|Systematic (IUPAC) name|
|Routes||Oral (333mg tablets of acamprosate calcium)|
|Half-life||20 to 33 hours|
|Mol. mass||181.211 g/mol|
|(what is this?)|
Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcohol withdrawal or benzodiazepine withdrawal, possibly by antagonizing glutaminergic N-methyl-D-aspartate receptors (NMDA) and agonizing gamma-aminobutyric acid (GABA) type A receptors. Reports indicate that acamprosate only works with a combination of attending support groups and abstinence from alcohol. Certain serious side effects include diarrhea, allergic reactions, irregular heartbeats, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence. Acamprosate should not be taken by people with kidney problems or allergies to the drug.
Until it became a generic in the United States, Campral was manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US. It is sold as 333 mg white and odorless tablets of acamprosate calcium, which is the equivalent of 300 mg of acamprosate.
Ethanol and benzodiazepine's act on the central nervous system by binding to the GABAA receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., it is a positive allosteric modulator). In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABAA receptors becoming downregulated (i.e. becoming generally less sensitive to the inhibitory effect of the GABA system). 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; compounded with the fact that GABA normally inhibits action potential formation, there are not as many receptors for GABA to bind to — meaning that sympathetic activation is unopposed, leading to sympathetic over-stimulation. Acamprosate's mechanism of action is supposed to be, at least partially, due to its agonist effect on GABA receptors. It opens the chloride ion channel in a novel way as it does not require gaba as a co-factor so it's not as addictive as benzodiazepines are. It's mode of action is similar to Methocarbamol as it also does not requiring gaba as a co-factor thus down regulation of the GABAA receptor is rare with Methocarbamol and Acamprosate. Methocarbamol only has 2 hour half life so it's not useful in long term therapy like Acamprosate is with a long 33 hour half life. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain and inner ear pressure during alcohol and benzodiazepine withdrawal 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 and excitotoxic neuronal death. Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs. Acamprosate reduces this glutamate surge. The drug also protects cultured cells from excitotoxicity induced by ethanol and benzodiazepine withdrawal and from glutamate exposure combined with ethanol withdrawal.
In contrast to the traditionally wide array of purported mechanisms of action (as described previously), one recent high-profile animal study suggests that acamprosate has by itself no psychotropic profile, no N-methyl-D-aspartate receptor or metabotropic glutamate receptor 5 activity, and that therapeutic effects are due to the active calcium moiety co-administered with the acamprosate salt form. However, these recent findings have not yet been reproduced.
In addition to its apparent ability to help patients refrain from drinking and aid in tapering benzodiazepines, some evidence suggests that acamprosate is neuroprotective (that is, it protects neurons from damage and death caused by the effects of alcohol and benzodiazepine withdrawal, and possibly other causes of neurotoxicity). For example, acamprosate has been found to protect cultured cells from damage induced by ischemia (inadequate blood flow). The drug also protected infant hamsters from brain damage induced by injections of the toxin ibotenic acid (which exacerbates excitotoxicity, the harmful over-activation of glutamate receptors).
While its mechanism of action is not fully understood, Campral is thought to act on the brain pathways related to alcohol abuse. Campral was demonstrated to be safe and effective by multiple placebo-controlled clinical studies involving alcohol-dependent patients who had already been withdrawn from alcohol, (i.e., detoxified). Campral proved superior to placebo in maintaining abstinence (keeping patients off alcohol consumption), as indicated by a greater percentage of acamprosate-treated subjects being assessed as continuously abstinent throughout treatment. Campral is not addicting and was generally well tolerated in clinical trials. The most common adverse events reported for patients taking Campral included headache, diarrhea, flatulence, and nausea.
Clinical study results
The Scripps Research Institute conducted a double blind study comparing acamprosate and placebos, in combination with psychotherapy, in the effectiveness of treating alcohol dependence. The researchers concluded that acamprosate is “safe and effective” as acamprosate increased the percentage of alcohol-free days.
Another study was conducted by Princess Alexandra Hospital in Brisbane comparing the use of acamprosate, naltrexone, or both drugs at once (with each pharmacological treatment also paired with cognitive behavioral therapy) in a 12-week study. This study concluded that a combination of medications was generally more popular and yielded better results than using either drug alone, as outlined below.
|Percentage attending program||Abstinence rates||Average number of days abstinence1||Days until first breach of abstinence1|
|Acamprosate group||66.1%||50.8%||45.07 days||26.79 days|
|Naltrexone group||79.7%||66.1%||49.95 days||26.7 days|
|Drug combination group||83.1%||67.8%||53.58 days||37.32 days|
- 1 This statistic applies to patients who could not remain abstinent throughout the entire 84-day period.
