Baclofen

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Baclofen
Baclofen.svg
Baclofen ball-and-stick model.png
Clinical data
Trade names Lioresal, Liofen, Gablofen, others
Other namesβ-(4-chlorophenyl)-γ-aminobutyric acid (β-(4-chlorophenyl)-GABA)
AHFS/Drugs.com Monograph
MedlinePlus a682530
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		oral, intrathecal, transdermal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Well-absorbed
Protein binding 30%
Metabolism 85% excreted in urine/faeces unchanged. 15% metabolised by deamination
Elimination half-life 1.5 to 4 hours
Excretion Kidney (70–80%)
Identifiers
  • (RS)-4-Amino-3-(4-chlorophenyl)butanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.013.170 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H12ClNO2
Molar mass 213.66 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • NCC(CC(=O)O)c1ccc(Cl)cc1
  • 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) Yes check.svgY
  • Key:KPYSYYIEGFHWSV-UHFFFAOYSA-N Yes check.svgY
   (verify)

Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. [7] [8] It may also be used for hiccups and muscle spasms near the end of life, [8] and off-label to treat alcohol use disorder [9] [10] or opioid withdrawal symptoms. [11] It is taken orally (swallowed by mouth) or by intrathecal pump (delivered into the spinal canal via an implantable pump device). [7] It is also sometimes used transdermally (applied topically to the skin) in combination with gabapentin and clonidine prepared at a compounding pharmacy. [12]

Contents

Common side effects include sleepiness, weakness, and dizziness. [7] Serious side effects may occur if baclofen is rapidly stopped including seizures and rhabdomyolysis. [7] Use in pregnancy is of unclear safety while use during breastfeeding is probably safe. [13] It is believed to work by decreasing levels of certain neurotransmitters. [7]

The adverse effects and safety profile associated with baclofen when it is combined with sedative drugs (for example alcohol or benzodiazepines) range depending on the dose and the individual. The interaction may increase the sedative effects of all ingested sedatives and as such is not generally recommended. [14] In high doses the interaction can cause de novo seizures. [15]

Baclofen was approved for medical use in the United States in 1977. [7] It is available as a generic medication. [8] [16] In 2021, it was the 103rd most commonly prescribed medication in the United States, with more than 6 million prescriptions. [17] [18]

Medical uses

Baclofen is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis. [19] Use in people with stroke or Parkinson's disease is not recommended. [19] Intrathecal baclofen is used for severe spasticity of spinal cord origin that is refractive to maximum doses of oral antispasmodic agents or who experience intolerable side effects. [20] [21] Baclofen is also used in the treatment of sleep-related painful erections. [22]

Baclofen is sometimes used off-label as a treatment for alcohol use disorder to reduce the risk of relapse and to increase the number of days that a person can go without drinking alcohol (abstinence days). [9] It is also sometimes used for the treatment of opioid withdrawal symptoms, and may be superior for this purpose to the more-commonly used clonidine. [10] [11]

Adverse effects

Adverse effects include drowsiness, dizziness, weakness, fatigue, headache, trouble sleeping, nausea and vomiting, urinary retention, or constipation. [2]

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 administered intrathecally or for long periods of time (more than a couple of months) and can occur from low or high doses. [23] The severity of baclofen withdrawal depends on the rate at which it is discontinued. Thus to minimise 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 eased or completely reversed by re-initiating therapy with baclofen. [24]

Withdrawal symptoms may include auditory hallucinations, visual hallucinations, tactile hallucinations, delusions, confusion, agitation, delirium, disorientation, fluctuation of consciousness, insomnia, dizziness, nausea, inattention, memory impairments, perceptual disturbances, itching, anxiety, depersonalization, hypertonia, hyperthermia (higher than normal temperature without infection), 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. [24] [23]

Abuse

Russian baclofen (trade name "Baclosan") 25 mg tablets with a warning: "Caution: the drug may suppress psychomotor reactions" Baclosan.JPG
Russian baclofen (trade name "Baclosan") 25 mg tablets with a warning: "Caution: the drug may suppress psychomotor reactions"

Baclofen, at standard dosing, does not appear to possess addictive properties, and has not been associated with any degree of drug craving. [25] [26] Euphoria is however listed as a common to very common side-effect of baclofen in the BNF 75. [27] There are very few cases of abuse of baclofen for reasons other than attempted suicide. [25] In contrast to baclofen, another GABAB receptor agonist, γ-hydroxybutyric acid (GHB), has been associated with euphoria, abuse, and addiction. [28] These effects are likely mediated not by activation of the GABAB receptor, but rather by activation of the GHB receptor. [28] Baclofen possesses both sedative and anxiolytic properties. [26]

Overdose

Reports of overdose indicate that baclofen may cause symptoms including vomiting, general weakness, sedation, respiratory insufficiency, seizures, unusual pupil size[ clarification needed ], dizziness, [2] headaches, [2] itching, hypothermia, bradycardia, cardiac conduction abnormalities, hypertension, hyporeflexia and coma sometimes mimicking brain death. [29] Overdose may require intubation and length of mechanical ventilation required may correlate with serum baclofen levels shortly after ingestion. Symptoms may persist even after the point at which serum baclofen levels are undetectable. [30]

