GABAPENTIN  is an alkylated γ-aminobutyric acid analog that was synthesized in 1977 1and first developed clinically as an anticonvulsant in the late 1980s. 2Recent experience suggests that it may also be useful in treating other neurologic and psychiatric conditions such as spasticity, anxiety, and pain. 1Following early case reports of use in “reflex sympathetic dystrophy,”3multicenter controlled trials have demonstrated analgesic efficacy and safety of gabapentin in chronic neuropathic pain. 4Other anticonvulsants such as carbamazepine, phenytoin, and topiramate have also shown efficacy in neuropathic pain but are generally not thought to be useful in other conditions such as inflammatory or postoperative pain. 5However, accumulating laboratory and clinical evidence, including a postoperative analgesic trial appearing in this issue of Anesthesiology, 6suggest that gabapentin and related analogs such as pregabalin (S -(+)-3-isobutylgaba) 7are analgesic across a wider spectrum of pain states. The role of certain neural changes, common both to neuropathic and post-tissue injury pain, 8may explain these recent observations.

Gabapentin and Injury-induced Neuroplasticity

Similar to nerve injury, surgical tissue injury has been shown to result in spinal sensitization—i.e. , metabolic activation and hyperexcitability of spinal nociceptive neurons, expansion of sensory receptive fields, and alterations in the processing of innocuous stimuli. 8These postoperative neuroplastic changes underlie the development of “pathologic” pain, which is characterized by (1) hyperalgesia (an increased response to a stimulus that is normally painful), which may be primary (at the site of injury) or secondary (distant to the site of injury); and (2) allodynia (pain due to a stimulus that does not normally provoke pain). 9Pharmacologic effects of gabapentin that may be important in pain modulation include binding to α2δ calcium channel subunits, 10suppression of glutamate, 11and substance P 12neurotransmission, as well as modulation of γ-aminobutyric acid receptors. 13However, the relative importance of these and other mechanisms of gabapentin remains uncertain, and intensive investigation continues. The most important site of action of gabapentin also remains unclear, although evidence supports effects at peripheral, 14primary afferent neuron, 15spinal neuron, 11and supraspinal sites 16(fig. 1). In any case, several animal 17–19and human 6,20,21studies support antihyperalgesic and antiallodynic effects of gabapentin in the setting of peripheral tissue injury (table 1).

Fig. 1. Putative sites of action of gabapentin. References in parentheses provide examples of evidence to support antinociceptive effects of gabapentin at respective sites within the nervous system.

Fig. 1. Putative sites of action of gabapentin. References in parentheses provide examples of evidence to support antinociceptive effects of gabapentin at respective sites within the nervous system.

Table 1. Examples of Antihyperalgesic and Antiallodynic Effects of Gabapentin after Peripheral Tissue Injury

Table 1. Examples of Antihyperalgesic and Antiallodynic Effects of Gabapentin after Peripheral Tissue Injury
Table 1. Examples of Antihyperalgesic and Antiallodynic Effects of Gabapentin after Peripheral Tissue Injury

Of particular relevance to injury-induced neuroplasticity, evidence suggests that gabapentin selectively reduces pain transmission in a “sensitized” nervous system but not in a normal nervous system. For example, a recent in vitro  study has demonstrated that gabapentin affects N -methyl-d-aspartate-mediated currents in spinal neurons from rats with experimental arthritis but not from normal rats. 22,In vivo , gabapentin has no effect on pain behaviors during phase 1 of the rat formalin test (which is thought to reflect brief physiologic pain) but does appear to be analgesic during phase 2 of this test, at which time formalin-induced spinal sensitization is, in part, thought to be driving pain behavior. 23Similarly, two studies of human volunteers showed that gabapentin had no effect on pain transmission in normal skin but significantly reduced hyperalgesia following an experimental thermal injury 20or heat-capsaicin sensitization. 21This pattern of activity is of considerable value in that gabapentin may serve to reduce “pathologic” pain while leaving other protective nociceptive mechanisms intact.

In this issue's study by Dirks et al. , 6a single dose of gabapentin prior to mastectomy reduced postoperative morphine use and pain during movement. Trends for analgesia at rest failed to reach statistical significance. Although additional work in this area should include larger trials extending further into the postoperative period, these early findings suggest the possibility that gabapentin selectively reduces movement-evoked pain over spontaneous pain. If so, this would parallel similar findings with the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA)/kainate antagonist LY293558, another antihyperalgesic agent that has been shown to reduce move-ment-evoked, but not spontaneous, postoperative pain. 24Whether or not gabapentin proves to have any effect on pain at rest, this observed reduction of movement-evoked pain is of particular clinical interest. Recent evidence suggests that movement-evoked pain may contribute to postoperative physiologic impairment, 25and numerous postoperative studies demonstrate that opioids, while effective for spontaneous pain, perform poorly for movement-evoked pain. 26Data from Dirks et al.  6support a favorable therapeutic profile in postoperative patients, suggesting that gabapentin may be a welcome addition to the anesthesiologist's pharmacopoeia of “coanalgesics” such as nonsteroidal antiinflammatory drugs and local anesthetics. However, before considering the routine use of gabapentin in postoperative pain, future studies are needed to (1) replicate the findings of Dirks et al.  6, (2) evaluate the safety and efficacy of postoperative multidose gabapentin administration, and (3) determine the optimal duration of use and dose of gabapentin in postoperative pain.