- "Campral Description" (PDF). Archived from the original on 2006-03-18. Retrieved 2006-04-02.
- Mann K, Kiefer F, Spanagel R, Littleton J (July 2008). "Acamprosate: recent findings and future research directions". Alcohol. Clin. Exp. Res. 32 (7): 1105–10. doi:10.1111/j.1530-0277.2008.00690.x. PMID 18540918.
- Williams, SH. (2005). "Medications for treating alcohol dependence". American Family Physician 72 (9): 1775–1780. PMID 16300039.
- Mason, BJ (2001). "Treatment of alcohol-dependent outpatients with acamprosate: a clinical review.". The Journal of clinical psychiatry. 62 Suppl 20: 42–8. PMID 11584875.
- GABA Agonist (Acamprosate) for Alcohol Treatment, Alcohol Rehab Thailand
- "Acamprosate". drugs.com. 2005-03-25. Archived from the original on 22 December 2006. Retrieved 2007-01-08.
- "Acamprosate Oral - Who should not take this medication?". WebMD.com. Retrieved 2007-01-08.
- Tsai, G; Coyle, JT (1998). "The role of glutamatergic neurotransmission in the pathophysiology of alcoholism". Annual review of medicine 49: 173–84. doi:10.1146/annurev.med.49.1.173. PMID 9509257.
- Tsai, GE; Ragan, P; Chang, R; Chen, S; Linnoila, VM; Coyle, JT (1998). "Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal". The American Journal of Psychiatry 155 (6): 726–32. PMID 9619143.
- De Witte, P; Littleton, J; Parot, P; Koob, G (2005). "Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action". CNS Drugs 19 (6): 517–37. doi:10.2165/00023210-200519060-00004. PMID 15963001.
- Mayer, S; Harris, BR; Gibson, DA; Blanchard, JA; Prendergast, MA; Holley, RC; Littleton, J (2002). "Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus". Alcoholism, clinical and experimental research 26 (10): 1468–78. doi:10.1097/01.ALC.0000033261.14548.D2. PMID 12394279.
- Al Qatari, M; Khan, S; Harris, B; Littleton, J (2001). "Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain". Alcoholism, clinical and experimental research 25 (9): 1276–83. doi:10.1111/j.1530-0277.2001.tb02348.x. PMID 11584146.
- Pechnick, RN; Manalo, CM; Lacayo, LM; Vit, JP; Bholat, Y; Spivak, I; Reyes, KC; Farrokhi, C (2011). "Acamprosate attenuates cue-induced reinstatement of nicotine-seeking behavior in rats". Behavioural Pharmacology 22 (3): 222–7. doi:10.1097/FBP.0b013e328345f72c. PMID 21522053.
- Spanagel R, Vengeliene V, Jandeleit B, Fischer WN, Grindstaff K, Zhang X, Gallop MA, Krstew EV, Lawrence AJ, Kiefer F (March 2014). "Acamprosate produces its anti-relapse effects via calcium.". Neuropsychopharmacology. 39 (4): 783–791. doi:10.1038/npp.2013.264. PMID 24081303.
- Engelhard, K; Werner C; Lu H; Mollenberg O; Zieglgansberger W; Kochs E (2006). "The neuroprotective effect of the glutamate antagonist acamprosate following experimental cerebral ischemia. A study with the lipid peroxidase inhibitor u-101033e". Anaesthesist 49 (9): 816–821. PMID 11076270.
- Adde-Michel, C; Hennebert O; Laudenbach V; Marret S; Leroux P (2005). "Effect of acamprosate on neonatal excitotoxic cortical lesions in in utero alcohol-exposed hamsters". Neuroscience Letters 374 (2): 109–112. doi:10.1016/j.neulet.2004.10.037. PMID 15644274.
- Azevedo AA, Figueiredo RR (2005). "Tinnitus treatment with acamprosate: double-blind study". Braz J Otorhinolaryngol 71 (5): 618–23. doi:10.1590/S0034-72992005000500012. PMID 16612523.
- "FDA Approves New Drug for Treatment of Alcoholism". FDA Talk Paper. Food and Drug Administration. 2004-07-29. Archived from the original on 2008-01-17. Retrieved 2009-08-15.
- Mason, BJ; Goodman AM; Chabac S; Lehert P (2006). "Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: The role of patient motivation". J Psychiatr Res 40 (5): 383–393. doi:10.1016/j.jpsychires.2006.02.002. PMID 16546214.
- Feeney, GF; Connor JP; Young RM; Tucker J; McPherson A (2006). "Combined acamprosate and naltrexone, with cognitive behavioural therapy is superior to either medication alone for alcohol abstinence: A single centre's experience with pharmacotherapy". Alcohol Alcohol 41 (3): 321–327. doi:10.1093/alcalc/agl007. PMID 16467406.