Opioid antagonist

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors. Opioid antagonists can work on receptors in the peripheral nervous system or central nervous system. They are different from opioid agonists, in which they bind to opioid receptors, often with more affinity than agonists, and they do not activate the receptor.

Not all opioid antagonists work the same. Some antagonists do not fully block agonists from binding to the receptor. These agonists are not necessarily considered partial antagonists, as they can act as agonists in some situations, and antagonists in others. Therefore, they are more often considered partial agonists. This means that they can block the activity of molecules that bind to opioid receptors by binding to the receptors with a higher affinity, making less opioid receptors available for agonists to bind. This may produce a partial response, rather than a full response.

Some opioid antagonists are not pure antagonists but do produce some weak opioid partial agonist effects, and can produce analgesic effects when administered in high doses to individuals who have never taken opioids previously. Examples of such compounds include nalorphine and levallorphan. However, the analgesic effects from these specific drugs are limited and tend to be accompanied by dysphoria, most likely due to additional agonist action at the κ-opioid receptor. As they induce opioid withdrawal effects in people who are taking, or have recently used, opioid full agonists, these drugs are generally considered to be antagonists for practical purposes.

The weak partial agonist effect can be useful for some purposes, and has previously been used for purposes such as long-term maintenance of former opioid addicts using nalorphine, however it can also have disadvantages such as worsening respiratory depression in patients who have overdosed on non-opioid sedatives such as alcohol or barbiturates. On the other hand, Naloxone has no partial agonist effects, and is in fact a partial inverse agonist at μ-opioid receptors, and so is the preferred antidote drug for treating opioid overdose.

Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This effectively blocks the receptor, preventing the body from responding to opioids and endorphins. Naloxone is a drug used to treat opioid overdose. During an overdose, the most dangerous symptom is respiratory depression. When antagonists such as Naloxone are given, they bind to the opioid receptors more tightly, and prevent agonists from binding. This restores normal respiratory function, allowing time for first responders to reach. This drug comes in many forms and can be administered intravenously, intramuscularly, and intranasally. Naltrexone can be administered as an injection or given orally.

Naltrexone is also a partial inverse agonist, and this property is exploited in treatment of opioid addiction, as a sustained course of low-dose naltrexone can reverse the altered homeostasis which results from long-term abuse of opioid agonist drugs. This is the only treatment available which can reverse the long-term after effects of opioid addiction known as post acute withdrawal syndrome, which otherwise tends to produce symptoms such as depression and anxiety that may lead to eventual relapse. A course of low-dose naltrexone is thus often used as the final step in the treatment of opioid addiction after the patient has been weaned off the substitute agonist such as methadone or buprenorphine, in order to restore homeostasis and minimize the risk of post acute withdrawal syndrome once the maintenance agonist has been withdrawn.

Methylnaltrexone is an opioid antagonist that works in the digestive tract. Another symptom of long-term opioid use is opioid-induced constipation. This drug is an FDA-approved treatment for this constipation, as binding to these peripheral opioid receptors work to make the digestive tract more mobile.

The following are all μ-opioid receptor (MOR) antagonists or inverse agonists. Many of them also bind to the κ-opioid receptor (KOR) and/or δ-opioid receptor (DOR), where they variously behave as antagonists and/or agonists.