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. 2016 Apr 22;4(4):CD003868.
doi: 10.1002/14651858.CD003868.pub4.

Oral morphine for cancer pain

Philip J Wiffen  1 , Bee Wee, R Andrew Moore
Affiliations

Oral morphine for cancer pain

Philip J Wiffen et al. Cochrane Database Syst Rev. .

Abstract

Background: This is the third updated version of a Cochrane review first published in Issue 4, 2003 of The Cochrane Library and first updated in 2007. Morphine has been used for many years to relieve pain. Oral morphine in either immediate release or modified release form remains the analgesic of choice for moderate or severe cancer pain.

Objectives: To determine the efficacy of oral morphine in relieving cancer pain, and to assess the incidence and severity of adverse events.

Search methods: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9); MEDLINE (1966 to October 2015); and EMBASE (1974 to October 2015). We also searched ClinicalTrials.gov (1 October 2015).

Selection criteria: Published randomised controlled trials (RCTs) using placebo or active comparators reporting on the analgesic effect of oral morphine in adults and children with cancer pain. We excluded trials with fewer than 10 participants.

Data collection and analysis: One review author extracted data, which were checked by another review author. There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNTs) for the analgesic effect. We extracted any available data on the number or proportion of participants with 'no worse than mild pain' or treatment success (very satisfied, or very good or excellent on patient global impression scales).

Main results: We identified seven new studies in this update. We excluded six, and one study is ongoing so also not included in this update. This review contains a total of 62 included studies, with 4241 participants. Thirty-six studies used a cross-over design ranging from one to 15 days, with the greatest number (11) for seven days for each arm of the trial. Overall we judged the included studies to be at high risk of bias because the methods of randomisation and allocation concealment were poorly reported. The primary outcomes for this review were participant-reported pain and pain relief.Fifteen studies compared oral morphine modified release (Mm/r) preparations with morphine immediate release (MIR). Fourteen studies compared Mm/r in different strengths; six of these included 24-hour modified release products. Fifteen studies compared Mm/r with other opioids. Six studies compared MIR with other opioids. Two studies compared oral Mm/r with rectal Mm/r. Three studies compared MIR with MIR by a different route of administration. Two studies compared Mm/r with Mm/r at different times and two compared MIR with MIR given at a different time. One study was found comparing each of the following: Mm/r tablet with Mm/r suspension; Mm/r with non-opioids; MIR with non-opioids; and oral morphine with epidural morphine.In the previous update, a standard of 'no worse than mild pain' was set, equivalent to a score of 30/100 mm or less on a visual analogue pain intensity scale (VAS), or the equivalent in other pain scales. Eighteen studies achieved this level of pain relief on average, and no study reported that good levels of pain relief were not attained. Where results were reported for individual participants in 17 studies, 'no worse than mild pain' was achieved by 96% of participants (362/377), and an outcome equivalent to treatment success in 63% (400/638).Morphine is an effective analgesic for cancer pain. Pain relief did not differ between Mm/r and MIR. Modified release versions of morphine were effective for 12- or 24-hour dosing depending on the formulation. Daily doses in studies ranged from 25 mg to 2000 mg with an average of between 100 mg and 250 mg. Dose titration was undertaken with both instant release and modified release products. A small number of participants did not achieve adequate analgesia with morphine. Adverse events were common, predictable, and approximately 6% of participants discontinued treatment with morphine because of intolerable adverse events.The quality of the evidence is generally poor. Studies are old, often small, and were largely carried out for registration purposes and therefore were only designed to show equivalence between different formulations.

Authors' conclusions: The conclusions have not changed for this update. The effectiveness of oral morphine has stood the test of time, but the randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants and did not provide appropriate data for meta-analysis. Only a few reported how many people had good pain relief, but where it was reported, over 90% had no worse than mild pain within a reasonably short time period. The review demonstrates the wide dose range of morphine used in studies, and that a small percentage of participants are unable to tolerate oral morphine. The review also shows the wide range of study designs, and inconsistency in cross-over designs. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing participants over in cross-over design studies. It was not clear if these trials were sufficiently powered to detect any clinical differences between formulations or comparator drugs. New studies added to the review for the previous update reinforced the view that it is possible to use modified release morphine to titrate to analgesic effect. There is qualitative evidence that oral morphine has much the same efficacy as other available opioids.

PubMed Disclaimer

Conflict of interest statement

PW none known.

RAM has received institutional grant support from RB relating to individual patient level analyses of trial data on ibuprofen in acute pain and the effects of food on drug absorption of analgesics (2013), and from Grünenthal relating to individual patient level analyses of trial data regarding tapentadol in osteoarthritis and back pain (2015). He has received honoraria for attended boards with Menarini concerning methods of analgesic trial design (2014), with Novartis (2014) about the design of network meta‐analyses, and RB on understanding pharmacokinetics of drug uptake (2015).

BW is a specialist palliative care practitioner and manages patients with cancer pain.

This review was identified in a 2019 audit as not meeting the current definition of the Cochrane Commercial Sponsorship policy. At the time of its publication it was compliant with the interpretation of the existing policy. As with all reviews, new and updated, at update this review will be revised according to 2020 policy update.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Percentage of participants with oral morphine reporting no worse than mild pain. The size of the symbol is proportional to the size of the sample
5
5
Percentage of participants with oral morphine reporting an outcome equivalent to treatment success. The size of the symbol is proportional to the size of the sample
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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References to studies excluded from this review

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Davis 1993 {published data only}
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De Bernardi 1997 {published data only}
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De Conno 1997 {published data only}
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Deng 1997 {published data only}
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Forman 1993 {published data only}
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Georgiou 2000 {published data only}
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Gourlay 1986 {published data only}
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Gourlay 1995 {published data only}
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Griffith 1990 {published data only}
    1. Griffith S, Dewberry HM, Titcombe JM, McNamara PJG, Harcourt JMV, Twycross RG. Evaluation of the palatability of Oramorph - a proprietary preparation of oral morphine sulphate. Palliative Medicine 1990;4:205-9.
Hagen 1995 {published data only}
    1. Hagen N, Thirlwell MP, Dhaliwal HS, Babul N, Harsanyi Z, Darke AC. Steady-state pharmacokinetics of hydromorphone and hydromorphone-3-glucuronide in cancer patients after immediate and controlled-release hydromorphone. Journal of Clinical Pharmacology 1995;35(1):37-44. - PubMed
Hanks 1984 {published data only}
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Hasselstrom 1991 {published data only}
    1. Hasselstrom J, Alexander N, Bringel C, Svensson JO, Sawe J. Single dose and steady state kinetics of morphine and its metabolites in cancer patients - a comparison of two oral formulations. European Journal of Clinical Pharmacology 1991;40(6):585-91. - PubMed
Hill 1990 {published data only}
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Hill 1992 {published data only}
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Hoffman 1997 {published data only}
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Houde 1981 {published data only}
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Kaiko 1979 {published data only}
    1. Kaiko R, Wallenstein S, Rogers A, Heidrich G 3rd, Houde R. Relative analgesic potency of intramuscular heroin and morphine in cancer patients with postoperative pain: a preliminary report. National Institute on Drug Abuse Research Monograph 1979;27:254-60. - PubMed
Kaiko 1984 {published data only}
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Kaiko 1987 {published data only}
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Kaiko 1989 {published data only}
    1. Kaiko RF, Grandy RP, Oshlack B, Pav J, Horodniak J, Thomas G, et al. The United States experience with oral controlled release morphine (MS Contin tablets). Parts I and II. Review of nine dose titration studies and clinical pharmacology of 15 mg, 30 mg, 60 mg, and 100 mg tablet strengths in normal subjects. Cancer 1989;63(Suppl 11):2348-54. - PubMed
Kalso 1996 {published data only}
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Khojasteh 1987 {published data only}
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Lakdja 1997 {published data only}
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Lauretti 1999 {published data only}
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Lazarus 1990 {published data only}
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Li 1994 {published data only}
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Marinangeli 2004 {published data only}
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Masood 1995 {published data only}
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Masood 1996 {published data only}
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Meed 1987 {published data only}
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Minotti 1989 {published data only}
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Minotti 1998 {published data only}
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Morgan 1992 {published data only}
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NCT00573937 2010 {published data only}
    1. Prommer E (lead investigator). Methadone versus morphine for cancer-related pain. https://clinicaltrials.gov/ct2/show/NCT00573937 2010.
NCT00660348 2014 {published data only}
    1. Erdek M (lead investigator). A randomized study of optimal pain management: standard pain control versus early intervention with intrathecal therapy in patients with advanced pancreatic cancer. https://clinicaltrials.gov/ct2/show/NCT00660348 2014.
NCT00726830 2012 {unpublished data only}
    1. Fisch M, Bearden J (lead investigators). A randomized comparison of oral methadone as a "first-switch" opioid versus opioid switching between sustained-release morphine and oxycodone for oncology-hematology outpatients with pain management problems: the "simply rotate" study. https://clinicaltrials.gov/ct2/show/NCT00726830 2010.
NCT01541124 2012 {published data only}
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Penn 1992 {published data only}
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Portenoy 1999a {published data only}
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Roca 1996 {published data only}
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References to ongoing studies

NCT01809106 2014a {unpublished data only}
    1. Corli O (lead investigator). RCT comparing the analgesic efficacy of 4 therapeutic strategies based on 4 different major opioids (fentanyl, oxycodone, buprenorphine vs morphine) in cancer patients with moderate/severe pain, at the moment of starting 3rd step of WHO analgesic ladder (CERP). https://clinicaltrials.gov/ct2/show/NCT01809106 2014.

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