Gabapentin

Gabapentin, an analogue of the inhibitory neurotransmitter GABA (γ-aminobutyric acid), is an anticon-vulsant medication with recognised efficacy in the treatment of both epilepsy and neuropathic pain. It is frequently used in diabetes for the treatment of painful neuropathy. Figure 1 outlines the proposed pharmacological action of gabapentin which was initially synthesised to mimic the chemical structure of the inhibitory neurotransmitter GABA. Its exact mechanism of action is unknown, with no evidence that it binds directly to GABA receptors nor that it has any effect on the uptake or breakdown of GABA. However, in neuropathic pain the therapeutic effect is thought to be related to its affinity for the α2δ1 subunit on pre-synaptic voltage-gated N-type calcium ion channels in the central nervous system. Gabapentin binds to the α2δ1 sub-unit, inhibiting calcium influx leading to reduced neurotransmitter release and attenuation of post-synaptic activity. Other effects include activation of GABAB recep-tors, modulation of pre-synaptic NMDA (N-methyl-D-aspartic acid) receptors and reduced release of glutamate and other excitatory neurotransmitters. The proposed pharmacological action of gabapentin (see ‘Notes’ below the diagram). Gabapentin is renally excreted and dose reduction is required in those with a creatinine clearance of < 60 ml/min. Gabapentin was first licensed in 1994 as adjunctive therapy for the treat-ment of partial seizures. Since then, over 8.7 million patients have received gabapentin in clinical trials and every-day practice without any evidence of any serious organ toxicity. In a double-blind, randomised, placebo-controlled study conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain, 305 patients were randomised to receive either gabapentin or placebo over an eight-week period. Patients had a wide range of neuropathic pain syn-dromes and were recruited based on the presence of two or more of the following symptoms: allodynia, burn-ing pain, shooting pain, or hyperalge-sia. Gabapentin was given in three divided doses, initially titrated to 900 mg/day over three days, followed by two further increases, to a maxi-mum of 2400 mg/day if required.1 In the gabapentin group there was a mean reduction of average daily pain score of 21% compared to a 14% reduction in placebo treated patients (p = 0.048). Improvements were also shown in patient-reported outcomes in quality of life. Gabapentin was well tolerated and the majority of patients completed the study (79% vs 73% for placebo). The most common adverse events were mild to moderate dizzi-ness and somnolence, most of which were transient and occurred during the titration phase. Several studies have examined the analgesic effects of gabapentin in patients with painful diabetic periph-eral neuropathy. The largest of these was an eight-week randomised, dou-ble-blind, placebo-controlled study conducted in the United States. In all, 165 patients with a one- to five-year history of painful diabetic peripheral neuropathy and a mini-mum 40 mm pain score on the Short-Form McGill Pain question-naire (SF-MPQ) visual analogue scale (VAS) were randomised to treatment with either placebo or gabapentin. The gabapentin dose was increased over a four-week period from 900 mg to 3600 mg per day or the maximum tolerated dose.2 Baseline mean daily pain scores were 6.3 in the gabapentin group and 6.5 in the placebo group. After eight weeks of treatment, mean daily pain scores in the gabapentin group were significantly lower than those reported in the placebo group (3.9 vs 5.1, p < 0.001). Improvements were also seen in the secondary endpoints including measures of sleep interfer-ence, SF-MPQ (total pain, p < 0.01; present pain intensity, p < 0.05; mean pain VAS, p < 0.01), mood disturbance (p = 0.03), and SF-QOL (bodily pain, p = 0.01; mental health, p = 0.03; vitality, p = 0.001). There was no significant alteration in HbA1c with gabapentin therapy although there was a high frequency of side effects in the treat-ment group, mainly somnolence and dizziness. This may reflect the rela-tively high doses of gabapentin that were used (3600 mg/day). Amitriptyline remains one of the standard therapies for painful diabetic peripheral neuropathy. One small study directly compared the use of amitriptyline to gabapentin in 28 patients in a randomised, double-blind, double-dummy, crossover study. Two patients withdrew prior to ran-domisation and five withdrew during the study. Both drugs were found to provide pain relief and no significant differences were found between the two, as assessed by mean pain scores and global pain scores. Both drugs had similar rates of adverse effects.3 Despite proven efficacy as monother-apy, approximately 50% of patients fail to respond to gabapentin therapy and, in the 50% who do respond, a significant proportion of these are left with significant residual pain. Two studies have looked at combina-tion therapy with opiates. One looked at gabapentin versus or in combination with morphine in a randomised, active placebo-controlled, clinical cross-over study.4 Fifty-seven patients with neuropathic pain, including 35 with painful dia-betic neuropathy, were randomised to receive morphine, gabapentin, a combination of gabapentin and mor-phine, or active placebo (lorazepam). Combination therapy with gabapentin and morphine resulted in lower daily pain scores than in the groups treated with morphine (p = 0.04), gabapentin (p < 0.001), and placebo (p < 0.001). Combination therapy was also associ-ated with less pain-related interfer-ence with mood and with higher scores for vitality and social function-ing. Lower doses of both gabapentin and morphine were required in the combination therapy group suggest-ing a possible additive effect. At the maximum tolerated doses the combi-nation group had a higher frequency of constipation than in the gabapentin group (p < 0.05) and a higher frequency of dry mouth than in the morphine alone group (p < 0.05), but the combination was otherwise well tolerated. It is difficult to comment on sedation frequency as a sedative placebo was used. In a larger multi-centre placebo-controlled study, 338 patients with a three-month history of pain due to diabetic neuropathy, on a stable maximum tolerated dose of gabapentin and with moderate to severe residual pain, were ran-domised to treatment with long act-ing oxycodone (OxyContin) or placebo.5 Combination therapy with oxycodone and gabapentin was found to reduce mean daily pain scores by 33% from baseline (p = 0.007). Patients in the combina-tion therapy group also required less breakthrough medication (paracetamol) (p = 0.03), had fewer nights of disturbed sleep (p < 0.05) and had a much lower rate of discontinuation due to lack of therapeutic effect (14% vs 54%) than those treated with gabapentin alone. Opiate-induced adverse events were not exacerbated by the combination therapy. Gabapentin appears to have a role in the treatment of painful diabetic peripheral neuropathy by providing partial pain relief and also appears to have positive effects on sleep disturbance, mood and quality of life. Combination therapy with either mor-phine or long acting oxycodone appears to provide more effective anal-gesia than monotherapy alone. This most likely reflects the multiple mech-anisms resulting in neuropathic pain. The most efficacious dose of gabapentin therapy is not entirely clear, with study doses ranging from 600–3600 mg per day. Most studies have attempted to mimic clinical practice by allowing the maximum tolerated dose aiming to achieve maximum efficacy while minimising the occurrence of adverse effects. The evidence described above is generally limited by small study numbers, and further research is required into specific doses and over a longer time period. Dr MacEwan and Dr McKay have no conflict of interest. Dr Fisher has received lecture fees from and has advised on advisory panels for Pfizer. Gabapentin is an anticonvulsant that has been shown to reduce symptoms of neuropathic pain In diabetic patients, gabapentin reduced pain and other symptoms of neuropathy compared to placebo Better symptomatic relief seems to be obtained when gabapentin is used in combination with opiate analgesics

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