Hormone replacement treatment

• CKS does not recommend the use of hormone replacement treatment (HRT) in women with breast cancer who are taking tamoxifen, because oestrogen is known to increase the risk of developing breast cancer, and there is a theoretical increased risk of recurrence.
• The use of hormonal treatments for the control of hot flushes is controversial in this group, and women with a history of breast cancer are generally encouraged not to use HRT [Bertelli et al, 2002; Duffy and Cyr, 2003; Bordeleau et al, 2007].

Clonidine

• Clonidine is licensed for the treatment of vasomotor symptoms. A systematic review found limited evidence for the efficacy of oral and transdermal clonidine for hot flushes.
• The recommendation regarding dose and titration is based on the manufacturer's information and the British National Formulary [BNF 56, 2008].

Venlafaxine

• Evidence from a systematic review [Nelson et al, 2006] and subsequent randomized controlled trial [Carpenter et al, 2007] suggests that venlafaxine can reduce hot flushes.
• When effective, antidepressants provide relief from hot flushes almost immediately. A 1-week trial is generally sufficient to determine whether an antidepressant is going to be effective [ICSI, 2008].
• The manufacturer of venlafaxine does not recommend a dose for hot flushes as it is not licensed for this purpose. CKS has therefore based its advice on dosages found to be effective for hot flushes in short-term studies.
• Venlafaxine (compared to SSRIs) is only a weak inhibitor of the cytochrome P450 2D6 enzyme (which is involved in the breakdown of tamoxifen to its active metabolite, endoxifen) [Boekhout et al, 2006].

Gabapentin

• Gabapentin is not licensed for the treatment of vasomotor symptoms, but CKS found evidence from two randomized controlled trials that suggested it is effective for reducing the frequency and severity of hot flushes [Guttuso et al, 2003; Pandya et al, 2005].
• Gabapentin has been less studied for hot flushes than selective serotonin reuptake inhibitors (SSRIs) or serotonin/norepinephrine reuptake inhibitors (SNRIs); current evidence suggests that it may be at least as effective, although head-to-head studies are lacking. It appears to be better tolerated than SNRIs for this indication, although adverse effects are relatively common, and it does not have withdrawal effects. It may be of particular use if sexual dysfunction is a problem or develops on SNRI treatment [Hickey et al, 2008].

Duration of treatment

• CKS found no evidence as to how long to prescribe these drugs. Opinion from expert reviewers suggested that:
• Treatment should be for the shortest duration possible.
• As efficacy is not established beyond 3 months, the need for treatment should be reassessed periodically (for example every 3–6 months), but could be continued while the woman is taking tamoxifen if adverse effects are not a problem.

Drugs not recommended

• Options which are not recommended by CKS for primary care use (some of which may be considered in secondary care for symptomatic treatment of hot flushes) include progestogens and SSRIs.
• Progestogens: there is good evidence that both low-dose megestrol acetate and depot intramuscular medroxyprogesterone acetate can reduce the frequency of hot flushes in post-menopausal women with breast cancer [SIGN, 2005]. However, CKS does not recommend these for primary care use because their effects on breast cancer are uncertain [Shapiro and Recht, 2001]. Some studies discussed concerns that the increased risk of breast cancer with HRT is due to the combination of oestrogen and progestogen (rather than oestrogen alone) [RCOG, 2006].
• SSRIs (including paroxetine, fluoxetine, and citalopram) have been extensively tested for menopausal hot flushes in women who have had breast cancer, and results suggest that they are more effective than placebo in short-term studies. They appear to be less effective compared with oestrogen, although there are currently no published head-to-head studies [Hickey et al, 2008].
• SSRIs may reduce the breakdown of tamoxifen to its active metabolite by inhibiting the cytochrome P450 2D6 enzyme [Hickey et al, 2008]. Plasma concentrations of endoxifen (the active metabolite of tamoxifen) were lower in women treated with paroxetine in combination with tamoxifen, compared with tamoxifen alone [Stearns et al, 2003; Boekhout et al, 2006]. In a trial of 80 women with newly-diagnosed breast cancer using tamoxifen, the plasma endoxifen concentration was reduced substantially in women taking paroxetine, but only slightly reduced in women taking venlafaxine (an SNRI) [Jin et al, 2005].
• Adverse effects (particularly nausea, but also headache, decreased appetite, gastrointestinal disturbance, dry mouth, anxiety or agitation, sleep disturbance, and sexual dysfunction) cause 10–20% of people to withdraw from treatment, but are less likely at low doses [RCOG, 2006; Hickey et al, 2008].
• Very few data are available about the safety of SSRIs in breast cancer [Antoine et al, 2007].