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Baclofen (brand names Kemstro, Lioresal, Liofen, Gablofen, Beklo and Baclosan) is a derivative of gamma-aminobutyric acid (GABA). It is primarily used to treat spasticity and is in the early research stages for use for the treatment of alcoholism. It is also used by compounding pharmacies in topical pain creams as a muscle relaxant.

It is an agonist for the GABA_B 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]

A beneficial property of baclofen is that tolerance does not seem to occur to a significant degree — baclofen retains its therapeutic anti-spasmodic effects even after many years of continued use.^[4] Newer studies, however, indicate that tolerance may develop in some patients receiving intrathecal baclofen treatment.^[5]^[6]^[7]

Oral dosage must be carefully regulated; significantly high doses of the drug, particularly 80 mg per day or higher, can cause excessive ataxia and/or drowsiness that can interfere with daily function.^{[citation needed]}

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 disease is not recommended.^[8]

Alcoholism[edit]

In 2012, baclofen was approved for use in the treatment of alcoholism on a case by case basis by the AFSSAPS.^[9]

Mechanism of action[edit]

Baclofen produces its effects by activating the GABA_B 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.^[10] The modulation of the GABA_B receptor is what produces baclofen's range of therapeutic properties.

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 in the unchanged form by the kidneys.^[11]The half life of baclofen is roughly 2-4 hours and 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 topically as part of a pain-relieving and muscle-relaxing cream mixed at a compounding pharmacy, orally^[12] or intrathecally^[13] (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.^{[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.^[14]

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.^[14]^[15]

Recreational use[edit]

One case series exists in which a group of adolescents overdosed on up to 600mg of Baclofen.^[16] The main danger of recreational use is high risk of overdose which may cause coma, hypothermia, bradycardia, hypertension, and hyporeflexia.^[16]

Overdose[edit]

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

Chemistry[edit]

Baclofen can be 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.^[17]^[18]

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.^[19]

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.^[20]^[21] 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^[update] 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.^[22] The trial started in January 2011, led by the team of Pr. Dr. Reinout Wiers.

References[edit]

^ 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.
^ 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.
^ Bexis S., Phillis B. D., Ong J., White J. M., Irvine R. J. (2004-04-09). "Baclofen prevents MDMA-induced rise in core body temperature in rats". Drug and Alcohol Dependence 74 (1): 89–96. doi:10.1016/j.drugalcdep.2003.12.004. PMID 15072812.
^ 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.
^ 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. edit
^ 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. PMID 11932045. edit
^ 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. edit
^ ^a ^b "Baclofen". The American Society of Health-System Pharmacists. Retrieved 2011-12-06.
^ "'Anti-alcoholism' drug cleared for use in France". http://medicalxpress.com. April 25, 2012.
^ 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.
^ 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.
^ CID 3738, Tablet
^ CID 2284
^ ^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.
^ 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.
^ ^a ^b Perry, HE; Wright, RO; Shannon, MW; Woolf, AD (1998). "Baclofen overdose: Drug experimentation in a group of adolescents". Pediatrics 101 (6): 1045–8. PMID 9606233.
^ US patent 3471548, KEBERLE H.; FAIGLE J. W.; WILHELM M., "GAMMA-AMINO-BETA-(PARA-HALOPHENYL)-BUTYRIC ACIDS AND THEIR ESTERS", issued 1969-10-07, assigned to Ciba-Geigy
^ US patent 3634428, KEBERLE H.; FAIGLE J. W.; WILHELM M., "BETA-(PARA-HALO-PHENYL)-GLUTARIC ACID IMIDES", issued 1972-01-11, assigned to Ciba-Geigy
^ F. Uchimaru, M. Sato, E. Kasasayama, M. Shiamuzu, H. Takashi,^{[dubious – discuss]}JP 45016692 (1970)
^ Froestl, W. (2010). "Chemistry and Pharmacology of GABAB Receptor Ligands". GABAReceptor Pharmacology - A Tribute to Norman Bowery. Advances in Pharmacology 58. pp. 19–62. doi:10.1016/S1054-3589(10)58002-5. ISBN 978-0-12-378647-0.
^ 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.
^ 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.

External links[edit]

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
Intrathecal Baclofen, from University Hospital Nottingham, Queen's Medical Centre)
U.S. National Library of Medicine: Drug Information Portal - Baclofen

UpToDate Contents

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1. 吃逆の概要 overview of hiccups
2. アルコール使用障害に対する薬物療法 pharmacotherapy for alcohol use disorder
3. 脊髄損傷および疾患の慢性合併症 chronic complications of spinal cord injury and disease
4. 脳性麻痺のマネージメントおよび予後 management and prognosis of cerebral palsy
5. ミオクローヌスの治療 treatment of myoclonus

English Journal

Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection.

