Abstract / Summary
Background/Objectives: Needle procedures cause acute pain through mechanical, chemical, sensory, and affective processes. We synthesized human and animal evidence and developed a framework spanning peripheral nociception, spinal/trigeminal modulation, central processing, and clinical outcomes. Methods: This PRISMA 2020 review was registered in PROSPERO (CRD420261477391). PubMed/MEDLINE, Embase, and Web of Science were searched from inception through June 2026. Eligible studies examined pain or mechanistic outcomes during needle procedures. Evidence was classified as peripheral, central, or mixed. Human comparisons were pooled as Hedges’ g using random-effects models. Results: Thirty-five studies were included: 18 peripheral (51.4%), 13 mixed central peripheral (37.1%), and four central (11.4%). Larger-diameter needles increased pain (painful insertions: 63% with 23-gauge versus 31% with 32-gauge; p < 0.001), while bevel geometry, injection pressure, and volume further modulated pain. A 1600 µL volume produced 7.2 mm more pain on a 100 mm scale than smaller volumes (p < 0.001). Warming local anesthetic reduced pain from 35.3 to 15.0 mm (p < 0.001). Counter stimulation, vibration, cold, distraction, virtual reality, and controlled or automated delivery reduced pain, anxiety, and autonomic responses. Across seven comparisons (625 participants), interventions reduced pain overall (Hedges’ g, −0.86; 95% CI, −1.71 to −0.02; I2 = 77.5%), with differences by nervous-system level (central, −1.65 [−2.60 to −0.70]; peripheral, −1.46 [−4.92 to 1.99]; mixed, −0.36 [−0.99 to 0.28]; subgroup p = 0.018). Most studies had moderate risk of bias (62.5%). Conclusions: Needle-related pain is a multilevel process. Mechanism-informed interventions reduce pain, although effects vary by mechanism and context. Future studies should integrate peripheral, behavioral, and central measures and adopt standardized outcomes to identify modifiable targets and support mechanism-informed, patient-centered pain reduction.