Background: Impaired pain inhibitory and enhanced pain facilitatory mechanisms are repeatedly reported in patients with central sensitization pain. However, the exact effects of frequently prescribed opioids on central pain modulation are still unknown. Methods: A randomized, double-blind, placebo-controlled cross-over trial was carried out. Ten chronic fatigue syndrome (CFS)/fibromyalgia (FM) patients, 11 rheumatoid arthritis (RA) patients and 20 controls were randomly allocated to the experimental (10mg morphine or 0.2mg/mL Naloxone) and placebo (2mL Aqua) group. Pressure pain thresholds (PPTs) and temporal summation at the Trapezius and Quadriceps were assessed by algometry. Conditioned pain modulation (CPM) efficacy and deep tissue pain pressure were assessed by adding ischemic occlusion at the opposite upper arm. Results: Deep tissue pain pressure was lower and temporal summation higher in CFS/FM (P=0.002 respectively P=0.010) and RA patients (P=0.011 respectively P=0.047) compared to controls at baseline. Morphine had only a positive effect on PPTs in both patient groups (Ptime=0.034). Accordingly, PPTs increased after placebo (P time=0.015), and no effects on the other pain parameterswere objectified. There were no significant effects of naloxone nor nocebo on PPT, deep tissue pain, temporal summation or CPM in the control group. Conclusions: This study revealed anti-hyperalgesia effects of morphine in CFS/FM and RA patients. Nevertheless, these effects were comparable to placebo. Besides, neither morphine nor naloxone influenced deep tissue pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom-up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA.