An opioid antagonist, or opioid receptor antagonist, is a
receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...
that acts on one or more of the
opioid receptors.
Naloxone
Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...
and
naltrexone are commonly used opioid antagonist drugs which are
competitive antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
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
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
s and
endorphin
Endorphins (contracted from endogenous morphine) are chemical signals in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in an area of the brain known as the pituitary gland.
His ...
s.
Some opioid antagonists are not pure antagonists but do produce some weak opioid
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
effects, and can produce
analgesic effects when administered in high doses to opioid-naive individuals. Examples of such compounds include
nalorphine and
levallorphan
Levallorphan (INN, BAN) (brand names Lorfan, Naloxifan, Naloxiphan), also known as levallorphan tartrate ( USAN), is an opioid modulator of the morphinan family used as an opioid analgesic and opioid antagonist/antidote. It acts as an antagonis ...
. 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
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind ...
. 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
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...
in patients who have
overdosed on non-opioid
sedative
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...
s such as
alcohol or
barbiturates
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...
. On the other hand, Naloxone has no partial agonist effects, and is in fact a partial
inverse agonist at
μ-opioid receptor
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
s, 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
Low-dose naltrexone describes the off-label, experimental use of the medication naltrexone at low doses for diseases such as Crohn's disease and multiple sclerosis.
Naltrexone is typically prescribed for opioid dependence or alcohol dependence, as ...
can reverse the altered
homeostasis
In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
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 (PAWS) is a hypothesized set of persistent impairments that occur after withdrawal from alcohol, opiates, benzodiazepines, antidepressants, and other substances. Infants born to mothers who used substances of depend ...
, which otherwise tends to produce symptoms such as
depression and
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
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.
List of opioid antagonists
The following are all
μ-opioid receptor
The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...
(MOR)
antagonists or
inverse agonists. Many of them also bind to the
κ-opioid receptor
The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind ...
(KOR) and/or
δ-opioid receptor (DOR), where they variously behave as antagonists and/or agonists.
Centrally active
These drugs are used mainly as
antidotes to reverse
opioid overdose and in the treatment of
alcohol dependence and
opioid dependence (by blocking the effects, namely
euphoria
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and d ...
, of opioids so as to discourage
abuse).
Marketed
*
Naloxone
Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...
*
Naltrexone
*
Nalmefene
*
Samidorphan
Diprenorphine
Diprenorphine (brand name Revivon; former developmental code name M5050), also known as diprenorfin, is a non-selective, high-affinity, weak partial agonist of the μ- (MOR), κ- (KOR), and δ-opioid receptor (DOR) (with equal affinity) which ...
is used in
veterinary medicine
Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...
only.
Discontinued or rarely used
*
Nalorphine
*
Nalorphine dinicotinate
*
Levallorphan
Levallorphan (INN, BAN) (brand names Lorfan, Naloxifan, Naloxiphan), also known as levallorphan tartrate ( USAN), is an opioid modulator of the morphinan family used as an opioid analgesic and opioid antagonist/antidote. It acts as an antagonis ...
Never marketed
*
Nalodeine
Peripherally restricted
These drugs are used mainly in the treatment of
opioid-induced constipation.
Marketed
*
Alvimopan
Alvimopan (trade name Entereg) is a drug which behaves as a peripherally acting μ-opioid receptor antagonist. With the limited ability to cross the blood–brain barrier and reach the μ-opioid receptors of the central nervous system, the clinic ...
*
Methylnaltrexone
Methylnaltrexone (MNTX, brand name Relistor), used in form of methylnaltrexone bromide (INN, USAN, BAN), is a medication that acts as a peripherally acting μ-opioid receptor antagonist that acts to reverse some of the side effects of opioid dru ...
*
Naloxegol
Naloxegol (INN; PEGylated naloxol; trade names Movantik and Moventig) is a peripherally acting μ-opioid receptor antagonist developed by AstraZeneca, licensed from Nektar Therapeutics, for the treatment of opioid-induced constipation. It was ap ...
Under development currently or previously
*
6β-Naltrexol
*
Axelopran
Axelopran (INN, USAN) (developmental code name TD-1211) is a drug which is under development by Theravance Biopharma and licensed to Glycyx for all indications. It acts as a peripherally acting μ-opioid receptor antagonist and also acts on κ ...
*
Bevenopran
Bevenopran (INN, USAN) (former developmental code names CB-5945, ADL-5945, MK-2402, OpRA III) is a peripherally acting μ-opioid receptor antagonist that also acts on δ-opioid receptors and was under development by Cubist Pharmaceuticals for the ...
