ArticlesGabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial
Introduction
Most women going through the menopause experience hot flashes, a symptom complex that includes a collection of vasomotor symptoms such as a sudden feeling of warmth and redness that begins in the chest and spreads to the neck and the face, accompanied by sweating, palpitations, and anxiety.1 Hot flashes are also among the most commonly reported symptoms in women receiving systemic therapy for breast cancer, adversely affecting quality of life.2
The pathophysiology of hot flashes is not entirely clear, but a working model has emerged, which hypothesises that physiological concentrations of oestrogen and progesterone maintain the concentrations of endorphin in the hypothalamus. At menopause, endorphin concentrations decrease with falling oestrogen concentrations, with the resulting release of the noradrenergic activity from its usual tonic inhibition, which culminates in increased hypothalamic release of norepinephrine and serotonin and leads to a lowering of the set point in the thermoregulatory nucleus. This process allows inappropriate heat-loss mechanisms to be triggered by subtle changes in core body temperature.3, 4, 5, 6, 7, 8
Treatment with oestrogen and progestagen can ameliorate these symptoms, but there is controversy about their use in women with breast cancer.9, 10, 11, 12 A trial of hormone replacement therapy in women with breast cancer was terminated early because of the finding that the treatment increased the risk of recurrence.13
Various non-hormonal agents have been tested. Clonidine, a centrally acting α-adrenergic agonist, was effective in a controlled trial with a transdermal patch14 and in a double-blind placebo-controlled trial given orally in women with breast cancer.15 Newer antidepressants, such as selective serotonin-reuptake inhibitors and inhibitors of serotonin and norepinephrine reuptake, are promising non-hormonal treatments for hot flashes. Randomised placebo-controlled trials have shown that venlafaxine,16 fluoxetine,17 and paroxetine18 are effective in control of hot flashes. Gabapentin is a GABA analogue used in the treatment of epilepsy, neurogenic pain, restless-leg syndrome, essential tremor, bipolar disorder, and migraine prophylaxis; it was first reported for its effects on hot flashes in five women and one man.19 A randomised double-blind, placebo-controlled trial has shown that gabapentin is effective in control of menopausal hot flashes,20 and a pilot study showed that it had promising effects in women with breast cancer.21
On the basis of these observations, we undertook a double-blind, placebo-controlled trial of gabapentin to assess its efficacy in the treatment of hot flashes in women with breast cancer. The most commonly used dose of gabapentin is 900 mg per day. However, we decided to study a lower dose (300 mg per day) also; if this dose could control hot flashes, the patients would benefit overall. The 8-week study duration was selected on the basis of our previous study of clonidine,15 to provide internal consistency.
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Patients
The patients were participants in a multicentre clinical trial at 18 geographically diverse member sites of the University of Rochester Community Clinical Oncology Program. Women aged 18 years or older who had breast cancer and were having an average of two or more hot flashes per day were eligible to take part in the study. Acceptable non-steroidal contraceptive measures were required. Patients currently receiving chemotherapy were not eligible, although endocrine therapies were allowed. Most
Results
Between June, 2001, and July, 2003, 420 women with breast cancer were enrolled and randomly assigned placebo, gabapentin 300 mg/day, or gabapentin 900 mg/day by mouth in three divided doses, for 8 weeks (figure 1). The mean age of the participants was 55 years, and most were married (75%) and white (95%). Demographic, clinical, and hot-flash characteristics at baseline are given in Table 1. The baseline hot-flash frequency ranged from 2 to 54 and the severity score from 2 to 191. Evaluable data
Discussion
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
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