Baclofen

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Baclofen
Baclofen.svg
Systematic (IUPAC) name
(RS)-4-amino-3-(4-chlorophenyl)butanoic acid
Clinical data
Trade namesLioresal, Liofen
AHFS/Drugs.commonograph
Licence dataUS FDA:link
Pregnancy cat.C (US)
Legal status-only (US)
RoutesOral, intrathecal
Pharmacokinetic data
Bioavailabilitywell absorbed
Protein binding30%
Metabolism85% excreted in urine/faeces unchanged. 15% metabolised by deamination
Half-life1.5 to 4 hours
Excretionrenal (70-80%)
Identifiers
CAS number1134-47-0 YesY
ATC codeM03BX01
PubChemCID 2284
IUPHAR ligand1084
DrugBankDB00181
ChemSpider2197 YesY
UNIIH789N3FKE8 YesY
KEGGD00241 YesY
ChEBICHEBI:2972 YesY
ChEMBLCHEMBL701 YesY
Chemical data
FormulaC10H12ClNO2 
Mol. mass213.661 g/mol
 YesY (what is this?)  (verify)
 
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Baclofen
Baclofen.svg
Systematic (IUPAC) name
(RS)-4-amino-3-(4-chlorophenyl)butanoic acid
Clinical data
Trade namesLioresal, Liofen
AHFS/Drugs.commonograph
Licence dataUS FDA:link
Pregnancy cat.C (US)
Legal status-only (US)
RoutesOral, intrathecal
Pharmacokinetic data
Bioavailabilitywell absorbed
Protein binding30%
Metabolism85% excreted in urine/faeces unchanged. 15% metabolised by deamination
Half-life1.5 to 4 hours
Excretionrenal (70-80%)
Identifiers
CAS number1134-47-0 YesY
ATC codeM03BX01
PubChemCID 2284
IUPHAR ligand1084
DrugBankDB00181
ChemSpider2197 YesY
UNIIH789N3FKE8 YesY
KEGGD00241 YesY
ChEBICHEBI:2972 YesY
ChEMBLCHEMBL701 YesY
Chemical data
FormulaC10H12ClNO2 
Mol. mass213.661 g/mol
 YesY (what is this?)  (verify)

Baclofen (brand names Kemstro, Lioresal, Liofen, Gablofen, Lyflex, 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 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]

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]

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]

In 2012, baclofen was approved for use in the treatment of alcoholism on a case by case basis by the AFSSAPS. Cardiologist Olivier Ameisen had claimed, in his book The Last Glass (2008), that he had cured himself of alcoholism by treating himself with high doses of baclofen.[9]

Mechanism of action[edit]

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.[10] The modulation of the GABAB 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.

Pharmacokinetics of Baclofen in alcohol-dependent patients[edit]

Baclofen exhibited a linear pharmacokinetics with a proportional relationship from 30 mg to 240 mg per day, the dose range currently used in alcoholic patients, but there is a wide interpatient variability which can explain the lack of response observed for some patients.[12]

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[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.

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.

Side Effects[edit]

Drowsiness, dizziness, weakness, tiredness, headache, trouble sleeping, nausea, or constipation may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: mental/mood changes (such as confusion, depression, hallucinations).

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Precautions[edit]

Before taking baclofen, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, mental/mood disorders (such as schizophrenia), brain disorders (such as seizures, stroke).

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Older adults may be more sensitive to the side effects of this drug, especially drowsiness and mental/mood changes (such as confusion).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This drug passes into breast milk. Consult your doctor before breast-feeding.

Interactions[edit]

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Tell your doctor or pharmacist if you are taking other products that cause drowsiness including alcohol, antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, diazepam, zolpidem), other muscle relaxants, and narcotic pain relievers (such as codeine).

Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

Currently displaying 6 drugs (27 brand and generic names) known to have a major interaction with baclofen: acetaminophen / propoxyphene, aspirin / caffeine / propoxyphene, buprenorphine, buprenorphine / naloxone, propoxyphene, sodium oxybate.

Disease interaction: There are 4 disease interactions with baclofen:

- Baclofen (Includes Baclofen) ↔ Renal Dysfunction

  Severe Potential Hazard, High plausibility 
  Applies to: Renal Dysfunction 

Baclofen is primarily eliminated by the kidney. Patients with impaired renal function may be at greater risk for adverse effects from baclofen due to decreased drug clearance. Therapy with baclofen should be administered cautiously in such patients. Dosage adjustments may be necessary.

