1. 2016;19;E55-E78Pneumogastric (Vagus) Nerve Activity Indexed by Heart Rate Variability in Chronic Pain Patients Compared to Healthy Controls: A Systematic Review and Meta-Analysis
   Systematic Review
   Julian F. Thayer, PhD, Robert J. Ellis, PhD, Cora Weber, PD, Marc N. Jarczok, PhD sc hum, Annika Clamor, MSc, Julia Wagner, BSc, Daniela Falvay, BA, and Julian Koenig, PhD sc hum.

BACKGROUND: A large body of scientific literature derived from experimental studies emphasizes the vital role of vagal-nociceptive networks in acute pain processing. However, research on vagal activity, indexed by vagally-mediated heart rate variability (vmHRV) in chronic pain patients (CPPs), has not yet been summarized.

OBJECTIVES: To systematically investigate differences in vagus nerve activity indexed by time- and frequency-domain measures of vmHRV in CPPs compared to healthy controls (HCs).

STUDY DESIGN: A systematic review and meta-analysis, including meta-regression on a variety of populations (i.e., clinical etiology) and study-level (i.e., length of HRV recording) covariates.

SETTING: Not applicable (variety of studies included in the meta-analysis)

METHODS: Eight computerized databases (PubMed via MEDLINE, PsycNET, PsycINFO, Embase, CINAHL, Web of Science, PSYNDEX, and the Cochrane Library) in addition to a hand search were systematically screened for eligible studies based on pre-defined inclusion criteria. A meta-analysis on all empirical investigations reporting short- and long-term recordings of continuous time- (root-mean-square of successive R-R-interval differences [RMSSD]) and frequency-domain measures (high-frequency [HF] HRV) of vmHRV in CPPs and HCs was performed. True effect estimates as adjusted standardized mean differences (SMD; Hedges g) combined with inverse variance weights using a random effects model were computed.

RESULTS: CPPs show lower vmHRV than HCs indexed by RMSSD (Z = 5.47, P < .0001; g = -0.24;95% CI [-0.33, -0.16]; k = 25) and HF (Z = 4.54, P < .0001; g = -0.30; 95% CI [-0.44, -0.17]; k = 61).Meta-regression on covariates revealed significant differences by clinical etiology, age, gender, and length of HRV recording.

LIMITATIONS: We did not control for other potential covariates (i.e., duration of chronic pain, medication intake) which may carry potential risk of bias.

CONCLUSION(S): The present meta-analysis is the most extensive review of the current evidence on vagal activity indexed by vmHRV in CPPs. CPPs were shown to have lower vagal activity, indexed by vmHRV, compared to HCs. Several covariates in this relationship have been identified. Further research is needed to investigate vagal activity in CPPs, in particular prospective and longitudinal follow-up studies are encouraged.