Repeated nociceptive stimulation for detecting drug effects

Abstract

Early seminal studies have revealed that prolonged nociceptive timulation induceshyperexcitability andprolongedfiringof spinal ord nociceptive neurones, both phenomena persisting after cessaion of the peripheral stimulus [1,2]. These observations provoked ubstantial changes in the understanding of pain pathophysiology. hey demonstrated that activity of central pain pathwaysmay perist in the absence of a peripheral nociceptive input, and neural athways may undergo long-lasting sensitisation. These findings ere mirrored by human studies showing that repeated periphral stimulation at constant intensity evokes an increase in pain ensation during the stimulation train, so that the last stimuli are erceived as painful [3,4]. This phenomenon is known as temporal ummation and is believed to reflect aspects of central sensitisation nduced by the peripheral nociceptive input. Due to the widely recognised importance of processes of entral sensitisation, the temporal summation model soon found pplication in human pain research. Clinical studies have found hat the threshold to evoke temporal summation is lower in hronic pain patients, compared to pain-free subjects. This has een observed in a variety of pain conditions, such as complex egional pain syndrome [5], whiplash [6] and fibromyalgia [7]. The educed temporal summation threshold suggests that sensitisation rocesses can be induced in patients at low stimulation intensities. his is expected to promote exaggerated pain even when nomajor issue damage is present. The temporal summation model has also been used to assess rug efficacy. Themain rationale for this application is the assumpion that certain drugs have a particular action on the mechanisms nderlying central sensitisation processes, which would make he temporal summation model suitable for detecting such drug ffects. The paper by Enggaard et al. [8] in the present issue of this ournal used amultimodal pain testing approach to investigate the nalgesic effect of gabapentin in healthy volunteers. The investiators found a clear effect of gabapentin on temporal summation, quantitatively lower influence of the drug on pain after single lectrical stimulation, and no significant effect on pain ratings after he cold pressor test. Similar findings were obtained by a previous tudy, in which gabapentin acted on part of the experimental tests mployed, including cutaneous temporal summation [9]. Perhaps he most striking case of selective drug action is ketamine, which ffects the pain thresholds after repeated stimulation while being neffective on pain after single nociceptive stimulation [10].