The authors concluded that the evidence did not suggest that rescue medication with short-acting opioids for breakthrough pain affected analgesic efficacy or the incidence of adverse effects among patients receiving long-acting opioids for chronic non-malignant pain. However, further research is needed. Limitations with the statistical analysis and potential for review bias should be borne in mind when interpreting the conclusions.

To assess the impact of opioid rescue medication on the effectiveness and tolerability of chronic opioid therapy for chronic non-malignant pain.

MEDLINE (from 1950) and EMBASE (from 1974) were searched to July 2006 for published studies in English, German, French, Spanish and Italian. Search terms (including study design terms) were reported.

Prospective studies of long-acting opioids for adults (aged at least 18 years) with chronic non-malignant pain were eligible for inclusion. Studies in which up to one third of participants had malignant pain were also eligible. Patients could be already receiving opioids or opioid-naïve. Long-acting opioids (including opioid formulations and weak opioids) were required to be administered for at least four weeks via any route except intrathecal or intraspinal, using a flexible dosing regimen. Studies were required to report whether an immediate-release opioid was used as a rescue medication. The control group could receive placebo, other types of opioid or active controls. Studies were also required to report efficacy (measured using a pain scale or global assessment) or tolerability (based on the number/percentage of patients reporting nausea, constipation or somnolence). Case reports, conference proceedings, surveys and audits were excluded.

Participants in the included studies received analgesia for a wide range of conditions including osteoarthritis, lower back pain, pancreatitis and neuropathic pain. The most commonly used opioids were oxycodone, tramadol and fentanyl, either by oral or transdermal delivery. Most studies were uncontrolled. The most commonly used control was placebo. Maximum duration of treatment was two years. None of the included studies directly compared use of long-term opioids with and without opioid rescue medication.

Full papers were checked for eligibility by two reviewers and disagreements were resolved by consensus. It was unclear how many reviewers decided which full papers should be retrieved.

Study quality was evaluated using the Jadad scale to assess adequacy of reported randomisation, double blinding and withdrawals or dropouts. Each study was awarded a score out of a maximum 5 points. Two reviewers independently conducted the validity assessment. Disagreements were resolved by a third party.

Estimates of within or between-group treatment effects and their standard errors (SEs) were extracted or calculated for the first-mentioned or primary analgesic outcome in each study. Adverse event rates and their SEs were calculated. If necessary, various assumptions (detailed in the review) were made about variability of data and/or use of rescue medication. Pain measures were converted to a 0 to 100 scale. Studies that compared two long-acting opioids were treated as two separate uncontrolled studies. The long-acting opioid arms of studies that compared long- and short-acting opioids were treated as uncontrolled studies. Studies that compared a long-acting opioid with a non-opioid analgesic were treated as placebo-controlled studies of long-acting opioids. Attempts were made to obtain additional information from study authors. The authors did not state how many reviewers performed the data extraction.

Studies were classified as rescue and no rescue. Meta-regression analysis was used to estimate the effectiveness and tolerability of rescue medication compared to the reference category (no rescue), while controlling for other variables (study design, quality, type of opioid). Sensitivity analyses were conducted and studies that had a Jadad score of 0, used weak opioids (tramadol, codeine, tolidine and dihydrocodeine) or included patients with malignant pain were omitted.

Forty-eight prospective studies were included in the review: 13 placebo-controlled (including three crossover); and 35 uncontrolled (n=17,960, range 12 to 6772). There were 24 rescue and 24 no-rescue studies. Jadad scores were 5 (eight studies), 4 (three studies), 2 (one study), 1 (32 studies) and 0 (four studies) out of a maximum of 5 points. Most ‘rescue’ studies were of low quality (Jadad score of 0 or 1), while under half of the ‘no rescue’ studies were of high quality (Jadad score of 4 or 5).

Meta-regression showed no statistically significant difference between 'rescue' and 'no rescue' studies in analgesic efficacy (40 studies) or incidence of adverse events (36 studies). Sensitivity analyses did not change these findings.

The evidence did not suggest that rescue medication with short-acting opioids for breakthrough pain affected analgesic efficacy or the incidence of adverse effects among patients who received long-acting opioids for chronic non-malignant pain. However, given the shortcomings of the evidence, conclusions must be drawn with caution and further research is needed to inform decisions on breakthrough pain management in this patient population.

The objectives and inclusion criteria of the review were clear. Only two databases were searched (so some studies may have been missed) and the restriction to published studies in specific languages meant that the review was prone to publication and language biases. It appeared that publication bias was not formally assessed. Steps were taken to reduce the risk of reviewer bias and error by having more than one reviewer to select studies and assess study validity; it was unclear whether similar precautions applied to data extraction.

The tool used for validity assessment was designed for randomised controlled trials (RCTs) and is unsuitable for validity assessment of observational studies. The authors acknowledged that the included studies differed widely in design, quality, population and treatment regimen, and that it was unclear whether pooling of the data was appropriate. However, the authors did make some attempt to adjust for potential confounding using meta-regression. The authors also acknowledged that the use of rescue medication in the included studies was not quantified, studies may have been of too short duration to show an effect, and that outcome measures were relatively crude. However, much of the analysis was based on untested assumptions and/or used data that had been manipulated by the reviewers. As no studies compared the interventions of interest, the review findings were based on indirect comparisons, and limitations with this type of analysis should be borne in mind.

The limitations of the included studies and issues associated with indirect analysis, as highlighted by the authors, should be borne in mind when interpreting the findings, as should the potential for bias in the review process. However, the authors’ recommendation for further research seems appropriate.

Practice: The authors stated that use of short-acting immediate release opioids for breakthrough pain among patients with chronic non-malignant pain treated with long-acting opioids confered no additional analgesic benefit, but did not reduce analgesic efficacy.

Research: The authors stated that a RCT was required to assess the effects of long-term treatment with a long-acting opioid with or without opioid rescue medication among patients with chronic non-malignant pain.

Janssen-Cilag Medical Affairs EMEA.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.