Opioid antagonist
Encyclopedia
An opioid antagonist is a receptor antagonist
that acts on opioid receptor
s.
Naloxone
and naltrexone
are commonly used opioid antagonist drugs which are competitive antagonist
s 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 opiates and endorphins.
Some opioid antagonists are not pure antagonists but in fact do produce some weak opioid partial agonist
effects, and can produce analgesic
effects when administered in high doses to opioid-naive individuals. Examples of such compounds include nalorphine
and levallorphan
. However the analgesic effects from these drugs are limited and tend to be accompanied by dysphoria
, most likely due to action at the kappa opioid receptor
. As they induce opioid withdrawal effects in people who are taking, or have recently used, opioid full agonists, these drugs are 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. Naloxone on the other hand has no partial agonist effects, and is in fact a partial inverse agonist
at mu opioid receptors, and so is the preferred antidote drug for treating opioid overdose.
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to restore homeostasis and minimise the risk of post acute withdrawal syndrome once the maintenance agonist has been withdrawn.
Other selective antagonists are also known, but the three listed above were the first selective antagonists discovered for each respective opioid receptor, and are still the most widely used.
. In a 2001 study with naloxone, three of fourteen patients lost their depersonalization symptoms entirely, and seven showed marked improvement . The findings of a 2005 naltrexone study were slightly less promising, with an average of a 30% reduction of symptoms, as measured by 3 validated dissociation scales . The more dramatic result of naloxone versus naltrexone is suspected to be due to different endogenous opioid receptor selectivity in naloxone, which is better suited to individuals suffering from depersonalization disorder.
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
that acts on opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
s.
Naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
and naltrexone
Naltrexone
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...
are commonly used opioid antagonist drugs which are competitive antagonist
Competitive antagonist
A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...
s 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 opiates and endorphins.
Some opioid antagonists are not pure antagonists but in fact do produce some weak opioid partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
effects, and can produce analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
effects when administered in high doses to opioid-naive individuals. Examples of such compounds include nalorphine
Nalorphine
Nalorphine trade names Lethidrone and Nalline. Nalorphine acts at two opioid receptors, at the mu receptor it has antagonistic effects and at the kappa receptors it exerts agonistic characteristics. It is used to reverse opioid overdose and in a challenge test to determine opioid dependence....
and levallorphan
Levallorphan
Levallorphan is a drug of the morphinan family which is used as an opioid antidote or antagonist. It acts as an antagonist on μ-opioid receptor and agonist on kappa receptors [hence called [partial agonist]], Levallorphan (Lorfan, Naloxiphan) is a drug of the morphinan family which is used as an...
. However the analgesic effects from these drugs are limited and tend to be accompanied by dysphoria
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
, most likely due to action at the kappa opioid receptor
Kappa Opioid receptor
The κ-opioid receptor is a protein that in humans is encoded by the OPRK1 gene. The κ-opioid receptor is one of five related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds...
. As they induce opioid withdrawal effects in people who are taking, or have recently used, opioid full agonists, these drugs are 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
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...
or barbiturates. Naloxone on the other hand has no partial agonist effects, and is in fact a partial inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
at mu opioid receptors, and so is the preferred antidote drug for treating opioid overdose.
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
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
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
Post Acute Withdrawal Syndrome
Post-acute-withdrawal syndrome is a set of persistent impairments that occur after withdrawal from alcohol, opiates, benzodiazepines and other substances...
, which otherwise tends to produce symptoms such as depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
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
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
or buprenorphine
Buprenorphine
Buprenorphine is a semi-synthetic opioid that is used...
, in order to restore homeostasis and minimise the risk of post acute withdrawal syndrome once the maintenance agonist has been withdrawn.
Selective antagonists
All of the opioid antagonists used in medicine are non-selective, either blocking all three opioid receptors, or blocking the mu-opioid receptor but activating the kappa receptor. However for scientific research selective antagonists are needed which can block one of the opioid receptors but without affecting the other two. This has led to the development of antagonists which are highly selective to one of the three receptors;- CyprodimeCyprodimeCyprodime is an opioid antagonist from the morphinan family of drugs.Cyprodime is a selective opioid antagonist which blocks the μ-opioid receptor, but without affecting the δ-opioid or κ-opioid receptors...
is a selective mu opioid receptorMu Opioid receptorThe μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
antagonist - NaltrindoleNaltrindoleNaltrindole is a highly potent, highly selective delta opioid receptor antagonist used in biomedical research.-Drug design:Since peptide compounds are unable to cross the blood brain barrier, researchers developed naltrindole to be a non-peptide antagonist analog of the delta-preferring endogenous...
is a selective delta opioid receptorDelta Opioid receptorThe δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as its endogenous ligands.-Function:...
antagonist - NorbinaltorphimineNorbinaltorphimineNorbinaltorphimine is an opioid antagonist used in scientific research. It is one of the few opioid antagonists available that is highly selective for the κ-opioid receptor, and blocks this receptor without affecting the μ- or δ-opioid receptors, although it has less selectivity in vivo than when...
is a selective kappa opioid receptorKappa Opioid receptorThe κ-opioid receptor is a protein that in humans is encoded by the OPRK1 gene. The κ-opioid receptor is one of five related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds...
antagonist
Other selective antagonists are also known, but the three listed above were the first selective antagonists discovered for each respective opioid receptor, and are still the most widely used.
Depersonalization disorder
Naloxone and naltrexone have both been studied for the treatment of depersonalization disorderDepersonalization disorder
Depersonalization disorder is a dissociative disorder in which the sufferer is affected by persistent or recurrent feelings of depersonalization and/or derealization. Diagnostic criteria include persistent or recurrent experiences of feeling detached from one's mental processes or body...
. In a 2001 study with naloxone, three of fourteen patients lost their depersonalization symptoms entirely, and seven showed marked improvement . The findings of a 2005 naltrexone study were slightly less promising, with an average of a 30% reduction of symptoms, as measured by 3 validated dissociation scales . The more dramatic result of naloxone versus naltrexone is suspected to be due to different endogenous opioid receptor selectivity in naloxone, which is better suited to individuals suffering from depersonalization disorder.
In fiction
- In the episode of HouseHouse (TV series)House is an American television medical drama that debuted on the Fox network on November 16, 2004. The show's central character is Dr. Gregory House , an unconventional and misanthropic medical genius who heads a team of diagnosticians at the fictional Princeton-Plainsboro Teaching Hospital in...
, "Skin Deep", opioid antagonist drugs were administered in order to completely remove the patient's heroin induced addiction/withdrawalWithdrawalWithdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
symptoms (during an induced coma in order to relieve the extreme pain of their use), so that an accurate diagnosis of paraneoplastic syndromeParaneoplastic syndromeA paraneoplastic syndrome is a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors excreted by tumor cells or by an immune response against the tumor...
caused by cancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
was differentiated. - In an episode of Royal Pains, a character dangerously tries to undergo a procedure (and go under anaesthesia) in his own home.
See also
- OpioidOpioidAn opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
- BuprenorphineBuprenorphineBuprenorphine is a semi-synthetic opioid that is used...
, an opioid with both partial agonist and antagonist actions
External links
- David S, Lancaster T, Stead LF. Opioid antagonists for smoking cessation (Cochrane Review), The Cochrane Library, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd.