Bottom line
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.
Background
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.
Study characteristics
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.
Key findings
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.
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.
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.