Review Palliative Medicine 25(5) 402–409 ! The Author(s) 2010 Is oral morphine still the first choice Reprints and permissions: sagepub.co.uk/journalsPermissions.nav opioid for moderate to severe cancer DOI: 10.1177/0269216310392102 pain? A systematic review within the pmj.sagepub.com European Palliative Care Research Collaborative guidelines project Augusto Caraceni Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Italy Alessandra Pigni Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Italy Cinzia Brunelli Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale Tumori, Italy Abstract The aim of this systematic review was to evaluate the evidence that oral morphine can be recommended as the first choice opioid in the treatment of moderate to severe cancer pain in updating the European Association for Palliative Care opioid recommendations. A systematic literature review was performed to update the 2007 Cochrane review ‘Oral morphine for cancer pain’. The literature search was conducted on MedLine, EMBASE and Cochrane Central Register of Controlled Trials databases. The search strategy, limited in time (from 1 July 2006 to 31 October 2009), was aimed to be as extensive as possible using both text words and MeSH/EMTREE terms; a hand search of the reference lists of identified papers was also performed. Randomized clinical trials, containing data on efficacy and/or side effects of morphine, were identified. Among the papers retrieved from the cited databases and the Cochrane review, 17 eligible studies, for a total of 2053 patients, and a meta-analysis were selected. These studies do not add significant information to the previous Cochrane review confirming the limitation of efficacy and tolerability data on opioid-naı¨ve and non-selected populations of cancer patients treated with morphine and suggesting that oral morphine, oxycodone and hydromorphone have similar efficacy and toxicity in this patient population. Keywords Neoplasm, morphine, opioid, pain Introduction analgesia, to adapt the dose to individual needs or to Oral morphine has been considered for 25 years the diminish side effects. The low cost of oral morphine drug of first choice for treating moderate to severe solution or other immediate-release preparations and cancer pain due to its historical background and for its potential availability are still relevant enough for being the most widely used and field tested by a very this drug to be considered essential in the World large clinical experience. Immediate-release oral mor- Health Organization (WHO) list of medication to be phine administered every four hours is effective and universally provided to relieve suffering in countries safe and was the first rational pharmacological with limited medical resources. For all these reasons it approach proposed to treat cancer pain, overcoming is recommended as a first-line opioid in the WHO professional prejudice and wariness and local tradi- Cancer Pain Relief Guidelines2 and in the European tional poorly systematized practices, such as Association for Palliative Care (EAPC) recommenda- Brompton Cocktail administration.1 Its short half-life tions, published first in 1996 and updated in 2001,3 allows for frequent changes in dosing to increase where morphine is considered the opioid of first Corresponding author: Augusto Caraceni, Palliative Care, Pain Therapy and Rehabilitation, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy Email: [email protected] Caraceni et al. 403 choice in the treatment of moderate–severe cancer pain; Table 1. Search strategy applied to retrieve papers from yet only level C evidence supports this recommenda- MEDLINE tion, reflecting the paucity of good quality clinical stud- 3 Query ies on this issue. number Query content The availability of other opioid drugs, orally (imme- diate, slow or modified release (MR) preparations) or #17 #16 Limits: English transdermally administered, with pharmacological #16 (#4 AND #15) AND ("2006/07/01" characteristics that largely overlap with those of mor- [Entrez Date]: "2009/10/31"[Entrez Date]) phine and all of which are in theory adequate to #15 #13 NOT #14 manage severe cancer pain, poses the question whether #14 animals [mh] NOT humans [mh] morphine should still be considered the drug of choice #13 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 and oral administration the route of choice for this OR #12 indication. The treatment of choice should combine #12 placebo [tiab] analgesic efficacy, safety of use and flexibility of #11 groups [tiab] dosing to respond in a short time to pain changes and #10 trial [tiab] to individual sensibility to opioid effect with simplicity #9 randomly [tiab] of prescription. #8 