Nitroglycerin Patches Flop for Cooling Hot Flashes

Apr 15, 2023

by Kristen Monaco, Senior Staff Writer, MedPage Today June 5, 2023

Continuous transdermal nitroglycerin did not lead to sustained improvements in hot flashes for perimenopausal and postmenopausal women, the randomized FRAN trial showed.

Over 5 weeks, the estimated change in any hot flash frequency associated with uninterrupted daily use of transdermal nitroglycerin versus placebo was -0.9 (95% CI -2.1 to 0.3) episodes per day (P=0.10), reported Alison Huang, MD, MAS, of the University of California San Francisco, and colleagues.

Of note, when looking just at moderate-to-severe hot flashes, women on nitroglycerin did see 1.1 fewer (95% CI -2.2 to 0) daily episodes compared with placebo (P=0.05), they noted in JAMA Internal Medicine.

However, these benefits were short-lived. By week 12 of the trial, there were no statistically significant differences in the frequency of any hot flashes (-0.1 daily episodes, 95% CI -1.2 to 0.4) or moderate-to-severe hot flashes (-0.5 daily episodes, 95% CI -1.6 to 0.7) compared with placebo.

"We were intrigued to see that the frequency of moderate-to-severe hot flashes decreased substantially in the continuous nitroglycerin group relative to the placebo group in the first 4 to 5 weeks, but we were sorry to see that this between-group difference was no longer significant by 12 weeks," Huang told MedPage Today. "It was a little surprising that the effects of this treatment approach weren't consistent across all time frames."

"We don't have a good explanation for why the greater benefits of continuous transdermal nitroglycerin for hot flashes would be expected to 'wear off' after a few months, for example," she added. "And because the potential early benefits at 5 weeks weren't sustained at 12 weeks, we can't conclude that this treatment approach is effective for moderate-to-severe hot flashes."

Furthermore, transdermal nitroglycerin was associated with side effects -- 67.1% of women on treatment experienced headache during the first week compared with only 5.6% of placebo patients. However, headache dwindled by the end of the trial, with only one participant in each group reporting headache by week 12. A handful of patients on nitroglycerin also reported chest pain and resting blood pressure abnormalities.

By the end of the 12-week trial, there was no significant difference in menopausal quality-of-life vasomotor score or hot flash-related daily interference scale score between groups.

"We don't have another trial in the immediate works that's testing a nonhormonal hot flash treatment," said Huang, "but personally I would be interested to see other researchers explore treatment approaches that focus on peripheral vasodilation mechanisms underlying the direct, physical manifestations of hot flashes, because almost all of our existing nonhormonal treatment approaches are directed at central nervous system [CNS] mechanisms that we think help to trigger hot flashes in the first place."

"Some of these may offer promise, but CNS-directed treatments also run the risk of causing central side effects," she added.

Few nonhormonal hot flash treatments exist on the market today, despite an estimated 80% of menopausal women experiencing them.

The first-in-class oral neurokinin 3 receptor antagonist fezolinetant (Veozah) gained FDA approval for moderate-to-severe hot flashes in May. The only other approved nonhormonal treatment option is the antidepressant paroxetine (Brisdelle). Other hot flash therapies include herbal remedies and drugs used off-label, like gabapentin, clonidine, and other selective serotonin reuptake inhibitors.

"When women have a hot flash, the flushing sensation that they experience is caused by dilation of blood vessels under the skin of the head, neck, and chest," Huang explained. "Previous studies have indicated that this phenomenon is mediated by nitric oxide-specific vasodilation mechanisms, which suggests that if we can suppress or decrease nitric oxide-related vasodilation, we can suppress the physical manifestations of the hot flash."

When used for only a few hours at a time, nitroglycerin triggers nitric oxide-related vasodilation, but when used continuously without interruption, patients can develop a tolerance to the vasodilating effects of both the nitroglycerin and the body's own endogenous nitrates. This is called "nitrate tolerance," said Huang.

"When we want to use nitroglycerin as a vasodilator, this phenomenon of nitrate tolerance is a problem or obstacle," she noted. "But if we're trying to decrease vasodilation -- such as hot flash vasodilation -- it may be in our interest to induce nitrate tolerance by having patients use nitroglycerin continuously; for example, by continuously using transdermal nitroglycerin patches that provide controlled release of nitroglycerin through the skin."

For the double-blinded FRAN (Flushing Reduction Associated with Nitrates) study, 141 women ages 40 to 62 were recruited from a single academic center in the San Francisco Bay area. All participants were late in the menopausal transition or postmenopausal and experiencing at least seven hot flashes per day.

Seventy patients (mean age 55.3, 71.4% white) were randomized to receive self-administered daily transdermal nitroglycerin patches that released continuous and sustained treatment starting at a 0.2-mg/h patch strength and were titrated to a maximum of 0.6 mg/h, while 71 control patients (mean age 53.9, 70.4% white) wore placebo patches.

Hot flashes were recorded throughout the trial by participants using a 7-day symptom dairy, where they noted the frequency and severity of flashes. At baseline, women experienced an average of 11 hot flashes per day; 8-9 were graded as moderate-to-severe.

Kristen Monaco is a senior staff writer, focusing on endocrinology, psychiatry, and nephrology news. Based out of the New York City office, she's worked at the company since 2015.

Disclosures

The trial was supported by National Institute on Aging grants.

Huang and co-authors reported grants from the National Institute on Aging and the National Institutes of Health and relationships with SomaLogic and Astellas Pharma.

Primary Source

JAMA Internal Medicine

Source Reference: Huang AJ, et al "Efficacy of continuous transdermal nitroglycerin for treating hot flashes by inducing nitrate cross-tolerance in perimenopausal and postmenopausal women" JAMA Intern Med 2023; DOI: 10.1001/jamainternmed.2023.1977.