Does Methadone Block Opiates?

The answer to this question is actually complicated. On the one hand, methadone is an opiate itself, binding to and activating mu-opioid receptors in the brain. It's this action which makes methadone a an opiate substitute that reduces cravings for "harder" opiates with more abuse potential, like heroin, morphine or fentanyl.

Methadone does block the euphoric or mood-elevating effects of "harder" opiates. In other words, methadone activates mu-opioid receptors (just like morphine or heroin), but in a manner that doesn't elicit euphoria.

Why does Methadone have a lower abuse potential compared to other opiates?

There are a number of explanations for why Methadone has limited abuse potential.

Methadone has a long elimination half-life

Because methadone is eliminated more slowly than other opiates, The effects of methadone last for about 24-36 hours. In general, longer acting drugs have a lower abuse potential and are less likely to elicit euphoria. For example, the sedative Xanax has the greatest abuse potential of all the benzodiazepines because it has a short duration of effects. This short duration prompts Xanax users to re-dose to avoid withdrawal.

Methadone toxicity

The addictive potential of methadone is also limited by its toxicity. If one were to try to get "high" from methadone, you would probably self-administer more than the prescribed dose. But since methadone is so slowly eliminated, a large methadone dose would result in the toxic accumulation of methadone in tissues as the drug gradually is released. Methadone's toxicity in large doses discourages its abuse.

Methadone is an NMDA-type glutamate receptor antagonist

Glutamate is the primary excitatory neurotransmitter in the brain. Glutamate can bind to three types of receptors, one of which is the NMDA-type glutamate receptor. It turns out that methadone is a NMDA receptor blocker (antagonist), which confers anti-addictive properties. NMDA antagonists like dextromethorphan, memantine, and ketamineo have been noted to reduce tolerance to opiates and also attenuate opiate cravings. The mechanism underlying this effect is poorly understood, but NMDA antagonists seems to reverse tolerance to other drugs, too. For example, memantine lowers tolerance to psychostimulants like Adderall.

Methadone receptor occupancy

Once methadone is in the brain, it occupies mu-opioid receptors for a relatively long time. When opioid receptors are occupied, other opiates (e.g., fentanyl) with greater abuse liability must compete for opioid receptor sites. Hence, methadone-induced opioid receptor blockade prevents other ligands from binding to the receptor.

Summary

Methadone both substitutes for opiates (since it's a mu-opioid agonist) while also blocking euphoric effects of "harder" opiates.