Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain Stable (no update expected for reasons given in 'What's new')



There is increasing focus on providing high quality care for people at the end of life, irrespective of disease or cause, and in all settings. In the last ten years the use of care pathways to aid those treating patients at the end of life has become common worldwide. The use of the Liverpool Care Pathway (LCP) in the UK has been criticised. In England the LCP was the subject of an independent review, commissioned by a Health Minister. The resulting Neuberger Review acknowledged that the LCP was based on the sound ethical principles that provide the basis of good quality care for patients and families when implemented properly. It also found that the LCP often was not implemented properly, and had instead become a barrier to good care; it made over 40 recommendations, including education and training, research and development, access to specialist palliative care services, and the need to ensure care and compassion for all dying patients. In July 2013, the Department of Health released a statement that stated the use of the LCP should be "phased out over the next 6‐12 months and replaced with an individual approach to end of life care for each patient".

The impact of opioids was a particular concern because of their potential influence on consciousness, appetite and thirst in people near the end of life. There was concern that impaired patient consciousness may lead to an earlier death, and that effects of opioids on appetite and thirst may result in unnecessary suffering. This rapid review, commissioned by the National Institute for Health Research, used standard Cochrane methodology to examine adverse effects of morphine, fentanyl, oxycodone, and codeine in cancer pain studies as a close approximation to possible effects in the dying patient.


To determine the impact of opioid treatment on patient consciousness, appetite and thirst in randomised controlled trials of morphine, fentanyl, oxycodone or codeine for treating cancer pain.

Search methods

We assessed adverse event data reported in studies included in current Cochrane reviews of opioids for cancer pain: specifically morphine, fentanyl, oxycodone, and codeine.

Selection criteria

We included randomised studies using multiple doses of four opioid drugs (morphine, fentanyl, oxycodone, and codeine) in cancer pain. These were taken from four existing or ongoing Cochrane reviews. Participants were adults aged 18 and over. We included only full journal publication articles.

Data collection and analysis

Two review authors independently extracted adverse event data, and examined issues of study quality. The primary outcomes sought were numbers of participants experiencing adverse events of reduced consciousness, appetite, and thirst. Secondary outcomes were possible surrogate measures of the primary outcomes: delirium, dizziness, hallucinations, mood change and somnolence relating to patient consciousness, and nausea, vomiting, constipation, diarrhoea, dyspepsia, dysphagia, anorexia, asthenia, dehydration, or dry mouth relating to appetite or thirst.

Comparative measures of harm were known to be unlikely, and we therefore calculated the proportion of participants experiencing each of the adverse events of interest with each opioid, and for all four opioid drugs combined.

Main results

We included 77 studies with 5619 randomised participants. There was potential bias in most studies, with small size being the most common; individual treatment groups had fewer than 50 participants in 60 studies. Participants were relatively young, with mean age in the studies typically between 50 and 70 years. Multiple major problems with adverse event reporting were found, including failing to report adverse events in all participants who received medication, all adverse events experienced, how adverse events were collected, and not defining adverse event terminology or whether a reporting system was used.

Direct measures of patient consciousness, patient appetite, or thirst were not apparent. For opioids used to treat cancer pain adverse event incidence rates were 25% for constipation, 23% for somnolence, 21% for nausea, 17% for dry mouth, and 13% for vomiting, anorexia, and dizziness. Asthenia, diarrhoea, insomnia, mood change, hallucinations and dehydration occurred at incidence rates of 5% and below.

Authors' conclusions

We found no direct evidence that opioids affected patient consciousness, appetite or thirst when used to treat cancer pain. However, somnolence, dry mouth, and anorexia were common adverse events in people with cancer pain treated with morphine, fentanyl, oxycodone, or codeine.

We are aware that there is an important literature concerning the problems that exist with adverse event measurement, reporting, and attribution. Together with the known complications concerning concomitant medication, data collection and reporting, and nomenclature, this means that these adverse events cannot always be attributed unequivocally to the use of opioids, and so they provide only a broad picture of adverse events with opioids in cancer pain. The research agenda includes developing definitions for adverse events that have a spectrum of severity or importance, and the development of appropriate measurement tools for recording such events to aid clinical practice and clinical research.


Philip J Wiffen, Sheena Derry, R Andrew Moore


Plain language summary

 Impact of morphine, fentanyl, oxycodone or codeine on patient consciousness, appetite and thirst when used to treat cancer pain 

 Description of the problem 

Care pathways are packages of care designed to ensure that patients have appropriate and effective care in particular situations. Such pathways are commonly used, and often produce good results, but they can also be used as a tick box solution that acts as a barrier to good care. Care pathways have been used to ensure appropriate care for people who are dying in hospice settings.

The Liverpool Care Pathway was devised for use in hospices, and has been used in general hospital settings to care for dying patients. Its use has been criticised. A government review of the use of end‐of‐life care pathways in the NHS in the UK recommended they should not be used because they were being misused.

