Compensatory Failure of Autonomic Regulation in Phantom Limb Pain and Its Correlation with Maladaptive Plasticity: A Cross-Sectional HRV Study in Amputees

<b>Background/Objectives</b>: Chronic pain is associated with autonomic nervous system (ANS) dysfunction, which can be indexed by heart rate variability (HRV). This cross-sectional study examined associations between ANS dysregulation and phantom limb pain (PLP) intensity in amputees and explored related clinical and psychosocial variables. <b>Methods</b>: Fifty-three adults with chronic PLP (mean age 57.7 ± 15.4; 60% male) were enrolled. Primary exposure was PLP intensity concurrent with HRV time- and frequency-domain metrics. Additional variables included residual limb pain, phantom limb sensations (PLS), telescoping and PLP-PLS index. <b>Results</b>: PLP intensity was not significantly associated with frequency-domain HRV measures. Time-domain parameters RMSSD (root mean square of successive differences) and pNN50 (percentage of successive normal RR intervals >50 ms) were lower in the positive PLP-PLS group. In multivariate models, depression (range of βs:-1.36 to -58.16), pain-medication use (range of βs: -12.3 to -953.4), and body mass index (range of βs: 0.55 to 45.8) were significantly associated with lower SDNN (standard deviation of NN intervals), RMSSD, pNN50, low-frequency (LF), and high-frequency (HF) power. Female sex and pre-amputation pain correlated with higher LF, whereas traumatic etiology correlated with lower LF. Poor sleep quality correlated with elevated HF. No predictors related to the LF/HF ratio. <b>Conclusions</b>: HRV alterations in PLP were associated with depression and pain-medication use rather than pain intensity. Findings support HRV dysfunction as a marker of brain compensatory failure within the autonomic circuit, and maladaptive plasticity, highlighting utility for identifying central dysfunction even when pain severity does not vary.