Overdose
Reports of overdose indicate that baclofen may cause symptoms including vomiting, general weakness, sedation, respiratory insufficiency, seizures, unusual pupil size, dizziness, headaches, itching, hypothermia, bradycardia, hypertension, hyporeflexia and coma sometimes mimicking brain death. 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. Its beneficial effects in spasticity result from its actions in the brain and spinal cord. 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. The modulation of the GABAB receptor is what produces baclofens 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). 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). 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.
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. 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 made at Ciba-Geigy, by the Swiss chemist Heinrich Keberle, in 1962. Its effect on epilepsy was disappointing, but it was found that in certain people, spasticity decreased. Currently, baclofen continues to be given by mouth, 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 (intrathecally) remains unclear, but as of 2012, this has become an established method of treating spasticity in many conditions.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.