Preceptor

Elizabeth Ann Ernst
Clinical Research Manager

Description

Chronic administration of opiate analgesics, such as the regimens used to control pain associated with cancer and non-malignant conditions, generally causes constipation. Therefore physicians who specialize in pain medicine are constantly attempting to balance analgesia and side effects for patients requiring opioids. Opioid-induced constipation, an effect that is often difficult to treat, may burden up to 90% of all patients treated with opioids. Significant symptoms such as: the infrequent, difficult passage of small hard pellets; abdominal pain, distension, bloating, gas, nausea and vomiting, urinary retention and anorexia are often a result of opioid-induced constipation. In more severe cases opioid-induced constipation can progress to obstipation and bowel obstruction if not properly diagnosed and treated.

Although the constipating effect of opioids is well known the precise mechanism by which they cause constipation is not understood. Opioid-induced constipation appears to be mediated both centrally and locally in the gut, which contributes to increased sphincter tone and non-propulsive motility in the ileum and colon. Desiccation of the intraluminal contents occurs because of increased fluid and electrolyte absorption. This could result from an increased absorption rate, prolonged absorption time or both.

Roxane Laboratories is currently conducting domestic and international trials to explore the efficacy and safety of a product that could potentially reverse opioid-induced constipation in patients with malignant and non-malignant pain. Therefore, further information regarding mechanism of action and the development of a clinical protocol to test the hypothesis generated will be the focus of this rotation.

Objectives

1.	Demonstrate efficient literature search strategies and proficiency in the use of computerized information databases.
2.	Critcally analyze and evaluate literature on the mechanism of action and pharmacokinetic characteristics of the compound under development.
3.	Analyze and evaluate potential ways to objectively measure in a clinical setting "constipation" and "relief of constipation" in patients who experience opioid-induced constipation.
4.	Interpret and combine literature sources into a concise written presentation ofproposed mechanism of action.
5.	Generate a clinical synopsis/outline that could be developed into a clinical study that would evaluate and assess the mechanism of action of the compound under development.

Requirements and Activities

During the rotation, the resident will be expected to do the following activities:

1.	To be present a the site for a minimum of 40 hours per week, or at off-stie location as dictated by the nature of the work being completed and agreed upon by the preceptor and resident
2.	Perform medline and other searches, obtain references and provide drug information/medical support for the compound under development.
3.	Interact with internal and external consultants in the pharmaceutical industry to establish a basic understanding of how clinical development of a new drug product is implemented
4.	A weekly review meeting will be held with the preceptor to review the status of the project.

Required Readings

1.	Spiker, B. Guide to Clinical Trial. Philadelphia, PA: Lippincott-Raven; 1996. (Specific chapters will be assigned)
2.	Borody, T.J., Quigley, E.M., Phillips, S.F., Wienbeck, M., Tucker, R.L., Haddad, A., and Zinsmeister, A.R. (1985): Effects of morphine and atropine on motility and transit in the human ileum. Gastroenterology, 89: 562-570
3.	Fotherby, K.J. and Hunter, J.O. (1987): Idiopathic slow-transit constipation: whole gut transit times, measured by a new simplified method, are not shortened by opioid antagonists. Aliment.Pharmacol.Ther., 1:331-338
4.	Kaufman, P.N., Krevsky, B., Malmud, L.S., Maurer, A.H., Somers, M.B., Siegel, J.A., and Fisher, R.S. (1988): Role of opiate receptors in the regulation of colonic transit. Gastroenterology, 94: 1351-1356.
5.	Pace, N.L., Parrish, R.G., Lieberman, M.M., Wong, K.C., and Blatnick, R.A. (1979): Pharmacokinetics of naloxone and naltrexone in the dog. J.Pharmacol.Exp.Ther., 208:254-256
6.	Wienbeck, M. and Blasberg, M. (1986): Effects of an enkephalin analog on motility of the small and large intestine in the cat. Z.Gastroenterol., 24: 179-187

Additional readings will be provided as a part of the rotation