extended-release injectable) is often the alternative.

Naltrexone induction is failing

If a patient can't complete the opioid-free window for naltrexone induction, buprenorphine or methadone is the practical option. Trying to force naltrexone induction on someone unable to tolerate the abstinence period typically fails and can trigger relapse.

High risk of overdose

Anyone with a recent overdose, high-dose fentanyl use, or period of abstinence followed by return to use is at extreme overdose risk. Buprenorphine or methadone are the interventions with strongest evidence for mortality reduction. Naloxone must be available. Family and support involvement.

Special considerations

Precipitated withdrawal

The most immediate risk with buprenorphine induction is precipitated withdrawal. In the fentanyl era, this is more common because fentanyl distributes into fat and has a variable washout even when patients feel withdrawal. Options include:

  • Standard induction: wait for moderate withdrawal (COWS 8+), then start buprenorphine 2 to 4 mg and titrate.
  • Extended wait: for fentanyl, waiting 24 to 36 hours (or longer) before first dose reduces risk.
  • Microdosing (Bernese method): start very low buprenorphine doses (0.5 mg or less) while continuing the full agonist, gradually escalating buprenorphine and reducing the full agonist over days.
  • Macrodose induction: for patients already in significant withdrawal, higher initial doses (8 to 16 mg) may resolve withdrawal more quickly.

If precipitated withdrawal occurs, the answer is more buprenorphine (not less), plus symptomatic management (clonidine or lofexidine, ondansetron, loperamide). The withdrawal typically resolves within 12 to 24 hours as buprenorphine takes over receptor occupancy.

Combined use with benzodiazepines

Buprenorphine plus benzodiazepines (or z-drugs) increases overdose risk. The 2016 FDA guidance updated to note that the combination is not an absolute contraindication in patients who need both, and that withholding buprenorphine because of concurrent benzodiazepine use is often worse than the combination. The clinical judgment sits on stability, patient history, and coordinated tapering when possible.

Pregnancy

Buprenorphine and methadone are both first-line for OUD in pregnancy. Buprenorphine (usually mono-product without naloxone, though the combined product is also used) has slightly less neonatal abstinence syndrome severity in some studies. Methadone has the longer track record. Discontinuing agonist maintenance during pregnancy is associated with high relapse and overdose risk. See the pregnancy safety reference.

Naltrexone in pregnancy is a nuanced decision. Some data suggest it's reasonable to continue naltrexone in patients stable on it before pregnancy; starting naltrexone during pregnancy is less commonly done.

Hepatitis C and HIV

OUD patients frequently have HCV or HIV. Treatment for both is compatible with OUD medications. Buprenorphine and methadone don't preclude HCV treatment (DAAs are compatible). ART for HIV is compatible with OUD medications, though methadone has interactions with several antiretrovirals that may require dose adjustment.

Chronic pain

Buprenorphine (especially at split dosing, BID or TID) has analgesic effect and can serve dual duty for chronic pain and OUD. Adjunctive non-opioid analgesia (NSAIDs, acetaminophen, gabapentin with caution, SNRI for neuropathic pain, TCA for neuropathic pain, topical agents) is often layered.

Patients on stable buprenorphine or methadone who need acute pain management (post-surgical, trauma) can safely receive additional opioid analgesia for the acute period, coordinated with the addiction team and surgical team.

Adolescents

Buprenorphine is FDA-approved for OUD in adolescents 16 and older. Methadone in adolescents requires special OTP consideration. Naltrexone use in adolescents is off-label but has been done. Family involvement and full-picture treatment matter especially in this population.

Older adults

OUD in older adults is increasing. Buprenorphine tends to be well-tolerated. Methadone has more QT concerns in older adults and requires close monitoring. Naltrexone is often better-tolerated. See Beers Criteria for psychiatric medications.

Incarceration transitions

Patients leaving incarceration are at extreme overdose risk because tolerance has been lost during confinement. Initiating buprenorphine or methadone before release (or extended-release naltrexone) has mortality benefit. Naloxone at release is standard.

