Clarifications on oxycodone–naloxone combination in cancer pain management

Abstract

Compagnone et al. raise a series of questions regarding thecase report recently published by our group [1]. Herein, werespond to their concerns, although in some parts, remarksappear to be contradictory.1. For the authors, it is unclear how titration with oxy-codone–naloxone combination (OXN PR) has beendone up to doses of 240/120 mg. The reason is probablydue to a low confidence with opioid dosages and mo-dality of titration [2] used in a high-volume acute painrelief and palliative care unit, where titration is oftenaccelerated to obtain an adequate pain relief in theshortest time to avoid unnecessary suffering of thepatients once they are admitted to a specialized unitwith a high level of monitoring. This is the basis ofunits of this kind, in comparison with oncological unitsor hospice setting [3]. A large experience with oxy-codone (CRO) showed that this drug is as effective asother opioids [4], even when used at very high doses[5]. In the case we have illustrated, the patient who wasalready receiving 40 mg/day of CRO unsuccessfully,was administered 80/40, 160/80, and then 240/120 mgof OXN PR for the subsequent 3 days. As doubling thedoses each subsequent day was unsuccessful, withoutreporting relevant adverse effects, we supposed thatdosesofnaloxonecouldhave limitedopioideffectswithsuch increasing doses (including up to 120 mg/day ofnaloxone). This was confirmed by the substitution withCRO, which provided a good analgesia with the samedose of oxycodone, but without naloxone. Traditionallaxatives were then prescribed successfully. The casereportedwasjustoneexampleofpreviouspatientswehavetreated,whererelativelyhighdosesofOXNPR,overabout200 mg daily, resulted in a decrease of analgesia.2. Compagnoni et al. seemed to be worried about the state-mentthatOXNPRisnotefficaciousinthemanagementofcancer pain. However, this was not the case, because weonlywarnedaboutthepossibledecreaseofanalgesiawhenpatientsreceivehighdosesofthiscombinationanddidnottake into consideration the effectiveness of an otherwiseinteresting news in the analgesic armamentarium.3. The authors contradict themselves when reporting thatthe maximum OXN PR dose allowed, recommended bythe summary product characteristics, is 80/40 mg/day,based on controlled studies performed in non-cancerpatients who may require low doses of opioids. Cancerpatients are candidates for receiving higher doses. For-tunately, this is not the case; otherwise, OXN PR shouldbe considered as a drug with a sort of ceiling effect atdoses of 80/40 mg/day. The paper they quoted confirmsexactly the contrary [6]. In this large double-blind con-trolled study, CRO patients were titrated up to 180 mg/day (not 120 mg/day, please check the paper now inpress), which is more than double the recommendeddoses, and adequate pain relief was obtained in mostpatients, although the authors did not mention the meandoses achieved after 4 weeks. Thus, it is likely thatmedium doses of OXN PR, in the range of 20–180 mg/day, are effective in cancer pain managementin most patients. Instead, our experience suggests thathigher dose (possibly over the limit of 180–240 mg/dayof OXN PR) could be challenging, and it is suggestedthat further studies be performed to observe eventualplasmatic changes in the ratio between oxycodone andnaloxone, which may be influenced by saturation of