Differences in central sensitisation between healthy men and women in Switzerland: a single-centre trial

Abstract

<h2>Abstract</h2><h3>Background</h3> Many chronic pain conditions exhibit differences between men and women regarding prevalence, pain intensity, or treatment effects. Mechanisms underlying these differences are poorly understood. Central sensitisation, defined as an increased responsiveness of nociceptive neurons in the CNS to normal or subthreshold afferent input, is considered an important mechanism that can differ between men and women with chronic pain conditions. We aimed to assess differences in central sensitisation between healthy men and women, with the hypothesis that central sensitisation is more pronounced in healthy women than in men. <h3>Methods</h3> This single-centre trial followed a within-subject design and was conducted at the Balgrist University Hospital in Switzerland after approval by the Cantonal Ethics Board of Zurich. Healthy, pain-free adults aged 18–40 years with a BMI of less than 30 kg/m² and no history of chronic pain were recruited using advertisement and word-of-mouth. Biological sex (male or female) was self-reported. A validated sensitisation protocol was used by applying a contact thermode to the innervation area of the sural nerve on one foot. A sham protocol was used on the other foot. The protocols were performed in counterbalanced order. All participants were masked to the study design and protocols. The primary endpoint before and after the protocols, was the area of secondary hyperalgesia relative to the thermode, serving as a proxy of central sensitisation. Additionally, the nociceptive withdrawal reflex was repeatedly elicited at the sural nerve with two currents (corresponding to 120% and 140% of the individual reflex threshold current) and recorded from the biceps femoris by surface electromyography. The magnitude of the reflex response in the 90 ms to 150 ms post-elicitation interval was compared before and after the protocols. This study was registered with ClinicalTrials.gov, NCT05031286. <h3>Findings</h3> Between April 22, 2021, and Feb 19, 2022, 66 healthy participants were included in the trial. The median age of participants was 26 years (IQR 21–31) and 33 (50%) were women. Following the sensitisation protocol, secondary hyperalgesia was greater in women than men (12·4 cm² [SD 8·41] <i>vs</i> 8·2 cm² [6·90]; two-sided <i>t</i> test p=0·031). The effect of the sensitisation protocol on the magnitude of the biceps femoris nociceptive withdrawal reflex was stronger in women than in men for both currents (Cohen's d 0·32 <i>vs</i> 0·07 for 120% and 0·31 <i>vs</i> 0·15 for 140% reflex threshold current) with 99·6% versus 95·6% probability (Bayesian normal–normal model). No adverse effects were recorded during the trial. <h3>Interpretation</h3> The two tested outcomes (extent of secondary hyperalgesia and magnitude of the nociceptive withdrawal reflex) indicate that central sensitisation processes are more pronounced in healthy women than men. Because central sensitisation is suggested to influence pain chronification, more pronounced central sensitisation processes might constitute a sex-specific risk factor for developing chronic pain. <h3>Funding</h3> The Swiss National Science Foundation.