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. 2017 Mar 8;2017(3):CD012592. doi: 10.1002/14651858.CD012592

Opioids for cancer pain ‐ an overview of Cochrane reviews

Philip J Wiffen 1,✉, Bee Wee 2, Sheena Derry 1, Rae F Bell 3, R Andrew Moore 1
PMCID: PMC6464501

Abstract

This is a protocol for a Cochrane Review (Overview). The objectives are as follows:

To provide an overview of the analgesic efficacy of opioids in cancer pain, and to report on adverse events associated with their use.

Background

Description of the condition

Cancers are among the leading causes of morbidity and mortality worldwide, with about 14 million new cases and over eight million deaths annually ‐ approximately 13% of deaths worldwide (IARC 2012; Stewart 2014). Globally, 32 million people are living with cancer. In the UK alone in 2014, there were around 350,000 new cases of cancer annually, with around 50% of people surviving for 10 years or more after diagnosis (CRUK 2016).

Cancer pain is perhaps one of the most feared symptoms associated with the disease. Pain may be the first symptom to cause someone to seek medical advice that leads to a diagnosis of cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain (Portenoy 1999). Pain can occur at any time as the disease progresses but the frequency and intensity of pain tends to increase as the cancer advances (Portenoy 1999; van den Beuken‐van Everdingen 2016). A systematic review published in 2016 has shown that approximately 40% of patients suffered pain after curative treatment, 55% during cancer treatment, and 66% in advanced disease (van den Beuken‐van Everdingen 2016).

Pain related to cancer is described as distressing or intolerable by more than one third of patients (Breivik 2009; van den Beuken‐van Everdingen 2016). For those people with advanced cancer, some 75% to 90% will experience pain that has a major impact on daily living (van den Beuken‐van Everdingen 2016). Pain had a significant negative correlation with quality of life in people with cancer, for example, patients in China, Palestine, and Japan (Deng 2012; Dreidi 2016; Mikan 2016), as is true generally with pain (Moore 2014). Significant relief of pain to a level equivalent to no pain or only mild pain is generally regarded as an important target for most people with pain (Moore 2013).

Cancer pain can be the result of the cancer itself, interventions to treat the cancer, and sometimes other underlying pains. Prevalence is also linked to cancer type, with head and neck cancer showing the highest prevalence. Age also has an impact with younger patients experiencing more pain (Prommer 2015). For the purposes of this overview review, we will focus on the use of opioids for the treatment of pain associated with active cancer where the pain is thought to be associated with the cancer or its treatment.

While children clearly suffer from pains associated with cancer, a separate review of cancer pain in children is underway.

Description of the interventions

Opioid analgesics, including codeine, play a significant role in major guidelines associated with the management of pain for patients diagnosed with cancer (Caraceni 2012; Jacox 1994; Miaskowski 2005; NICE 2016; Ripamonti 2012a; SIGN 2008; WHO 1996).

Opioids are used to manage moderate to severe pain. Morphine is the oldest drug in the class of opioids and is still generally considered to be the gold standard. Many other opioids are comparable to morphine in terms of analgesia and also adverse effects. Codeine is considerably less potent than morphine and recommended for mild to moderate cancer pain. The majority of opioids are administered orally, often in the form of modified‐release formulations to reduce dosing to once or twice daily. Rectal administration is also possible. Fentanyl and buprenorphine can also be administered by transdermal patch. Some opioids are suitable for parenteral administration, but this review will not consider this route of administration.

Morphine and codeine are the two opioids included in the World Health Organization (WHO) essential drugs list (WHO 2011); other opioids are generally similar, but have differences in potency, lipophilicity (the ability of a chemical compound to dissolve in fats, oils, lipids), and routes of administration. These can be important in certain circumstances. All opioids are eligible for inclusion but details are given for morphine and codeine as examples in this background description.

Morphine

Morphine in one form or another has been available for centuries, and appeared in Pliny's Historia Naturalis (AD 77) as opium, the resin derived from poppy sap. Morphine was extracted from opium in 1803 and named as such by Sertürner, a German pharmacist from Einbeck, in 1817 (Rey 1993). Oral morphine was first recommended in England in the 1950s for the treatment of cancer pain. This was often in the form of the so‐called 'Brompton cocktail' containing cocaine and alcohol in addition to morphine or diamorphine. Treatment moved towards oral morphine alone as morphine demonstrated effective pain relief without the side effects linked to the 'cocktail'.