Criminal justice contact

Patients in drug courts, on probation, or in similar settings should be able to receive medications for OUD. Court-mandated abstinence-only requirements are not evidence-based and increase overdose deaths.

What tips the choice

  • Newly diagnosed OUD, active use: buprenorphine is the practical default in office-based settings. Methadone for patients preferring or requiring higher-intensity structure at an OTP.
  • Highly motivated, opioid-free for at least 7 to 10 days, prefers non-agonist: extended-release naltrexone.
  • Prior buprenorphine failure or difficulty tolerating buprenorphine: methadone via OTP.
  • Adherence problems or diversion concerns: extended-release buprenorphine (Sublocade, Brixadi) or extended-release naltrexone.
  • Pregnancy: buprenorphine or methadone. Don't discontinue if stable.
  • Adolescent: buprenorphine is FDA-approved for 16 and older.
  • Chronic pain plus OUD: buprenorphine at split doses can cover both.
  • Fentanyl use, difficult induction: microdosing protocols or extended-wait induction.
  • Recent release from incarceration or residential treatment: initiate medication immediately, plus naloxone.
  • Comorbid stimulant use disorder: focus on retention on OUD medication (buprenorphine or methadone), add contingency management for stimulant use if available.
  • Comorbid alcohol use disorder: naltrexone (oral or injectable) covers both. If on buprenorphine or methadone, adding acamprosate is compatible.
  • Overdose history: buprenorphine or methadone (strongest mortality reduction evidence), plus naloxone.

Common questions

Is buprenorphine or methadone just replacing one drug with another? Both are opioids, and both create physical dependence, so in that sense yes. What matters is what changes: overdose risk drops substantially, criminal-justice involvement drops, employment and function improve, and untreated OUD is a leading cause of death in young adults. Treating OUD with buprenorphine or methadone is more like treating diabetes with insulin than "replacing" anything. The evidence for mortality reduction with agonist treatment is as strong as almost anything in medicine.

How long do I stay on buprenorphine? For most patients, the answer is indefinite. OUD is a chronic condition, and discontinuation of medication carries a substantial risk of relapse and overdose (particularly because tolerance drops during abstinence). Some patients successfully taper off after years of stability, but there's no time limit and no rule that requires it. The decision to taper is made with the treating clinician and usually done very slowly.

What if I use again while on buprenorphine? Return to use during treatment is common and doesn't mean the medication has failed. Reasons include comorbid mental health issues, life stressors, ongoing polysubstance use, or dosing that hasn't been optimized. The answer is usually to continue the medication, address the trigger, and consider dose adjustment. Stopping the medication because of a return to use increases overdose risk.

Do I need therapy for buprenorphine to work? Behavioral treatment adds value, and combined care is better on average. But medication alone still reduces overdose deaths and improves function, and mandating therapy as a condition of medication access is not evidence-based. If therapy access is a barrier, that shouldn't be a barrier to medication.

Should everyone at risk carry naloxone? Yes. Naloxone is now OTC as Narcan and easy to obtain. Every patient on chronic opioid therapy, in OUD treatment, or with any history of overdose should have naloxone at home, and family members should know how to use it. Fentanyl overdoses may require multiple doses, so having 2 to 4 doses available is reasonable.

Sources

This guide draws on current prescribing information, treatment guidelines, and public health references. It is reviewed for clinical accuracy and updated as guidance changes.

  1. American Society of Addiction Medicine. National practice guideline for the treatment of opioid use disorder.
  2. SAMHSA. Medications for opioid use disorder TIP 63.
  3. Larochelle MR et al. Medication for opioid use disorder after nonfatal opioid overdose and association with mortality.
  4. National Institute on Drug Abuse. Medications to treat opioid use disorder research report.

THE KNOWLEDGE PATH

Walk this topic outward.

  1. GUIDE Medications for opioid use disorder (current)
  2. CLASS SSRIs
  3. MEDICATION Sertraline (Zoloft)
  4. CONDITION Major Depressive Disorder (on Shrinkopedia)
  5. CARE Consider depression evaluation at shrinkMD

The Knowledge Path is a curated walk. Every step is one decision away from the next.

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