Samidorphan (, ) (developmental code names ALKS-33, RDC-0313), is an

opioid antagonist An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors. Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the ...

which in the form of

olanzapine/samidorphan Olanzapine/samidorphan (OLZ/SAM), sold under the brand name Lybalvi, is a fixed-dose combination medication for the treatment of schizophrenia and bipolar I disorder. It contains olanzapine, an atypical antipsychotic, and samidorphan, an opioid ...

(brand name Lybalvi) is used in the treatment of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

. Samidorphan reduces the

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

associated with

olanzapine Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is ta ...

. Samidorphan is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. Samidorphan was under development as a standalone medication for various indications but has been discontinued. Buprenorphine/samidorphan for the treatment of major depressive disorder was rejected by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

due to insufficient evidence of effectiveness but remains in preregistration as of September 2021. Development of baclofen/samidorphan has also been discontinued.

Development

Samidorphan has been investigated for the treatment of

alcoholism Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomina ...

and

cocaine addiction Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use o ...

by its developer, Alkermes, showing similar efficacy to

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found to ...

but possibly with reduced

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s. However, it has attracted much more attention as part of the combination product ALKS-5461 (buprenorphine/samidorphan), where samidorphan is combined with the mixed MOR weak

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 antagonist ...

and

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 o ...

(KOR) antagonist

buprenorphine Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal ...

, as an

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness ...

. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequent abuse potential. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such as

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 dan ...

substance dependence Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...

being evident. Samidorphan was also studied in combination with

, as ALKS-3831 (

), for use in

. A Phase 3 study found that the addition of samidorphan to olanzapine significantly reduced weight gain compared to olanzapine alone, and the combination was approved for the treatment of schizophrenia and

by the US

in May 2021, under the brand name Lybalvi.

Side effects

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of samidorphan include

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

and gastrointestinal disturbances among others.

Pharmacology

Pharmacodynamics

Samidorphan acts primarily an antagonist or very weak

of the

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) and to a lesser extent as a

of the

(KOR) and

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous lig ...

(DOR). In accordance with this profile, samidorphan has been observed to produce some

s that are potentially consistent with activation of the KOR such as

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ethe ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical ...

, and

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...

s in some patients in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

Pharmacokinetics

The

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of samidorphan is 7 to 9 hours.

Chemistry

Samidorphan, also known as 3-carboxamido-4-hydroxynaltrexone, has its origins in

academia An academy ( Attic Greek: Ἀκαδήμεια; Koine Greek Ἀκαδημία) is an institution of secondary or tertiary higher learning (and generally also research or honorary membership). The name traces back to Plato's school of philosophy ...

where 8-Carboxamidocyclazocine and

were utilized in its design and synthesis.

References

External links

Buprenorphine/samidorphan (ALKS-5461 - AdisInsight

Olanzapine/samidorphan (ALKS-3831) - AdisInsight
{{Opioid receptor modulators Abandoned drugs Cyclopropanes Delta-opioid receptor agonists Kappa-opioid receptor agonists Ketones Morphinans Mu-opioid receptor antagonists Synthetic opioids