Following the publication of WHO guidelines in the mid‐1980s, the oral administration of aqueous morphine solution every four hours by the clock became commonplace for moderate to severe cancer pain (WHO 1986). Morphine in a modified‐release tablet was first marketed around the same time, allowing the dosage interval to be extended to 12 hours.

The wide range of formulations and dosages allows great flexibility in the management of severe pain (Grahame‐Smith 2002). Potent opioid analgesics are particularly indicated for the relief of pain in malignant disease and often have the additional very useful actions of relieving anxiety, producing drowsiness, and allowing sleep (Grahame‐Smith 2002). However, all opioid analgesics have the potential to produce adverse events: respiratory depression, nausea and vomiting, constipation, increased pain sensitivity (hyperalgesia) and itching. During chronic opioid therapy, larger doses may be required to sustain the analgesic effect (tolerance) and people can be at risk of opioid withdrawal syndrome upon sudden cessation of the opioid or administration of an antagonist (physiological dependence).

This overview will not consider evidence relating to opioid combinations, for which it is known that there is only a small amount of weak evidence (Fallon 2011).

Codeine

Guidelines generally recommend codeine as an analgesic for moderate pain or for situations where simple analgesics (for example, nonsteroidal anti‐inflammatory drugs (NSAIDs) or paracetamol) alone are ineffective or provide suboptimal analgesia. Codeine is the most widely used, naturally occurring narcotic in medical treatment in the world (Opiates 2013). Codeine can also be synthesised from morphine. It is most commonly administered by mouth (as tablets or syrup), but is also available for intramuscular and subcutaneous injections, and in some countries as suppositories. In many countries it is a controlled substance.

In some clinical guidelines, codeine is referred to as a 'weak' opioid analgesic. Codeine and tramadol are defined as step II opioids on the WHO analgesic ladder. The role and utility of step II opioids in cancer pain are controversial (Ripamonti 2012b), and there is currently a discussion as to whether step II opioids should be omitted from the ladder since low doses of step III opioids are equally, or in the case of 'poor metabolisers', more effective. The European Association for Palliative Care currently recommends both options (Caraceni 2012).

How the intervention might work

Morphine is known to bind to opioid receptors to produce pain relief (Mandal 2015). Three different receptors have been identified.

  1. Mu receptors (subdivided into μ1, μ2, and μ3). These are found in the brainstem and the thalamus. Activation can result in pain relief, sedation, and euphoria, and can also lead to respiratory depression, constipation, and physical dependence.

  2. Kappa receptor. This is found in the limbic system, the brain stem, and spinal cord. Activation can result in pain relief, sedation, breathlessness, dysphoria (a state of unease or dissatisfaction), and dependence.

  3. Delta receptor. This is found in the brain, spinal cord, and digestive tract. Activation can result in analgesic as well as antidepressant effects. It can also lead to respiratory depression.

The majority of the opioids are metabolised by the liver and this can lead to poor or extensive metabolisers which affects the analgesia experienced by users. The most affected drugs are codeine and tramadol.

Morphine

The analgesic effect of morphine is due to its action on the mu opioid receptor. Morphine is metabolised in the liver and brain, the predominant metabolites being morphine‐3‐glucuronide and morphine‐6‐glucuronide. The total production of morphine‐3‐glucuronide is approximately five times higher than that of morphine‐6‐glucuronide. Morphine‐3‐glucuronide has low potency at the mu receptor and is considered to be inactive in humans, while morphine‐6‐glucuronide is a mu receptor agonist with analgesic effect and is more potent than morphine (Paul 1989; Wittwer 2006).

Therapeutic concentrations of morphine and morphine‐6‐glucuronide have been suggested (Faura 1996), though a systematic review of factors affecting the ratios of morphine and its major metabolites shows some additional complexities (Faura 1998). Peak plasma concentrations after oral administration depend on the formulation used (Collins 1998). Renal failure can lead to reduced excretion of morphine‐6‐glucuronide and build up in the body, necessitating dose adjustments (Ball 1985; Sear 1985; Sear 1989).