Leggio L, Ferrulli A, Zambon A, Caputo F, Kenna GA, Swift RM, Addolorato G.SourceCenter for Alcohol and Addiction Studies, Brown University, Providence, RI, USA; Institute of Internal Medicine, Catholic University of Rome, Italy.
Addictive behaviors.Addict Behav.2012 Apr;37(4):561-4. Epub 2011 Dec 27.
Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclof
PMID 22244707

Alcohol-dependence: the current French craze for baclofen.

Rolland B, Bordet R, Cottencin O.SourceUniversité Lille Nord de France, Lille, France Department of Addictionology, CHU Lille, Lille, France Department of Pharmacology, CHU Lille, Lille, France EA 4559, Lille, France. E-mail: benjamin.rolland@chru-lille.fr.
Addiction (Abingdon, England).Addiction.2012 Apr;107(4):848-9. doi: 10.1111/j.1360-0443.2011.03752.x. Epub 2012 Feb 11.
PMID 22324452

Japanese Journal

有機触媒反応の発展とプロセス化学への応用

池本哲哉
有機合成化学協会誌 69(5), 562-570, 2011-05-01
… Our applications to the practical synthesis of the intermediate of (S)-Oxybutynin, the intermediate of anti-AIDS drug BFOL, and (R)-Baclofen were also introduced in this review. …
NAID 10028293568

痙縮に対する外科治療(<特集>最新のニューロモデュレーション)

佐々木寿之,平孝臣,岡田芳和
脳神経外科ジャーナル 20(2), 103-111, 2011-02-20
痙縮はさまざまな神経疾患で引き起こされ, 患者の活動性を阻害する.適切な治療法は痙縮患者にとって有用である.髄腔内バクロフェン治療は, 他の痙縮に対する治療効果が不十分な場合に行われる.トライアルにて効果を確認し, ポンプの埋め込みが行われる.カテーテルやポンプの不具合は, 重篤な離脱症状を引き起こすので注意が必要である.選択的脊髄後根遮断術は, 脳性麻痺の小児に対して行われる.いくつかのバリエー …
NAID 110008441007

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リンク元

「バクロフェン」

Baclofen
Systematic (IUPAC) name
	(RS)-4-amino-3-(4-chlorophenyl)butanoic acid
Clinical data
Trade names	Lioresal, Liofen
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	DB00181
ChemSpider	2197
UNII	H789N3FKE8
KEGG	D00241
ChEBI	CHEBI:2972
ChEMBL	CHEMBL701
Chemical data
Formula	C10H12ClNO2
Mol. 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) ; Key:KPYSYYIEGFHWSV-UHFFFAOYSA-N ;
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　　[★]

英: baclofen
商: ギャバロン、リオレサール Lioresal
関: 筋弛緩薬

作用機序：GABA受容体に選択的に結合　→　反射の抑制
痙性麻痺

交通事故による頚損の患者さんに使われていた(20100801)

[pmid11168554-1] 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.

[pmid12692303-2] 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] Bexis S., Phillis B. D., Ong J., White J. M., Irvine R. J. (2004-04-09). "Baclofen prevents MDMA-induced rise in core body temperature in rats". Drug and Alcohol Dependence 74 (1): 89–96. doi:10.1016/j.drugalcdep.2003.12.004. PMID 15072812.

[4] 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.

[5] 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. edit

[6] 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. PMID 11932045. edit

[7] 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. edit

[AHFS-8] "Baclofen". The American Society of Health-System Pharmacists. Retrieved 2011-12-06.

[9] "'Anti-alcoholism' drug cleared for use in France". http://medicalxpress.com. April 25, 2012.

[Carter-2009-10] 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] 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.

[12] CID 3738, Tablet

[13] CID 2284

[dawbw-14] 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.

[15] 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.

[Perry-16] Perry, HE; Wright, RO; Shannon, MW; Woolf, AD (1998). "Baclofen overdose: Drug experimentation in a group of adolescents". Pediatrics 101 (6): 1045–8. PMID 9606233.

[17] US patent 3471548, KEBERLE H.; FAIGLE J. W.; WILHELM M., "GAMMA-AMINO-BETA-(PARA-HALOPHENYL)-BUTYRIC ACIDS AND THEIR ESTERS", issued 1969-10-07, assigned to Ciba-Geigy

[18] US patent 3634428, KEBERLE H.; FAIGLE J. W.; WILHELM M., "BETA-(PARA-HALO-PHENYL)-GLUTARIC ACID IMIDES", issued 1972-01-11, assigned to Ciba-Geigy

[19] F. Uchimaru, M. Sato, E. Kasasayama, M. Shiamuzu, H. Takashi,^{[dubious – discuss]}JP 45016692 (1970)

[20] Froestl, W. (2010). "Chemistry and Pharmacology of GABAB Receptor Ligands". GABAReceptor Pharmacology - A Tribute to Norman Bowery. Advances in Pharmacology 58. pp. 19–62. doi:10.1016/S1054-3589(10)58002-5. ISBN 978-0-12-378647-0.

[21] 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.

[SCIAMEISEN-22] 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.

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