Baclofen

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Baclofen
Baclofen.svg
Baclofen ball-and-stick model.png
Systematic (IUPAC) name
(RS)-4-Amino-3-(4-chlorophenyl)butanoic acid
Clinical data
Trade names Lioresal, Liofen, Gablofen
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral, intrathecal
Legal status
Legal status
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 YesY
ATC code M03BX01 (WHO)
PubChem CID 2284
IUPHAR/BPS 1084
DrugBank DB00181 YesY
ChemSpider 2197 YesY
UNII H789N3FKE8 YesY
KEGG D00241 YesY
ChEBI CHEBI:2972 YesY
ChEMBL CHEMBL701 YesY
Synonyms β-(4-chlorophenyl)-γ-aminobutyric acid (β-(4-chlorophenyl)-GABA)
Chemical data
Formula C10H12ClNO2
Molar mass 213.661 g/mol
Chirality Racemic mixture
  (verify)

Baclofen, 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 as a muscle relaxant by compounding pharmacies in topical pain creams.

It is a GABA receptor agonist, specifically of the GABAB receptors.[1][2] 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.[3] Newer studies, however, indicate that tolerance may develop in some people receiving intrathecal baclofen treatment.[4][5][6] As of 2015 the cost for a typical course of treatment in the United States is less than 25 USD.[7]

Medical uses[edit]

Spasticity[edit]

Baclofen is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis.[8] Its use in people with stroke or Parkinson's disease is not recommended.[8]

Alcoholism[edit]

Baclofen is being studied for the treatment of alcoholism.[9] While evidence is promising that it may help with alcohol withdrawal syndrome, as of 2015 it is not strong enough to recommend its use for this purpose.[9][10]

In 2014 the French drug agency ANSM issued a 3-year temporary recommendation allowing the use in of baclofen in alcoholism.[11]

Other[edit]

It is being studied along with naltrexone and sorbitol for Charcot-Marie-Tooth disease (CMT), a hereditary disease that causes peripheral neuropathy.[12] It is also being studied for cocaine addiction.[13]

Side effects[edit]

Withdrawal syndrome[edit]

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.[14]

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.[14][15]

Abuse potential[edit]

Russian baclofen (branded Baclosan) 25 mg tablets with a warning: "This drug may suppress psychomotor skills"

Clinical research has characterized baclofen and indicated that it does not produce euphoria or other pleasant effects, does not possess addictive properties, and has not been associated with any degree of drug craving.[16][17] There are very few cases of abuse of baclofen for reasons other than attempted suicide.[16] In contrast to baclofen, another GABAB receptor agonist, γ-hydroxybutyric acid (GHB), has been associated with euphoria, abuse, and addiction.[18] These effects are likely mediated not by activation of the GABAB receptor, but rather by activation of the GHB receptor.[18] Although baclofen does not produce euphoria or other reinforcing effects, which is unlike alcohol and benzodiazepines (as well as GHB), it does similarly possess sedative and anxiolytic properties.[17]

Baclofen is a very well-known drug of abuse in Russia. Unlike another gabapentinoid pregabalin, it is uncontrolled in Russia and available by simple prescription, though many pharmacies would sell it as an OTC. It is mostly popular among teens and young adults due to its low price and availability.[19][20][21]

Overdose[edit]

Reports of overdose indicate that baclofen may cause symptoms including vomiting, weakness, sedation, somnolence, respiratory depression, seizures, unusual pupil size, dizziness,[22] headaches,[22] itching, hypothermia, bradycardia, hypertension, hyporeflexia, coma, and death.[23]

Mechanism of action[edit]

Baclofen produces its effects by activating the GABAB 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.[24] The modulation of the GABAB 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).[25] However, it is weaker relative to phenibut in this action (Ki = 23 and 39 μM for R- and S-phenibut and 156 μM for baclofen).[25] Moreover, baclofen is in the range of 100-fold more potent by weight as an agonist of the GABAB 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 are likely not clinically-relevant.[25]

Description of compound[edit]

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[edit]

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.[26] 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.

History[edit]

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.[27][28] The effect on epilepsy was disappointing but it was found that in certain people spasticity decreased.

Baclofen was and is still given by mouth with variable effects. In severely affected children, the by mouth 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.[citation needed]

In the 2008 book Le Dernier Verre (translated as The End of my Addiction), French-American cardiologist Olivier Ameisen described how he treated his alcoholism with baclofen. Inspired by this book, an anonymous donor gave $750,000 to the University of Amsterdam in the Netherlands to initiate a clinical trial of high-dose baclofen which Ameisen had called for since 2004.[29]

Society and culture[edit]

Routes of administration[edit]

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[30] or intrathecally[31] (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 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.

Other names[edit]

Other names include: chlorophenibut.
Brand names include:

  • Beklo (Opsonin Pharma Ltd.)
  • Baclosan (Polpharma)
  • Baclodol (Astra Biopharmaceuticals Ltd.)
  • Flexibac (Beacon Pharmaceuticals)
  • Gablofen (Mallinckrodt)
  • Kemstro (Schwarz Pharma)
  • Liofen (Sun Pharmaceutical)
  • Lioresal (Novartis)
  • Lyflex (Chemidex Pharma)
  • Clofen (Alphapharm)
  • Muslofen (Organic Health Care Ltd.)

References[edit]

  1. ^ Mezler M.; Müller T.; Raming K. (February 2001). "Cloning and functional expression of GABA(B) receptors from Drosophila". Eur. J. Neurosci. 13 (3): 477–486. doi:10.1046/j.1460-9568.2001.01410.x. PMID 11168554. 
  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): 5485–5490. Bibcode:2003PNAS..100.5485D. doi:10.1073/pnas.0830111100. PMC 154371free to read. PMID 12692303. 
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  11. ^ "Une recommandation temporaire d’utilisation (RTU) est accordée pour le baclofène - Point d'information", ANSM, 14. March 2014.
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  28. ^ Yogeeswari, P.; Ragavendran, J. V.; Sriram, D. (2006). "An update on GABA analogs for CNS drug discovery" (PDF). Recent patents on CNS drug discovery. 1 (1): 113–118. doi:10.2174/157488906775245291. PMID 18221197. 
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  30. ^ CID 3738, Tablet
  31. ^ CID 2284

External links[edit]