Codeine

Codeine is a prodrug that is metabolised to morphine in the liver. In most people, 5% to 10% of codeine is converted to morphine; a 30 mg dose of codeine is considered equivalent to a 3 mg dose of morphine. The ability to metabolise codeine varies between individuals. Some (up to 10% of Caucasians, 2% of Asians, and 1% of Arabs) are 'poor metabolisers' (Cascarbi 2003) with low rates of conversion, and in these people codeine is a relatively ineffective analgesic. At the other extreme, a few individuals are 'extensive metabolisers' with high rates of conversion, and this puts them at increased risk of toxicity from standard doses. There are rare case reports of deaths attributed to ultrarapid metabolism of codeine administered at recommended doses (Ciszkowski 2009; Madadi 2007).

A number of medications can interfere with the enzymes that catalyse the metabolism of codeine, and by increasing or decreasing the extent of conversion they can change the analgesic effect. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine (used for the treatment of depression which may present as a co‐morbidity along with malignant disease), as well as the serotonin and noradrenaline reuptake inhibitor duloxetine (which may be used for pain management) for example, reduce conversion, and other drugs, such as rifampicin and dexamethasone, increase it.

Why it is important to do this overview

In many countries, strong opioids such as morphine are severely restricted, if available at all. This leaves many people with cancer at risk of severe life‐limiting pain.

Morphine has long been considered the preferred choice of opioid. It is widely, though still not universally, available across the world, is comparatively inexpensive, and is effective orally. It is listed in the WHO essential medicines list (WHO 2011). This overview of Cochrane reviews is important to determine the effectiveness of morphine compared to other interventions used in cancer pain. Codeine is inexpensive and has a long track record of use since the late 1800s. However, there is an ongoing controversy as to whether there is a place for step II opioids such as tramadol and codeine in the treatment of cancer pain.

This overview will provide a summary of the evidence for the majority of opioid medicines available internationally and will cover those on the WHO essential medicines list, namely: codeine and morphine. This review will inform policy makers such as the WHO on the evidence for analgesic efficacy and adverse effects of opioids (Wiffen 2016) to treat cancer‐related pain.

Objectives

To provide an overview of the analgesic efficacy of opioids in cancer pain, and to report on adverse events associated with their use.

Methods

Criteria for considering reviews for inclusion

We will include all Cochrane reviews of randomised, controlled double‐blind trials (RCTs) of opioid drugs for the treatment of cancer pain in adults.

Search methods for identification of reviews

We will search the most recent issue of the Cochrane Database of Systematic Reviews (the Cochrane Library). The search strategy is presented in Appendix 1.

Data collection and analysis

Two review authors will independently select reviews for inclusion, carry out assessment of methodological quality, and extract data. We will resolve any disagreements by discussion, involving a third review author if necessary.

Selection of reviews

Included reviews will assess RCTs evaluating the effects of an opioid drug given for relief of moderate to severe cancer pain, compared with placebo or a different active treatment, and will include:

  1. details of inclusion and exclusion criteria;

  2. details of databases searched and relevant search strategies;

  3. patient‐reported pain relief; and

  4. summary results for at least one desired outcome.

Data extraction and management

We will extract data from the included reviews using a standard data extraction form, using original study reports only if specific data are missing.

We will collect information on:

  1. number of included studies and participants;

  2. drug, dose, and route of administration;

  3. any additional methodological information that may be of importance.

We will extract information on risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT), number needed to treat to prevent an event (NNTp), and number needed to treat for an additional harmful outcome (NNH), or calculate these.

Primary outcomes

  1. Proportion of participants reporting no worse than mild pain on treatment by 14 days after start of treatment.

  2. Patient Global Impression of Change (PGIC) of much or very much improved.

  3. Withdrawals due to adverse events.

These outcomes will also be extracted when reported as moderate or substantial improvement according to the relevant Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) criteria (Dworkin 2008).

Secondary outcomes

Description of adverse events including:

  1. withdrawals due to lack of efficacy;

  2. participants experiencing any adverse event;

  3. participants experiencing any serious adverse event, including death. Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an 'important medical event' that may jeopardise the patient, or may require an intervention to prevent one of the above characteristics or consequences;

  4. specific adverse events, such as thirst, appetite, somnolence and dizziness, as reported.

Assessment of methodological quality of included reviews

Quality of included reviews

We will assess each included review to determine if it satisfies the criteria specified in the 'assessment of multiple systematic reviews' (AMSTAR) measurement tool for rigorous methodological quality (Shea 2007).

