High anthracycline cumulative dose without cardiac toxicity: A possible protective role of morphine.

To the Editor,

Improvements in global anticancer strategy have resulted in better outcomes for a large proportion of cancer patients. Anthracyclines (A) are the best studied anticancer drugs with an established clinically significant dose-dependent cardiotoxicity. One of the strategies developed to reduce their well-known dose-dependent toxicity is dose limitation to 400-450 mg/m2 for doxorubicin (DOX) and 900 mg/m2 for epirubicin (E) (1). Preclinical evidences have pointed out a possible role for morphine as a cardioprotective agent (2,3). On the basis of these, we conducted a retrospective database search to determine patients receiving a higher E dose without cardiotoxicity so as to look for clinical or pharmacological protective factors while focusing on concomitant opioid use.

We collected data of patients who were receiving a cumulative dose of E >900 mg/m2 (representing the threshold warning dose) and who had undergone regular appropriate cardiac monitoring (1) without any evidence of cardiotoxicity. All available clinical/pathological characteristics were recorded focusing on concomitant medication with known cardioprotective effects as well as concomitant opioid use. We identified 10 such patients [median age, 58 (range, 49-71) years, F/M=9/1]. Their cumulative epirubicin dose was 1600 (range, 1350-2220) mg. None of the clinical parameters (age, sex, body mass index, comorbidities, and previous anticancer agent use) was associated with non-cardiotoxic effect. All patients concomitantly received opioids for long term for pain control [median morphine dose, 60 (range, 20-160) mg/die] started before weekly E therapy and kept after treatment stop. Only for the purpose of generating hypotheses, we compared the identified population with eight patients who had developed cardiotoxicity after or during A treatment. The two groups showed overlapping prevalences of cardiovascular risk factors and cardioprotective agent [β-blockers, sartans, and renin-angiotensin-aldosterone system (RAAS) inhibitors] use; however, those developing cardiotoxicity were slightly older [median age 67 (range, 59-82) yrs] and reported diabetes more frequently in their medical history; furthermore, only three of those eight patients received concomitant opioids.

Excessive reactive oxygen species (ROS) generation by A, together with iron complexes formation, is the most accepted hypothesis on anthracycline-induced cardiomyopathy (4). Morphine can exert a cardioprotective role in preclinical models. Molecular mechanisms underlying the cardioprotective effect of morphine are poorly understood; however, a theory on prevention of ROS-induced cell apoptosis in neuroblastoma cells has proposed inhibition of ROS generation as well as blockade of nuclear factor-kappa B transcription signaling pathway by morphine (5). Morphine inhibits ROS generation and prevents DOX-mediated caspase-3 activation, cytochrome-c release, and changes in Bax and Bcl-2 protein expression, leading to inhibition of cell apoptosis (5). We found that all patients receiving higher than usual cumulative dose of E without cardiotoxicity concomitantly received long-term morphine treatment for pain control. Interestingly, when checked for concomitant “cardioprotective” medications (β-blockers, sartans, and RAAS inhibitors) to exclude possible confounding factors, none but two were found to have received such agents, making a protective effect unlikely.

Keeping in mind study limitations (small sample size, selection bias, single-center experience, and descriptive hypothesis-generating only comparison), our results represent the first clinical data supporting the preclinical hypothesis of a cardioprotective effect of morphine pretreatment. A prospective confirmation of our results on a larger population is needed.