Agonists And Antagonists

What's the difference between an  opiate agonist and an opiate antagonist? 

An agonist is an agent that binds to a receptor and activates that receptor in order to elicit an effect (typically transmitting a signal to the inside of the cell, either by opening a channel to allow ions to flow in/out, or changing the receptor's shape to cause a cascade of intracellular events to occur).   Drugs that are agonists essentially mimic the action of the endogenous (naturally occuring) neurotransmitters, typically with the same or a stronger affinity than the neurotransmitter itself.  

An antagonist is an agent that binds to a receptor but does not elicit the response that the neurotransmitter or an agonist would cause. The antagonist blocks the receptor and prevemts activation by neurotransmitters or other drugs.

So in the case of opiates, lets look at the opiate agonist, morphine. When morphine enters the brain, it binds to opiate receptors and activates them. This binding is what produces the effects of Morphine.

In the case of a Morphine overdose, where a hospital is concerned that the high dose of morphine may be dangerous (depressing breathing and heartrate), they may administer Naloxone (an opiate antagonist). The Naloxone finds its way to your opiate receptors and "competes" with Morphine for binding of the receptors. Because Naloxone has a higher affinity for the receptors than Morphine, the Naloxone will generally win out, replacing much of the Morphine at the receptor sites.

Within 1-3 minutes of a sufficient Naloxone injection (2-4mg), a patient who has overdosed on Morphine will generally wake up, usually quite agitated.  If given to an otherwise "normal" person (not in the midst of an overdose) who happens to be addicted to an opioid or opiate, Naloxone can immediately precipitate withdrawal symptoms (Nausea, vomiting, hallucinations, disorientation, excretion, tremors, convulsions, agitation, anxiety and so forth).   

Current Pharmacotherapy Treatment Options For Opioid Addiction

Three traditional types of pharmacotherapy for opioid addiction are described briefly in this section: (1) agonist treatment (e.g., methadone pharmacotherapy), (2) antagonist treatment (e.g., naltrexone), and (3) the use of these and other agents (e.g., clonidine) to help withdrawal from opioid drugs as a means of entry into treatment. A discussion of the new treatment option using buprenorphine follows.

Agonist Pharmacotherapy

Methadone is the most commonly used medication for opioid addiction treatment in the United States. Well-run OTPs with appropriate drug monitoring, counseling services (individual, group, family), and vocational resources and referrals have been demonstrated to decrease heroin use and related crime, increase employment, improve physical and mental health (McLellan et al. 1993), and markedly reduce mortality (see the forthcoming TIP Medication-Assisted Treatment for Opioid Addiction [CSAT in development]), as well as the incidence of needle sharing (Metzger et al. 1991) and HIV transmission (Metzger et al. 1993). Methadone suppresses opioid withdrawal, blocks the effects of other opioids, and decreases craving for opioids.

Antagonist Pharmacotherapy

Naltrexone is an opioid antagonist that blocks the effects of heroin and most other opioids. It does not have addictive properties or produce physical dependence, and tolerance does not develop. It has a long half -life, and its therapeutic effects can last up to 3 days. Naltrexone is not a stigmatized treatment. It also decreases the likelihood of alcohol relapse when used to treat alcohol dependence.

From a purely pharmacological point of view, naltrexone would appear to have the properties of a useful medication for the treatment of opioid addiction. Its usefulness in the treatment of opioid addiction, however, has been limited because of certain disadvantages. First, many addicted patients are not interested in taking naltrexone because, unlike methadone and LAAM, it has no opioid agonist effects; patients continue to experience cravings and are thereby not motivated to maintain adherence to the medication regimen. Second, a patient addicted to opioids must be fully withdrawn for up to 2 weeks from all opioids before beginning naltrexone treatment. Unfortunately, during this withdrawal period, many patients relapse to use of opioids and are unable to start on naltrexone. Furthermore, once patients have started on naltrexone, it may increase the risk for overdose death if relapse does occur.

Naltrexone has demonstrated some utility among subgroups of addicted patients with strong motivation and psychosocial support for treatment and medication adherence (e.g., healthcare professionals, business executives, younger patients, patients involved in the criminal justice system). Because most addicted patients will not voluntarily take naltrexone, however, the number of individuals maintained on it continues to be low. Research is under way on a number of sustained -release, injectable forms of naltrexone in an effort to increase adherence, particularly in the early stages of treatment.

Agents Used To Assist With Withdrawal From Opioid Drugs

Medically supervised withdrawal (detoxification) from opioids is an initial component of certain treatment programs but, by itself, does not constitute treatment of addiction. A variety of agents and methods are available for medically supervised withdrawal from opioids. These include methadone dose-reduction, the use of clonidine and other alpha-adrenergic agonists to suppress withdrawal signs and symptoms, and rapid detoxification procedures (e.g., with a combination of naltrexone or naloxone and clonidine and, more recently, buprenorphine).

Each of these methods has strengths and weaknesses. When used properly, various pharmacological agents can produce safe and less uncomfortable opioid withdrawal. As a result of the increasing purity of street heroin, however, physicians are reporting more difficulty managing patients with the use of clonidine and other alpha-adrenergic agonists during withdrawal.  

Unfortunately, the majority of individuals addicted to opioids relapse to opioid use after withdrawal, regardless of the withdrawal method used. Too often, physicians and facilities use dose-reduction and withdrawal in isolation without adequate arrangements for the appropriate treatment and support services that decrease the likelihood of relapse and that are usually necessary for long-term recovery. (For more information about agents used to assist with withdrawal, see TIP 43 Medication-Assisted Treatment for Opioid Addiction)

Reference:    (1) Clinical Guidelines For The Use Of Buprenorphine In  Opioid Addiction (TIP 40) 
                      (2)  Pharmacy Today 2004 Agonists and Antagonists


Compiled and Edited By: D. Shrira   Dated: 17 February 2007