Baclofen: Wikis

  
  

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1 : 1 mixture (racemate)
Systematic (IUPAC) name
(RS)-4-amino-3-(4-chlorophenyl)butanoic acid
Identifiers
CAS number 1134-47-0
ATC code M03BX01
PubChem 2284
DrugBank APRD00551
ChemSpider 2197
Chemical data
Formula C 10H12ClNO2  
Mol. mass 213.661 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability well absorbed
Protein binding 30%
Metabolism 85% excreted in urine/faeces unchanged. 15% metabolised by deamination
Half life 1.5 to 4 hours
Excretion renal (70-80%)
Therapeutic considerations
Pregnancy cat. C(US)
Legal status
Routes Oral, intrathecal
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Baclofen (brand names Kemstro and Lioresal) is a derivative of gamma-aminobutyric acid (GABA) primarily used to treat spasticity.

It is an agonist specific to mammalian but not fruit fly (Drosophila) GABAB receptors.[1][2] Its beneficial effects result from actions at spinal and supraspinal sites. Baclofen can also be used to treat hiccups. It has been shown to prevent rises in body temperature induced by the drug MDMA in rats. [3] A very beneficial property of baclofen is that tolerance does not seem to occur to any significant degree — baclofen retains its therapeutic anti-spasmodic effects even after many years of continued use.[4] However, oral dosage must be carefully regulated; significantly high doses of the drug, particularly 80 milligrams per day or higher, can cause excessive drowsiness that can interfere with daily function.

Contents

Use

Baclofen is used for the treatment of spastic movement, especially in instances of spinal cord injury, spastic diplegia, multiple sclerosis, amyotrophic lateral sclerosis (Lou Gehrig's Disease) and trigeminal and glossopharyngeal neuralgias.

Baclofen has also been shown to be as effective as diazepam in uncomplicated alcohol withdrawal syndrome.[5] An Italian study showed that it was effective in promoting alcohol abstinence in patients with severe liver cirrhosis.[6]

Mechanism of action

Baclofen produces its effect via modulating the GABAB receptor, similar to the drug GHB which also has the same mechanism of action and also similar effects. However, there are some pharmacological differences in that baclofen appears to have reduced abuse and dependence potential.[7][8] The modulation of the GABAB receptor is what produces baclofen's range of therapeutic properties.

History

Historically baclofen was designed to be a drug for epilepsy in the 1920s. The effect on epilepsy was disappointing but it was found that in certain patients spasticity decreased. Baclofen was and is still given orally with variable effects. In severely affected children, the oral dose is so high that side effects appear and the treatment loses its benefit. How and when baclofen came to be used in the spinal sac is not really clear but this is now an established method for the treatment of spasticity in many conditions.

As a treatment for addictions

Dr. Olivier Ameisen, a French-American associate professor of medicine and a cardiologist at Weill Cornell Medical College of Cornell University, reported in 2004 in the journal Alcohol and Alcoholism that he successfully used Baclofen to completely suppress his own alcohol addiction. In his paper, he called for randomized trials of high-dose baclofen to be conducted to test the therapeutic model he had proposed. He renewed his call for clinical trials in the Journal of the American Medical Association (JAMA). His therapeutic model was reproduced by Dr. William Bucknam, who published a case report in Alcohol and Alcoholism, and by Roberta Agabio et al. who published another case in Journal of Clinical Psychopharmacology. Ameisen believes, based on his own experience and other anecdotal evidence, that Baclofen acts on some mechanism within the brains of addicts to suppress cravings brought on by addiction to various substances such as alcohol, cocaine, and heroin.

Ameisen, who currently is a visiting professor of medicine at State University of New York Downstate Medical Center, authored Le Dernier Verre (The Last Glass, titled The End of My Addiction in English) to inform public opinion and physicians. [9][10] Since his book has been released, hundreds of patients have been treated in academic centers and rapidly become "indifferent to alcohol". Also, clinical trials are being mounted as a result of public pressure.

Recently, based on Ameisen's therapeutic model, some trials have been conducted in using Baclofen to treat cocaine addiction. In 2007, an Italian team has demonstrated the effectiveness and the safety of baclofen as a treatment for alcohol-addiction[11] People have said once they took Baclofen they felt their desire for cocaine plummet almost overnight. There is also a report that baclofen has beneficial role in the management of reflux disease.[12]

Description of compound

Baclofen is a white (or off white) mostly odorless crystalline powder, with a molecular weight of 213.66 g/mol. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.

Pharmacokinetics

The drug is rapidly absorbed after oral administration and is widely distributed throughout the body. Biotransformation is low and the drug is predominantly excreted in the unchanged form by the kidneys.

Routes of administration

Baclofen can be administered either orally or intrathecally (directly into the cerebral spinal fluid). Intrathecal administration is often preferred in spasticity patients, as very little of the oral dose actually reaches the spinal fluid. Intrathecal administration is particularly used in patients with multiple sclerosis who have severe painful spasms which are not controllable by oral baclofen, or patients with spastic diplegia in whom management of spasticity is made easier by regular self-administering of the drug through its pump.

With pump administration, a test dose is given to assess the effect, and if successful a chronic intrathecal catheter is inserted and connected to a computer-controlled implanted pump. The reservoir in the pump can be replenished by percutaneous injection.

These pump systems are quite sophisticated and expensive, so careful patient selection is required. In about 5% of patients, the intrathecal route has no effect on the nervous system. Because of their placement just beneath the skin, baclofen pumps are notably vulnerable to infection at least, or at worst, to breakage which releases the whole of the baclofen supply.

