Pharmacological FMRI in the development of new analgesic compounds

Abstract

Chronic pain is a major problem for the individual and for society. Despite a range of drugs being available to treat chronic pain, only inadequate pain relief can be achieved for many patients. There is therefore a need for the development of new analgesic compounds. The assessment of pain depends to date entirely on the subjective report of the patient, in contrast to many other clinical conditions where biomarkers that help determine the severity and stage of the disease enable the physician to monitor the course of the disease and treatment effects longitudinally. In this article, we illustrate that magnetic resonance-based imaging techniques have the potential to provide sensitive and specific biomarkers of the pain experience, as well as clarifying disease mechanisms. Functional magnetic resonance imaging (FMRI) is particularly suited to investigating the effects of pharmacological agents on pain processing within the human central nervous system. Combination of FMRI and drug administration is termed pharmacological FMRI (phFMRI). In addition to outlining several methodological considerations that have to be taken into account when performing phFMRI, we discuss phFMRI studies that have already used this technique to study the effects of analgesic compounds. These studies provide promising data for the use of phFMRI as sensitive tool in assessing a potential drug effect. Such pharmacodynamic readouts obtained early in the process of drug development would not only save the pharmaceutical industry substantial amounts of money, but would also avoid the unnecessary exposure of patients to molecules with limited or no therapeutic value. We are therefore optimistic that phFMRI will be used as a tool with high sensitivity and specificity for evaluating analgesic agents in early drug development and clinicalstudies.

Multivariate Granger causality analysis of fMRI data

“…Previous studies have circumvented this limitation with summary time series, such as mean BOLD or mean reaction time by block [Toni et al, 2002] or condition [Tracy et al, 2003]. The present framework of analysis is expected to be useful in the investigation of other slowly varying neurophysiological processes such as learning [Floyer-Lea et al, 2005], habituation [Pfleiderer et al, 2002], chronic pain [Borsook et al, 2006], and therapeutic effects [Schweinhardt et al, 2006].…”

Spontaneous pain and brain activity in neuropathic pain: Functional MRI and pharmacologic functional MRI studies

“…Recent reviews [1][2][3][4][5][6][7] emphasize the limited progress in understanding brain activity in clinical neuropathic pain conditions. In contrast, the literature regarding brain circuitry for acute or experimental pain is now firmly established and continues to generate new findings.…”

Funktionelle Bildgebung in der Schmerzforschung

“…Hierbei wird die Veränderung der zentralen Schmerzrepräsentation als Surrogatmarker für die spezifische Wirkung pharmakologischer Substanzen benutzt. Damit ermöglicht die phFMRT differenzierte Aussagen über dosis-und krankheitsspezifische Effekte verschiedener Wirksubstanzen an ihren zentralen Wirkorten (für einen Überblick s. [39]). Als ein Beispiel sei eine aktuelle phFMRT-Studie genannt, die die Wirkung von Alfentanyl in Abhängigkeit des μ-Opioid-Rezeptor-Genotyps untersuchte.…”