Opioids for cancer pain ‐ an overview of Cochrane reviews
Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Opioid (morphine‐like) drugs are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. The most commonly‐used opioid drugs are buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, tramadol, and tapentadol.
To provide an overview of the analgesic efficacy of opioids in cancer pain, and to report on adverse events associated with their use.
We identified systematic reviews examining any opioid for cancer pain published to 4 May 2017 in the Cochrane Database of Systematic Reviews in the Cochrane Library. The primary outcomes were no or mild pain within 14 days of starting treatment, withdrawals due to adverse events, and serious adverse events.
We included nine reviews with 152 included studies and 13,524 participants, but because some studies appeared in more than one review the number of unique studies and participants was smaller than this. Most participants had moderate or severe pain associated with a range of different types of cancer. Studies in the reviews typically compared one type of opioid or formulation with either a different formulation of the same opioid, or a different opioid; few included a placebo control. Typically the reviews titrated dose to effect, a balance between pain relief and adverse events. Various routes of administration of opioids were considered in the reviews; oral with most opioids, but transdermal administration with fentanyl, and buprenorphine. No review included studies of subcutaneous opioid administration. Pain outcomes reported were varied and inconsistent. The average size of included studies varied considerably between reviews: studies of older opioids, such as codeine, morphine, and methadone, had low average study sizes while those involving newer drugs tended to have larger study sizes.
Six reviews reported a GRADE assessment (buprenorphine, codeine, hydromorphone, methadone, oxycodone, and tramadol), but not necessarily for all comparisons or outcomes. No comparative analyses were possible because there was no consistent placebo or active control. Cohort outcomes for opioids are therefore reported, as absolute numbers or percentages, or both.
Reviews on buprenorphine, codeine with or without paracetamol, hydromorphone, methadone, tramadol with or without paracetamol, tapentadol, and oxycodone did not have information about the primary outcome of mild or no pain at 14 days, although that on oxycodone indicated that average pain scores were within that range. Two reviews, on oral morphine and transdermal fentanyl, reported that 96% of 850 participants achieved that goal.
Adverse event withdrawal was reported by five reviews, at rates of between 6% and 19%. Participants with at least one adverse event were reported by three reviews, at rates of between 11% and 77%.
Our GRADE assessment of evidence quality was very low for all outcomes, because many studies in the reviews were at high risk of bias from several sources, including small study size.
The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low, although the evidence we have indicates that around 19 out of 20 people with moderate or severe pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days. This accords with the clinical experience in treating many people with cancer pain, but overstates to some extent the effectiveness found for the WHO pain ladder. Most people will experience adverse events, and help may be needed to manage the more common undesirable adverse effects such as constipation and nausea. Perhaps between 1 in 10 and 2 in 10 people treated with opioids will find these adverse events intolerable, leading to a change in treatment.
Philip J Wiffen, Bee Wee, Sheena Derry, Rae Frances Bell, R Andrew Moore
Plain language summary
Morphine‐like drugs for cancer pain
In about 19 of 20 people with moderate to severe pain from cancer, morphine‐like drugs (opioids) can probably reduce pain to mild or no pain within 14 days if they can tolerate the side effects. Most people will have side effects, and about 1 in 10 to 2 in 10 will need to change their treatment because of side effects.
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 (WHO) recommended taking morphine‐like drugs for moderate to severe pain from cancer. A number of different drugs are available, some taken by mouth, but others applied in stick‐on patches.
In this overview of Cochrane Reviews we examined all the evidence on how well morphine‐like drugs worked, mostly when taken by mouth or through a skin patch, how many people had side effects, and how severe or troublesome those side effects were — for example, whether they caused participants to stop taking their medicines.
In May 2017, we found nine reviews with 152 included studies and 13,524 participants. The studies were often small, and compared many different preparations. They used different study designs and different ways of showing their pain results. Outcomes of importance to people with cancer pain were often not reported.
For two drugs (morphine by mouth and fentanyl patches) more than 19 in 20 people had pain that went from moderate or severe before taking morphine‐like drugs, to pain that was no worse than mild within 14 days if they can tolerate the side effects. Most people taking a morphine‐like drug had at least one side effect. Only about 1 person in 10 to 2 people in 10 stopped taking it because of side effects. The most common side effects were constipation, and nausea and vomiting.
Quality of the evidence
At one level these are encouraging results, and generally agree with surveys of how well the WHO advice works in cancer pain. On another level, the quality of studies in the reviews was generally poor. We would like better study design, and especially better study reporting, which should include the outcome of pain reduced to a level where people with cancer can cope with it (no pain or mild pain).
We found that the Cochrane Reviews were of high quality.
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results. We rated the evidence in the reviews as very low quality.
