Baclofen

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Baclofen (INN, USAN, BAN, JAN)
Baclofen.svg
Baclofen ball-and-stick model.png
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
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 YesY
ATC code M03BX01
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
Chemical data
Formula C10H12ClNO2
Molar mass 213.661 g/mol
  (verify)

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 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 patients receiving intrathecal baclofen treatment.[4][5][6]

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.[7] Its use in people with stroke or Parkinson's disease is not recommended.[7]

Addiction[edit]

As of 2013 baclofen is not recommended as a treatment of alcohol withdrawal syndrome even though evidence is promising.[8][9] It is, however, being studied for alcoholism.[8]

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.[10] 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).[11] 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).[11] 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.[11]

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.[12] 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[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[13] or intrathecally[14] (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.[citation needed] A similar lack of any effect have been reported by those with spasticity who try the oral route,[citation needed] 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[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.[15]

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.[15][16]

Abuse potential[edit]

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.[17][18] There are very few cases of abuse of baclofen for reasons other than attempted suicide.[17] In contrast to baclofen, another GABAB receptor agonist, γ-hydroxybutyric acid (GHB), has been associated with euphoria, abuse, and addiction.[19] These effects are likely mediated not by activation of the GABAB receptor, but rather by activation of the GHB receptor.[19] 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.[18]

Baclofen is a very well-known drug of abuse in Russia. Unlike another gabapentinoid pregabalin, it is uncontrolled and available by simple prescription, though almost all pharmacies would sell it without it. It is mostly popular among teens and young adults due to its low price and availability.[20][21][22]

Overdose[edit]

Reports of overdose indicate that baclofen may cause symptoms including vomiting, weakness, sedation, somnolence, respiratory depression, seizures, unusual pupil size, dizziness,[23] headaches,[23] itching, hypothermia, bradycardia, hypertension, hyporeflexia, coma, and death.[24]

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.[25][26] 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[edit]

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.[27]

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), etc.

Research[edit]

It is being studied along with naltrexone and sorbitol for Charcot-Marie-Tooth disease (CMT), a hereditary disease that causes peripheral neuropathy.[28]

