The effect of M-current activation on controller gain and obstructive sleep apnoea severity: a randomised controlled trial using flupirtine

Abstract

Ventilatory control instability, or high loop gain (LG), contributes towards upper airway collapse in approximately one-third of people with obstructive sleep apnoea (OSA). A high LG can be the product of elevated chemosensitivity (controller gain) and/or an excessive ventilatory output (plant gain). Therapies such as carbonic anhydrase inhibitors (targeting plant gain) have been shown to reduce OSA severity; however, there is a lack of viable pharmacological options targeting controller gain. This study investigated the effect of flupirtine (400 mg), a KCNQ potassium channel opener, on LG and OSA severity in fifteen moderate-to-severe OSA patients through a randomised, double-blind, placebo-controlled trial. Despite the hypothesised potential of flupirtine to reduce LG by attenuating chemosensory activity, our findings revealed no significant effect on LG and OSA severity. The lack of overall efficacy of flupirtine is most likely due to multifactorial nature of OSA and the challenges of its management. Our findings suggest a need for a nuanced understanding of OSA pathogenesis and caution against the use of flupirtine in managing OSA. While, pharmacological modulation of ionic channels within the ventilatory control system presents a promising strategy, given the plethora of robust targets available, it remains to be determined whether an effective treatment can capitalise on a single predominant ionic current ubiquitous throughout the ventilatory system, or if a more successful approach necessitates the simultaneous modulation of multiple targets. This research enhances our understanding of the ventilatory control system's contribution to OSA and the complexity of finding a one-size-fits-all treatment. KEY POINTS: Around one-third of obstructive sleep apnoea (OSA) cases involve an unstable control of breathing, leading to airway collapse. This research examined whether the drug flupirtine could stabilise breathing control and reduce OSA severity in 15 patients. Flupirtine, which was expected to improve breathing control by reducing chemosensitivity, showed no significant benefit for OSA. While targeting ionic channels in the breathing system is promising, the search for an effective OSA treatment may require addressing multiple targets simultaneously.

Keywords: loop gain; potassium channel opener; sleep apnea pharmacotherapy.

Figure 1. Quantifying the obstructive sleep apnoea (OSA) endotype traits from polysomnographic (PSG) data

A, top panel: electroencephalogram (EEG) power (black) showing scored arousals (green) and calibrated flow signal (l/min), with obstructive events (apnoeas or hypopnoeas) highlighted in purple. Bottom panel: breath‐by‐breath observed ventilation (purple line), along with retrofitted models of chemical drive (black line) and ventilatory drive (combining chemical and arousal components; green line), are shown. Loop gain is derived from the proportional increase in chemical drive (ventilatory response) following ventilation reductions (ventilatory disturbance). The arousal threshold is defined as the ventilatory drive preceding arousal‐associated events (e.g. dashed black line). The ventilatory response to arousal (VRA) is quantified as the difference between chemical drive (black) and overall ventilatory drive (green) during arousal‐related events. B, the endogram summarises how ventilatory drive (modelled) and ventilation (observed) vary across the whole sleep period (continuous black line shows median values and red shaded area represents interquartile range). Once this relationship is known the other remaining traits are derived. V _MIN represents the ventilation at the lowest decile of drive (minimal drive), V _PASSIVE corresponds to ventilation under passive neuromuscular conditions (when eupnoeic drive = 100%), and V _ACTIVE represents ventilation achieved during maximal neuromuscular stimulation (i.e. at the arousal threshold). The arousal threshold is quantified as the median level of drive preceding the termination of any scored obstructive event. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2. Consort diagram

[Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3. The overall apnoea‐hypopnoea index (primary outcome) was not different between placebo and flupirtine

Black squares indicate the mean (SD) for each condition. Individual responses (open circles) showed wide variation (n = 15). Data were compared using paired t test (P = 0.780).

Figure 4. Exploratory responder analysis of two groups: good and poor responders

Good responders, blue circles (n = 5); poor responders, red squares; n = 5. Main graphs show between‐condition effects as means and 95% confidence intervals and inset graphs show the individual data (black bars indicate means in inset). A, total AHI; B, arousal threshold; C, collapsibility measured as V _MIN; D, collapsibility measured as V _PASSIVE. Note all endotypes values were measured from total sleep time as %eupnoeic ventilation. Two‐way repeated measure ANOVAs (condition [placebo × flupirtine], responder [good × poor]) were utilised to determine any main effects and/or interactions that may help explain the variability in treatment response. The main graphs A–D show P values for post hoc tests comparing responder groups (good (blue circles) vs. poor (red squares)) across both drug conditions. Inset graphs show individual data separately for each responder group. Post hoc test P values reveal within group changes between drug conditions: placebo (P) and flupirtine (F). [Colour figure can be viewed at wileyonlinelibrary.com]