Review

Palliative Medicine 25(5) 402–409 ! The Author(s) 2010 Is oral still the first choice Reprints and permissions: sagepub.co.uk/journalsPermissions.nav for moderate to severe cancer DOI: 10.1177/0269216310392102 pain? A systematic review within the pmj.sagepub.com European 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 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 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 , 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 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 itself. Full text examination of these papers constituted a study limitation. led to the exclusion of the following seven studies: The basic purpose of this work was to perform a Mercadante et al.,15 Leppert16 and Wilder-Smith systematic search and conduct a meta-analysis if the et al.17 because they compare morphine with weak opi- quality of the studies retrieved allowed it. oids; Coluzzi et al.18 because it concerns morphine in breakthrough pain; in Broomhead et al.19 patient out- come evaluation is poorly reported; in Ferrell et al.20 Results patients who were already receiving opioids (oxyco- done, hydromorphone, codeine or morphine) were ran- Initially 672 papers were identified using the search domized either to a ‘no change’ group or changed strategy described above on the three databases to morphine. However, no data were presented on

Records identified through database searching Medline 343 Embase 238 Cochrane register of controlled trial databases 91

Abstracts screening for duplicity and eligibility Records excluded (n=672) (n=663)

Additional records identified through Cochrane syst. Full-text articles assessed review on oral morphine for eligibility (n=9) for cancer pain (n=20)

Full-text articles selected, after exclusion with reasons (n=13) Full-text articles selected, after exclusion with reasons (n=4)

Additional records identified through hand Studies included in qualitative search (n=1) synthesis (n=18)

Figure 1. Flow diagram. Caraceni et al. 405 the numbers of patients receiving each opioid. One randomized controlled trial25 compared mor- Heiskanen et al.21 present the same data of a previous phine MR with methadone in patients who were study.22 either opioid naı¨ ve or on WHO step II drugs and Finally, 16 studies1,12–14,22–33 and a meta-analysis11 showed no statistical differences in terms of efficacy. were selected. A hand search allowed one to retrieve One study planned as an equivalence trial12 demon- one further eligible study.34 strated equivalence between oral hydromorphone and One study,19 which was excluded because it did not morphine in both the immediate and slow-release report patient evaluation data on efficacy or side effects, phases of the study. Comparisons of the use of TTS was the only one comparing morphine to placebo. In a fentanyl versus oral morphine are also available in pilot pre-study phase, 17 patients were randomly unblinded trials showing no evidence of difference assigned to placebo (four patients) or different schedule between treatments.29,30 Again all these studies are lim- doses of morphine (13 patients). Immediate-release ited by the significant attrition due to patients who are morphine tablets ad libitum were available for all lost to follow up ranging from 20% to 40% of cases. patients as rescue medications. Compared to morphine, Interestingly, unpublished results from Napp placebo treated patients had shorter average time to Laboratories34 show better analgesia with morphine remedication (p ¼ 0.003) and their mean rescue dose than with hydromorphone, but 44% of patients were was also higher (p ¼ 0.0006). lost to follow up. Table 2 reports a summary of the main characteris- The comparison of the tolerability profile of mor- tics of the included studies, which enrolled a total of phine did not show any clinically significant difference 2053 patients (without those included in the meta-ana- with other opioids, but less constipation in comparison lysis) and it is hierarchically organized in a way with TTS fentanyl,11 and more drop outs for adverse that studies conducted on opioid-naı¨ ve patients are effects with methadone for excessive sedation.25 first reported, followed by studies with patients on Tassinari et al.’s meta-analysis11 comparing side step II and step III WHO ladder analgesic drugs, and effects of transdermal opioids versus slow-release mor- by studies that do not reported this datum or are phine took into consideration four articles14,23,29,30 for unclear. a total of 425 patients. Three studies were on fenta- There is only one study on opioid-naı¨ ve patients,14 nyl23,29,30 and one on buprenorphine.14 No significant comparing morphine with transdermal buprenorphine differences in the side effects global assessment was and showing a better efficacy and side effects profile for found, but when considering side effects individually buprenorphine. Unfortunately the sample size is limited transdermal opioids produced less constipation. and the quality of the study is very low, as no treatment Worthy of notice is that eight out of 17 of the allocation concealment is provided and no drop-out considered studies have received some kind of sponsor- rate is reported, raising some doubts about data ship from the pharmaceutical industry; in the other quality. papers, except one, details on sponsorship were not There are not many studies of good methodological reported. quality. A few experiences demonstrated, in controlled double blind clinical trials, that oral morphine is an Discussion effective analgesic in patients with cancer pain and that no difference could be demonstrated in efficacy, To establish a first choice role for oral morphine to in comparison with diamorphine,1 methadone25 and treat moderate to severe cancer pain there should be oxycodone24; other experiences report, in unblinded evidence that oral morphine is an effective analgesic conditions, the same type of result comparing morphine and that it is better than other analgesics alternatively with methadone and transdermal therapeutic system proposed. Studies should therefore compare the use of (TTS) fentanyl.13,26 oral morphine in an opioid-naı¨ ve population of All these studies have significant methodological patients with severe cancer pain or with pain no problems, in particular due to low statistical power longer relieved with lower potency analgesics, such as often caused by a loss of patient information during those classified as step II in the WHO ladder. The the study period. absence of good quality comparison with morphine Randomized double blind studies of better quality and other opioids in opioid-naı¨ ve patients makes it are available to compare patients who are screened impossible to give a final answer to the main question. as already responsive to morphine; such trials failed The amount of relief offered by oral morphine admin- to show any difference between morphine (both in istration to unselected opioid-naı¨ ve patients is therefore immediate and slow-release oral preparation) and difficult to estimate and the evidence that morphine and oxycodone22,27,31,32 and between slow-release hydro- other opioids have similar effects in patients with a morphone versus slow-release morphine.28 favourable analgesic response to opioids has limited 406 Table 2. Summary of the main characteristics and of the outcomes of included studies