drug therapy [sh] A systematic review of oral morphine for cancer pain treatment is available in the Cochrane Library,4 and #7 randomized [tiab] it includes also studies on cancer patients with mild to #6 controlled clinical trial [pt] moderate pain and studies comparing different routes #5 randomized controlled trial [pt] of administration of morphine. It was last updated in #4 ("2006/07/01"[Entrez Date]: "3000"[Entrez Date]) August 2007. Within the process of revision and update AND (#1 AND (#2 OR #3)) of the EAPC guidelines on the use of opioids for cancer #3 cancer OR neoplasm OR tumour OR oncol* pain, promoted by the European Palliative Care OR carcinoma* OR malignan* Research Collaborative (EPCRC),5 a systematic litera- #2 palliative care OR hospice OR terminal care ture review was conducted with the aim to give an OR terminally ill answer to the following question: ‘In adult patients #1 morphine with moderate to severe pain directly due to cancer Note: Commands above reported are automatically expanded by and never treated with strong opioids, which is the evi- PubMed into more complex ones using both text words and MeSH dence that oral morphine is better than placebo, or terms, i.e. #2 palliative care OR hospice OR terminal care OR terminally other oral/transdermal opioids in the management of ill is expanded to: pain?’ (‘‘palliative care’’[MeSH Terms] OR (‘‘palliative’’[All Fields] AND ‘‘care’’[All Fields]) OR ‘‘palliative care’’[All Fields]) OR (‘‘hospices’’[MeSH Terms] OR ‘‘hospices’’[All Fields] OR ‘‘hospice’’[All Methods Fields] OR ‘‘hospice care’’[MeSH Terms] OR (‘‘hospice’’[All Fields] AND ‘‘care’’[All Fields]) OR ‘‘hospice care’’[All Fields]) OR (‘‘terminal The Cochrane review od ‘Oral morphine for cancer care’’[MeSH Terms] OR (‘‘terminal’’[All Fields] AND ‘‘care’’[All Fields]) pain’4 was used as a first basis for the retrieval of rele- OR ‘‘terminal care’’[All Fields]) OR (‘‘terminally ill’’[MeSH Terms] OR (‘‘terminally’’[All Fields] AND ‘‘ill’’[All Fields]) OR ‘‘terminally ill’’[All vant studies and a new search was conducted to identify Fields]). studies covering the period between 2007 and 2009, The same expansion was then applied also to the EMBASE and Cochrane after the Cochrane review was published. The literature Controlled Trial Database searches. search was conducted on MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials data- bases, over a time frame ranging from 1 January 2007 data on patient reported efficacy and/or side effects of to 31 October 2009. The search strategy for the morphine administered orally in comparison with pla- MEDLINE database, which used both text words cebo or other opioids, such as methadone, oxycodone, and MeSH/EMTREE terms, is reported in Table 1, hydromorphone, fentanyl, and buprenorphine also in and appropriately revised strategies were developed the transdermal mode of administration; to be written for each database; a hand search of the reference lists in the English language. Studies dealing with the use of of identified papers was also performed. morphine for breakthrough pain management were Inclusion criteria for relevant study selection of both excluded. Papers identified using the search strategy the Cochrane review4 and the new search were: to have were separately screened and assessed for inclusion by been conducted in human, adult patients with chronic two review authors (AP and CB). Disagreements were cancer pain; to use a randomized controlled trial design resolved by discussion and reasons for excluding trials or to be a meta-analysis of reported data; to contain were reported. 404 Palliative Medicine 25(5) The content and the quality of each included study (Figure 1); abstract screening lead to the full text was analysed following methodological indications examination of nine papers,6–14 five of which were from the Cochrane Handbook for Systematic Reviews excluded for the following reasons: Dale et al.,6 of Interventions and summarized according to a stan- Homsi et al.7 and Currow et al.8 have no comparator; dardized form, including the assessment of type of Tassinari et al.’s meta-analysis9 on transdermal fenta- comparator, previous analgesic treatment, number of nyl and morphine includes both cancer and non-cancer enrolled patients, study limitations (no allocation con- pain; in Kress et al.10 no data on morphine were cealment; large losses to follow up; no intention to treat reported. analysis; early stopping for benefit; failure to report In the Cochrane review4 54 studies met the inclusion outcomes), drop-out rate and efficacy and side effects criteria, but only 20 had a comparator different from reported outcomes. Failure to discuss study limitations morphine