Pharmacology

Chemically, baclofen is a derivative of the neurotransmitter γ-aminobutyric acid (GABA). It is believed to work by activating (or agonizing) GABA receptors, specifically the GABAB receptors. [31]

Pharmacodynamics

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 ligand, inhibiting the release of excitatory neurotransmitters. However, baclofen does not have significant affinity for the GHB receptor, and has no known abuse potential. [32] Agonism of the GABAB receptor is responsible for 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). [33] 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). [33] 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 VGCCs are likely not clinically relevant. [33]

For drug-reward and addiction, baclofen's mechanism of action is thought to be through its affect on the mesolimbic dopamine pathway, specifically leading to a decrease in dopamine release associated with alcohol. [9] GABAB receptor activation (GABAB receptor agonist activity) may decrease or inhibit alcohol's ability to activate or fire dopaminergic neurons following exposure to alcohol. Baclofen's mechanism of action is not thought to be mediated through its muscle-relaxing or sedative properties, however there is evidence to suggest that the GABAB receptor-activation in the limbus may also reduce feelings of anxiety in people with alcohol use disorder. [9]

Pharmacokinetics

The drug is rapidly absorbed after oral administration and is widely distributed throughout the body. Biotransformation is low: the drug is predominantly excreted unchanged by the kidneys. [34] The half-life of baclofen is roughly 2–4 hours; it therefore needs to be administered frequently throughout the day to control spasticity appropriately.

Chemistry

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.

History

Historically, baclofen was designed as a drug for treating epilepsy. It was first synthesized at Ciba-Geigy, by the Swiss chemist Heinrich Keberle, in 1962. [35] [36] Its effect on epilepsy was disappointing, but it was found that in certain people, spasticity decreased. In 1971, it was introduced as a treatment for certain form of spasticity. It was approved by the US Food and Drug Administration (FDA) in 1977. [37]

Intrathecal baclofen was first introduced in 1984 to treat severe spinal spasticity. This administration route aimed to avoid supraspinal side effects. [38] [39]

In his 2008 book, Le Dernier Verre (translated literally as The Last Glass or 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. [40] The trial concluded, "In summary, the current study did not find evidence of a positive effect of either low or high doses of baclofen in AD patients. However, we cannot exclude the possibility that baclofen is an effective medication for the treatment of severe, heavy drinking AD patients not responding to or not accepting routine psychosocial interventions." [41]

Society and culture

Routes of administration

Baclofen 20 mg oral tablet 005915731lg Baclofen 20 MG Oral Tablet.jpg
Baclofen 20 mg oral tablet

Baclofen can be administered, orally, intrathecally (directly into the cerebral spinal fluid) using a pump implanted under the skin, or transdermally as part of a pain-relieving and muscle-relaxing topical cream mix (also containing gabapentin and clonidine) prepared at a compounding pharmacy. [12] [42]

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. A drug concentration in the cerebrospinal fluid more than 10 times greater than when given orally is achieved with this route. At the same time the blood concentration levels are almost undetectable, thus minimizing side effects. [42]

Besides those with spasticity, intrathecal administration is also used in patients with cerebral palsy [42] or multiple sclerosis who have severe painful spasms which are not controllable by oral baclofen.[ citation needed ] 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.[ citation needed ] The pump is computer-controlled for automatic dosage and its reservoir can be replenished by percutaneous injection.[ citation needed ] The pump also has to be replaced every five to seven years or so. [43]

Other names

Synonyms include chlorophenibut. Brand names include Beklo, Baclodol, Flexibac, Gablofen, Kemstro, Liofen, Lioresal, Lyflex, Clofen, Muslofen, Bacloren, Baklofen, Sclerofen, Pacifen and others.

Research

Baclofen is being studied for the treatment of alcoholism. [25] Evidence as of 2019 is not conclusive enough to recommend its use for this purpose. [25] [44] In 2014, the French drug agency ANSM issued a three-year temporary recommendation allowing the use of baclofen in alcoholism. [45] In 2018, baclofen received a Marketing Authorization for use in alcoholism treatment from the agency if all other treatments are not effective. [46]

It is being studied along with naltrexone and sorbitol for Charcot–Marie–Tooth disease (CMT), a hereditary disease that causes peripheral neuropathy. [47] It is also being studied for cocaine addiction. [48] Baclofen and other muscle relaxants are being studied for potential use for persistent hiccups. [49] [50]

From 2014 to 2017 baclofen misuse, toxicity and use in suicide attempts among adults in the US increased. [51]

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<i>gamma</i>-Hydroxybutyric acid Chemical compound

gamma-Hydroxybutyric acid is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. It acts on the GHB receptor and is a weak agonist at the GABAB receptor. GHB has been used in the medical setting as a general anesthetic and as treatment for cataplexy, narcolepsy, and alcoholism. The substance is also used illicitly for various reasons, including as a performance-enhancing drug, date rape drug, and as a recreational drug.