References

1.
Bryans JS, Wustrow DJ: 3-Substituted GABA analogs with central nervous system activity: A review. Med Res Rev 1999; 19: 149–77
2.
Gabapentin in partial epilepsy. UK Gabapentin Study Group. Lancet 1990; 335: 1114–7
NA
3.
Mellick GA, Mellicy LB, Mellick LB: Gabapentin in the management of reflex sympathetic dystrophy. J Pain Symptom Manage 1995; 10: 265–6
4.
Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA 1998; 280: 1831–6
5.
Rowbotham MC, Petersen KL: Anticonvulsants and local anesthetic drugs, Bonica's Management of Pain, 3rd edition. Edited by Loeser JD, Turk D, Chapman CR, Butler S. Baltimore, Williams & Wilkins, 2001, pp 1727–35
6.
Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB: A randomized study of the effects of single-dose gabapentin versus  placebo on postoperative pain and morphine consumption after mastectomy. A nesthesiology 2002; 97: 560–4
7.
Hill CM, Balkenohl M, Thomas DW, Walker R, Mathe H, Murray G: Pregabalin in patients with postoperative dental pain. Eur J Pain 2001; 5: 119–24
8.
Woolf CJ, Chong MS: Preemptive analgesia: Treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77: 362–79
9.
IASP Task Force on Taxonomy: Classification of Chronic Pain, 2nd edition. Edited by Merskey H, Bogduk N. Seattle, IASP Press, 1994, pp 209–14
10.
Field MJ, Hughes J, Singh L: Further evidence for the role of the alpha(2)delta subunit of voltage dependent calcium channels in models of neuropathic pain. Br J Pharmacol 2000; 131: 282–6
11.
Shimoyama M, Shimoyama N, Hori Y: Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn. Pain 2000; 85: 405–14
12.
Partridge BJ, Chaplan SR, Sakamoto E, Yaksh TL: Characterization of the effects of gabapentin and 3-isobutyl-gamma-aminobutyric acid on substance P-induced thermal hyperalgesia. A nesthesiology 1998; 88: 196–205
13.
Bertrand S, Ng GY, Purisai MG, Wolfe SE, Severidt MW, Nouel D, Robitaille R, Low MJ, O'Neill GP, Metters K, Lacaille JC, Chronwall BM, Morris SJ: The anticonvulsant, antihyperalgesic agent gabapentin is an agonist at brain gamma-aminobutyric acid type B receptors negatively coupled to voltage-dependent calcium channels. J Pharmacol Exp Ther 2001; 298: 15–24
14.
Carlton SM, Zhou S: Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin. Pain 1998; 76: 201–7
15.
Sutton KG, Martin DJ, Pinnock RD, Lee K, Scott RH: Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones. Br J Pharmacol 2002; 135: 257–65
16.
Singh L, Field MJ, Ferris P, Hunter JC, Oles RJ, Williams RG, Woodruff GN: The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed by D-serine. Psychopharmacology 1996; 127: 1–9
17.
Field MJ, Holloman EF, McCleary S, Hughes J, Singh L: Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain. J Pharmacol Exp Ther 1997; 282: 1242–6
18.
Jun JH, Yaksh TL: The effect of intrathecal gabapentin and 3-isobutyl gamma-aminobutyric acid on the hyperalgesia observed after thermal injury in the rat. Anesth Analg 1998; 86: 348–54
19.
Cheng JK, Pan HL, Eisenach JC: Antiallodynic effect of intrathecal gabapentin and its interaction with clonidine in a rat model of postoperative pain. A nesthesiology 2000; 92: 1126–31
20.
Werner MU, Perkins FM, Holte K, Pedersen JL, Kehlet H: Effects of gabapentin in acute inflammatory pain in humans. Reg Anesth Pain Med 2001; 26: 322–8
21.
Dirks J, Petersen KL, Rowbotham MC, Dahl JB: Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. A nesthesiology 2002; 97: 102–7
22.
Gu Y, Huang LY: Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent. Pain 2001; 93: 85–92
23.
Kaneko M, Mestre C, Sanchez EH, Hammond DL: Intrathecally administered gabapentin inhibits formalin-evoked nociception and the expression of Fos-like immunoreactivity in the spinal cord of the rat. J Pharmacol Exp Ther 2000; 292: 743–51
24.
Gilron I, Max MB, Lee G, Booher SL, Sang CN, Chappell AS, Dionne RA: Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain. Clin Pharmacol Ther 2000; 68: 320–7
25.
Gilron I, Tod D, Bell A, Orr B: Effects of evoked vs. spontaneous pain on postoperative lung function (abstract). Can J Anaesth 2002; 49: A18
26.
Tverskoy M, Oren M, Dahkovsky I, Kissin I: Alfentanil dose-res-ponse relationships for relief of postoperative pain. Anesth Analg 1996; 83: 387–93