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 derm ...

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 t ...

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "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. 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; blo ...

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 comp ...

, while Merck KGaA 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 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 less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys ( creatinine clearance 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 ...

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

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

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, ri ...

and positive allosteric modulator 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 GABAB receptors (GABABR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels. The changing potassium concentrations hyperpolariz ...

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.

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

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. Neu ...

GABA (i.e., they act as positive allosteric modulators at these receptors). In

, one of the main mechanisms of

tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...

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 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, ca ...

, GABA_A receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentials 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, 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) 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 Delirium tremens (DTs) is a rapid onset of confusion usually caused by withdrawal from alcohol. When it occurs, it is often three days into the withdrawal symptoms and lasts for two to three days. Physical effects may include shaking, shiver ...

and excitotoxic neuronal death. Withdrawal 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 synt ...

, 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. Mo ...

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 ...

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

absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which s ...

of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys. 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 ...

of over 30 hours.

History

Acamprosate was developed by Lipha, a subsidiary of Merck KGaA. 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 Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features ma ...

. 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 and

BAN Ban, or BAN, may refer to: Law * Ban (law), a decree that prohibits something, sometimes a form of censorship, being denied from entering or using the place/item ** Imperial ban (''Reichsacht''), a form of outlawry in the medieval Holy Roman ...

for this substance. "Acamprosate calcium" is the USAN and JAN. 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 (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 ...

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

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