Friday, September 5, 2008

Constipation: IV vs Oral Morphine

In a short article in American Journal of Hospice and Palliative Medicine a palliative care team in India describe their observation that some patients who did not experience constipation while receiving IV morphine required laxatives for constipation when converted to oral morphine. They did a 5-month retrospective chart review and found 11 patients who did not experience constipation while on moderate doses of intravenous morphine. They had a pretty "clean" sample: opioid-naive patients admitted for severe pain, no malignant or comorbid GI pathology, not using laxatives prior to admission. When switched to equianalgesic doses of oral morphine, 7 of the 11 patients required laxatives for the remainder of their inpatient stay and were discharged on laxatives.

This is the first published description I have seen of this phenomenon, although I heard it described years ago. This is one of those mysteries of individual patient response to opioids. These authors (as did my first informant years ago) suggest that it is related to mu receptors in the gut. That makes a lot of sense at first blush and is reinforced by the observation that transdermal fentanyl seems to cause less constipation than oral morphine. Oral methadone is also reputed to cause less constipation. These authors propose that methadone's wide and rapid distribution may be responsible: the mu receptors in the gut are perhaps not "bathed" in opioid for as long as with morphine.

I have no argument with the observed phenomena, but herewith are my musings on pharmacokinetics and dynamics. Once steady state is reached, isn't there a constant rate of "bathing" of the receptors, where ever they may be? I would guess that most of the oral dose of any opioid is absorbed into the blood stream long before it gets to the large intestine, which is where constipation is produced. We can certainly pick up opioid concentrations in the urine; how much ends up in stool? Unlike most opioids, more methadone is eliminated via the gut than the kidneys; how does that fit into the "receptor bathing" hypothesis? How much of opioid-induced constipation is at the individual patient level and how much is inherent in specific drugs?

I have had patients on quite high doses of opioids who do not have a problem with constipation. More than one has reported something like: "as long as I have my morning cup of coffee, I'm fine, just like before I started this (opioid)." Patients at highest risk for opioid-induced constipation are those who had a problem with chronic constipation prior to opioid use. Those who "hate to take pills" are hard to convince to stay on their bowel regimen and end up with both pain and constipation.

A semi-related issue: Mu receptors have been identified in peripheral tissues and are reported to be expressed in larger numbers in damaged tissues. This is the basis for the use of topical opioids. If methylnaltrexone works only in the periphery, because it doesn't cross the blood-brain barrier, should we expect to see transient increases in certain kinds of pain--surface wounds, pressure ulcers, fungating tumors--when methylnaltrexone is administered?

The vast majority of patients experience constipation on any opioid by any route. Our practice should be to prescribe stimulant laxatives for every patient who can take oral medications, then back off if not needed.

Reference: Mazumdar A, Mishra S, Bhatnagar S, Gupta D. Intravenous morphine can avoid distressing constipation associated with oral morphine: a retrospective analysis of our experience in 11 patients in the palliative care in-patient unit. Am J Hosp Palliat Care. 2008 Aug-Sep;25(4):282-4

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