A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as "centrally acting" muscle relaxant, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxant, the term is commonly used to refer to spasmolytics only.

Colloquially known as "downers", depressants or central depressants are drugs that lower neurotransmission levels, or depress or reduce arousal or stimulation in various areas of the brain. Depressants do not change the mood or mental state of others. Stimulants, or "uppers", increase mental or physical function, hence the opposite drug class from depressants are stimulants, not antidepressants.

<span class="mw-page-title-main">Gabapentin</span> Anticonvulsant medication

Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is commonly used medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.

<span class="mw-page-title-main">Clonidine</span> Pharmaceutical drug

Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. The drug is often prescribed off-label for tics. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.

Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

<span class="mw-page-title-main">Intrathecal administration</span> Drug injected into the spinal canal

Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain management applications. This route is also used to introduce drugs that fight certain infections, particularly post-neurosurgical. The drug needs to be given this way to avoid being stopped by the blood–brain barrier. The same drug given orally must enter the blood stream and may not be able to pass out and into the brain. Drugs given by the intrathecal route often have to be compounded specially by a pharmacist or technician because they cannot contain any preservative or other potentially harmful inactive ingredients that are sometimes found in standard injectable drug preparations.

<span class="mw-page-title-main">Tizanidine</span> Muscle relaxant medication

Tizanidine, sold under the brand name Zanaflex among others, is an alpha-2 (α2) adrenergic receptor agonist, similar to clonidine, that is used to treat muscle spasticity due to spinal cord injury, multiple sclerosis, and spastic cerebral palsy. Effectiveness appears similar to baclofen or diazepam. It is taken by mouth.

<span class="mw-page-title-main">Acamprosate</span> Medication

Acamprosate, sold under the brand name Campral, is a medication which reduces alcoholism withdrawal symptoms. It is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal. When used alone, acamprosate is not an effective therapy for alcohol use disorder in most individuals, as it only addresses withdrawal symptoms and not psychological dependence. It facilitates a reduction in alcohol consumption as well as full abstinence when used in combination with psychosocial support or other drugs that address the addictive behavior.

An intrathecal pump is a medical device used to deliver medications directly into the space between the spinal cord and the protective sheath surrounding the spinal cord. Medications such as baclofen, bupivacaine, clonidine, morphine, hydromorphone, fentanyl or ziconotide may be delivered in this manner to minimize the side effects often associated with the higher doses used in oral or intravenous delivery of these drugs.

<span class="mw-page-title-main">Succinic semialdehyde dehydrogenase deficiency</span> Rare disorder involving deficiency in GABA degradation

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

<span class="mw-page-title-main">Phenibut</span> CNS depressant medication

Phenibut, sold under the brand names Anvifen, Fenibut, and Noofen among others, is a central nervous system depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications. It is usually taken by mouth as a tablet, but may be given intravenously.

<span class="mw-page-title-main">Alcohol detoxification</span> Abrupt cessation of alcohol intake

Alcohol detoxification is the abrupt cessation of alcohol intake in individuals that have alcohol use disorder. This process is often coupled with substitution of drugs that have effects similar to the effects of alcohol in order to lessen the symptoms of alcohol withdrawal. When withdrawal does occur, it results in symptoms of varying severity.

<span class="mw-page-title-main">GABA receptor agonist</span> Category of drug

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.

<i>gamma</i>-Amino-<i>beta</i>-hydroxybutyric acid Anticonvulsant drug

γ-Amino-β-hydroxybutyric acid (GABOB), also known as β-hydroxy-γ-aminobutyric acid (β-hydroxy-GABA), and sold under the brand name Gamibetal among others, is an anticonvulsant which is used for the treatment of epilepsy in Europe, Japan, and Mexico. It is a GABA analogue, or an analogue of the neurotransmitter γ-aminobutyric acid (GABA), and has been found to be an endogenous metabolite of GABA.

<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, the continued use seems to be typically associated with the avoidance of unpleasant withdrawal reaction rather than with the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, often without the described drug seeking behavior and tolerance.

<span class="mw-page-title-main">Gabapentinoid</span> Calcium channel blockers

Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor, as it is the target of the drugs gabapentin and pregabalin.

<span class="mw-page-title-main">GABA analogue</span> Class of drugs

A GABA analogue is a compound which is an analogue or derivative of the neurotransmitter gamma-Aminobutyric acid (GABA).

<span class="mw-page-title-main">Opioid withdrawal</span> Withdrawal symptoms of opiates

Opioid withdrawal is a set of symptoms arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, nausea, vomiting, diarrhea, sweating, and an increased heart rate. Opioid use triggers a rapid adaptation in cellular signalling pathways that means, when rapidly withdrawn, there can be adverse physiological effects. All opioids, both recreational drugs and medications, when reduced or stopped, can lead to opioid withdrawal symptoms. When withdrawal symptoms are due to recreational opioid use, the term opioid use disorder is used, whereas when due to prescribed medications, the term prescription opioid use disorder is used. Opioid withdrawal can be helped by the use of opioid replacement therapy, and symptoms may be relieved by the use of medications including lofexidine and clonidine.

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