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The major discovery is that the classic opioids like morphine, oxycodone, fentanyl, and Dilaudid (hydromorphone) break down into metabolites that are 'hyperalgesic', that is, molecules that can actually cause pain when they accumulate under conditions of chronic administration.

This might explain the experience of switching to more and more potent opioids which in turn produce more and more hyperalgesic molecules, and so a vicious cycle develops.

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