In this guest blog, Consultant in Pain Medicine Cathy Stannard and pain researcher Andrew Moore discuss some unpalatable truths about traditional opioids for chronic non-cancer pain.
What are opioids?
There are two main types of opioids. Traditional opioids, which we discuss here, are drugs that work only on opioid receptors in the nervous system; they include morphine, hydromorphone, codeine, hydrocodeine, methadone, oxycodone, fentanyl, and buprenorphine. Some opioids (tramadol, tapentadol) have additional methods of action, and need to be considered separately on another occasion.
What is chronic non-cancer pain?
If you ignore pain lasting less than three months, and headache, and cancer pain, then what you have left is chronic pain that isn’t cancer. Chronic non-cancer pain (CNCP) is typically defined as pain that is moderate or severe lasting six months or more, and includes conditions like low back pain, osteoarthritis, rheumatoid arthritis, neuropathic pain, fibromyalgia, and a range of other conditions.
People with CNCP of any sort have a lot in common – their lives are often pretty awful and they don’t enjoy it. They find it hard to sleep, they are fatigued and depressed, they struggle to work or look after the family, relationships with friends and family are strained, and they have low quality of life (the lowest of any medical condition for people living in the community). CNCP is common, and affects 10%-20% of adults, particularly older adults. Long-term opioid users with CNCP in Australia typically had their pain for 10 years or more, had low employment and income levels, were depressed, and had a 1-in-5 history of a suicide attempt.
How is CNCP treated?
Not awfully well. In chronic pain no drug treatment works well for most people; long-term opioid use is beset by problems with side effects without good evidence of long-term benefit. Prescribing effective treatments for neuropathic pain (duloxetine, pregabalin) is often discouraged at local level, even when approved for a condition and suggested by guidelines like NICE. Drugs are frequently used off-license. Switching to try and find a drug that works is uncommon.
Non-drug interventions might be useful for a few and are encouraged, but evidence of efficacy for most of them is scant or non-existent. For psychological therapies, some of which might have a modest benefit if delivered by trained and experienced staff, a hard-hitting Cochrane Reviews are systematic reviews of research in health care and health policy. Each review addresses a clearly formulated question; for example: Can antibiotics help in alleviating the symptoms of a sore throat? All the existing research on a topic that meets certain criteria is searched for and collated, and then assessed using stringent guidelines, to establish whether or not there is conclusive evidence about a specific treatment. argued for no new RCTs without considerable introspection on methods and outcomes.
What are the prescribing trends?
The trend is for drug therapy to avoid using NSAIDs (seen to be dangerous) and some licensed medicines (seen to be expensive), with the result that traditional opioid use has soared. This is the conclusion from the most recent UK survey, but the picture is similar around the world:
“There has been a huge increase in strong opioid prescribing in the United Kingdom, with the majority of prescriptions for non-cancer pain. Morphine was the most frequently prescribed, but the utilization of oxycodone, buprenorphine and fentanyl increased markedly over time.”
Why does rising opioid prescribing matter?
Several reasons. One is cost. In primary care in England 2015 spending on opioids was £314 ($412; €364) million; that compares with the combined spending on paracetamol, paracetamol/opioid preparations, and NSAIDs of £270 ($354; €313) million. Now not all of that spending is for CNCP, but it gives an indication of the size of the problem: a lot of money for an intervention of marginal efficacy.
Of greater concern is the association of rising prescribing with rising opioid-related death, particularly in the USA, though not (so far) the UK. Dose levels with opioids can often be eye-wateringly high. It is not unusual to see people taking the equivalent of 1 gram of oral morphine a day; this dose would kill most people who have not been exposed to opioids and is five times what is considered to be a high dose in clinical practice. There are instances of daily consumption being much, much, greater. Perhaps none of which might matter if lots of people had really good pain relief. Some undoubtedly do, but high opioid consumption with high pain scores seems to be the norm.
How well do opioids work in CNCP?
A number of Cochrane reviews try to provide answers. There have been many new reviews in the past few years, and many more are on their way. There is a sea change in approach – no longer lumping together all opioids, irrespective of drug, dose, duration of study, or imputation method used for dropouts. New reviews are more focused – this drug, at this dose, in this condition, in longer duration studies (for a long-term problem), and highlighting problems with imputation methods because that comes with very high risk of bias. They also look for outcomes that have clinical utility, typically the proportion of people who experience a long-term reduction in pain of at least 50% or 30%, or who have no worse than mild pain with treatment. In short, trying to provide results that are useful to people with pain and professionals trying to help them.
