by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

I am lecturing next week in our graduate level Principles of Pharmacology and Toxicology course (PHM 819).  I will be discussing drug tolerance, dependence and withdrawal.  These are topics usually associated with drug addiction but as I will convey to the class, drug tolerance, dependence and withdrawal are associated with many non-addictive drugs.  My lectures will focus on cellular and molecular mechanisms responsible for tolerance, dependence and withdrawal. We will discuss in great (some say nauseating) detail what happens to individual molecules and cells when they are exposed chronically to drugs.

Questions often posed by the students include: So what? Who cares?  What does this really mean?  How is this useful for using drugs to treat illness?  I admit that these are all good questions.

It is a coincidence then that the Food and Drug Administration has just come out with a News Release (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm172366.htm) that is highly relevant to these questions.  The release is related to a new drug called Onsolis (fentanyl).  Fentanyl is a very strong opioid narcotic that is not easy to use because it is highly potent (only a very little of the drug is needed to produce pain relief or to produce respiratory depression which can be lethal).

The Onsolis preparation of fentanyl is novel in that is contained in a film (like some breath mints) that is placed in the mouth and the drug is absorbed directly from the mouth.  Onsolis is approved for use in chronic pain patients who are taking opiates regularly for pain relief.  Onsolis is for use only for breakthrough pain that is not suppressed by the patient’s normal opiate medication.

Now what does this have to do with PHM 819?  Well because these patients take opiates regularly they are highly tolerant to the effects of opiates.  So a fatal overdose due to respiratory depression is much less likely because these patients are much less sensitive to the respiratory depression caused by opiates.  They also develop tolerance to the pain relieving effects of opiates but because fentanyl is such a strong analgesic, it still provides some relief even in the opiate tolerant patient.

This is a real world application of the principle of drug tolerance and how we can take advantage of this to improve patient health.  This is also a good reason for students to understand drug tolerance, dependence and withdrawal.  Finally, it is a good example of why understanding the mechanisms responsible for drug tolerance is important for drug development and patient care (and not just for passing exams)!

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