Each review will be required to:

  1. provide an a priori design;

  2. carry out duplicate study selection and data extraction;

  3. carry out a comprehensive literature search;

  4. include published and unpublished studies irrespective of language of publication;

  5. provide a list of studies (included and excluded);

  6. assess and document the scientific quality of the included studies;

  7. use the scientific quality of the included studies appropriately in formulating conclusions;

  8. use appropriate methods to combine the findings of studies; and

  9. state conflicts of interests.

For each review, we will assess the likelihood of publication bias by calculating the number of participants in studies with zero effect (RR = 1) that would be needed to give an NNT too high to be clinically relevant (Moore 2008). In this case, we will use as a cut‐off for clinical relevance, an NNT of 10 or above for the outcome of participant reported pain relief of 30% or greater. We use this method because statistical tests for presence of publication bias have been shown to be unhelpful (Thornton 2000).

Data synthesis

We will use information on the selected efficacy outcomes to draw up comparisons of analgesic efficacy, using indirect comparisons of different drugs from almost identical clinical trial conditions, with placebo as a common comparator (Glenny 2005; Song 2003). It is known that direct comparison studies are almost completely absent, and probably too small to be of value, but where they impart useful observations, that will be noted.

If the selected efficacy outcomes are not provided in an individual review, wherever possible we will calculate them from the data provided. We plan no further data synthesis.

At least 200 participants will have to be available for any outcome before studies are pooled (Moore 1998). Where appropriate we will use or calculate RR or risk difference (RD) with 95% confidence intervals (CI) using a fixed‐effect model (Morris 1995). NNT and NNH with 95% CIs will be used or calculated using the pooled number of events, using the method devised by Cook and Sackett (Cook 1995). We will assume a statistically significant difference from control when the 95% CI of the RR does not include the number one or for the RD the number zero.

We will organise the results based on a series of categories, as has been done previously in overview reviews (Moore 2015).

  1. Interventions for which Cochrane reviews found no information.

  2. Interventions for which Cochrane reviews found inadequate information (fewer than 200 participants in comparisons in two studies).

  3. Interventions for which Cochrane reviews found no evidence of effect or evidence of no effect.

  4. Interventions for which Cochrane reviews found evidence of effect, but where results were potentially subject to publication bias.

  5. Interventions for which Cochrane reviews found evidence of effect, where results were reliable and not subject to potential publication bias.

Quality of the evidence

We will use the GRADE system to assess the quality of the evidence related to the key outcomes listed in 'Types of outcome measures', as appropriate (Appendix 2). Two review authors will independently rate the quality of each outcome independently of any GRADE evaluation in the original reports.

We will pay particular attention to inconsistency, where point estimates vary widely across studies, or CIs of studies show minimal or no overlap (Guyatt 2011). Small studies have been shown to overestimate treatment effects, probably because the conduct of small studies is more likely to be less rigorous, allowing critical criteria to be compromised (Dechartres 2013; Nüesch 2010), and large studies often have smaller treatment effects (Dechartres 2014).

In addition, there may be circumstances where the overall rating for a particular outcome needs to be adjusted as recommended by GRADE guidelines (Guyatt 2013a). For example, if there are so few data that the results are highly susceptible to the random play of chance, or if studies use last observation carried forward (LOCF) imputation in circumstances where there are substantial differences in adverse event withdrawals, one would have no confidence in the result, and would need to downgrade the quality of the evidence by three levels, to very low quality. In circumstances where there are no data reported for an outcome, we will report the level of evidence as very low quality (Guyatt 2013b).

We will use the following descriptors for levels of evidence (EPOC 2015); substantially different in this context implies a large enough difference that it might affect a decision.

  1. High: This research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low.

  2. Moderate: This research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.

  3. Low: This research provides some indication of the likely effect. However, the likelihood that it will be substantially different is high.

  4. Very low: This research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high.

We will use the amount and quality of evidence to report results in a hierarchical way. We will split the available information into five groups, essentially according to the GRADE descriptors.

  1. Drugs and doses for which Cochrane reviews found no information (very low‐quality evidence).

  2. Drugs and doses for which Cochrane reviews found inadequate information: fewer than 200 participants in comparisons, in at least two studies (very low‐quality evidence).

