Current Opinion in Investigational Drugs

34 Current Opinion in Investigational Drugs 2006 Vol 7 No 1
combination of gabapentin and morphine achieves a
significant further reduction in pain scores in a large
majority of patients with neuropathic pain [27•].
Importantly, gabapentin has relatively minor side effects
and, as supported by the data from the available trials,
withdrawal of treatment owing to side effects has not been
significantly more common than in placebo groups. The
numbers needed to harm (NNH) for minor harm (tolerable
adverse effects) was 3.7. The relative frequencies of adverse
effects included dizziness (24%), somnolence (20%),
headache (10%), diarrhea (10%), confusion (7%) and nausea
(8%) [18]. Dose titrations up to 3600 mg/day have been used
in trials, although the maximum licensed dose in the UK is
1800 mg/day. The available evidence suggests little
potential for adverse interactions with other agents.
Although gabapentin exists at physiological pH as a
zwitterion, and hence would be expected to exhibit limited
permeability across membrane barriers, radiolabeling
studies have shown that it accumulates rapidly within
neuronal cytosol [28]. This accumulation may be explained
by the carriage of gabapentin by system L amino acid
transporters, which operate across gut membranes [29] and
neuronal and glial cell membranes [30]. This system
becomes saturated at higher doses, which accounts for the
non-linear relationship between oral doses and plasma
concentration [29]. Gabapentin competes with amino acids
such as L-leucine, L-phenylalanine and L-valine at this
transporter [30], although this is unlikely to be directly
related to its mechanism of action [15].
Gabapentin exhibits very little protein binding [31] and is
excreted unchanged by the kidneys, with a first-order
elimination pattern. Its plasma half-life is predictable and
correlates with creatinine clearance [32].
Anatomical site of action
Binding sites for gabapentin are concentrated in the outer layer
of the rat cerebral cortex [33] and in the superficial laminae of
the dorsal horn [34••]. Peak anti-epileptic activity in rats occurs
approximately 2 h after peak brain interstitial concentration
[28]. The time course of antineuropathic activity after
intrathecal injection is similar [35], suggesting that intraneural
transport is prerequisite for both actions of gabapentin.
In isolated slices of rat brainstem, gabapentin inhibits
substance P-mediated release of the excitatory neurotransmitter
Figure 2. The structures of anti-epileptic drugs used to treat neuropathic pain.
O
H
N
N
H
O
N
H N 2 O H N N
2
Cl
Cl
N
N
glutamate [36]. Furthermore, in vivo experiments have
shown that gabapentin prevents the release of excitatory
neurotransmitters, including glutamate, in spinal cord
microdialysate following nociceptive stimulation by
intraperitoneal acetic acid [37] or neuropathic pain caused
by sciatic nerve ligation [13].
Possible mechanisms of action
Does the mechanism of antineuropathic action of gabapentin
differ from its anti-epileptic action? Until both mechanisms
are elucidated, we can infer from the widely differing
chemical structures of those anti-epileptic drugs that are
used for neuropathic pain (gabapentin, phenytoin,
carbamazepine, lamotrigine, clonazepam and valproate;
Figure 2) [10•] that it is unlikely that they all act at the same
site. It would therefore be unlikely that all of these drugs
each act at two distinct sites to produce two different, but
common, effects; control of seizures and relief of
neuropathic pain. Given the relative specificity of these
agents for neuropathic pain, and the epileptiform activity
observed in damaged sensory afferent fibers [5], it seems
more plausible that both effects are mediated through a
single mechanism of action.
Receptor-mediated actions
Although gabapentin was originally designed as an analog of
the central inhibitory neurotransmitter GABA [9], no conclusive
evidence has been found of a direct interaction with any of the
key receptors in central pain transmission. Initial studies
demonstrated that it has no direct agonist activity at GABA
receptors [38] and does not bind with high affinity to any
GABA receptor subtype [39••]. More recent investigations
using cloned receptors have found evidence of selective agonist
activity at a subtype of presynaptic GABAB receptors on
excitatory neurons [40•] (discussed below).
Although D-serine, which acts as an agonist at the inhibitory
glycine binding site on N-methyl-D-aspartate (NMDA)
receptors, reverses some of the actions of gabapentin [41], it
has been shown that gabapentin itself does not directly
interact with the glycine-NMDA complex [39••,42] and
gabapentin reduces downstream excitatory neurotransmitter
release from rat brain slices, even after NMDA receptorblocking
drugs have been administered [43]. Finally,
gabapentin exhibits a profound synergistic anti-allodynic
action with the AMPA receptor antagonist 6-cyano-7nitroquinoxaline-2,3-dione
(CNQX) [35], suggesting that the
two drugs do not act at the same site.
NH 2
H
N
N N +
O
phenytoin carbamazepine lamotrigine clonazepam valproate
O
Cl
O
C
H 3
O
OH
CH 3