References 1.Himmelsbach FA, Kohler E, Zanker B "Toxic effect of baclofen in chronic haemodialysis and renal transplantation." Dtsch Med Wochenschr 117 (1992): 733-7 2.Krahn A, Penner SB "Use of baclofen for intractable hiccups in uremia." Am J Med 96 (1994): 391 3."Product Information. Lioresal (baclofen)." Medtronic Inc, Minneapolis, MN.


Baclofen (Includes Baclofen) ↔ Autonomic Dysreflexia Moderate Potential Hazard, Moderate plausibility

Applies to: Autonomic Dysreflexia

Therapy with intrathecal baclofen should be administered cautiously in patients with a history of autonomic dysreflexia, since the presence of nociceptive stimuli or abrupt withdrawal of the medication may trigger an episode of dysreflexia.

References 1."Product Information. Lioresal Intrathecal (baclofen)." Medtronic Inc, Minneapolis, MN.


Baclofen (Includes Baclofen) ↔ Psychoses

Moderate Potential Hazard, Moderate plausibility

Applies to: Psychosis, History - Psychiatric Disorder

Baclofen may precipitate or exacerbate psychotic symptoms, both during therapy and following abrupt withdrawal of the drug. Therapy with baclofen should be administered cautiously in patients with a history of psychiatric disorders.

References 1."Product Information. Lioresal (baclofen)." Medtronic Inc, Minneapolis, MN. 2.Kirubakaran V, Mayfield D, Rengachary S "Dyskinesia and psychosis in a patient following baclofen withdrawal." Am J Psychiatry 141 (1984): 692-3 3.Sommer BR, Petrides G "A case of baclofen-induced psychotic depression." J Clin Psychiatry 53 (1992): 211-2

Baclofen (Includes Baclofen) ↔ Seizure Disorders

Moderate Potential Hazard, Moderate plausibility

Applies to: Seizures

Deterioration in seizure control and electroencephalographic (EEG) changes have been reported occasionally in epileptic patients treated with baclofen. Therapy with baclofen should be administered cautiously in patients with a history of seizures. Clinical status and EEG should be monitored at regular intervals during treatment. Except in cases of overdose or severe adverse reactions, cessation of baclofen therapy, whenever necessary, should occur gradually with incrementally reduced dosages. Abrupt withdrawal has been associated with central nervous system effects including seizures, hallucinations, and psychosis.

References 1."Product Information. Lioresal (baclofen)." Medtronic Inc, Minneapolis, MN. 2.Kirubakaran V, Mayfield D, Rengachary S "Dyskinesia and psychosis in a patient following baclofen withdrawal." Am J Psychiatry 141 (1984): 692-3 3.Penn RD "Intrathecal baclofen for spasticity of spinal origin: seven years of experience." J Neurosurg 77 (1992): 236-40

Baclofen ↔ Alcohol (Ethanol)

Moderate Drug Interaction

Using baclofen together with ethanol can increase nervous system side effects such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with baclofen. Do not use more than the recommended dose of baclofen, and avoid activities requiring mental alertness such as driving or operating hazardous machinery until you know how the medication affects you. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medication without first talking to your doctor.

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]

Recreational use[edit]

One case series exists in which a group of adolescents overdosed on up to 600mg of Baclofen.[17] The main danger of recreational use is high risk of overdose which may cause coma, hypothermia, bradycardia, hypertension, and hyporeflexia.[17]

Overdose[edit]

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

If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: vomiting, severe drowsiness, slow/shallow breathing, seizures. NOTES: Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another condition unless your doctor directs you to do so. A different medication may be necessary in that case. MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

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.[18][19]

Baclofen synthesis.png

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.[20]

Baclofen synthesis 2.png

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.[21][22] 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.[23] The trial started in January 2011, led by the team of Pr. Dr. Reinout Wiers.

See also[edit]

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. ^ 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
  8. ^ a b "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. 
  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. ^ Marsot, A.; Imbert, B.; Alvarez, J.C.; Grassin-Delyle, S.; Jaquet, I.; Lançon, C.; Simon, N. (2013). "High Variability in the Exposure of Baclofen in Alcohol-Dependent Patients". Alcoholism: Clinical and Experimental Research 38 (2): 316–21. doi:10.1111/acer.12235. PMID 24033763. 
  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 Perry, HE; Wright, RO; Shannon, MW; Woolf, AD (1998). "Baclofen overdose: Drug experimentation in a group of adolescents". Pediatrics 101 (6): 1045–8. doi:10.1542/peds.101.6.1045. PMID 9606233. 
  18. ^ 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 
  19. ^ 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 
  20. ^ F. Uchimaru, M. Sato, E. Kasasayama, M. Shiamuzu, H. Takashi,[dubious ]JP 45016692  (1970)
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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]