The results of this randomised, double-blind placebo-controlled trial accord with those of our pilot study of menopausal women;21
there was a 46% reduction in the hot-flash severity score with gabapentin 900 mg/day, compared with a 54% reduction versus placebo reported in postmenopausal women treated with gabapentin 900 mg/day for 12 weeks.20
We analysed our data in two different ways, and in each approach we observed a significant effect on hot flashes with gabapentin 900 mg/day, whereas gabapentin 300 mg/day was no better than placebo for any comparison. An even higher dose of gabapentin might be more effective. Evidence in support of that idea comes from the study by Guttuso and colleagues,20
in which an open-label dose escalation was allowed after the 12-week study period. 75% of patients who elected to continue requested an increase of their dose beyond 900 mg/day (maximum allowable dose 2700 mg/day); among these patients there was a 67% reduction in the hot-flash severity score, which suggests a strong dose effect in the control of hot flashes.
Short-term (<4 weeks) side-effects were not assessed in this study, because the first symptom inventory was obtained during week 4 of the study. We examined the reasons given for withdrawing from the study owing to side-effects and found that somnolence or fatigue was given as the reason by one, three, and six patients in the placebo, gabapentin 300 mg, and gabapentin 900 mg groups, respectively; the overall numbers withdrawing because of side-effects were six, six, and ten. The opposite pattern was noted in patients who withdrew because the study treatment was not helpful (seven, five, and two patients in the placebo, gabapentin 300 mg, and gabapentin 900 mg groups, respectively). Thus, although a slightly higher proportion of women withdrew owing to side-effects from gabapentin 900 mg/day, a very small proportion withdrew because the treatment was not helpful. The opposite was true for placebo, and gabapentin 300 mg/day was intermediate, which accords with our overall results.
We found a 46% reduction in hot flashes with gabapentin 900 mg. Previous studies have found reductions of 37% with clonidine in a placebo-controlled double-blind trial;15
61% with venlafaxine at 75 mg or 150 mg;16
62.2% and 64.6% with controlled-release paroxetine at 12.5 mg and 25.0 mg/day, respectively;18
and 50% with fluoxetine.17
Gabapentin 900 mg/day provides similar control of hot flashes in women with breast cancer. The side-effect profiles of these drugs differ. Oral clonidine was associated with sleeping difficulty,15
and transdermal clonidine was associated with dryness of mouth, constipation, drowsiness, and pruritus at the site of the patch.14
Side-effects of venlafaxine included dryness of mouth, decreased appetite, nausea, and constipation,16
and the most common side-effects of controlled-release paroxetine were headache, nausea, and insomnia.18
Without a randomised trial directly comparing not only the effect on hot flashes but also the side-effects of each of these drugs, the optimum non-hormonal drug for alleviation of hot flashes remains to be identified.
The selective serotonin-reuptake inhibitors are regarded as the most promising non-hormonal treatment for hot flashes in women with breast cancer, but a study by Stearns and colleagues has raised concern about the possible interaction between these agents and tamoxifen, a selective oestrogen-receptor modulator, because selective serotonin-reuptake inhibitors inhibit the cytochrome P450 enzymes that are important in converting tamoxifen to its active metabolites.24
Stearns and colleagues found that coadministration of paroxetine with tamoxifen decreased the plasma concentration of endoxifen, an active metabolite of tamoxifen, which is generated by N-demethylation mediated by cytochrome P450 3A4 and hydroxylation mediated by cytochrome P450 2D6 (CYP2D6), which suggests that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen. A subsequent study25
found that paroxetine was the most potent inhibitor of CYP2D6, followed by fluoxetine, sertraline, and citalopram. Venlafaxine was the least potent inhibitor of CYP2D6.25
Gabapentin is not metabolised in human beings and is excreted unchanged, mainly in the urine. Concurrent administration of gabapentin has been studied extensively with respect to its interaction with other antiseizure drugs, and it does not affect plasma concentrations of phenytoin, carbamazepine, phenobarbital, or valproate, all of which are affected by the cytochrome P450 system.26
Therefore, even though gabapentin has not been specifically studied in terms of its interaction with tamoxifen, the assumption that no such interaction is to be expected is reasonable.
The mechanism of action of gabapentin remains unknown. A 37-year-old patient with known hypothalamic dysfunction who took gabapentin for 6 months for control of his seizure disorder had an increase in the frequency of hypothermic episodes of 100 times. The frequency of these episodes returned to baseline once gabapentin was discontinued.19
Gabapentin inhibits neuronal calcium currents in vitro,27
and its binding site is known to be on the α2
δ subunit of voltage-gated calcium channels.28
This binding site was upregulated by 17 times selectively in rat dorsal root ganglion in response to peripheral-nerve injury.28
This process could be one of the mechanisms of action of gabapentin in the treatment of neuropathic pain.29
We speculate that similar upregulation of the gabapentin binding site could be involved in the hypothalamus as a result of oestrogen withdrawal, leading to increased activity of the neurotransmitters in the hypothalamus. Gabapentin might exert its effect on hot flashes by this mechanism.
Our study was designed to test the intervention for 8 weeks; therefore, we cannot comment on long-term use of gabapentin. However, gabapentin is used for long durations for various other symptoms and certainly could be considered for hot flashes also. We did not obtain data on immediate side-effects of gabapentin, but we did examine the reasons for withdrawing from the study. We might have underestimated the adverse effects of gabapentin, and the withdrawal rate of 12% at 4 weeks and 17% at 8 weeks might be due entirely to the side-effects of the treatment. However, the withdrawal rate was much the same in all three study groups and thus cannot be attributed to side-effects of gabapentin. We cannot think of any systematic bias that can explain these results, and we believe that random errors have been kept to a minimum by means of the randomised, double-blind, placebo-controlled design.
We believe gabapentin can be added to the list of non-hormonal agents for the control of hot flashes in women with breast cancer, and the effects of doses higher than 900 mg/day merit further study.