Chirality counts?

Baclofen is the P-chlorophenyl derivative of gamma-aminobutyric acid (GABA) derivative with an antispasmodic action and is used as a central acting muscle relaxant. GABA is a suppressive neurotransmitter widely distributed in the peripheral and central nervous systems (1). Baclofen [3-(p-Chlorophenyl)4-aminobutanoic acid], is a GABA B agonist. Baclofen has both presynaptic and post synaptic actions. At the presynaptic site, baclofen decreases calcium conductance with resultant decreased excitatory amino acid release. At the postsynaptic site, baclofen increases potassium conductance, leading to neuronal hyperpolarization. Additionally, baclofen may inhibit the release of substance P. Since 1975 baclofen has been reported to produce analgesic effects by systemic administration in various experimental pain models (2-5), It has been reported that low concentrations of baclofen depress synaptic transmission, primarily by a presynaptic action, because it occurs without any significant change in the passive membrane properties of the motoneuron (6, 7). Furthermore, this effect of baclofen was blocked by the two GABAB receptor antagonists, CGP 35348 and CGP 55845A (6), but not by phaclofen (7). Advokat and colleagues suggest that, at spinal doses below those that produce muscle relaxation (i.e., <1.2 μg), baclofen may exert a slight antihyperalgesic/allodynic action (8). Rats were pretreated 24 min earlier with 1 or 3 mg/kg of s.c. baclofen. Subsequently, microinjection of 0.5 or 3 micrograms of CGP 35348, a GABA antagonist, at sites in the VMM produced at best only a very modest attenuation of the antinociceptive effects of baclofen. These data suggest that systemically-administered baclofen acts at sites in both the spinal cord and the VMM, but that its antinociceptive effects are likely to be mediated to a greater extent by a spinal, rather than medullary site of action (9). Baclofen hydrocholoride in addition to being used orally as a centrally acting muscle relaxant or to combat spasticity has also been reported to be clinically effective for the management of neuropathic pain such as trigeminal neuralgia (5, 10-15). Twenty-five patients received 10 to 40 mg of baclofen for cancer pain relief (16). Twenty patients (80%) were thought to have neuropathic pain and complained of such as paroxysmal, lancing, sharp pain, or an electric shocklike pain. Baclofen was effective in 21 of 25 patients and significantly reduced Numeric Rating Scale (pain score, 0-10; P < .0001) (16). Baclofen is available in the United States (US) as a tablet for oral administration and as a sterile preservativefree liquid for intrathecal administration. Intrathecal baclofen is largely utilized to combat spasticity (17-20), but anecdotal reports exist for its use to help pain and dystonia (21-24). In the US both the oral and intrathecal formulations are racemates and consist of a 50:50 racemic mixture of R(+)-baclofen (also referred to by some authors as L-baclofen) and S(-)-baclofen (also referred to by some authors as D-baclofen). Multiple studies have demonstrated that the more active isomer is R(+)baclofen hydrochloride (25-27) Doses of R(+)-baclofen one fifth its From: Albany Medical College, Albany, NY;