Acamprosate
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Acamprosate, sold under the brand name Campral, is a medication which reduces cravings in
alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...
. It is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by
alcohol withdrawal Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in or cessation of alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, a ...
. When used alone, acamprosate is not an effective therapy for
alcohol use disorder Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...
in most individuals, as it only addresses withdrawal symptoms and not
psychological dependence Psychological dependence is a cognitive disorder and a form of dependence that is characterized by emotional–motivational withdrawal symptoms upon cessation of prolonged drug use or certain repetitive behaviors. Consistent and frequent expos ...
. It facilitates a reduction in
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
consumption as well as full abstinence when used in combination with psychosocial support or other drugs that address the addictive behavior. Serious side effects include
allergic reaction Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
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 Circulatory system, 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 ...
, while less serious side effects include
headache A headache, also known as cephalalgia, 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 (mood), depression in those with severe ...
s,
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
, and
impotence Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...
.
Diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
is the most common side effect. It is unclear if use is safe during pregnancy. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
.


Medical uses

Acamprosate is useful when used along with counseling in the treatment of
alcohol use disorder Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...
. 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 use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been ...
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. Difference in severity may also play a role.


Compliance

Some struggle to take the full course of medication (2 tablets, 3 times a day), which makes acamprosate less effective. Standard support to help people take their medication involves monthly check-ins with addiction services or a GP. Research found that compared to standard support alone, extra telephone support by a pharmacist, plus financial incentives, increased the numbers who took medication as prescribed and was cost-effective. The same telephone support without financial incentives did not significantly increase the numbers taking their medication as prescribed and was less cost-effective.


Contraindications

Acamprosate is primarily removed by the kidneys. 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 in 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 depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
, 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 biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...
of acamprosate are complex and not fully understood.
Ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
(alcohol) acts on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...
(i.e., it acts as
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 stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...
s at these receptors). In
alcohol use disorder Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...
, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e., these receptors become less sensitive to
GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...
). When alcohol is no longer consumed, these down-regulated GABAA 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, GABAA 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 GABAA receptors), leading to neuronal over-excitation (i.e., more
action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...
s in the postsynaptic neuron). In addition, alcohol also inhibits the activity of NMDA receptors (NMDARs). Chronic alcohol consumption leads to the overproduction (
upregulation In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as R ...
) 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, sh ...
and excitotoxic neuronal death. Withdrawal from alcohol induces a surge in release of excitatory
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
s like
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
, which activates NMDARs. Acamprosate reduces this glutamate surge. The drug also protects cultured cells from excitotoxicity induced by alcohol withdrawal and from glutamate exposure combined with ethanol withdrawal. Although its ability to correct an overabundance of glutamate is well-established, the actual molecular target behind this action is poorly known. Knowledge on this topic has seen several major revisions.


GABA/NMDA hypothesis

It is originally 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 predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.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 stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...
of GABAA 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 GABAA 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. At high concentrations, well above those that occur clinically (1 μM to 3 μM), reports of inhibition of
glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...
-activated responses (1 mM), enhancement of
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
function (300 μM), weak antagonization of the NMDA receptor, and partial agonism of the
polyamine A polyamine is an organic compound having two or more amino groups. Alkyl polyamines occur naturally, but some are synthetic. Alkylpolyamines are colorless, hygroscopic, and water soluble. Near neutral pH, they exist as the ammonium derivatives. ...
site of the NMDA receptor. However, no direct action of acamprosate at clinically relevant concentrations has yet been reported. At clinical levels, any inhibiton of the NMDA receptor probably occurs in a allosteric way. One of acamprosate's purported mechanisms of action is the enhancement of GABA signaling at GABAA 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 a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
, hyperacusis, ear pain, and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.


mGluR hypothesis

Two later hypothesized targets are mGluR1 and mGluR5 (10 μM). The idea originated from the fact that acamprosate blocked the neurotoxicity of an agonist of mGluR1 and mGluR5. However, a subsequent study found no action of acamprosate on the mGluR1 or mGluR5 at concentrations as high as 100 μM, nor at GABAA or
glycine receptor The glycine receptor (abbreviated as GlyR or GLR) is the receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochem ...
s or
voltage-gated sodium channel Voltage-gated sodium channels (VGSCs), also known as voltage-dependent sodium channels (VDSCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeability t ...
s. In addition, even if the 10 μM figure is correct, it would still be clinically irrelevant.


Calcium hypothesis

Spanagel et al. (2014) show that the effects of acamprosate calcium can mostly be attributed to the calcium component. Replacing calcium with sodium produces an inactive drug. Calcium chloride has a similar effect on glutamate neurotransmission. Moreover,
calcium carbonate Calcium carbonate is a chemical compound with the chemical formula . It is a common substance found in Rock (geology), rocks as the minerals calcite and aragonite, most notably in chalk and limestone, eggshells, gastropod shells, shellfish skel ...
has a similar craving-reducing effect on human alcoholics.


Synergy hypothesis

Ademar et al. (2023) report that acamprosate sodium does, in fact, enhance the effect of calcium chloride in an animal alcoholism model, and hence is not a fully inactive molecule. They also show a role of increased dopamine levels in the nucleus accumbe downstream of the glycine receptor, partly mimicking ethanol.


Other effects

The product also increases the endogenous production of
taurine Taurine (), or 2-aminoethanesulfonic acid, is a naturally occurring amino sulfonic acid that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine. It is named after Latin (cogna ...
. 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 ''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 cellular processes; the co ...
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%. H ...
from
oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
is approximately 11%, and its
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%. H ...
is decreased when taken with food. Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the
kidneys In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retro ...
. Co-administration with
naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been ...
increases plasma levels. Its absorption and elimination are very slow, with a ''t''max of 6 hours and an elimination half life of over 30 hours. Steady-state levels are reached by day 5 of oral treatment.


History

Acamprosate was developed by Lipha, a subsidiary of
Merck KGaA The Merck Group, branded and commonly known as Merck, is a German Multinational corporation, multinational science and technology company headquartered in Darmstadt, with about 60,000 employees and a presence in 66 countries. The group include ...
. and was approved for marketing in Europe in 1989. In October 2001 Forest Laboratories acquired the rights to market the drug in the US. It was approved by the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(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 neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...
. The drug was granted
orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...
designation for this use by the FDA in 2013, and by the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
(EMA) in 2014.


Society and culture


Names

Acamprosate is the International Nonproprietary Name (INN) and the
British Approved Name A British Approved Name (BAN) is the official, non-proprietary, or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia (BP). The BAN is also the official name used in some countries around the world, because ...
(BAN). Acamprosate calcium is the United States Adopted Name (USAN) and the
Japanese Accepted Name A (JAN) is the official non-proprietary or generic name given to a pharmaceutical substance by the Government of Japan. See also * International Nonproprietary Name (INN) * United States Adopted Name (USAN) * British Approved Name (BAN) * ...
(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 people refrain from drinking, some evidence suggests that acamprosate is neuroprotective (that is, it protects
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
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 – specifical ...
). It has been tried for
autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...
, both ideopathic and
fragile X syndrome Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...
-linked. It appears to reduce
amyloid-beta precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, ...
levels.


References

{{Authority control Acetamides Addiction psychiatry Drug rehabilitation Drugs with unknown mechanisms of action Drugs developed by AbbVie Drugs developed by Merck Neuroprotective agents Sulfonic acids Substance-related disorders World Health Organization essential medicines