A concern, mainly raised by relatives, was that opioids were over‐prescribed, used to hasten death, to reduce consciousness, and diminish the patient's desire or ability to accept food or drink.

 The purpose of this review 

This Cochrane review was commissioned to look at harms (adverse events) associated with the use of opioids to treat cancer pain particularly relating to patient consciousness, appetite or thirst.

 How the information was gathered 

Ideally, when writing this review we would have looked at medical trials of opioid use in older people receiving end‐of‐life care, but there are no trials in this area. So, we looked at trials of people being treated with opioids for cancer pain, as the
 information these trials provide is likely to be the closest that is available to opioid use in end‐of‐life care ‐ although people treated for cancer pain are not usually at the end of their lives.

 What we found 

This review identified 77 studies with over 5,000 people who received various treatments. The population in these trials was mainly aged between 50 and 70 years. Trial quality was generally poor; particular problems included small study size, and not reporting adverse events in all patients, or all recorded adverse events. Known problems with adverse event measurement, recording, and reporting made assessment even more difficult.

For all four opioids together, 1 in 4 people experienced constipation and somnolence (sleepiness, drowsiness), 1 in 5 experienced nausea and dry mouth, and 1 in 8 experienced vomiting, loss of appetite, and dizziness. Weakness, diarrhoea, insomnia (difficulty in sleeping), mood change, hallucinations and dehydration occurred at rates of 1 in 20 people and below. These results may contribute to understanding the effects of opioids on consciousness, appetite, and thirst in end‐of‐life care in all patients deemed to be people who are dying.


Philip J Wiffen, Sheena Derry, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions

Implications for practice

We found no evidence that opioids were associated with patient consciousness, appetite or thirst when used to treat cancer pain. However, somnolence, dry mouth, and anorexia were common adverse events in people with cancer pain treated with morphine, fentanyl, oxycodone, or codeine. Rates were similar to those in chronic non‐cancer pain. Both these populations entered into randomised trials were likely to be considerably younger and much less frail than people treated with opioids at the end of life. It is likely that opioids used for end‐of‐life care will to some degree affect patient consciousness, appetite, and thirst, but it is not possible to quantify the effect or to identify circumstances where problems may be greater or lesser.

Implications for research

In order to address the issues raised by the Neuberger Review, research into the effect of opioids on levels of consciousness, and effects on appetite and thirst in dying patients should be commissioned. This is no easy task, however, and there are many, possibly major, issues that would need to be overcome in defining what that research may comprise.

There are two immediate implications for research, and we limit comments to these two.


Perhaps the most frustrating aspect is the issue of how adverse events are recorded, and the issues of seriousness, severity, and definition. There are a number of systems for recording diagnoses and adverse events, including the International Statistical Classification of Diseases and Related Health Problems (ICD), and MedDRA (the Medical Dictionary for Regulatory Activities Terminology), a controlled vocabulary widely used as a medical coding scheme for adverse events. These are often used, but because of their broad, generic, nature, often fail to pick up important nuances in specific circumstances.

Adverse events often display a spectrum of seriousness. For example, the induction agent propofol exhibits cardiac events that include bradycardia (1 in 9), asystole (1 in 660), and bradycardia‐related death (1 in 100,000) (Tramèr 1997), and a spectrum of gastrointestinal harm exists with NSAIDs, encompassing dyspepsia, endoscopically detected ulcers and erosions, hospital admission for bleeding ulcer, and death from bleeding ulcer (Tramèr 2000).

One of the issues with spectrums of harm is that the most serious events are rare and difficult to capture, and often more common, surrogate, measures are used in their place. All of which is fine as long as the spectrum can be well established, and there are well‐established definitions that can be followed. Even then, establishing the value of a surrogate measure can be difficult despite very considerable evidence (Moore 2009; Moore 2013).

It is likely that there are spectrums of outcome for consciousness (from fully alert, to drowsy, sleepy, somnolent, sedated, and then unconscious). But this all depends on how words are used. For example, in discussing results from one RCT done more than 20 years ago with an author, it was clear that the trial report of sedation actually meant fatigue, or tiredness. For eating and drinking it is likely that similar principles apply.

Therefore one clear implication for research is for:

  • a set of clear definitions of the various sections of each spectrum that is of clinical interest;
  • the development of measurement tools or aids;
  • testing the tools;
  • investigating whether a spectrum of response can be determined.

Data recording and reporting

Some studies produced good quality adverse event data in tables, but most studies did not do this. There are groups working on adverse event reporting standards, and the CONSORT group has provided useful guidance on adverse event reporting (Ioannidis 2004). A Cochrane Adverse Effects Methods Group also exists.

The problem, though, is that while such groups do excellent work on the generic problems of adverse event recording and reporting, this may still fail to be useful to a specific set of harms in specific circumstances. A key need, therefore, is to develop a set of recommendations on adverse events (and perhaps beneficial events) that are specific to end‐of‐life care, in order that they may be tested and used in clinical practice and clinical trials.

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