BACKGROUND: Many people with cancer experience moderate to severe pain that requires treatment with strong opioids, such as oxycodone and morphine. Strong opioids are, however, not effective for pain in all people, neither are they well tolerated by all people. The aim of this review was to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for adults with cancer pain. This is an updated Cochrane review previously published in 2017.
OBJECTIVES: To assess the effectiveness and tolerability of oxycodone by any route of administration for pain in adults with cancer.
SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and MEDLINE In-Process (Ovid), Embase (Ovid), Science Citation Index, Conference Proceedings Citation Index - Science (ISI Web of Science), BIOSIS (ISI), and PsycINFO (Ovid) to November 2021. We also searched four trial registries, checked the bibliographic references of relevant studies, and contacted the authors of the included studies. We applied no language, date, or publication status restrictions.
SELECTION CRITERIA: We included randomised controlled trials (parallel-group or cross-over) comparing oxycodone (any formulation or route of administration) with placebo or an active drug (including oxycodone) for cancer background pain in adults by examining pain intensity/relief, adverse events, quality of life, and participant preference.
DATA COLLECTION AND ANALYSIS: Two review authors independently sifted the search, extracted data and assessed the included studies using standard Cochrane methodology. We meta-analysed pain intensity data using the generic inverse variance method, and pain relief and adverse events using the Mantel-Haenszel method, or summarised these data narratively along with the quality of life and participant preference data. We assessed the overall certainty of the evidence using GRADE.
MAIN RESULTS: For this update, we identified 19 new studies (1836 participants) for inclusion. In total, we included 42 studies which enrolled/randomised 4485 participants, with 3945 of these analysed for efficacy and 4176 for safety. The studies examined a number of different drug comparisons. Controlled-release (CR; typically taken every 12 hours) oxycodone versus immediate-release (IR; taken every 4-6 hours) oxycodone Pooled analysis of three of the four studies comparing CR oxycodone to IR oxycodone suggest that there is little to no difference between CR and IR oxycodone in pain intensity (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.1 to 0.34; n = 319; very low-certainty evidence). The evidence is very uncertain about the effect on adverse events, including constipation (RR 0.71, 95% CI 0.45 to 1.13), drowsiness/somnolence (RR 1.03, 95% CI 0.69 to 1.54), nausea (RR 0.85, 95% CI 0.56 to 1.28), and vomiting (RR 0.66, 95% CI 0.38 to 1.15) (very low-certainty evidence). There were no data available for quality of life or participant preference, however, three studies suggested that treatment acceptability may be similar between groups (low-certainty evidence). CR oxycodone versus CR morphine The majority of the 24 studies comparing CR oxycodone to CR morphine reported either pain intensity (continuous variable), pain relief (dichotomous variable), or both. Pooled analysis indicated that pain intensity may be lower (better) after treatment with CR morphine than CR oxycodone (SMD 0.14, 95% CI 0.01 to 0.27; n = 882 in 7 studies; low-certainty evidence). This SMD is equivalent to a difference of 0.27 points on the Brief Pain Inventory scale (0-10 numerical rating scale), which is not clinically significant. Pooled analyses also suggested that there may be little to no difference in the proportion of participants achieving complete or significant pain relief (RR 1.02, 95% CI 0.95 to 1.10; n = 1249 in 13 studies; low-certainty evidence). The RR for constipation (RR 0.75, 95% CI 0.66 to 0.86) may be lower after treatment with CR oxycodone than after CR morphine. Pooled analyses showed that, for most of the adverse events, the CIs were wide, including no effect as well as potential benefit and harm: drowsiness/somnolence (RR 0.88, 95% CI 0.74 to 1.05), nausea (RR 0.93, 95% CI 0.77 to 1.12), and vomiting (RR 0.81, 95% CI 0.63 to 1.04) (low or very low-certainty evidence). No data were available for quality of life. The evidence is very uncertain about the treatment effects on treatment acceptability and participant preference. Other comparisons The remaining studies either compared oxycodone in various formulations or compared oxycodone to different alternative opioids. None found any clear superiority or inferiority of oxycodone for cancer pain, neither as an analgesic agent nor in terms of adverse event rates and treatment acceptability. The certainty of this evidence base was limited by the high or unclear risk of bias of the studies and by imprecision due to low or very low event rates or participant numbers for many outcomes.
