Ph.D Thesis

Ph.D StudentSuzan Erica
SubjectAdvanced Psychophysics for Studying Mechanisms of Opioid
Induced Analgesia and Hyperalgesia in Humans
DepartmentDepartment of Medicine
Supervisors PROF. Elon Eisenberg
DR. Dorit Pud
Full Thesis textFull thesis text - English Version


A major increase in the use of opioids for chronic non-malignant pain has been reported over the past two decades in many western countries . Opioids exhibit their analgesic effects via acting at the spinal and supraspinal levels of the central nervous system (CNS). Along with their beneficial analgesic effects, opioid use may be associated with significant negative effects such as opioid induced hyperalgesia (OIH). The current dissertation presents the results of three lines of investigation. The first focused on the study of the effects of opioids on advanced dynamic psychophysics based experimental paradigms, which are believed to represent spinal and supraspinal pain mechanisms. These effects were studied both in healthy volunteers and patients with chronic neuropathic pain (NP). The second line of investigation concentrated on the study of OIH in patients with chronic NP. This line consisted of presenting a new model for testing OIH in patients with chronic NP and studying the correlations between the effect of opioid treatment on the intensities of both clinical NP and experimental thermal-evoked pain. Lastly, the third line of investigation aimed at testing an alternative method of calculation of one of the advanced paradigms, used for testing the effects of opioids in this study.

The findings of the first constituent of this work suggest that opioids attenuate temporal summation (TS), a paradigm representing a spinal key excitatory pain mechanism. Furthermore, a positive correlation was found between the decline in the magnitude of TS and the decrease in the intensity of clinical NP in response to administrating an ultra-short opioid agonist, pointing to the involvement of spinal mechanisms in opioid induced analgesia. In contrast, opioids had no effect on conditioned pain modulation (CPM) and offset analgesia (OA), which are manifestations of the supraspinal descending inhibitory pain systems in humans.

The findings of the second constituent present an experimental model for testing OIH in patients with chronic NP.  Using this model, we were able to demonstrate the development of experimental OIH in 57% of the tested patients (17 out of 30 tested patients) and to identify correlations between experimental OIH, opioid dose and opioid-induced analgesia. These correlations demonstrated the development of dose-dependent OIH, which negatively correlated with the analgesic effect of the administered opioid.  If verified in further studies, this model can help identifying patients who are susceptible to having a poor response to opioid treatment. In addition, clinical criteria for diagnosing OIH were introduced.

The third constituent introduces an alternative method of calculating the magnitude of TS produced by tonic heat pain model, based on individual differences in a large sample size of healthy subjects and emphasizes the importance of individual examination of different paradigms of experimental pain.

If utilized correctly, these paradigms can help understanding mechanisms which underlie opioid analgesia in humans on the one hand, and be used clinically for identifying individual patients who are susceptible for developing OIH on the other hand. This can improve patient selection for proper opioid therapy.