| Systematic (IUPAC) name | |
|---|---|
| (RS)-4-amino-3-(4-chlorophenyl)butanoic acid | |
| Clinical data | |
| Trade names | Lioresal |
| AHFS/Drugs.com | monograph |
| Licence data | US FDA:link |
| Pregnancy cat. | C(US) |
| Legal status | ℞-only (US) |
| Routes | Oral, intrathecal |
| 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%) |
| Identifiers | |
| CAS number | 1134-47-0 |
| ATC code | M03BX01 |
| PubChem | CID 2284 |
| IUPHAR ligand | 1084 |
| DrugBank | APRD00551 |
| ChemSpider | 2197 |
| UNII | H789N3FKE8 |
| KEGG | D00241 |
| ChEBI | CHEBI:2972 |
| ChEMBL | CHEMBL701 |
| Chemical data | |
| Formula | C10H12ClNO2 |
| Mol. mass | 213.661 g/mol |
| SMILES | eMolecules & PubChem |
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Baclofen (brand names Kemstro, Lioresal, and Gablofen) 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 for the GABAB receptors.[1][2] 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.[3]
In addition, research has shown baclofen to be effective in the treatment of alcohol dependence and withdrawal, by inhibiting both withdrawal symptoms and cravings.[4]
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.[5] 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.
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Baclofen is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis.[6] Its use in people with stroke or Parkinson disease is not recommended.[6]
Baclofen as of 2011 is not recommended as a treatment of alcohol withdrawal syndrome even though evidence is promising.[7][8] It however may be a promising treatment for alcoholism.[8]
Baclofen produces its effects by activating the GABAB receptor, similar to the drug GHB which also activates this receptor and shares some of its effects. However, baclofen does not have significant affinity for the GHB receptor, and has no known abuse potential.[9] The modulation of the GABAB receptor is what produces baclofen's range of therapeutic properties.
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.
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.
Baclofen can be administered either orally or intrathecally (directly into the cerebral spinal fluid) using a pump implanted under the skin.
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.
In about 5% of patients, the intrathecal route has absolutely no effect on the nervous system, no matter how great a dose is administered. A similar lack of any effect have been reported by those with spasticity who try the oral route, but for some, the oral route works while the intrathcal route does not. Again, there are no known clinical theories as to why these discrepancies are present in the baclofen-spastic CP pairing. Additionally, for some people with spasticity, a lower dose of baclofen may be less effective, while for others that same dose will be very effective. This is why clinicians always insist to a spastic diplegic or similar person that s/he must start out with a low dose of baclofen and increase the dosage slowly.
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.[10]
Withdrawal symptoms may include auditory hallucinations, visual hallucinations, tactile hallucinations, delusions, confusion, agitation, delirium, disorientation, fluctuation of consciousness, insomnia, dizziness, nausea, feeling faint, inattention, memory impairments, perceptual disturbances, pruritus/itching, 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.[10][11]
Symptoms of a baclofen overdose include vomiting, weakness, drowsiness, slow breathing, seizures, unusual pupil size, pruritus/itching and coma.
Baclofen, 4-amino-3-(4-chlorophenyl)butyric acid, is synthesized in two ways. According to the first, 4-chlorobenzaldehyde is condensed with two moles of acetoacetic ester, giving the product, which initially undergoes alkaline hydrolysis and decarboxylation forming 3-(4-chlorphenyl)glutaric acid. Dehydration of this gives 3-(4-chlorophenyl)glutaric acid anhydride, and further treatment with ammonia gives the corresponding glutarimide. Reacting this with an alkaline solution of a halogen (Hofmann rearrangement) gives baclofen.[12][13]
The second way of synthesizing baclofen is started from ethyl ester of 4-chlorocinnamic acid. Adding nitromethane to this in the presence of base gives ethyl ester of β-(4-chlorophenyl)-γ-nitrobutyric acid, the nitro group of which is reduced by hydrogen over Raney nickel to the ethyl ester of β-(4-chlorophenyl)-γ-aminobutyric acid, which is further hydrolyzed into the desired baclofen.[14]
Historically baclofen was designed to be a drug for epilepsy. It was synthesized for the first time in Ciba-Geigy by the Swiss chemist Heinrich Keberle in 1962.[15][16] 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.
Inspired by reading Olivier Ameisen’s The End of My Addiction, an anonymous donor gave $750,000 to the University of Amsterdam (UvA) in the Netherlands to initiate the clinical trial of high-dose baclofen Ameisen had called for since 2004.[17] The trial is scheduled to start in January 2011 and will be led by the team of Pr. Dr. Reinout Wiers. Ameisen has been contacted by the team.[18] In May 2011 a Scottish team from Glasgow presented: "Baclofen at a Tailored Dose Reduces Alcohol Use, Craving and Consequences of Drinking in Alcoholics with Medical Disease due to Alcohol Dependence" at the "Royal College of Pscychiatrists Faculty of Addictions Psychiatry Annual Meeting". They used doses between 15 and 360 mg of baclofen per day and winning the conference prize for the best poster raised the profile and increased interest in baclofen as anticraving drug.
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