Philip J Wiffen, Bee Wee, Sheena Derry, Rae Frances Bell, R Andrew Moore
Implications for practice
For people with cancer pain
The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low, although the evidence we have is that around 19 out of 20 people with moderate or severe pain who are given opioids and are able to tolerate them should have that pain reduced to mild or no pain within 14 days. This accords with the clinical experience in treating many people with cancer pain over many years. Most people will experience adverse events, and help may be needed to manage the more common undesirable adverse effects such as constipation and nausea. Perhaps 1 in 10 people treated with opioids will find these adverse events intolerable, leading to a change in treatment.
The amount and quality of evidence around the use of opioids for cancer pain is low. But around 95% of people with moderate or severe pain should be able to titrate to no or only mild pain within 14 days (Wiffen 2016). This is a clinically important treatment goal judged to be valuable by patients, and probably with economic benefits to health services. Adverse events will be common, but withdrawals due to adverse events uncommon. Oral morphine remains the gold standard for treating moderate to severe cancer pain.
For policy makers
The amount and quality of evidence around the use of opioids for cancer pain is low. But around 95% of people with moderate or severe pain should be able to titrate to no or only mild pain within 14 days (Wiffen 2016). This is a clinically important treatment goal judged to be valuable by patients, and probably with economic benefits to health services. Adverse events will be common, but withdrawals due to adverse events uncommon. Oral morphine remains the gold standard for treating moderate to severe cancer pain. The WHO ladder has strong opioids as the top rung of the ladder, and the evidence we have, such as it is, supports that position; the WHO ladder is under review at the time of writing. We suggest that policy makers have a duty to ensure that opioids such as morphine are available to all who need them for treating cancer 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 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, so other opioids need to be included in formularies. Oral morphine remains the gold standard for treating moderate to severe pain. The WHO ladder has strong opioids as the top rung of the ladder, and the evidence we have, such as it is, supports that position.
Opioids are tried and tested for the treatment of cancer pain. Morphine remains the first line treatment in guidelines and textbooks, although oxycodone is the major opioid in the USA. Fentanyl as a transdermal patch is widely used in higher income countries and may cause less constipation than oral opioids. Codeine has no proven role from clinical trial data in treating cancer pain.
Implications for research
The reviews on opioids for cancer pain reveal some major problems with our evidence. The WHO pain ladder is now over 30 years old, and remains probably the most‐used and best‐understood pain guidance worldwide. Despite its obvious importance there are few studies that clearly demonstrate how best to perform a study on the most important top rung relating to the treatment of moderate to severe pain.
Relatively few reviews were able to obtain data from studies that would be useful in clinical practice, namely the proportion of people with cancer having no or only mild pain within a relatively short time, for example one week after starting treatment. Many individual studies reported statistical outcomes only, rather than absolute pain intensity values. And even when absolute pain intensity values were given, they were often given as average values, rather than in terms of the number who achieved a useful degree of pain relief.
Given that many of the better‐quality studies in this review were completed within the last 20 years, the obvious implication for research is to instigate an opioid 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 opioid titration), and time taken to achieve that benefit. Trialist collaborations have proved highly informative, with the Antiplatelet Trialists' Collaboration probably the largest example of how retrospective pooling and analysis of clinical trial data can lead to improvements in treatment.
Several methodological issues stand out.
The first is the use of outcomes of value to people with cancer pain. Existing trials are designed more for purposes of registration and marketing than informing and improving clinical practice, often because the outcomes chosen are average pain scores, or statistical differences, and rarely how many individuals achieve satisfactory pain relief.
The second is the time taken to achieve good pain relief. Some of the reviews — but not individual trials — have defined this as no worse than mild pain within 14 days. This allows for the needs of a titrating dose, but is within a reasonable time. Some might argue that seven days or less would be preferable, but the fact is that we do not have the data available to investigate this point, even though several better‐quality and more modern studies may well have the measurements needed to elucidate it.
The third is design. Many studies had a cross‐over design; even though some were relatively short there was significant attrition. Parallel group designs may be preferable.
The fourth is size. Many of the studies were very small, and, combined with cross‐over design and consequent attrition, ended up reporting on very few participants. Much larger studies of at least several hundred participants are needed.
There are some other design issues that might be addressed. Most important might well be a clear decision concerning the gold‐standard treatment comparator. Placebo‐controlled studies in cancer pain are unlikely to be ethically feasible. In that case an effective and commonly‐available therapy is the ideal common comparator in randomised trials. Oral immediate‐release morphine may be that common comparator. Another is the use of prospective cohort studies rather than randomised trials. Studies could incorporate initial randomisation but a pragmatic design in order to provide immediately‐relevant information on effectiveness and costs. Such designs in pain conditions have been published (Moore 2010).
Trials need to consider additional endpoints of no worse than mild pain as well as the impact of opioids on symptoms that raise serious concerns such as consciousness, appetite, and thirst. The choice of measures to be used in cancer pain studies is not necessarily straightforward.