Oral morphine for cancer pain
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.
To determine the efficacy of oral morphine in relieving cancer pain, and to assess the incidence and severity of adverse events.
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).
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).
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.
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.
Philip J Wiffen, Bee Wee, R Andrew Moore
Plain language summary
Oral morphine for cancer pain
Morphine taken by mouth produced good pain relief for most people with moderate or severe cancer pain.
One person in two or three who gets cancer will suffer from pain that becomes moderate or severe in intensity. The pain tends to get worse as the cancer progresses. Morphine taken by mouth has been used since the 1950s for controlling cancer pain. In 1986 the World Health Organization recommended taking an oral solution of morphine every four hours. Morphine is now available in a number of different formats that release the morphine over various periods of time. Morphine immediate release is rapidly absorbed, and would usually be taken every four hours. Modified release tablets are available that release morphine more slowly, so that they can be taken only twice a day or even only once a day.
In this updated review we set out to estimate how well morphine worked, how many people had side effects, and how severe those side effects were – for example, whether they were so severe that participants stopped taking their oral morphine.
We found 62 studies with 4241 participants. The studies were often small, compared many different preparations, and used different study designs. This made it difficult to work out whether any one tablet or preparation of oral morphine was better than any other. There did not seem to be much difference between them.
More than 9 in 10 participants had pain that went from moderate or severe before taking morphine to pain that was no worse than mild when taking morphine. More than 6 in 10 participants were very satisfied with the morphine treatment, or considered the result to be very good or excellent. Only about 1 person in 20 stopped taking morphine because of side effects. Morphine is associated with some unwanted effects, mainly constipation, and nausea and vomiting.
Quality of the evidence
At one level these are good results. On another level, the quality of studies is generally poor and we could wish for more consistency in study design, and especially in study reporting, which should include the outcome of pain reduced to tolerable levels – no worse than mild pain – so that people with cancer are not bothered by pain.
Philip J Wiffen, Bee Wee, R Andrew Moore
Implications for practice
We identified no new studies for inclusion in this update, and the conclusions remain unchanged.
For people with cancer pain
This literature review, and many years of use, shows oral morphine to be an effective analgesic in patients who suffer pain associated with cancer. Oral morphine remains the gold standard for treating moderate to severe pain. Help may be needed to manage the more common undesirable adverse effects such as constipation and nausea.
This literature review, and many years of use, shows oral morphine to be an effective analgesic in patients who suffer pain associated with cancer. Oral morphine remains the gold standard for treating moderate to severe pain. This review demonstrates that it is possible to titrate with oral morphine of any formulation, and to be confident that most patients will achieve a high level of pain relief within at least two weeks. There is likely to be a small number of patients who do not benefit from morphine, or who may develop intolerable adverse events.
For policy makers
This literature review, and many years of use, shows oral morphine to be an effective analgesic in patients who suffer pain associated with cancer. Oral morphine remains the gold standard for treating moderate to severe pain.
This review demonstrates that it is possible to titrate with oral morphine of any formulation, and to be confident that most patients will achieve a high level of pain relief within at least two weeks. There is likely to be a small number of patients who do not benefit from morphine, or who may develop intolerable adverse effects and so other opioids need to be included in formularies. Oral morphine remains the gold standard for treating moderate to severe pain.
Implications for research
The quality of reporting of trials in this area continues to be disappointing. Despite this, the review shows that even with very variable descriptions of outcomes, it is possible to discern that a high proportion of patients with cancer pain can obtain good pain relief (or low pain levels) within a sensible time after beginning titration with oral morphine.
Two methodological issues stand out. The quality of reporting of trials continues to be poor and small studies are far too common.
Trials need to consider additional endpoints of no worse than mild pain as well as the impact of morphine on symptoms that raise serious concerns such as consciousness, appetite, and thirst.
Given that most of the studies in this review were completed within the last 20 years the obvious implication for research is to instigate a morphine trialists' collaboration in order to undertake retrospective analyses of clinical trial data, using outcomes of clear patient benefit (no worse than mild pain within two weeks of starting morphine titration). Trialist collaborations have proved highly informative, with the Antiplatelet Trialists Collaboration probably the largest example of how retrospective analysis and pooling of clinical trial data can lead to improvements in treatment. With oral morphine in cancer pain, the 62 studies with 4241 participants should provide useful information about outcomes, titration schedules, and formulations to be translated into better results for patients, and a cost‐effective approach for healthcare providers.
A second goal would be to extend the collaboration to include other drug interventions, including other oral opioids, and formulations of opioids other than oral.
A third goal of the collaboration would be to set guidelines for future clinical trials and systematic reviews to assess pain and pain relief by means of patient‐reported validated scales, and to present data that can be related to individual participants rather than aggregated or mean data.