Baclofen

Baclofen

File:(±)-Baclofen Enantiomers Structural Formulae.png
Systematic (IUPAC) name
(RS)-4-amino-3-(4-chlorophenyl)butanoic acid
Clinical data
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Oral, intrathecal
Pharmacokinetic data
Bioavailability	well absorbed
Protein binding	30%
Metabolism	85% excreted in urine/faeces unchanged. 15% metabolised by deamination
Biological half-life	1.5 to 4 hours
Excretion	renal (70-80%)
Identifiers
CAS Number	1134-47-0
ATC code	M03BX01 (WHO)
PubChem	CID 2284
IUPHAR/BPS	1084
DrugBank	APRD00551
ChemSpider	2197
Chemical data
Formula	C10H12ClNO2
Molar mass	213.661 g/mol[[]]
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Baclofen (brand names Kemstro and Lioresal) is a derivative of gamma-aminobutyric acid (GABA). It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism.

It is an agonist specific to mammalian, but not fruit fly (Drosophila) GABA_B receptors. Its beneficial effects in spasticity result from actions at spinal and supraspinal sites. Baclofen can also be used to treat hiccups, and has been shown to prevent rises in body temperature induced by the drug MDMA in rats.

In addition, research over the last five years has shown baclofen to be effective in the treatment of alcohol dependence and withdrawal, by inhibiting both withdrawal symptoms and cravings.

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. 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.

Use

Baclofen is widely used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, spastic diplegia cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis (Lou Gehrig's disease), peripheral neuropathy and trigeminal and glossopharyngeal neuralgias. Research has not shown it to be consistently effective in improving function for people with spastic movement disorders . It appears that intrathecal baclofen may be more effective than oral baclofen, but surgical implantation of a baclofen pump is a risky procedure which is only undertaken in a small proportion of patients who trial baclofen.

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

Mechanism of action

Baclofen produces its effect via modulating the GABA_B 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. The modulation of the GABA_B 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 alcohol and other 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. 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 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.

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) using a pump implanted under the skin.

Oral doses are typically 10-20 milligrams per pill. It can take anywhere from 10 to 100 milligrams per day on the oral dose to produce an adequate relief of spasticity, but for most people, 60-80 milligrams is too high and 10 milligrams is too low. Careful titration of the medication upwards from the minimum dose should provide a good enough indicator of how much is needed for adequate spasticity relief.

Intrathecal pumps offer much lower doses of Baclofen because they are designed to deliver the medication directly to the spinal fluid rather than going through the digestive and blood system first. They are often preferred in spasticity patients such as those with spastic diplegia, as very little of the oral dose actually reaches the spinal fluid. Besides those with spasticity, intrathecal administration is also used in patients with multiple sclerosis who have severe painful spasms which are not controllable by oral baclofen. With pump administration, a test dose is first injected into the spinal fluid to assess the effect, and if successful in relieving spasticity, a chronic intrathecal catheter is inserted from the spine through to the abdomen and attached to the pump which is implanted under the abdomen's skin, usually by the ribcage. The pump is computer-controlled for automatic dosage and 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. Also, because of their placement just beneath the skin, baclofen pumps, like all intrathecal pumps, are notably vulnerable to infection. Breakage of the pump, which can happen at any time for almost any reason, releases the whole of the baclofen supply at once, causing immediate overdose, coma and possibly death.

In about 5% of patients, the intrathecal route has no effect on the nervous system. Similar complaints of lack of any effect have been reported by those with spasticity who try the oral route.

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. However, it is common to titrate the dosage until symptomatic control or relief is attained; there is no inherent danger of baclofen in any dose in people with non-impaired renal function as long as the dose is titrated properly, so as not to cause undue side-effects such as oversedation. It is more common to use higher dosages when attempting to treat drug cravings instead of spasticity.

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.

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.

Overdose

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

External links

• Intrathecal Baclofen Therapy Cleveland Clinic Information Center. 15 June 2001.
• FYI: Baclofen (Lioresal), from the New York State Office of Alcoholism and Substance Abuse Services
• http://www.baclofen.info/ (from University Hospital Nottingham - QMC)
• U.S. National Library of Medicine: Drug Information Portal - Baclofen

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