SHORT COMMUNICATION

High doses of oxycodone–naloxone combination may providepoor analgesia

Sebastiano Mercadante & Patrizia Ferrera &

Claudio Adile

Received: 2 February 2011 /Accepted: 30 May 2011 /Published online: 9 June 2011# Springer-Verlag 2011

Abstract Several studies have shown that an oxycodone/naloxone combination (ratio 2:1) provides analgesia andless constipation in non-cancer patients receiving relativelylow doses of this formulation. A case report of a cancerpatient who was receiving increasing doses of oxycodonewith an unexpected declining analgesia is presented. Thesubstitution with the same doses (240 mg/day) of regularcontrolled-release oxycodone was effective in regainingadequate analgesia.

Keywords Cancer pain . Oxycodone . Naloxone .

Constipation

Oral morphine has been widely used for treating cancerpain of moderate to severe intensity and remains the opioidof choice for its familiarity, availability, and costs ratherthan proven superiority [2]. Oxycodone has been usedclinically for the same indications and has been found toprovide analgesia comparable to that of morphine andmediated primarily in the central nervous system.Controlled-release oxycodone (CRO) is widely acceptedas an alternative to morphine, resulting as safe and effectiveas controlled-release morphine [9, 10]. The use of relativelyhigh doses of CRO in advanced cancer patients was safe,

efficient, and unrelated to shorter survival times [1, 8].Opioid-induced constipation (OIC) occurs in approximately40% of patients receiving opioid therapy, and in manycases, OIC causes patients to reduce or discontinue theiropioid therapy, resulting in analgesic undertreatment [3].

As the impact of opioids on gastrointestinal function isprimarily due to local interactions between opioids and theirreceptors in the gut, the administration of an opioid antagonistselectively acting in the gut could block the local effects ofopioids on bowel function without impairing central analgesicefficacy [6]. In several studies, coadministration of oraloxycodone with an opioid antagonist, such as naloxone, hasbeen found to confer advantages with regard to constipationin patients with chronic pain [5, 7, 9, 11–13]. Thiscombination is available in many countries in Europe.However, these studies were performed in non-cancer patientsreceiving relatively low doses of an oxycodone–naloxonecombination. Here, we present a case of a cancer patient whowas receiving increasing doses of oxycodone with anunexpected declining analgesia. The substitution with regularCRO was effective in regaining adequate analgesia.

Case report

A patient with lung cancer, 72 years old, was admitted tohospital for a pain due to the involvement of the thoracicwall. He was receiving oxycodone 40 mg/day and hadserious constipation. Pain intensity was 6/10 on a numericalscale of 0 to 10. For these reasons, an increase in the doseof oxycodone was planned, preferring a combination withnaloxone. Thus, oxycodone doses were progressivelyincreased in the subsequent days. While constipationclearly improved, however, pain intensity did not change.After 4 days, the patient was receiving an oxycodone–

S. Mercadante (*) : P. Ferrera : C. AdilePain Relief and Palliative Care Unit,La Maddalena Cancer Center,Via San Lorenzo 312,90146 Palermo, Italye-mail: terapiadeldolore@lamaddalenanet.it

S. MercadanteDepartment of Anesthesia and Intensive Care,University of Palermo,Palermo, Italy

Support Care Cancer (2011) 19:1471–1472DOI 10.1007/s00520-011-1205-x

naloxone combination of 240/120 mg per day, unsuccess-fully. No other problems were recorded. It was supposedthat naloxone in doses of 120 mg/day could have reducedthe expected analgesia of increasing doses of oxycodone.The combination was discontinued, and a traditionalformulation of CRO at the same doses was started. Paincontrol was rapidly obtained with 240 mg/day of oxy-codone, and pain intensity was 3/10 the day after. Thepatient was discharged home with the prescription ofoxycodone 240 mg/day and adequate doses of senna andlactulose for constipation.

Discussion

A new formulation oxycodone/naloxone that combinesprolonged-release oxycodone and prolonged-release nalox-one with a ratio of 2:1 has been recently developed. Theaim of this formulation is to counteract OIC developmentthrough naloxone local antagonist effect on the opioidreceptors in the gut wall while maintaining analgesia due tothe slow absorption of the formulation and the lowbioavailability of naloxone, due to extensive first-passmetabolism [6]. Following oral administration, naloxonehas a low oral availability of <2% and a negligible systemicavailability and might reduce the risk of overburdening thehepatic enzymatic systems, responsible for its metabolism[9, 13], thereby reducing the risk of antagonism, at least atthe doses used in these studies, which were in the range of20–80 mg [5, 7, 11–13].

In this cancer patient receiving higher doses of oxy-codone/naloxone combination, opioid analgesia was poordespite increasing doses of oxycodone/naloxone combina-tion. It is likely the attenuation of oxycodone analgesia withincreasing doses of the combination was possibly due to theabsorption of a certain amount of naloxone which canaccount for a central agonistic effect on analgesia, over-coming the capability of hepatic enzymes to limit systemicavailability [4]. Liver tests were within the limits ofnormality. No data regarding possible polymorphisms wereavailable. The use of the same doses of oxycodone alone,without naloxone, provided an adequate analgesia. No otherwithdrawal signs were observed, as whether the increasingdoses of naloxone would counteract the analgesic effects ofincreasing doses of oxycodone, resulting in a negativeanalgesic balance. This seems to suggest that the combina-tion of drugs in high doses may produce some unexpectedcentral effect of naloxone, reducing the global analgesiaprovided by oxycodone.

According to this observation, high doses of a combina-tion of oxycodone–naloxone could provide limited analge-sia. Further studies with an appropriate design should beperformed, particularly in cancer patients requiring highdoses of opioids and having more complex pain situations.

Conflict of interest There are no conflicts of interest.

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