Efficacy of Continuous Transdermal Nitroglycerin for Treating Hot Flashes by Inducing Nitrate Cross-tolerance in Perimenopausal and Postmenopausal Women

Abstract

ImportanceDue to the potential risks of long-term systemic estrogen therapy, many menopausal women are interested in nonhormonal treatments for vasomotor symptoms. Physiologic studies indicate that nitric oxide plays a key role in mediating hot flash–related vasodilation, suggesting that nonhormonal medications that induce nitrate tolerance in the vasculature may offer therapeutic benefit for vasomotor symptoms.ObjectiveTo determine whether uninterrupted administration of transdermal nitroglycerin (NTG) to induce nitrate cross-tolerance decreased the frequency or severity of menopause-related hot flashes.Design, Setting, and ParticipantsThis randomized, double-blinded, placebo-controlled clinical trial included perimenopausal or postmenopausal women reporting 7 or more hot flashes per day who were recruited from northern California by study personnel at a single academic center. Patients were randomized between July 2017 and December 2021, and the trial ended in April 2022 when the last randomized participant completed follow-up.InterventionsUninterrupted daily use of transdermal NTG (participant-directed dose titration from 0.2-0.6 mg/h) or identical placebo patches.Main Outcome MeasuresValidated symptom diaries assessing changes in any hot flash frequency (primary outcome) and moderate-to-severe hot flash frequency over 5 and 12 weeks.ResultsAmong the 141 randomized participants (70 NTG [49.6%], 71 placebo [50.4%]; 12 [85.8%] Asian, 16 [11.3%] Black or African American, 15 [10.6%] Hispanic or Latina, 3 [2.1%] multiracial, 1 [0.7%] Native Hawaiian or Pacific Islander, and 100 [70.9%] White or Caucasian individuals), a mean (SD) of 10.8 (3.5) hot flashes and 8.4 (3.6) moderate-to-severe hot flashes daily was reported at baseline. Sixty-five participants assigned to NTG (92.9%) and 69 assigned to placebo (97.2%) completed 12-week follow-up (P = .27). Over 5 weeks, the estimated change in any hot flash frequency associated with NTG vs placebo was −0.9 (95% CI, −2.1 to 0.3) episodes per day (P = .10), and change in moderate-to-severe hot flash frequency with NTG vs placebo was −1.1 (95% CI, −2.2 to 0) episodes per day (P = .05). At 12 weeks, treatment with NTG did not significantly decrease the frequency of any hot flashes (−0.1 episodes per day; 95% CI, −1.2 to 0.4) or moderate-to-severe hot flashes (−0.5 episodes per day; 95% CI, −1.6 to 0.7) relative to placebo. In analyses combining 5-week and 12-week data, no significant differences in change in the frequency of any hot flashes (−0.5 episodes per day; 95% CI, −1.6 to 0.6; P = .25) or moderate-to-severe hot flashes (−0.8 episodes per day; 95% CI, −1.9 to 0.2; P = .12) were detected with NTG vs placebo. At 1 week, 47 NTG (67.1%) and 4 placebo participants (5.6%) reported headache (P < .001), but only 1 participant in each group reported headache at 12 weeks.Conclusions and RelevanceThis randomized clinical trial found that continuous use of NTG did not result in sustained improvements in hot flash frequency or severity relative to placebo and was associated with more early but not persistent headache.Trial RegistrationClinicaltrials.gov Identifier: NCT02714205