Gabapentin for Neuropathic Pain
abstracts & commentary
Sources: Backonja M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA 1998;280: 1831-1836; Rowbotham M, et al. Gabapentin for the treatment of postherpetic neuralgia: A randomized controlled trial. JAMA 1998;280:1837-1842.
One hundred sixty-five diabetic patients with diabetic polyneuropathy were enrolled in this randomized, multicenter, double-blind, placebo-controlled, eight-week trial of gabapentin to determine its safety and efficacy. Pain had to have been present for 1-5 years, be ascribed to diabetic neuropathy, and rate at least 40/100 on the visual-analog scale (VAS) of the Short-Form McGill Pain Questionnaire (SF-MPQ). Exclusionary criteria included other severe pain, treatment with investigational drugs within the previous 30 days, amputations other than toes, and impaired renal function. Use of analgesic agents, other than aspirin or Tylenol, was prohibited for 30 days before and during the trial, including tricyclic antidepressants, anticonvulsants, nonsteroidal anti-inflammatory agents, dextromethorphan, capsaicin, opioids, muscle relaxants, and benzodiazepines. Following a seven-day screening, placebo (n = 81) or gabapentin 300 mg/capsule (n = 84) was titrated upward to tolerability or 3600 mg/d during the initial four weeks followed by four weeks of fixed-dose therapy. Pain severity rating, using the 11-point Likert scale (0 = no pain, 10 = worst possible pain) was the primary end point measurement. Secondary end points included SF-MPQ scores, patient global impression of change, clinician’s global impression of change, and weekly sleep scores (ranging from 0 = no problem to 10 = unable to sleep due to pain). Statistical analysis included the intent-to-treat population; all testing was two-sided at the 0.05 a level.
Gabapentin was significantly better than placebo for mean pain score, sleep score, pain questionnaires, and quality of life. Seven gabapentin patients withdrew due to side effects—most frequently dizziness or somnolence (n = 2, each), nausea, diarrhea, headache, or confusion (n = 1, each), as compared to five placebo withdrawals, and most side effects were of mild-to-moderate intensity. Gabapentin is safe and efficacious for the treatment of painful diabetic polyneuropathy.
In a similarly designed eight-week trial, 229 patients with intractable pain due to postherpetic neuralgia (PHN) were randomized to receive either placebo (n = 116) or gabapentin (n = 113), up to 3600 mg/d. Inclusion criteria included at least three months of pain following healing of the rash, measuring 40/100 on the VAS of the SF-MPQ, and daily pain of at least 4 on a 10-point scale. Other significant pain, prior treatment or allergy to gabapentin, neurosurgical therapy for PHN, hepatic, renal, or hematological disease, or unstable medical or psychiatric disease excluded participation. Dosage began at 300 mg/d and was increased to maximal tolerable dose or 3600 mg, whichever came first. Change in average daily pain was the primary end point. Secondary end points included change in average daily sleep rating score and SF-MPQ total affective and sensory subscores. Analysis of covariance and the Cochran-Mantel-Haenszel test were used to measure pain intensity at the last visit.
Over the eight weeks, average daily pain score significantly declined in the gabapentin group (by 33%) as compared to placebo (7.7% reduction). Average daily sleep rating score and total affective and sensory subscores significantly improved. Quality of life also favored gabapentin. More than 80% of patients (n = 184) completed the study, with 15% dropping out due to adverse events, most often dizziness and somnolence, with ataxia, edema, and infection also occurring more frequently with gabapentin. Gabapentin is safe and efficacious for the treatment of PHN.
Commentary
At the cellular level, the pharmacologic mechanism of gabapentin remains unclear and may be different for its anticonvulsant and analgesic effects.1 As an amino acid that easily crosses membrane barriers, gabapentin is able to penetrate and accumulate in the brain cytosol in concentrations that greatly exceed, by 10-fold, those of the surrounding extracellular space.2 Although its antiepileptic action is delayed following bolus intravenous injection in rats,2 its analgesic action is rapid, suggesting a different mechanism of action for its analgesic and anticonvulsant activity.3
Although there is ample evidence that gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter, gabapentin does not interfere with binding at GABAA or GABAB receptors. It neither inhibits GABA uptake in neuronal or glial cultures, nor neuronal responses to GABA application in cultured rodent neurons.4,5 Rather, as distinct from benzodiazepines and barbiturates that modulate GABAA receptors, gabapentin appears to enhance GABA synthesis from glutamate by increasing the activity of glutamic acid decarboxylase (GAD), and the resultant brain GABA elevation may be operative in seizure control.6 Additionally, gabapentin appears to bind to a novel, membrane-associated protein in the outer layers of the cerebral cortex, so-called gabapentin binding protein (GBP), which demonstrates an N-terminal sequence identical to the a2d subunit of the voltage-dependent, skeletal muscle, calcium channel. As a consequence of this interaction, monoamine neurotransmitter release, including noradrenaline, dopamine, and serotonin, may be inhibited as may total cellular calcium current. Though unlikely to be related to its anticonvulsant effect, this mechanism may underlie the analgesic effects of gabapentin.
Furthermore, gabapentin blocks thermal and mechanical hyperalgesia when administered intrathecally and, thus, may also operate at the spinal cord level, possibly by altering N-methyl-D-aspartate (NMDA) responses.7 It does not, however, activate opiate receptors, nor is there cross tolerance between gabapentin and morphine.3 Gabapentin, thus, appears to interact with a subunit of the voltage gated calcium channel, and modulates brain glutamate, glutamine, and GABA. What is precisely responsible for analgesia and what underlies seizure control remains to be defined.
References
1. Taylor CP, et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998; 29:233-249.
2. Welty D, et al. Gabapentin anticonvulsant action in rats: Disequilibrium with peak drug concentration in plasma and brain microdialysate. Epilepsy Res 1993; 16:175-181.
3. Field MJ, et al. Gabapentin and isobutyl GABA represent a novel class of selective antihyperalgesic agents. Br J Pharmacol 1997;121:1513-1522.
4. Su T, et al. Transport of gabapentin by system L amino acid transporters. J Neurochem 1995;64: 2125-2131.
5. Rock DM, et al. Gabapentin actions on ligand and voltage gated responses in cultured rodent neurons. Epilepsy Res 1993;16:89-98.
6. Petroff OA, et al. The effect of gabapentin on brain GABA in patients with epilepsy. Ann Neurol 1996; 39:95-99.
7. Hwang JH, Yaksh TL. Effect of subarachnoid gabapentin on tactile evoked allodynia in a surgically induced neuropathic pain model in the rat. Reg Anesthesia 1997;22:249-256.
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