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For Moderate Cancer Pain, Low-Dose Morphine Is Significantly More Effective Than Weak Opioids

Dec 07, 2015

By Shira Klapper, Senior Writer/Editor

In a randomized, controlled trial carried out in multiple cancer centers across Italy, 240 patients with moderate cancer pain received either weak opioids, such as codeine in combination with paracetamol or tramadol, or low-dose morphine, which is categorized as a strong opioid. The study, “A Randomized Trial of Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain,” published in the Journal of Clinical Oncology (JCO), online, ahead of print, December 7, found a significant advantage to low-dose morphine in terms of pain: Among the 118 patients who received low-dose morphine, 88.2% experienced a 20% reduction in pain, whereas among the 122 patients who received weak opioids, 57.7% experienced a 20% reduction. As early as one week into the trial, patients in the low-dose morphine group experienced significantly lower pain.

The study also found that patients in the weak opioid group were more likely to require a switch to a stronger analgesic. There were no differences between groups in terms of analgesic-related side effects such as constipation or dizziness. 

A challenge to WHO guidelines on pain

According to the study’s first author, Elena Bandieri, MD, and coauthor Mario Luppi, MD, PhD, the study’s findings challenge WHO’s pain guidelines, which recommend a three-step ladder as the basis for treating pain in patients with cancer. The guidelines state that patients with mild pain should receive non-opioids, such as non-steroidal anti-inflammatory drugs (step I); patients with mild to moderate pain should receive weak opioids (step II); and patients with moderate to severe pain should receive strong opioids (step III).

“In most countries strong opioids are highly regulated and oncologists, family physicians, and internists may prefer to prescribe weak opioids due to lower regulatory requirements, including special prescriptions forms,” said Dr. Bandieri. “However, our data show that this intermediate step may be less effective and more expensive. The findings of the study are quite clearly in favor of starting directly with a step three opioid, and hence may well change the basis of the WHO guidelines.”

According to Professor Luppi, “Current international guidelines recognize that low doses of a step III opioid may be used instead of codeine or tramadol for patients with mild-moderate pain.” However, he said, only a few trials have systematically studied whether patients with moderate pain should go directly to step III of the pain ladder—and all of these studies had methodological flaws.

“In current daily clinical practice, step II is often bypassed in favor of strong opioids, although the strategy is not supported by strong scientific evidence, since it has been investigated only  by two randomized controlled studies, enrolling only 92 and 54 terminally-ill patients, respectively, and one prospective study,” said Professor Luppi. “Thus, conclusive data are lacking as to whether moderate pain should be treated with either step II weak opioids or low-dose step III strong opioids.”

Clinical significance

Dr. Bandieri commented on the implications of the study for clinical practice.

“This study lends support to abolishing the second step of WHO guidelines in many patients. This will simplify treatments and perhaps provide better cancer pain control. Further phase IIIb/IV studies are urgently warranted to confirm our results.”

Elena Bandieri, MD, is a medical oncologist and palliative care doctor responsible for Early Palliative Care activity in the Oncologic Medicine Division at Unità Sanitaria Locale, in Modena, Italy.

Mario Luppi, MD, PhD, is Full Professor of Hematology and the Director of the Hematology Branch in the Department of Medical and Surgical Sciences at Azienda Ospedaliera-Universitaria Policlinico, Università degli Studi di Modena e Reggio Emilia, in Modena, Italy.



Abstract of the original JCO article.

PDF of the original JCO article.


Bandieri E, Romero M, Ripamonti CA, et al. A randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. Epub December 7.

The Exclusive Coverage series on ASCOconnection.org highlights selected research from JCO, JGO, and JOP, with additional perspective provided by the lead or corresponding author.

@ 2015 American Society of Clinical Oncology


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