Previous opioid treat- Number Study Drop-out Reported Author/year Comparator ment (WHO ladder) of patients limitations rate efficacy Outcomes side effects

1 Pace et al.14 2007 MR vs. BU Randomized N 52 NAC NR BU > MO MO > vertigo, constipation, open label prospective nausea trial 2 van Seventer et al.23 2003 MR vs. FE Parallel II 30% opioid naı¨ve 131 NAC 20% NED MO: 23/64 drop-out AE FE: 3/67 drop-out AE 3 Lauretti et al.24 2003 MR vs. OXY Double-blind II (tramadol) 26 15% NED MO > nausea &vomiting crossover 4 Bruera et al.25 2004 MR vs. ME Double blind, 70% II 30% 103 LLFU 36% NED ME > drop-out AE (NED) parallel completely naı¨ve 5 Ventafridda et al.26 1986 IR vs. ME Parallel group II 66 LLFU 34% NED MO > dry mouth ME > headache 6 Mercadante et al.13 2008 MR vs. FE and ME II 108 NAC LLFU 35% NED NED prospective random- ized control trial 7 Heiskanen and Kalso22 MR vs. OXY Double-blind III 45 LLFU 40% NED 1st OXY > constipation 1997 crossover phase MO > vomiting MO > O- XY 2nd phase 8 Mucci LoRusso et al.27 MR vs. OXY Double- III 100 20% NED NED MO > dry mouth 1998 dummy parallel 9 Moriarty et al.28 1999 MR vs. HY parallel III Opioid dose titrated 100 NAC 11% NED NED to effect and stabi- lized before evalua- tion period beginning. 10 Ahmedzai and Brooks29 MR vs. FE cross-over III 202 NAC LLFU 45% NED Badly reported 1997 11 Wong et al.30 1997 MR vs. FE parallel III 47 NAC 15% NED NED alaieMdcn 25(5) Medicine Palliative 12 Kalso and Vainio31 1990 IR vs. OXY Double-blind III 20 LLFU 5% NED NED (sedation in both groups. crossover >nausea for MO, not SD) 13 Hanna et al.12 2008 MR vs. HY Double-blind III 200 LLFU 18%(IR) EQUIVAL EQUIVAL 33%(SR) 14 Napp Laboratories34 2000 Not reported (baseline 87 LLFU-NAC- 44% MO > HY HY > diarrhoea VAS < 30) NITT (p < 0.04) (continued) Caraceni et al. 407