Dosage

Baclofen therapy is usually started with an initial low dose of about 10 mg daily in divided doses and gradually titrated up in a stepwise fashion until symptomatic relief occurs. The usual maximum dose is 80 mg per day.[13]

Withdrawal syndrome

Discontinuation of baclofen can be associated with a withdrawal syndrome which resembles benzodiazepine withdrawal and alcohol withdrawal. Withdrawal symptoms are more likely if baclofen is used for long periods of time (more than a couple of months) and can occur from low or high doses. The severity of baclofen withdrawal depends on the rate at which baclofen is discontinued. Thus to minimise baclofen withdrawal symptoms the dose should be tapered down slowly when discontinuing baclofen therapy. Abrupt withdrawal is most likely to result in severe withdrawal symptoms. Acute withdrawal symptoms can be stopped by recommencing baclofen.[14]

Withdrawal symptoms may include auditory hallucinations, visual hallucinations, tactile hallucinations, delusions, confusion, agitation, delirium, disorientation, fluctuation of consciousness, insomnia, inattention, memory impairments, perceptual disturbances, anxiety, depersonalization, hypertonia, hyperthermia, formal thought disorder, psychosis, mania, mood disturbances, restlessness, and behavioral disturbances, tachycardia, seizures, tremors, autonomic dysfunction, hyperpyrexia, extreme muscle rigidity resembling neuroleptic malignant syndrome and rebound spasticity.[14][15]

Overdose

Symptoms of a baclofen overdose include vomiting, weakness, drowsiness, slow breathing, seizures, unusual pupil size, and coma.

References

  1. ^ Mezler M, Müller T, Raming K (February 2001). "Cloning and functional expression of GABA(B) receptors from Drosophila". Eur. J. Neurosci. 13 (3): 477–86. PMID 11168554. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0953-816X&date=2001&volume=13&issue=3&spage=477. Retrieved 2009-03-26.  
  2. ^ Dzitoyeva S, Dimitrijevic N, Manev H (April 2003). "Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5485–90. doi:10.1073/pnas.0830111100. PMID 12692303.  
  3. ^ Bexis S, Phillis BD, Ong J, White JM, Irvine RJ. (2004-04-09). "Baclofen prevents MDMA-induced rise in core body temperature in rats". Drug and Alcohol Dependence (mdma.net) 74 (1): 89–96. http://www.mdma.net/baclofen/index.html. Retrieved 2008-12-06.  
  4. ^ Gaillard JM (May-Jun 1977). "Comparison of two muscle relaxant drugs on human sleep: diazepam and parachlorophenylgaba". Acta Psychiatr Belg 77 (3): 410–25. PMID 200069.  
  5. ^ Addolorato G; Leggio L, Abenavoli L, Agabio R, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G (March 2006). "Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam". Am J Med 119 (3): 276.e13–8. doi:10.1016/j.amjmed.2005.08.042. PMID 16490478.  
  6. ^ Susan Jeffrey (December 7, 2007), Baclofen Aids in Alcohol Abstinence in Cirrhosis Patients, Medscape, http://www.medscape.com/viewarticle/567102  
  7. ^ McDonald LM, Sheppard WF, Staveley SM, Sohal B, Tattersall FD, Hutson PH (May 2008). "Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats". Psychopharmacology (Berl.) 197 (4): 591–600. doi:10.1007/s00213-008-1077-z. PMID 18264695. http://www.springerlink.com/content/66235wh679711r50/fulltext.html.  
  8. ^ Carter LP, Koek W, France CP (October 2008). "Behavioral analyses of GHB: Receptor mechanisms". Pharmacol. Ther.. doi:10.1016/j.pharmthera.2008.10.003. PMID 19010351. http://linkinghub.elsevier.com/retrieve/pii/S0163-7258(08)00196-4.  
  9. ^ "Cheap pill is 'miracle cure' for alcoholism". Independent.ie. 2008-12-08. http://www.independent.ie/health/latest-news/cheap-pill-is-miracle-cure-for-alcoholism-1566925.html.  
  10. ^ "France abuzz over alcoholic 'cure'". BBC News. 2008-12-06. http://news.bbc.co.uk/2/hi/europe/7768141.stm. Retrieved December 6 2008.  
  11. ^ Addolorato, G.; Leggio, L.; Ferrulli, A.; Cardone, S.; Vonghia, L.; Mirijello, A.; Abenavoli, L.; D'Angelo, C. et al. (Dec 2007). "Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.". Lancet 370 (9603): 1915-22. doi:10.1016/S0140-6736(07)61814-5. PMID 18068515.  
  12. ^ Zhang Q et al. (2001). "Control of transient lower oesophageal sphincter relaxations and reflux by the GABAb agonist baclofen in patients with gastro-oesophageal reflux disease". Gut 50: 19–24.  
  13. ^ "Kemstro (Baclofen) drug indications and dosage - prescription drugs and medications". RxList. pp. 2. http://www.rxlist.com/cgi/generic/baclofen_ids.htm. Retrieved September 21 2008.  
  14. ^ a b Leo RJ; Baer D (Nov-Dec 2005). "Delirium Associated With Baclofen Withdrawal: A Review of Common Presentations and Management Strategies". Psychosomatics 46 (6): 503–507. doi:10.1176/appi.psy.46.6.503. PMID 16288128. http://psy.psychiatryonline.org/cgi/content/full/46/6/503.  
  15. ^ Grenier B, Mesli A; Cales J, Castel JP, Maurette P (1996). "[Severe hyperthermia caused by sudden withdrawal of continuous intrathecal administration of baclofen]". Ann Fr Anesth Reanim 15 (5): 659–62. PMID 9033759.  

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