Fibromyalgia and Nociceptive Flexion Reflex (NFR) Threshold: A Systematic Review, Meta-Analysis, and Identification of a Possible Source of Heterogeneity

Background The nociceptive flexion reflex is a physiological, polysynaptic reflex and refers to the level that an appropriate withdrawal response activates when a painful stimulus is detected. The nociceptive flexion reflex threshold (NFRthr) is defined as the lowest noxious stimulation intensity required to trigger a reflex motor response. Despite wide utilization and reports of the NFRthr, there has been no consensus on a standard and/or best method in assessment of the NFRthr. Objective To systematically review the literature that compared the NFRthr between individuals with fibromyalgia (FM) and healthy controls; and to identify a source of heterogeneity in these trials. Methods Employing the Cochrane methodology, we systematically searched Ovid MEDLINE, Embase, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and PsycINFO for clinical case-controlled trials assessing the NFRthr in individuals with and without fibromyalgia from inception to July 2019. Selected articles were passed for data extraction and meta-analyses. We utilized the random-effects model for meta-analysis assuming the true effect size may vary between studies. The sample sizes as a possible source of heterogeneity in multiple meta-regressions were investigated. This systematic review and meta-analysis were registered in PROSPERO before data extraction. Results Nine studies met our criteria and were included in the meta-analysis. Methodologies and settings varied between studies, eg, stimulation intensity, duration, and the current increments. Only two articles comprehensively described and reported details about electromyogram amplification, latency, and sampling rate. Evidence from 423 patients with fibromyalgia and 326 healthy individuals suggested that there may not be a meaningful decreased NFRthr in patients (overall mean difference = -3.16; 95% CI:-6.82 to 0.50; Z = 1.69; P=0.09). Published effect sizes were not homogenous (I2 = 0.91, τ2 = 25.04, χ2 = 91.22, df = 8, P < 0.00001). The multiple meta-regression analyses indicated that total and female sample sizes might be the main sources of heterogeneity for the effect sizes SStotal = -0.0570, P = 0.040; SSfemale = -0.0569; P = 0.047. Conclusion Evidence suggests that the nociceptive flexion reflex threshold may not be different between patients with fibromyalgia and healthy controls. A unified and rigorous methodology and sample size calculation (probably sex specific investigation) is required for the assessment of nociceptive flexion reflex threshold in patients with fibromyalgia.