AUTHORS' CONCLUSIONS: The conclusions have not changed since the previous version of this review (in 2017). We found low-certainty evidence that there may be little to no difference in pain intensity, pain relief and adverse events between oxycodone and other strong opioids including morphine, commonly considered the gold standard strong opioid. Although we identified a benefit for pain relief in favour of CR morphine over CR oxycodone, this was not clinically significant and did not persist following sensitivity analysis and so we do not consider this important. However, we found that constipation and hallucinations occurred less often with CR oxycodone than with CR morphine; but the certainty of this evidence was either very low or the finding did not persist following sensitivity analysis, so these findings should be treated with utmost caution. Our conclusions are consistent with other reviews and suggest that, while the reliability of the evidence base is low, given the absence of important differences within this analysis, it seems unlikely that larger head-to-head studies of oxycodone versus morphine are justified, although well-designed trials comparing oxycodone to other strong analgesics may well be useful. For clinical purposes, oxycodone or morphine can be used as first-line oral opioids for relief of cancer pain in adults.
BACKGROUND: A 2007 American College of Physicians guideline addressed pharmacologic options for low back pain. New evidence and medications have now become available.
PURPOSE: To review the current evidence on systemic pharmacologic therapies for acute or chronic nonradicular or radicular low back pain.
DATA SOURCES: Ovid MEDLINE (January 2008 through November 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists.
STUDY SELECTION: Randomized trials that reported pain, function, or harms of systemic medications versus placebo or another intervention.
DATA EXTRACTION: One investigator abstracted data, and a second verified accuracy; 2 investigators independently assessed study quality.
DATA SYNTHESIS: The number of trials ranged from 9 (benzodiazepines) to 70 (nonsteroidal anti-inflammatory drugs). New evidence found that acetaminophen was ineffective for acute low back pain, nonsteroidal anti-inflammatory drugs had smaller benefits for chronic low back pain than previously observed, duloxetine was effective for chronic low back pain, and benzodiazepines were ineffective for radiculopathy. For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain; trials were not designed to assess serious harms. Skeletal muscle relaxants are effective for short-term pain relief in acute low back pain but caused sedation. Systemic corticosteroids do not seem to be effective. For effective interventions, pain relief was small to moderate and generally short-term; improvements in function were generally smaller. Evidence is insufficient to determine the effects of antiseizure medications.
LIMITATIONS: Qualitatively synthesized new trials with prior meta-analyses. Only English-language studies were included, many of which had methodological shortcomings. Medications injected for local effects were not addressed.
CONCLUSION: Several systemic medications for low back pain are associated with small to moderate, primarily short-term effects on pain. New evidence suggests that acetaminophen is ineffective for acute low back pain, and duloxetine is associated with modest effects for chronic low back pain.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).
BACKGROUND: This is the third updated version of a Cochrane review first published in Issue 4, 2003 of The Cochrane Library and first updated in 2007. Morphine has been used for many years to relieve pain. Oral morphine in either immediate release or modified release form remains the analgesic of choice for moderate or severe cancer pain.
OBJECTIVES: To determine the efficacy of oral morphine in relieving cancer pain, and to assess the incidence and severity of adverse events.
SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9); MEDLINE (1966 to October 2015); and EMBASE (1974 to October 2015). We also searched ClinicalTrials.gov (1 October 2015).
SELECTION CRITERIA: Published randomised controlled trials (RCTs) using placebo or active comparators reporting on the analgesic effect of oral morphine in adults and children with cancer pain. We excluded trials with fewer than 10 participants.
DATA COLLECTION AND ANALYSIS: One review author extracted data, which were checked by another review author. There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNTs) for the analgesic effect. We extracted any available data on the number or proportion of participants with 'no worse than mild pain' or treatment success (very satisfied, or very good or excellent on patient global impression scales).