What these newer reviews find is that there is little or no evidence from high quality RCTs: basically, we don’t know whether traditional opioids work or not. The language used is that there is no evidence to support or refute their use. Reviews typically highlight methodological issues such as short duration, small size, and major potential bias from imputation method. In head-to-head comparisons opioids are not as good as non-opioid drugs. But we do know four important things from recent research.
- Withdrawal rates in trials of traditional opioids in CNCP are usually high – 40% over the first three weeks, and 60% or more over 12 weeks, usually because of side effects.
- Imputation methods like last-observation-carried-forward (LOCF) are used in most trials. These take the pain score of someone who withdraws at three weeks and carries that forward to the end of the trial, as if they continued to have the same pain relief even though they are not taking the tablets. The bias can be so high that it can change a result from ‘this drug works’ to ‘this drug is no better than placebo’.
- To our knowledge, there are only two studies showing that a traditional opioid can provide good long term pain relief, but then only for about 5%-10% of people. Both have an enriched enrolment randomised withdrawal design, and are done to the highest current standards. For those who do get pain relief, oral morphine 120 mg daily does the job for most.
- Opioid adverse events are common and not innocuous. There is considerable observational evidence linking opioid use (especially high doses) to mortality, suicide, fracture, cardiovascular events, and hospital admission.
What should we do with this thinking?
Let’s be clear: there will be some people with CNCP who will and do get pain relief with opioids, and can use them in the longer term without harm, though the evidence is weak (as shown by a Cochrane review). They won’t be many and we have no way of predicting who they will be. The catch is that trial and error may lead to significant adverse events, or real difficulty stopping the opioid. Some people take heroic opioid doses, but with unrelieved pain. Getting them off opioids is very difficult, with little high quality evidence to help (as shown by yet another Cochrane review).
The aim should be to avoid high doses except in very exceptional circumstances. Daily doses above 180 mg of morphine equivalent have not been validated in trials involving patients with chronic pain. A consensus is coalescing around the suggestion that the upper limit of opioid dosing should be limited to between 50 mg and 180 mg oral morphine equivalents daily; the trend is towards lower daily dosing. Higher doses may be prescribed if benefits and risks are properly assessed, and probably under the guidance of an experienced pain physician.
Certain sorts of dosing regimens can be safer than others. Prolonged release formulations were encouraged for patients who have pretty continuous pain. But it is difficult to get fixed doses right, particularly when pain will vary in intensity depending on type and level of activity. If people are given flexibility in dosing, most will look for opportunities to avoid taking medicines when pain is more tolerable; this allows them to keep doses as low as possible.
The emerging consensus is sensible, giving people with chronic pain the chance of pain relief, but with a brake on runaway dosing, and on drug diversion. A British Pain Society pathway on the initial treatment of chronic pain has a useful mnemonic of the four-As for effective treatment monitoring:
- Analgesia (pain relief).
- Activities of daily living (physical and psychosocial functioning).
- Adverse effects (side-effects).
- Aberrant drug taking (addiction-related outcomes).
People with chronic pain who take opioids can be upset at the suggestion that their medicines may be withdrawn or limited. US patient blogs can be particularly vociferous; they find reviews that point out a lack of evidence of efficacy of opioids unwelcome.
The evidence is certainly untidy and unsatisfactory, and opioids will be unsuitable for many people in the longer term. The situation for opioids is no different from that of other drug and non-drug treatments where a small number of people benefit immensely, but most do not. Scrutinizing the evidence is not about taking sides – it is about finding ways where people who can benefit do, and where those who won’t are protected from risk.
The core message is stark. Opioids are dangerous and often expensive drugs. They should be started only with caution and with upper dosing limits, and continued only with demonstrably reduced pain – ideally to mild or no pain. If the opioid isn’t working after a decent trial – six weeks should be enough –it should be stopped. People already on opioids are often unsure if opioids are working or not, but they are certainly still in a lot of pain. They should be encouraged to slowly and safely reduce the dose to get a better idea of how helpful the drug is for their pain.
Cathy Stannard has nothing to disclose. Andrew Moore reports grants and personal fees from RB, grants and personal fees from Gruenenthal, personal fees from Menarini, grants and personal fees from Novartis, personal fees from Futura, personal fees from Omega, outside the submitted work.
References can be found here.