TREATMENT DEVELOPMENT: HOPE ON THE HORIZON
Bivalent δ-µ Opioid Ligands: Potential for Pain Control Without Tolerance or Dependence
David J. Daniels, M.D., Ph.D.
The relationship between morphine-induced tolerance and dependence, and pharmacological interaction between δ- and µ-opioid receptors has been observed for more than 20 years. Studies have revealed that morphine-induced tolerance and dependence can be reduced without compromising analgesic activity by antagonizing the δ-opioid receptor. Because it has not yet been determined whether this is a consequence of the direct association between δ- and µ-opioid receptors, or due to functional modulation involving neuronal circuitry, we have designed bivalent opioid ligands that contain µ-agonist and δ-antagonist pharmacophores to address this issue. Bivalent ligands with the shorter spacers produced both tolerance and dependence similar to both morphine and control monovalent ligands on chronic administration to mice. However, when the distance between the two pharmacophores of the bivalent ligand exceeded 18 atoms, the compounds no longer produced tolerance or dependence. These data suggest that physical interaction between the d- and µ-opioid receptors modulates µ-mediated tolerance and dependence. Additionally, one of these compounds was found to be 50-fold more potent than morphine by intravenous administration, suggesting a previously uncharacterized approach for the development of analgesics, devoid of tolerance or dependence.
New Opioid Formulations: Hope on the Horizon
Pamela P. Palmer, M.D., Ph.D.
Although there are many complex issues to discuss regarding the use and abuse of opioids, three major areas of concentrated effort should have a direct impact over the next decade on the overall safety of prescribing and using opioids to treat acute and chronic pain. First, there are new abuse-resistant formulations of opioids. We present key aspects of opioid formulations that resist abuse, including safer extended-release formulations. We also highlight the importance of high-bioavailable opioid formulations. Second, we discuss the safer dispensing of opioids, including novel drug-device products in development for the safer dosing of analgesics in both the inpatient and outpatient setting. Third, we report on efforts at mitigating dose escalation by developing opioid formulations with less tolerance development. Clinical aspects of opioid tolerance development, and key molecular targets for novel therapies to deter opioid tolerance are covered.
Real-Time fMRI: A New Method for Controlling Targeted Brain Activation Through Training, With Application to Pain Control and Addiction
R. Christopher deCharms, Ph.D.
It is now possible to visualize brain activation in real time using real-time functional magnetic resonance imaging (rtfMRI). This may allow patients to observe and learn to control the brain mechanisms underlying their own disease processes. Pain regulation is mediated through a powerful and highly developed endogenous modulatory system spanning multiple brain regions. Bringing this system under conscious control could provide a novel mechanism to decrease pain, using rtfMRI training.
In experiments designed to test this hypothesis, we provided healthy experimental subjects and chronic pain patients with rtfMRI information from the regions associated with pain perception and pain control, including the rostral anterior cingulate cortex (rACC). When subjects deliberately induced increased versus decreased rACC activation, there were corresponding changes in the perceived pain intensity caused by an applied noxious thermal stimulus or ongoing chronic pain. This was not observed in four independent control groups that received training without rtfMRI. Thus, it is possible that subjects may learn explicit control over brain activation using rtfMRI-based training, with a concomitant impact on cognitive processes. This procedure is being actively investigated in ongoing clinical trials on chronic pain and addiction.
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