clinical relevance to influence the decision about the first choice drug. On the other hand the available evidence suggests that oral morphine, hydromorphone, oxycodone and methadone offer similar pain relief in this patient pop- ulation with a similar pattern of side effects. Transdermal opioids may be associated with less 11

constipation constipation and good patient compliance, but their nausea and vomiting >

> pharmacokinetic and dynamic characteristics can, how- ever, be viewed as obstacles35 to consider these drugs a first choice in the opioid-naı¨ ve or strong opioid-naı¨ ve patient and these considerations are particularly impor- tant due to the absence of better evidence about the

al Analogue Scale use of TTS opioids in this indication. Methadone, due

Reported efficacy Outcomes side effects 36 e, IR: immediate release morphine, BC: Brompton Cocktail to its very long and unpredictable half-life, is better reserved for more skilled professionals and not recom- mended as a first-line prescription. While it can be concluded that the strategy to treat

30% NED NED cancer pain has not been significantly changed since the Drop-out rate WHO ladder was launched in 1986, it is also evident that oxycodone, hydromorphone and morphine oral prepa- rations can be considered clinically very similar in the balance between efficacy and side effects. The choice ///MO Study limitations among these drugs can be influenced by several factors, including availability, cost and other local consider- ations, but it should be recognized that the role of mor- phine as a reference drug is still extremely important.4 44 LLFU 38% NED NED Number of patients Conclusion These studies do not add significant information to the previous Cochrane review4 confirming the limitation of efficacy and tolerability data on opioid-naı¨ ve and non- selected populations of cancer patients treated with rphine TTS, OXY: oxycodone, MR: modified release morphine, ME: methadon morphine and suggesting that oral morphine, oxyco- pain to warrant use of narcotics done and hydromorphone have similar efficacy and N-II-III 425 NR Sufficient severe NR 699 LLFU 79% NED BC Previous opioid treat- ment (WHO ladder) NR 32 LLFU toxicity in this patient population. There is strong need to provide valid evidence to identify the relative role of different opioids in cancer pain treatment. ¨ve, I: WHO I ladder, II: WHO II ladder, III: WHO III ladder Funding analysis crossover crossover double dummy, cross- over crossover This work was funded by the EPCRC through the EU Sixth

MR vs. HY Double-blind, Framework Programme, contract no 037777 and the Floriani Foundation of Milan. The EPCRC has the overall aim to improve treatment of pain, depression and fatigue through translation research.

1979 IR vs. BC Double-blind The core scientific group/work package leaders are: Stein 1998 MR vs. OXY Double-blind

33 Kaasa (project coordinator), Frank Skorpen, Marianne 32 2008 MR vs. FE and BU Meta- 1976 IR vs. BC Double-blind Jensen Hjermstad and Jon Ha˚ vard Loge, Norwegian 1 11 University of Science and Technology (NTNU); Geoffrey Continued Hanks, University of Bristol; Augusto Caraceni and Franco De Conno, Fondazione Istituto Di Ricovero e Cura a Author/year Comparator Carattere Scientifico (IRCCS) Istituto Nazionale dei 17 Twycross 18 Tassinari NED: not evidence of difference, EQUIVAL: equivalence, AE: adverse events Previous Opioid Treatment (WHO ladder):Study N: limitations: naı NAC: no allocation concealment, LLFU: large losses to follow up, NITT: no intention to treat analysis, NR: not reported, VAS: Visu Table 2. Comparator:MO:morphine,HY:hydromorphone,FE:FentanylTTS,BU:bupreno 16 Melzack et al. 15 Bruera et al. Tumori, Milan; Irene Higginson, King’s College London; 408 Palliative Medicine 25(5)

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