  3. Drugs and doses for which Cochrane reviews found evidence of effect, but where results were potentially subject to publication bias. We will consider the number of additional participants needed in studies with zero effect (relative benefit of one) required to change the NNT for at least 50% maximum pain relief to an unacceptably high level (in this case the arbitrary NNT of 10) (Moore 2008). Where this number is less than 400 (equivalent to four studies with 100 participants per comparison, or 50 participants per group), we will consider the results to be susceptible to publication bias and therefore unreliable (low‐quality evidence).

  4. Drugs and doses for which Cochrane reviews found no evidence of effect or evidence of no effect: more than 200 participants in comparisons, but where there was no statistically significant difference from placebo (moderate‐ or high‐quality evidence).

  5. Drugs and doses for which Cochrane reviews found evidence of effect, where results were reliable and not subject to potential publication bias (high‐quality evidence).

Acknowledgements

Institutional support is provided by the Oxford Pain Relief Trust.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pain, Palliative and Supportive Care Review Group.

Disclaimer: the views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the NIHR, National Health Service (NHS), or the Department of Health.

Appendices

Appendix 1. Search strategy

#1 MeSH descriptor: [Pain] explode all trees #2 pain*:ti,ab,kw (Word variations will be searched) #3 #1 or #2 #4 MeSH descriptor: [Neoplasms] explode all trees #5 (cancer* or neoplas* or tumo* or carcinoma* or hodgkin* or nonhodgkin* or adenocarcinoma* or leuk?emia* or metasta* or malignan* or lymphoma* or sarcoma* or melanoma* or myeloma* or oncolog*):ti,ab,kw (Word variations will be searched) #6 #4 or #5 #7 MeSH descriptor: [Narcotics] this term only #8 MeSH descriptor: [Analgesics, Opioid] explode all trees #9 (morphine or buprenorphine or codeine or dextromoramide or diphenoxylate or dipipanone or dextropropoxyphene or propoxyphene or diamorphine or dihydrocodeine or alfentanil or fentanyl or remifentanil or meptazinol or methadone or nalbuphine or oxycodone or papaveretum or pentazocine or meperidine or pethidine or phenazocine or hydrocodone or hydromorphone or levorphanol or oxymorphone or butorphanol or dezocine or sufentanil or ketobemidone):ti,ab,kw (Word variations will be searched) #10 #7 or #8 or #9 #11 #3 and #6 and #10 #12 non‐cancer* or noncancer*:ti,ab,kw (Word variations will be searched) #13 #11 not #12

Appendix 2. GRADE: criteria for assigning grade of evidence

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Chapter 12, Higgins 2011).

  • High: randomised trials; or double‐upgraded observational studies.

  • Moderate: downgraded randomised trials; or upgraded observational studies.

  • Low: double‐downgraded randomised trials; or observational studies.

  • Very low: triple‐downgraded randomised trials; or downgraded observational studies; or case series/case reports.

Factors that may decrease the quality level of a body of evidence are:

  1. limitations in the design and implementation of available studies suggesting high likelihood of bias;

  2. indirectness of evidence (indirect population, intervention, control, outcomes);

  3. unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);

  4. imprecision of results (wide confidence intervals);

  5. high probability of publication bias.

Factors that may increase the quality level of a body of evidence are:

  1. large magnitude of effect;

  2. all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect;

  3. dose‐response gradient.

Contributions of authors

SD, PW, and RAM drafted the protocol, and all authors contributed to the final version

SD, PW, and RAM will search for and select studies for inclusion and carry out data extraction.

All review authors will be involved in the analysis and in writing the full review.

Sources of support

Internal sources

  • Oxford Pain Relief Trust, UK, UK.

    General institutional support

External sources

  • The National Institute for Health Research (NIHR), UKNIHR Cochrane Programme Grant: 13/89/29 ‐ Addressing the unmet need of chronic pain: providing the evidence for treatments of pain., UK.

Declarations of interest

PW: none known.

BW: none known; BW is a specialist palliative care physician and manages patients with cancer pain.

SD: none known.

RB: none known.

RAM has received grant support from Grünenthal relating to individual patient level analyses of trial data regarding tapentadol in osteoarthritis and back pain (2015). He has received honoraria for attending boards with Menarini concerning methods of analgesic trial design (2014), with Novartis (2014) about the design of network meta‐analyses, and RB on understanding pharmacokinetics of drug uptake (2015). He has received honoraria from Omega Pharma (2016) and Futura Pharma (2016) for providing advice on trial and data analysis methods.

New

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