Active Ingredient: Gabapentin
Specifically, gabapentin has been clearly demonstrated to be effective for the treatment of neuropathic pain in diabetic neuropathy 22,23, postherpetic neuralgia 24, trigeminal neuralgia 25, painful neuropathy from HIV infection 26, cancer 27-29, and complex regional pain syndromes 30,31.
Gabapentin was originally developed as a gamma-aminobutyric acid GABA -mimetic compound.
The molecular weight of the drug is 171. Although it is stable at room temperature, a small amount of lactam formation occurs in aqueous solutions and this is minimized at a pH of 6.
Gabapentin, available only as oral preparations, is absorbed in the small intestine by a combination of diffusion and facilitated transport.
Its transport from the gut is facilitated by its binding to a receptor linked to a saturable l-amino acid transport mechanism 32-34.
In humans it exists in a highly ionized state at physiological pH 21. Gabapentin is not metabolized in humans and is eliminated unchanged in the urine.
It undergoes first-order kinetic elimination and renal impairment decreases gabapentin elimination in a linear fashion with a good correlation with creatinine clearance. Unlike other anticonvulsant drugs, it does not induce or inhibit hepatic microsomal enzymes.
Other effects of gabapentin have been described but are not considered to play a significant role with regard to pharmacodynamics.
These include small decreases in the release of monoamine neurotransmitters dopamine, noradrenaline and serotonin 37,38, and the attenuation of sodium-dependent action potentials suggesting sodium channel blockade after prolonged exposure to the drug 39.
Although early studies indicated a central anti-allodynic effect 40, gabapentin has been shown to inhibit ectopic discharge activity from injured peripheral nerves, as well 41.
With regards to site of action, Patel et al. Field et al. Receptor binding studies have also failed to demonstrate a direct binding site for gabapentin at the NMDA receptor 44.
Because only gabapentin and the S-isomer of pregabalin produce antihyperalgesic effects, it has been postulated that the antihyperalgesic action for gabapentin is mediated by its binding to this site on the voltage-gated calcium channel 46.
Available studies investigating the effects of gabapentin on calcium currents in neuronal cells initially produced controversial results.
Of note is the fact that gabapentin acts as a KATP channel opener in central neurons 58-60, wherein inhibits neurotransmitter release via this mechanism, but most likely this is not the case on peripheral nociceptive pathways 57.
Nevertheless, the gabapentin effect on VGCC is rapid, concentration-dependent and reversible, and the inhibition is partly voltage dependent 56.
Inward calcium currents have a well-demonstrated role in mediating several neuronal physiological processes 64,65 including synaptic neurotransmitter release 66,67, and are altered by nociception and neuronal injury 68,69.
Additionally, other studies have suggested that gabapentin decreases excitatory neurotransmitter release at presynaptic dorsal horn sites 42,51, a consequence of VGCC inhibition. The pharmacological effects of gabapentin most likely are complex, and have been shown to be mediated at central 40,70, as well as at peripheral sites 46,56.