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 154371. PMID 12692303. 
  3. ^ Gaillard J. M. (May–Jun 1977). "Comparison of two muscle relaxant drugs on human sleep: diazepam and parachlorophenylgaba". Acta Psychiatr Belg 77 (3): 410–425. PMID 200069. 
  4. ^ Heetla, H. W.; Staal, M. J.; Kliphuis, C.; Van Laar, T. (2009). "The incidence and management of tolerance in intrathecal baclofen therapy". Spinal Cord 47 (10): 751–756. doi:10.1038/sc.2009.34. PMID 19333246. 
  5. ^ Nielsen, J. F.; Hansen, H. J.; Sunde, N.; Christensen, J. J. (2002). "Evidence of tolerance to baclofen in treatment of severe spasticity with intrathecal baclofen". Clinical neurology and neurosurgery 104 (2): 142–145. doi:10.1016/s0303-8467(02)00009-4. PMID 11932045. 
  6. ^ Heetla, H. W.; Staal, M. J.; Van Laar, T. (2009). "Tolerance to continuous intrathecal baclofen infusion can be reversed by pulsatile bolus infusion". Spinal Cord 48 (6): 483–486. doi:10.1038/sc.2009.156. PMID 19918253. 
  7. ^ a b "Baclofen". The American Society of Health-System Pharmacists. Retrieved 2011-12-06. 
  8. ^ a b Leggio, L.; Garbutt, J. C.; Addolorato, G. (Mar 2010). "Effectiveness and safety of baclofen in the treatment of alcohol dependent patients". CNS & neurological disorders drug targets 9 (1): 33–44. doi:10.2174/187152710790966614. PMID 20201813. 
  9. ^ Liu, J; Wang, LN (Feb 28, 2013). "Baclofen for alcohol withdrawal.". The Cochrane database of systematic reviews 2: CD008502. doi:10.1002/14651858.CD008502.pub3. PMID 23450582. 
  10. ^ Carter, L. P.; Koek, W.; France, C. P. (October 2008). "Behavioral analyses of GHB: Receptor mechanisms". Pharmacol. Ther. 121 (1): 100–114. doi:10.1016/j.pharmthera.2008.10.003. PMC 2631377. PMID 19010351. 
  11. ^ a b c Zvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Liepins V, Kalvinsh I, Dambrova M (2015). "R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects". Pharmacol. Biochem. Behav. 137: 23–9. doi:10.1016/j.pbb.2015.07.014. PMID 26234470. 
  12. ^ Wuis, E. W.; Dirks, M. J. M.; Termond, E. F. S.; Vree, T. B.; Kleijn, E. (1989). "Plasma and urinary excretion kinetics of oral baclofen in healthy subjects". European Journal of Clinical Pharmacology 37 (2): 181–4. doi:10.1007/BF00558228. PMID 2792173. 
  13. ^ CID 3738, Tablet
  14. ^ CID 2284
  15. ^ a b Leo, R. J.; 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. 
  16. ^ Grenier, B.; Mesli, A.; Cales, J.; Castel, J. P.; Maurette, P. (1996). "[Severe hyperthermia caused by sudden withdrawal of continuous intrathecal administration of baclofen]". Ann Fr Anesth Reanim 15 (5): 659–662. doi:10.1016/0750-7658(96)82130-7. PMID 9033759. 
  17. ^ a b Liu, Jia; Wang, Lu-Ning; Liu, Jia (2015). "Baclofen for alcohol withdrawal". doi:10.1002/14651858.CD008502.pub4. 
  18. ^ a b Agabio, Roberta; Preti, Antonio; Gessa, Gian Luigi (2013). "Efficacy and Tolerability of Baclofen in Substance Use Disorders: A Systematic Review". European Addiction Research 19 (6): 325–345. doi:10.1159/000347055. ISSN 1421-9891. 
  19. ^ a b van Nieuwenhuijzen, P.S.; McGregor, I.S.; Hunt, G.E. (2009). "The distribution of γ-hydroxybutyrate-induced Fos expression in rat brain: Comparison with baclofen". Neuroscience 158 (2): 441–455. doi:10.1016/j.neuroscience.2008.10.011. ISSN 0306-4522. 
  20. ^ "Таблетки Баклофен — «легальный» наркотик (Baclofen tablets — a "legal" narcotic)". Narko-pomosh.ru (Drug addiction help) (in Russian). Retrieved 6 February 2016. 
  21. ^ "Баклофен – инструкция по применению, аналоги, отзывы. (Baclofen — prescribing information, generic baclofen, opinions)". Tiensmed.ru (in Russian). 11. Наркотическая зависимость и немедицинское применение препарата. (11. Drug dependence and nonmedical use). Retrieved 6 February 2016. 
  22. ^ Burya SA. "Лекомания (баклофен, гликодин, корвалол и др.) — "Lecomania" (baclofen, Glycodin (dextromethorphan), Corvalol (phenobarbital) etc.)". Narcolikbez.ru (in Russian). Retrieved 6 February 2016. 
  23. ^ a b "Gablofen (Baclofen) FDA Full Prescribing Information" (PDF). US Food and Drug Administration. Retrieved 2016-01-21. 
  24. ^ "Baclofen Overdose: Drug Experimentation in a Group of Adolescents". PEDIATRICS 101 (6): 1045–1048. 1998. doi:10.1542/peds.101.6.1045. ISSN 0031-4005. 
  25. ^ Froestl, W. (2010). "GABAReceptor Pharmacology - A Tribute to Norman Bowery". Advances in Pharmacology 58: 19–62. doi:10.1016/S1054-3589(10)58002-5. ISBN 978-0-12-378647-0.  |chapter= ignored (help)
  26. ^ 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. 
  27. ^ Enserink, M. (2011). "Anonymous Alcoholic Bankrolls Trial of Controversial Therapy". Science 332 (6030): 653. doi:10.1126/science.332.6030.653. PMID 21551041. Archived from the original on 11 May 2011. Retrieved 2011-05-06. 
  28. ^ Attarian, Shahram; Vallat, Jean-Michel; Magy, Laurent; Funalot, Benoît; Gonnaud, Pierre-Marie; Lacour, Arnaud; Péréon, Yann; Dubourg, Odile; Pouget, Jean; Micallef, Joëlle; Franques, Jérôme; Lefebvre, Marie-Noëlle; Ghorab, Karima; Al-Moussawi, Mahmoud; Tiffreau, Vincent; Preudhomme, Marguerite; Magot, Armelle; Leclair-Visonneau, Laurène; Stojkovic, Tanya; Bossi, Laura; Lehert, Philippe; Gilbert, Walter; Bertrand, Viviane; Mandel, Jonas; Milet, Aude; Hajj, Rodolphe; Boudiaf, Lamia; Scart-Grès, Catherine; Nabirotchkin, Serguei; Guedj, Mickael; Chumakov, Ilya; Cohen, Daniel (2014). "An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A". Orphanet Journal of Rare Diseases 9 (1): 199. doi:10.1186/s13023-014-0199-0. 

External links[edit]