How buprenorphine, naltrexone, and methadone work to treat opioid use disorder

According to New York's Office of Addiction Services and Supports (OASAS), the Food and Drug Administration has approved three medications for opioid use disorder: methadone, buprenorphine, and the extended-release naltrexone injection. Each works through a different mechanism. That distinction matters in practice. It determines how often a patient visits a clinic, what happens if they use an opioid again during treatment, and which access barriers they may face depending on where they live.

The mu-opioid receptor: what all three medications target

Opioid drugs produce their effects primarily by binding to mu-opioid receptors in the brain. Heroin, fentanyl, and prescription opioids all attach to these receptors and activate them strongly and rapidly, which produces both intense euphoria and, over time, physical dependence. When the drug clears the body, withdrawal sets in because those same receptors are now understimulated.

The three FDA-approved medications all work on that same receptor system, but they interact with it differently. Methadone activates the receptor fully, slowly, and for a long time. Buprenorphine activates it partially and can also block other opioids from binding. Naltrexone does not activate it at all; it just occupies the receptor and blocks incoming opioids. Those differences in receptor behavior explain most of the differences in how and when each medication is used.

How methadone works: full agonist, slow and long-lasting

Methadone is a full opioid agonist, meaning it activates mu-opioid receptors completely. What makes it useful for treatment rather than harmful is its kinetics. According to the National Institute on Drug Abuse (NIDA), methadone activates mu-opioid receptors more slowly and remains in the body longer than drugs like heroin or fentanyl. That slow onset means the intense rush that reinforces compulsive use does not occur. The extended duration means a single daily dose keeps withdrawal symptoms and cravings suppressed throughout the day.

Because methadone is a full agonist with real misuse potential, federal law restricts how it is dispensed for opioid use disorder. According to OASAS, federal regulations require that the prescribing and dispensing of methadone for this purpose happen only in opioid treatment programs (OTPs), under staff supervision, with medication dispensed onsite at the program or its approved extensions. At the start of treatment, patients typically attend daily.

That access picture has shifted somewhat. NIDA reports that since 2020, updated regulations allow many patients who have been in treatment for a period to receive up to 28 doses of methadone to take home. NIDA-funded research has found that expanded take-home access is safe and may support treatment retention and better outcomes.

How buprenorphine works: partial agonist with a blocking effect

Buprenorphine operates differently from methadone in two connected ways. First, it is a partial agonist at the mu-opioid receptor: it activates those receptors, but not fully. According to NIDA, buprenorphine can reduce cravings and withdrawal symptoms without producing intense feelings of pleasure and intoxication in people with opioid use disorder. Second, buprenorphine can also block other opioid drugs from attaching to those receptors. This partial activation combined with receptor blockade gives buprenorphine a distinct safety and treatment profile compared to methadone.

Buprenorphine also offers more formulation options. According to OASAS, current preparations include:

• Sublingual or buccal tablets or films dissolved under the tongue or inside the cheek (brand names include Suboxone, Zubsolv, and Subutex)
• An extended-release subcutaneous injection given once monthly (Sublocade)
• A newer extended-release injection (Brixadi) approved by the FDA that can be administered once weekly or once monthly

The injectable formulations matter in rural settings. When the nearest pharmacy is an hour away and daily scheduling is not realistic, a once-monthly injection changes what treatment actually looks like. The MAT outcomes case study on this site covers how that access gap has played out on Colorado's Western Slope.

How naltrexone works: pure blockade, no activation

Naltrexone is an opioid antagonist. It binds to opioid receptors in the brain but does not activate them. According to OASAS, this binding blocks the effects of opioids if a person returns to use during treatment. Someone taking naltrexone who uses heroin or fentanyl will not experience the usual high from those drugs.

Two details about naltrexone are worth knowing before assuming it is interchangeable with the other two options. The first is that only the extended-release injection (Vivitrol) carries the opioid use disorder indication. Both the oral tablet and the ER injection are approved for alcohol use disorder, but the OUD-specific FDA approval belongs to the injection only. The second is that patients must be fully detoxified before starting naltrexone. Taking it while opioids are still present triggers sudden, severe withdrawal. For patients who have not yet completed detox, that requirement is a real entry barrier.

Comparing the three medications side by side

Medication	Receptor action	Reduces withdrawal and cravings	Blocks other opioids	Access requirement
Methadone	Full mu-opioid agonist (slow onset, long duration)	Yes	No	OTP clinic only; take-home doses possible after stabilization
Buprenorphine	Partial mu-opioid agonist + receptor blocker	Yes	Yes	Office-based prescribing; sublingual or injectable formulations
Naltrexone ER injection	Opioid antagonist (blocks, does not activate)	Removes reward signal; requires prior detox	Yes (complete blockade)	Full opioid detox required before starting; clinic or office-based

Why these medications reduce cravings and withdrawal

Methadone and buprenorphine both work by occupying the same receptors that heroin and fentanyl target, but on a much slower, longer-lasting schedule. According to NIDA, methadone's slow receptor activation and extended presence in the body suppress withdrawal symptoms and cravings through the day. Buprenorphine does the same at a lower activation level, which means it controls withdrawal without producing the degree of intoxication that full agonists can. Patients often describe it as feeling stable rather than high.

Naltrexone works through a different channel. Rather than providing any receptor activation, it just occupies those receptors and blocks anything else from binding. If a person on naltrexone uses an opioid, the drug cannot produce its usual effect. The idea is that removing the reward removes the reinforcement. That works well when patients are already detoxed and motivated; it does nothing for withdrawal because it does not activate the receptor at all.

What this means for treatment planning

Matching a patient to a medication requires more than a chart comparison. Access to an OTP clinic, the severity of physical dependence, living situation, co-occurring alcohol use (where naltrexone's dual approval becomes relevant), and prior treatment history all play a role. For people in rural Western Colorado where the nearest OTP may be an hour or more away, buprenorphine's office-based availability and long-acting injectable forms have a practical advantage that pure pharmacology does not capture.

None of these medications is intended to work alone. Medication controls the biological piece, the cravings, withdrawal, and blocked reward signal. Behavioral therapy and peer support address the psychological and social side. Research consistently shows that combining medication with behavioral treatment produces better retention and long-term outcomes than either approach does by itself. The overview of effective addiction treatment approaches on this site covers how that combination gets built into a treatment plan.

Patients who want a closer look at how evidence-based treatment works in practice may find the evidence-based substance abuse treatment review useful alongside this explanation of the medications themselves.

Frequently asked questions