Baclofen

Baclofen (INN, USAN, BAN, JAN)

1 : 1 mixture (racemate)
Systematic (IUPAC) name
(RS)-4-Amino-3-(4-chlorophenyl)butanoic acid
Clinical data
Trade names	Lioresal, Liofen, Gablofen
AHFS/Drugs.com	monograph
Licence data	US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
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 Y
ATC code	M03BX01 (WHO)
PubChem	CID: 2284
IUPHAR/BPS	1084
DrugBank	DB00181 Y
ChemSpider	2197 Y
UNII	H789N3FKE8 Y
KEGG	D00241 Y
ChEBI	CHEBI:2972 Y
ChEMBL	CHEMBL701 Y
Chemical data
Formula	C10H12ClNO2
Molecular mass	213.661 g/mol
SMILES ClC1=CC=C(C(CC(O)=O)CN)C=C1
InChI InChI=1S/C10H12ClNO2/c11-9-3-1-7(2-4-9)8(6-12)5-10(13)14/h1-4,8H,5-6,12H2,(H,13,14) Y Key:KPYSYYIEGFHWSV-UHFFFAOYSA-N Y
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Baclofen also known as β-(4-chlorophenyl)-γ-aminobutyric acid (β-(4-chlorophenyl)-GABA) and sold under the brand name Lioresal among others is a central nervous system depressant used as a skeletal muscle relaxant. It is primarily used to treat spasticity. It is also used by compounding pharmacies in topical pain creams as a muscle relaxant.

It is a GABA receptor agonist, specifically of the GABA_B receptors. Its beneficial effects in spasticity result from actions at spinal and supraspinal sites. It is a derivative of γ-aminobutyric acid (GABA).

A beneficial property of baclofen is that tolerance to its muscle-related therapeutic benefits does not seem to occur to a significant degree — baclofen retains its therapeutic anti-spasmodic effects even after many years of continued use. Newer studies, however, indicate that tolerance may develop in some patients receiving intrathecal baclofen treatment.

Medical uses

Spasticity

Baclofen is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis. Its use in people with stroke or Parkinson's disease is not recommended.

Addiction

As of 2013 baclofen is not recommended as a treatment of alcohol withdrawal syndrome even though evidence is promising. It is, however, being studied for alcoholism.

Mechanism of action

Baclofen produces its effects by activating the GABA_B receptor, similar to the drug phenibut which also activates this receptor and shares some of its effects. Baclofen is postulated to block mono-and-polysynaptic reflexes by acting as an inhibitory neurotransmitter; blocking the release of excitatory transmitters. However, baclofen does not have significant affinity for the GHB receptor, and has no known abuse potential. The modulation of the GABA_B receptor is what produces baclofen's range of therapeutic properties.

Similarly to phenibut (β-phenyl-GABA), as well as pregabalin (β-isobutyl-GABA), which are close analogues of baclofen, baclofen (β-(4-chlorophenyl)-GABA) has been found to block α₂δ subunit-containing voltage-gated calcium channels (VGCCs). However, it is weaker relative to phenibut in this action (K_i = 23 and 39 μM for R- and S-phenibut and 156 μM for baclofen). Moreover, baclofen is in the range of 100-fold more potent by weight as an agonist of the GABA_B receptor in comparison to phenibut, and in accordance, is used at far lower relative dosages. As such, the actions of baclofen on α₂δ subunit-containing VDCCs may not be clinically-relevant.

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 unchanged by the kidneys. The half life of baclofen is roughly 2–4 hours and it therefore needs to be administered frequently throughout the day to control spasticity appropriately.

Routes of administration

Baclofen 20 mg oral tablet

Baclofen can be administered transdermally as part of a pain-relieving and muscle-relaxing cream mix at a compounding pharmacy, 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. The pump also has to be replaced about every 5 years due to the battery life and other wear.

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 intrathecal 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.

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 more 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, dizziness (feeling faint), nausea, 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 (fever), extreme muscle rigidity resembling neuroleptic malignant syndrome and rebound spasticity.

Recreational use

One case series exists in which a group of adolescents overdosed on up to 600 mg of Baclofen. The main danger of recreational use is high risk of overdose which may cause coma, hypothermia, bradycardia, hypertension, and hyporeflexia.

Overdose

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

History

Historically baclofen was designed as a drug for treating epilepsy. It was synthesized for the first time in Ciba-Geigy by the Swiss chemist Heinrich Keberle in 1962. 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 remains unclear, but as of 2012 this has become an established method for the treatment of spasticity in many conditions.

Alcohol and other addictions

Inspired by reading Olivier Ameisen's The End of My Addiction (2009), an anonymous donor gave $750,000 to the University of Amsterdam (UvA) in the Netherlands to initiate the clinical trial of high-dose baclofen which Ameisen had called for since 2004.

Other names

Other names include: chlorophenibut.
Brand names include:

• Beklo (Opsonin Pharma Ltd.)
• Baclosan (Polpharma)
• Flexibac (Beacon Pharmaceuticals)
• Gablofen (Mallinckrodt)
• Kemstro (Schwarz Pharma)
• Liofen (Sun Pharmaceutical)
• Lioresal (Novartis)
• Lyflex (Chemidex Pharma), etc.

Research

It is being studied along with naltrexone and sorbitol for Charcot-Marie-Tooth disease (CMT), a hereditary disease that causes peripheral neuropathy.

External links

• U.S. National Library of Medicine: Drug Information Portal - Baclofen