Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat

alcohol use disorder 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. Predomin ...

. For label updates se
FDA index page for NDA 021431
/ref> Acamprosate is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. When used alone, acamprosate is not an effective therapy for

in most individuals; studies have found that acamprosate works best when used in combination with psychosocial support since the drug facilitates a reduction in alcohol consumption as well as full abstinence. Serious side effects include

allergic reaction Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

s, abnormal heart rhythms, and low or

high High may refer to: Science and technology * Height * High (atmospheric), a high-pressure area * High (computability), a quality of a Turing degree, in computability theory * High (tectonics), in geology an area where relative tectonic uplift ...

blood pressure, while less serious side effects include

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

, and

impotence Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of mal ...

. Diarrhea is the most common side-effect. Acamprosate should not be taken by people with

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

problems or allergies to the drug. Until it became generic in the United States, Campral was manufactured and marketed in the United States by

Forest Laboratories Forest Laboratories was a company in the pharmaceutical industry incorporated in Delaware, with its principal office in New York City. It was known for licensing European pharmaceuticals for sale in the United States. On July 1, 2014, the compan ...

, while

Merck KGaA The Merck Group, branded and commonly known as Merck, is a German multinational science and technology company headquartered in Darmstadt, with about 60,000 employees and present in 66 countries. The group includes around 250 companies; the ma ...

markets it outside the US.

Medical uses

Acamprosate is useful when used along with counseling in the treatment of

. Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol. It appears to work as well as

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 foun ...

for maintenance of abstinence from alcohol, however naltrexone works slightly better for reducing alcohol cravings and heavy drinking, and acamprosate tends to work more poorly outside of Europe where treatment services are less robust.

Contraindications

Acamprosate is primarily removed by the kidneys and should not be given to people with severely impaired kidneys (

creatinine clearance Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...

less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys (

between 30 mL/min and 50 mL/min). It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components.

Adverse effects

The US label carries warnings about increases of suicidal behavior,

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

, and kidney failure. Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety. Potential adverse effects include headache, stomach pain, back pain, muscle pain, joint pain, chest pain, infections, flu-like symptoms, chills, heart palpitations, high blood pressure, fainting, vomiting, upset stomach, constipation, increased appetite, weight gain, edema, sleepiness, decreased sex drive, impotence, forgetfulness, abnormal thinking, abnormal vision, distorted sense of taste, tremors, runny nose, coughing, difficulty breathing, sore throat, bronchitis, and rashes.

Pharmacology

Pharmacodynamics

The

pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

of acamprosate are complex and not fully understood; however, it is believed to act as an NMDA receptor

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

and

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

of GABA_A receptors. Its activity on those receptors is indirect, unlike that of most other agents used in this context. An inhibition of the GABA-B system is believed to cause indirect enhancement of GABA_A receptors. The effects on the NMDA complex are dose-dependent; the product appears to enhance receptor activation at low concentrations, while inhibiting it when consumed in higher amounts, which counters the excessive activation of NMDA receptors in the context of alcohol withdrawal. The product also increases the endogenous production of

taurine Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. I ...

Ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...

and benzodiazepines act on the central nervous system by binding to the GABA_A receptor, increasing the effects of the inhibitory

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

GABA (i.e., they act as

s at these receptors). In

, one of the main mechanisms of tolerance is attributed to GABA_A receptors becoming downregulated (i.e. these receptors become less sensitive to GABA). When alcohol is no longer consumed, these down-regulated GABA_A receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms; since GABA normally inhibits neural firing, GABA_A receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer

inhibitory postsynaptic potential An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...

s occur through GABA_A receptors), leading to neuronal over-excitation (i.e., more

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

s in the postsynaptic neuron). One of acamprosate's mechanisms of action is the enhancement of GABA signaling at GABA_A receptors via positive allosteric receptor modulation. It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control

tinnitus Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...

, hyperacusis, ear pain, and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle. In addition, alcohol also inhibits the activity of ''N''-methyl-D-aspartate receptors (NMDARs). Chronic alcohol consumption leads to the overproduction (

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...

) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremens and

excitotoxic In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...

neuronal death.

Withdrawal Withdrawal means "an act of taking out" and may refer to: * Anchoresis (withdrawal from the world for religious or ethical reasons) * ''Coitus interruptus'' (the withdrawal method) * Drug withdrawal * Social withdrawal * Taking of money from a ban ...

from alcohol induces a surge in release of excitatory

s like

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

, which activates NMDARs. Acamprosate reduces this glutamate surge. The drug also protects cultured cells from excitotoxicity induced by

ethanol withdrawal Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. ...

and from glutamate exposure combined with ethanol withdrawal. The substance also helps re-establish a standard sleep architecture by normalizing stage 3 and REM sleep phases, which is believed to be an important aspect of its pharmacological activity.

Pharmacokinetics

Acamprosate is not

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

by the human body. Acamprosate's

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100 ...

from

oral administration 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 in ...

is approximately 11%, and its bioavailability is decreased when taken with food. Following administration and absorption of acamprosate, it is

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

unchanged (i.e., as acamprosate) via the

kidneys The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

. Its absorption and elimination are very slow, with a Tmax of 6 hours and an elimination

half life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

of over 30 hours.

History

Acamprosate was developed by Lipha, a subsidiary of

. and was approved for marketing in Europe in 1989. In October 2001

acquired the rights to market the drug in the US. It was approved by the FDA in July 2004. The first generic versions of acamprosate were launched in the US in 2013. As of 2015 acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan status for this use by the FDA in 2013 and by the EMA in 2014.

Society and culture

"Acamprosate" is the

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

and BAN for this substance. "Acamprosate calcium" is the

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...

and

JAN Jan, JaN or JAN may refer to: Acronyms * Jackson, Mississippi (Amtrak station), US, Amtrak station code JAN * Jackson-Evers International Airport, Mississippi, US, IATA code * Jabhat al-Nusra (JaN), a Syrian militant group * Japanese Article Num ...

. It is also technically known as ''N''-acetylhomotaurine or as calcium acetylhomotaurinate. It is sold under the brand name Campral.

Research

In addition to its apparent ability to help patients refrain from drinking, some evidence suggests that acamprosate is

neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...

(that is, it protects

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s from damage and death caused by the effects of alcohol withdrawal, and possibly other causes of

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

References

{{Authority control Acetamides Addiction psychiatry Drug rehabilitation Drugs with unknown mechanisms of action AbbVie brands Merck brands Neuroprotective agents Sulfonic acids Substance-related disorders