Human experimental pain models : methodological and analgesic studies

Pain is an important clinical issue with great impact on society and individuals' well being. It is well established that sensory abnormalities induced by tissue trauma and inflammation are clinically important in various acute and chronic pain conditions. However, the underlying neurophysiological mechanisms and their pharmacological modulation are not yet completely understood. In order to better characterize and study different pain phenomena in detail under standardized conditions, several human experimental pain models have been developed.

This thesis addresses these issues from two angles: in the methodological part, the relevance of human experimental pain models reflecting different clinical pain phenomena was studied and the sensitivity of the models to various analgesics was examined in the pharmacological part. Thus, the aim was to study how experimentally induced pain, especially reflecting hype hyperexcitability of the nervous system, can be assessed in a more standardized manner. The goal was also to evaluate the sensitivity of experimentally induced cutaneous and muscle pain in human volunteers to opioids and the NMDA receptor antagonist ketamine.

First, the relative importance of central versus peripheral mechanisms and their relation to the development of mechanical hypersensitivity in the surrounding of a skin burn injury, secondary hyperalgesia (SH), was investigated. No correlation was found between peripheral inflammatory flare reaction and the spatial extension of SH, reflecting central sensitization (CS), indicating that the two phenomena are separable. Further, with a computer-assisted algometry method it was possible to show that pain upon repetitive stimulation (40g, 3Hz), wind-up like pain, another crucial phenomenon also reflecting CS, can almost be abolished by combined treatment with morphine and ketamine, whereas monotherapy with either drug had no effect. Thus, a clear synergistic analgesic effect was shown on wind-up like pain, which has not been demonstrated in a human experimental pain model before. In addition, experimental muscle pain, as induced by intramuscular electrical stimulation or infusion of hypertonic saline was investigated.

It was demonstrated that experimentally induced muscle pain is sensitive to pharmacological modulation with ketamine, a finding similar to what has been demonstrated in preclinical animal tests as well as in clinical trials. Additionally, morphine and the shortacting opioid alfentanil were shown to exert dose-dependent analgesic effects on phasic and tonic muscle pain. Hence, the results provide evidence that drugs acting via the µopioid or the NMDA receptor, administered in doses shown to be effective in other experimental models and pain states, have the ability to modulate experimentally induced cutaneous as well as muscle pain in humans.

In conclusion, the results imply that human experimental pain models provide a standardized way of assessing pain phenomena reflecting clinical pain and are therefore valuable for the investigation of the effects of analgesic drugs. Hopefully, these pain models can serve as a valuable link between animal tests and clinical trials for the development of new analgesic drugs in the future.

List of scientific papers

I. Schulte H, Sollevi A, Segerdahl M (2004). The distribution of hyperaemia induced by skin burn injury is not correlated with the development of secondary punctate hyperalgesia. J Pain. 5(4): 212-7.
https://doi.org/10.1016/j.jpain.2004.03.002

II. Schulte H, Jansson Y, Kinnman E, Johansson B, Segerdahl M (2005). A computerised algometry method for assessment of mechanical sensory changes induced by experimental skin burn in healthy volunteers. [Submitted]

III. Schulte H, Sollevi A, Segerdahl M (2004). The synergistic effect of combined treatment with systemic ketamine and morphine on experimentally induced windup-like pain in humans. Anesth Analg. 98(6): 1574-80.
https://pubmed.ncbi.nlm.nih.gov/15155308

IV. Schulte H, Graven-Nielsen T, Sollevi A, Jansson Y, Arendt-Nielsen L, Segerdahl M (2003). Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers. Acta Anaesthesiol Scand. 47(8): 1020-30.
https://doi.org/10.1034/j.1399-6576.2003.00204.x

V. Schulte H, Sollevi A, Segerdahl M (2005). Dose-dependent effects of morphine on experimentally induced cutaneous pain in healthy volunteers. Pain. [Accepted]
https://doi.org/10.1016/j.pain.2005.05.005

VI. Schulte H, Segerdahl M, Graven-Nielsen T, Grass S (2005). Reduction of human experimental musclepain by alfentanil and morphine. [Submitted]