κ Agonists as a novel therapy for menopausal hot flashes

Abstract

Objective: The etiology of postmenopausal hot flashes is poorly understood, making it difficult to develop and target ideal therapies. A network of hypothalamic estrogen-sensitive neurons producing kisspeptin, neurokinin B and dynorphin-called KNDy neurons-are located adjacent to the thermoregulatory center. KNDy neurons regulate pulsatile secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Dynorphin may inhibit this system by binding κ opioid receptors within the vicinity of KNDy neurons. We hypothesize that hot flashes are reduced by KNDy neuron manipulation.

Methods: A double-blind, cross-over, placebo-controlled pilot study evaluated the effects of a κ agonist. Hot flash frequency was the primary outcome. Twelve healthy postmenopausal women with moderate to severe hot flashes (aged 48-60 y) were randomized. Eight women with sufficient baseline hot flashes for statistical analysis completed all three interventions: placebo, standard-dose pentazocine/naloxone (50/0.5 mg), or low-dose pentazocine/naloxone (25/0.25 mg). In an inpatient research setting, each participant received the three interventions, in randomized order, on three separate days. On each day, an intravenous catheter was inserted for LH blood sampling, and skin conductance and Holter monitors were placed. Subjective hot flash frequency and severity were recorded.

Results: The mean (SEM) hot flash frequency 2 to 7 hours after therapy initiation was lower than that for placebo (standard-dose κ agonist, 4.75 [0.67] hot flashes per 5 h; low-dose κ agonist, 4.50 [0.57] hot flashes per 5 h; placebo, 5.94 [0.78] hot flashes per 5 h; P = 0.025). Hot flash intensity did not vary between interventions. LH pulsatility mirrored objective hot flashes in some--but not all--women.

Conclusions: This pilot study suggests that κ agonists may affect menopausal vasomotor symptoms.

Trial registration: ClinicalTrials.gov NCT02070718.

Figures

Figure 1

A model of the GnRH/LH pulse generator, which comprises KNDy and other neurons within the arcuate nucleus. According to this model, those KNDy neurons also connect to warm-sensing (WS) neurons in the median preoptic nucleus to drive hot flashes. Activation of kappa opiate receptor signaling in the arcuate nucleus with a kappa agonist could block both GnRH/LH pulses and hot flashes.

Figure 2

Consolidated Standards of Reporting Trials (CONSORT) Flow Diagram.

Figure 3

LH pulse patterns with skin conductance (objective) hot flashes in a menopausal woman treated with placebo with 20-minute blood samples assayed for LH (closed circles) and subjective hot flashes indicated with arrows.

Figure 4

Hot flash frequency 2-7 hours following initiation of generic Talwin NX (kappa agonist) treatment (mean ± SEM) among menopausal women with moderate to severe hot flashes. Frequencies of hot flashes differed between placebo, low-dose and standard-dose kappa agonist groups, p=0.025. Analyses were performed using Friedman analysis of variance.