Opioid Specific Effects on Central Processing of Sensation and Pain: A Randomized, Cross-Over, Placebo-Controlled Study

  • Dina Lelic
    Address reprint requests to Dina Lelic, MSc, PhD, Mech-Sense, Department of Gastroenterology and Hepatology, Mølleparkvej 4, Aalborg University Hospital, 9000 Aalborg, Denmark
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
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  • Anne Estrup Olesen
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark

    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • Debbie Grønlund
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark

    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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  • Fabricio Ariel Jure
    Integrative Neuroscience, Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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  • Asbjørn Mohr Drewes
    Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark

    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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      • Morphine effects were greatest for long lasting and deep structure stimulations.
      • Opioid-specific effects were seen on tetanic and bone pressure pain thresholds.
      • Opioid-specific effects were seen on cold-pressor pain ratings.
      • Opioid-specific spinal effect was evidenced as reduced spinal nociceptive withdrawal reflexes size.
      • Opioid-specific supra-spinal effects were evidenced as changes in tonic pain electroencephalography.


      Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, 2-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and 3 sets of assessments were done at each of the 2 visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing, spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test – hand in 2° water for 2 minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive quantitative sensory testing measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia.


      This exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.

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