MAIN RESULTS: We identified seven new studies in this update. We excluded six, and one study is ongoing so also not included in this update. This review contains a total of 62 included studies, with 4241 participants. Thirty-six studies used a cross-over design ranging from one to 15 days, with the greatest number (11) for seven days for each arm of the trial. Overall we judged the included studies to be at high risk of bias because the methods of randomisation and allocation concealment were poorly reported. The primary outcomes for this review were participant-reported pain and pain relief.Fifteen studies compared oral morphine modified release (Mm/r) preparations with morphine immediate release (MIR). Fourteen studies compared Mm/r in different strengths; six of these included 24-hour modified release products. Fifteen studies compared Mm/r with other opioids. Six studies compared MIR with other opioids. Two studies compared oral Mm/r with rectal Mm/r. Three studies compared MIR with MIR by a different route of administration. Two studies compared Mm/r with Mm/r at different times and two compared MIR with MIR given at a different time. One study was found comparing each of the following: Mm/r tablet with Mm/r suspension; Mm/r with non-opioids; MIR with non-opioids; and oral morphine with epidural morphine.In the previous update, a standard of 'no worse than mild pain' was set, equivalent to a score of 30/100 mm or less on a visual analogue pain intensity scale (VAS), or the equivalent in other pain scales. Eighteen studies achieved this level of pain relief on average, and no study reported that good levels of pain relief were not attained. Where results were reported for individual participants in 17 studies, 'no worse than mild pain' was achieved by 96% of participants (362/377), and an outcome equivalent to treatment success in 63% (400/638).Morphine is an effective analgesic for cancer pain. Pain relief did not differ between Mm/r and MIR. Modified release versions of morphine were effective for 12- or 24-hour dosing depending on the formulation. Daily doses in studies ranged from 25 mg to 2000 mg with an average of between 100 mg and 250 mg. Dose titration was undertaken with both instant release and modified release products. A small number of participants did not achieve adequate analgesia with morphine. Adverse events were common, predictable, and approximately 6% of participants discontinued treatment with morphine because of intolerable adverse events.The quality of the evidence is generally poor. Studies are old, often small, and were largely carried out for registration purposes and therefore were only designed to show equivalence between different formulations.
AUTHORS' CONCLUSIONS: The conclusions have not changed for this update. The effectiveness of oral morphine has stood the test of time, but the randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants and did not provide appropriate data for meta-analysis. Only a few reported how many people had good pain relief, but where it was reported, over 90% had no worse than mild pain within a reasonably short time period. The review demonstrates the wide dose range of morphine used in studies, and that a small percentage of participants are unable to tolerate oral morphine. The review also shows the wide range of study designs, and inconsistency in cross-over designs. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing participants over in cross-over design studies. It was not clear if these trials were sufficiently powered to detect any clinical differences between formulations or comparator drugs. New studies added to the review for the previous update reinforced the view that it is possible to use modified release morphine to titrate to analgesic effect. There is qualitative evidence that oral morphine has much the same efficacy as other available opioids.
BACKGROUND: A large proportion of people with advanced cancer will experience moderate to severe pain. Tapentadol is a novel, centrally acting analgesic medicine acting at the μ-opioid receptor and inhibiting noradrenaline reuptake. The efficacy of tapentadol is stated to be comparable to morphine and oxycodone.
OBJECTIVES: To assess the analgesic efficacy of tapentadol for the relief of cancer pain in adults, and the adverse events associated with its use in clinical trials.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from January 2005 to July 2015, together with reference lists of retrieved papers and review articles, and two clinical trial registries. Searches started from 2005 because this covered the period during which clinical trials were conducted. We contacted the manufacturer of tapentadol in the UK to find additional trials not identified by electronic searches. We did not restrict searches by language.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) of tapentadol compared with placebo or active controls in adults with moderate to severe cancer pain. Pain had to be measured using a validated assessment tool, and studies had to include at least 10 participants per treatment arm.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standard form and assessed risk of bias. We extracted available data on study design, participant details, interventions, and outcomes, including analgesic outcome measures, withdrawals, and adverse events.
MAIN RESULTS: We included four studies with 1029 participants. All the studies used a parallel-group design, and included an initial titration phase to determine the maximum effective and tolerated dose, followed by a maintenance phase. Tapentadol medication was taken twice daily and doses ranged from 50 to 500 mg per day. Rescue medication (morphine or oxycodone immediate-release) was available to participants in all studies.Overall, 440 participants were randomised in classically designed RCTs, and 589 participants were enrolled in enriched-enrolment, randomised-withdrawal (EERW) trials. A total of 476 participants were randomised to titration with tapentadol and 338 participants took tapentadol throughout the maintenance phase of their trial.All studies used numerical rating scores, Patient Global Impression of Change scores, and use of rescue medication as measures of efficacy, and all reported on adverse events and withdrawals.All studies enrolled fewer than 200 participants per treatment arm and were therefore at risk of overestimating efficacy. One study was terminated early due to problems with supply of rescue medication, with fewer than 20 participants enrolled per treatment arm in the maintenance phase of the trial. We judged another study at high risk of bias due to an open-label design.There were insufficient data for pooling and statistical analysis. Response rates for pain intensity were comparable across treatment groups in each study. In one EERW study, response rates were high across both treatment and placebo arms during the maintenance phase (62% tapentadol, 69% morphine, 50% placebo). For pain relief, tapentadol is no more and no less effective than oxycodone or morphine (low quality evidence).Treatment emergent adverse event rates were high, approximately 50% to 90%. The most common adverse events were gastrointestinal (nausea, vomiting, constipation) (low quality evidence). There was no advantage of tapentadol over morphine or oxycodone in terms of serious adverse events. The number of people experiencing effects on consciousness, appetite, or thirst was low.