*
Methylsamidorphan
*
Naldemedine
Naldemedine (brand name Symproic in the US and Rizmoic in the European Union) is a medication that is used for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. It is a peripherally acting μ-opioid receptor an ...
Miscellaneous
Buprenorphine and
dezocine are
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
s of the MOR but antagonists of the KOR. Contrarily,
eptazocine
Eptazocine (Sedapain) is an opioid analgesic which was introduced in Japan by Morishita in 1987. It acts as a mixed κ-opioid receptor agonist and μ-opioid receptor antagonist.
See also
* Benzomorphan
Benzomorphan is a chemical compound tha ...
is an antagonist of the MOR but an agonist of the KOR; the same is also true for nalorphine and levallorphan. A variety of partial agonists or mixed agonists-antagonists of the MOR and KOR are also marketed, and include
butorphanol,
levorphanol
Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain. It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan.
It was first described in Germa ...
,
nalbuphine,
pentazocine
Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such it is called an ...
, and
phenazocine. All of the aforementioned drugs may be described as
opioid modulator
An opioid modulator (or opioid receptor modulator) is a drug which has mixed agonist and antagonist actions at different opioid receptors and thus cannot clearly be described as either an opioid ''agonist'' or ''antagonist''. An example of an opio ...
s instead of as pure antagonists. With the sole exception of nalorphine, all of the preceding are used as analgesics (by virtue of the fact that both MOR and KOR agonism independently confer pain relief). However, these opioid analgesics have atypical properties in comparison to the prototypical pure MOR full agonist opioid analgesics, such as less or no risk of
respiratory depression
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...
for MOR partial agonists and antagonists, reduced or no
euphoria
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and d ...
,
abuse potential, and
dependence liability with MOR partial agonists/antagonists, and use- and dose-limiting
side effects such as
dysphoria and
hallucinations with KOR agonists. In addition, by virtue of its KOR antagonism, buprenorphine (as
buprenorphine/samidorphan
Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment-resistant depression (TRD).
ALKS-5461 failed to ...
(ALKS-5461) or
buprenorphine/naltrexone to block its MOR agonism) is under investigation for the treatment of
depression and
cocaine dependence, as are other KOR antagonists such as
CERC-501 (LY-2456302) and, previously,
JDTic and
PF-4455242 (both discontinued due to
toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
concerns).
Selective antagonists
All of the centrally active opioid antagonists used widely in
medicine
Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pr ...
are non-selective, either blocking multiple opioid receptors, or blocking the MOR but activating the KOR. However, for
scientific research, selective antagonists are needed which can block one of the opioid receptors but without affecting the others. This has led to the development of antagonists which are highly selective to one of the four receptors:
*
Cyprodime is a selective MOR antagonist
*
Naltrindole is a selective DOR antagonist
*
Norbinaltorphimine is a selective KOR antagonist
*
J-113,397 is a selective
nociceptin receptor (NOP) antagonist
Other selective antagonists are also known, but the four listed above were the first selective antagonists discovered for each respective opioid receptor, and are still the most widely used.
In addition to selective antagonists,
AT-076 is a non-selective, balanced antagonist of all four of the opioid receptors, and was the first such agent to be discovered.
Depersonalization disorder
Naloxone and naltrexone have both been studied in the treatment of
depersonalization disorder. 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 three validated
dissociation scales.
The more dramatic result of naloxone versus naltrexone is suspected to be due to different opioid receptor affinity/selectivity with naloxone (specifically, more potent KOR blockade), which appears to be better suited to individuals with depersonalization disorder.
In popular culture
* In the episode of ''
House'', "
Skin Deep", opioid antagonist drugs were administered in order to completely remove the patient's
heroin
Heroin, also known as diacetylmorphine and diamorphine among other names, is a potent opioid mainly used as a recreational drug for its euphoric effects. Medical grade diamorphine is used as a pure hydrochloride salt. Various white and bro ...
induced addiction/
withdrawal symptoms (during an induced coma in order to relieve the extreme pain of their use), so that an accurate diagnosis of
paraneoplastic syndrome caused by
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
was differentiated.
* In an episode of ''Royal Pains'', a character dangerously tries to undergo a procedure (and go under
anaesthesia) in his own home.
* In an episode of
Hannibal
Hannibal (; xpu, 𐤇𐤍𐤁𐤏𐤋, ''Ḥannibaʿl''; 247 – between 183 and 181 BC) was a Carthaginian general and statesman who commanded the forces of Carthage in their battle against the Roman Republic during the Second Pu ...
, Dr.Lecter administers
Naloxone
Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin withi ...
to Jack Crawford's wife after she tries to commit suicide by overdosing on
morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...
.
References
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.
*
{{DEFAULTSORT:Opioid Antagonist