Which medications work best for menorrhagia?
EVIDENCE-BASED ANSWER:
Four medications have been shown to reduce menstrual blood loss (MBL) significantly in placebo-controlled randomized controlled trials (RCTs): the levonorgestrel-releasing intrauterine system (LNG-IUS), tranexamic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), and danazol, a synthetic steroid (strength of recommendation: A, meta-analyses of RCTs).
A single trial showed that the LNG-IUS reduced MBL by about 100 mL, compared with placebo. In a meta-analysis of 4 placebo-controlled RCTs, tranexamic acid reduced MBL by about 53 mL, roughly a 40% to 50% decrease. The 8 NSAID trials (5 mefenamic acid, 2 naproxen, 1 ibuprofen) demonstrated effectiveness, but the effect size is difficult to quantify. The single danazol RCT used a subjective scoring system without reporting MBL.
No studies compared all effective medical therapies against one another. In head-to-head comparisons, women were more likely to experience improvement with the LNG-IUS than with tranexamic acid (number needed to treat [NNT] = 2 to 6). Both treatments are superior to NSAIDs. Danazol is also more efficacious than NSAIDs, but its use is limited by its adverse effects, including teratogenicity.
No placebo-controlled trials have studied oral contraceptive pills (OCPs) or oral progesterone to treat menorrhagia. However, multiple comparative RCTs have demonstrated that these commonly prescribed medications significantly decrease MBL. Trials have shown the reduction to be inferior to LNG-IUS and danazol and equivalent to NSAIDs.
Danazol linked to weight gain and other adverse effects
A 2010 Cochrane review evaluated 9 RCTs, including 1 (66 patients) comparing danazol 200 mg with placebo that showed a significant decrease in subjectively assessed MBL in the danazol group.6 The study, which only 22 women finished, didn’t address intention-to-treat and used an unidentified scoring system. Patients also reported a significant 6.7-kg weight gain (95% CI, 1-12.4) after 3 months of treatment.
In addition to the 2013 meta-analysis showing danazol to be superior to NSAIDs, several studies6 compared danazol favorably with oral progesterone, although not all results reached significance. One study (37 patients) showed that women were more likely to rate the efficacy of danazol as moderate or high compared with progesterone (OR = 4.3; 95% CI, 1.1-17.0), but the mean difference in MBL (–36 mL; 95% CI, −102 to 31 mL) wasn’t statistically significant.
Of note, both a meta-analysis of 4 of the studies (117 patients) and another study comparing danazol with NSAIDs (20 patients) found significantly more adverse effects in the danazol group. Commonly reported adverse effects were acne, weight gain, headache, nausea, and tiredness.
RECOMMENDATIONS
A comparative effectiveness review by the Agency for Healthcare Research and Quality concluded that evidence showed efficacy for 4 primary care interventions for heavy cyclic bleeding: LNG-IUS, NSAIDs, tranexamic acid, and combination OCPs.7
The United Kingdom’s National Institute for Health Care and Excellence (NICE) recommends pharmaceutical treatment when no structural or histologic abnormality is present or when fibroids are < 3 cm in diameter.8 NICE advises considering pharmaceutical treatments in the following order: first, LNG-IUS if long-term use (at least 12 months) is anticipated; second, tranexamic acid or NSAIDs; and third, combination OCPs, norethisterone (15 mg) daily from Days 5 to 26 of the menstrual cycle, or injected long-acting progestogen.
Editor’s takeaway
I was taught to use combination OCPs as first-line treatment for menorrhagia, but better evidence supports using any of these 4: LNG-IUS, tranexamic acid, danazol, or NSAIDs. In the absence of clear evidence demonstrating differences in efficacy, I would use them in the reverse order for cost-effectiveness reasons.