AUTHORS' CONCLUSIONS: Information from RCTs on the effectiveness and tolerability of tapentadol was limited. The available studies were of moderate or small size and used different designs, which prevented pooling of data. Pain relief and adverse events were comparable between the tapentadol and morphine and oxycodone groups.
Background: Increases in prescriptions of opioid medications for chronic pain have been accompanied by increases in opioid overdoses, abuse, and other harms and uncertainty about long-term effectiveness.
Purpose: To evaluate evidence on the effectiveness and harms of long-term (>3 months) opioid therapy for chronic pain in adults.
Data Sources: MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL (January 2008 through August 2014); relevant studies from a prior review; reference lists; and ClinicalTrials.gov.
Study Selection: Randomized trials and observational studies that involved adults with chronic pain who were prescribed long-term opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies.
Data Extraction: Dual extraction and quality assessment.
Data Synthesis: No study of opioid therapy versus no opioid therapy evaluated long-term (>1 year) outcomes related to pain, function, quality of life, opioid abuse, or addiction. Good- and fair-quality observational studies suggest that opioid therapy for chronic pain is associated with increased risk for overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction, although there are few studies for each of these outcomes; for some harms, higher doses are associated with increased risk. Evidence on the effectiveness and harms of different opioid dosing and risk mitigation strategies is limited.
Limitations: Non-English-language articles were excluded, meta-analysis could not be done, and publication bias could not be assessed. No placebo-controlled trials met inclusion criteria, evidence was lacking for many comparisons and outcomes, and observational studies were limited in their ability to address potential confounding.
Conclusion: Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain and function. Evidence supports a dose-dependent risk for serious harms.
Primary Funding Source: Agency for Healthcare Research and Quality.
PURPOSE: The objective of this systematic review was to assess the clinical efficacy, safety, tolerability, and health-related quality of life outcomes associated with management of moderate-to-severe chronic pain with oxycodone/naloxone and tapentadol, focusing on the effect of these treatments on patients' daily functioning.
METHODS: Literature from a wide range of sources, including Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials, was searched to identify randomized controlled trials investigating tapentadol or oxycodone/naloxone for the treatment of patients with chronic pain. A network meta-analysis was conducted to determine the relative efficacy and safety profiles of these treatments.
FINDINGS: Oxycodone/naloxone was significantly better than tapentadol with respect to the Patient Assessment of Constipation Symptoms total score (risk ratio = -3.60; 95% credible interval, -5.36 to -2.11) and revealed a significantly lower risk of dizziness (risk ratio = 0.72; 95% credible interval, 0.42-0.98). Oxycodone/naloxone was directionally favored, although not significantly superior to tapentadol for headache, fatigue, dry mouth, dyspepsia, and withdrawals due to lack of efficacy. For the AE outcomes of constipation, nausea, and vomiting, as well as pain efficacy and all-cause withdrawals from studies, tapentadol was directionally favored without any statistical difference from oxycodone/naloxone. However, the two treatments were not wholly comparable for the evaluation of pain efficacy because of differences in on-study rescue medication and a higher baseline pain severity in the tapentadol studies.
IMPLICATIONS: Oxycodone/naloxone offers significant improvements in Patient Assessment of Constipation Symptoms total score and dizziness and was directionally favored for fatigue and headache compared with extended-release tapentadol, which may translate to improved patient daily functioning and health-related quality of life.
BACKGROUND: 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 in the UK has been criticised. In England the LCP was the subject of an independent review, commissioned by a Health Minister. The 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.
OBJECTIVES: 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.
Despite the increased availability of strong analgesics and evidence-based recommendations for pain management, under-treatment of cancer-related pain is still common. Extended-release (ER) opioids, in contrast to immediate-release opioids, provide prolonged analgesia. In this review, we aimed to compare the efficacy and safety of ER opioid analgesics in managing moderate-to-severe pain in patients with cancer. We identified randomized controlled trials (RCTs) and controlled observational studies that compared ER opioids in cancer pain by searching several databases, including MEDLINE, EMBASE and the Cochrane Library. Two independent reviewers screened and evaluated retrieved records to select relevant studies. We dually assessed the risk of bias for included studies and evaluated the overall strength of evidence for six critical outcomes using Grading of Recommendations Assessment, Development and Evaluation level of evidence. A total of three double-blind RCTs (comparative efficacy and adverse events), two non-blinded RCTs and four observational studies (comparative adverse events) were included in this review. All randomized trials and one observational study were of high risk of bias, and three observational studies of unclear risk of bias. The level of evidence for the selected efficacy and safety outcomes was low and very low. We synthesized the findings qualitatively because of the paucity of relevant studies as well as variable study design and quality. This systematic review indicates no substantial differences in efficacy and frequent adverse events among ER opioids for cancer pain. The body of evidence, however, is limited to few comparisons and fraught with methodological shortcomings.
Background: Pain is very common in patients with cancer. Opioid analgesics, including codeine, play a significant role in major guidelines on the management of cancer pain, particularly for mild to moderate pain. Codeine is widely available and inexpensive, which may make it a good choice, especially in low-resource settings. Its use is controversial, in part because codeine is not effective in a minority of patients who cannot convert it to its active metabolite (morphine), and also because of concerns about potential abuse, and safety in children. Objectives: To determine the efficacy and safety of codeine used alone or in combination with paracetamol for relieving cancer pain. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2014, Issue 2), MEDLINE and EMBASE from inception to 5 March 2014, supplemented by searches of clinical trial registries and screening of the reference lists of the identified studies and reviews in the field. Selection criteria: We sought randomised, double-blind, controlled trials using single or multiple doses of codeine, with or without paracetamol, for the treatment of cancer pain. Trials could have either parallel or cross-over design, with at least 10 participants per treatment group. Studies in children or adults reporting on any type, grade, and stage of cancer were eligible. We accepted any formulation, dosage regimen, and route of administration of codeine, and both placebo and active controls. Data collection and analysis: Two review authors independently read the titles and abstracts of all studies identified by the searches and excluded those that clearly did not meet the inclusion criteria. For the remaining studies, two authors read the full manuscripts and assessed them for inclusion. We resolved discrepancies between review authors by discussion. Included studies were described qualitatively, since no meta-analysis was possible because of the small amount of data identified, and clinical and methodological between-study heterogeneity. Main results: We included 15 studies including 721 participants with cancer pain due to diverse types of malignancy. All studies were performed on adults; there were no studies on children. The included studies were of adequate methodological quality, but all except for one were judged to be at a high risk of bias because of small study size, and six because of methods used to deal with missing data or high withdrawal rates. Three studies used a parallel group design; the remainder were cross-over trials in which there was an adequate washout period, but only one reported results for treatment periods separately. Twelve studies used codeine as a single agent and three combined it with paracetamol. Ten studies included a placebo arm, and 14 included one or more of 16 different active drug comparators or compared different routes of administration. Most studies investigated the effect of a single dose of medication, while five used treatment periods of one, seven or 21 days. Most studies used codeine at doses of 30 mg to 120 mg. There were insufficient data for any pooled analysis. Only two studies reported our preferred responder outcome of 'participants with at least 50% reduction in pain' and two reported 'participants with no worse than mild pain'. Eleven studies reported treatment group mean measures of pain intensity or pain relief; overall for these outcome measures, codeine or codeine plus paracetamol was numerically superior to placebo and equivalent to the active comparators. Adverse event reporting was poor: only two studies reported the number of participants with any adverse event specified by treatment group and only one reported the number of participants with any serious adverse event. In multiple-dose studies nausea, vomiting and constipation were common, with somnolence and dizziness frequent in the 21-day study. Withdrawal from the studies, where reported, was less than 10% except in two studies. There were three deaths, in all cases due to the underlying cancer. Authors' conclusions: We identified only a small amount of data in studies that were both randomised and double-blind. Studies were small, of short duration, and most had significant shortcomings in reporting. The available evidence indicates that codeine is more effective against cancer pain than placebo, but with increased risk of nausea, vomiting, and constipation. Uncertainty remains as to the magnitude and time-course of the analgesic effect and the safety and tolerability in longer-term use. There were no data for children.
