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Dinges HC, Otto S, Stay DK, et al. Side Effect Rates of Opioids in Equianalgesic Doses Via Intravenous Patient-Controlled Analgesia: A Systematic Review and Network Meta-analysis. Anesth Analg. 2018 Nov 9. doi: 10.1213/ANE.0000000000003887. (Systematic review)
Abstract

BACKGROUND: Side effects of opioids used for the treatment of acute pain frequently limit their analgesic quality. Many studies have compared opioid side effects in patient-controlled analgesia (PCA), but it remains unclear whether there are specific side effect profiles that can be exploited when choosing an opioid for a patient. In this review, we wanted to determine the risk ratios (RRs) for the most common side effects when using different opioids for intravenous PCA in equianalgesic doses and rank the substances accordingly.

METHODS: A search of MEDLINE, EMBASE, the Cochrane Library (CENTRAL), and Web of Science identified 63 randomized controlled trials comparing opioids under equianalgesic conditions. Inclusion criteria were comparable pain stimulus between groups, equal coanalgesic treatment, and comparable resulting pain scores. Quality of studies was assessed using the Cochrane risk of bias tool with 6 items. Frequentistic network meta-analysis was conducted with morphine as the comparator. This method not only summarizes all estimated effects from direct comparisons of different interventions but also allows for indirect comparisons between interventions that can be linked via the common comparator, in which case the indirect evidence can be used to enhance the precision of the direct comparisons. Primary end points of this study were RRs for nausea and vomiting, pruritus, and events of sedation, as well as mean differences for scores of sedation. Events of respiratory depression were counted. Secondary end point was patient satisfaction (mean difference). The study protocol was registered at PROSPERO (CRD42017062355).

RESULTS: Sixteen opioid interventions were compared in the largest network (nausea and vomiting outcome) and 7 opioid interventions in the smallest network (sedation events outcome). Most interventions did not differ from morphine on the primary outcomes (side effects), with some exceptions. Buprenorphine had a significantly higher RR of nausea and vomiting, whereas fentanyl had a lower RR of nausea and vomiting. Nalbuphine, butorphanol, methadone, and pethidine/meperidine had a lower risk of pruritus. Respiratory depression was rare (22 of 2452 patients). Pethidine/meperidine, fentanyl, and oxymorphone caused significantly lower sedation scores. Tramadol caused significantly lower satisfaction scores, whereas oxycodone, alfentanil, remifentanil, fentanyl, and pethidine/meperidine caused significantly higher satisfaction scores.

CONCLUSIONS: The opiate chosen for treatment most likely has little effect on the incidence of pruritus and nausea/vomiting, although considerable differences exist in terms of better and worse opioids in the presented rankings. Larger differences between drugs were observed with regard to sedation and patient satisfaction, and choosing the appropriate opioid may help to improve PCA in this regard.

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Comments from MORE raters

Physician rater

Systematic review/meta-analysis on the side effect rates of opioids used for IV PCA. 63 RCTs selected comparing opioids under equianalgesic conditions. Morphine was the comparator. Primary endpoints were risk ratio for nausea/vomiting, pruritus, events and scores of sedation, and respiratory depression. Secondary endpoint was patient satisfaction. Correction factors were considered. Studies included ranged between 16 to 7 opioid interventions, and between 17 and 500 patients, mainly postoperative. A ranking for each side effect is presented. This can be used in the specific patient, and if a change in analgesic drug is necessary. Well designed study with some data that managed to provide clinically useful information. The results are useful to choose the most appropriate opioid in IV PCA regimens.

Physician rater

This study used a complex analytical methodology poorly mastered by practitioners in the field. However, the rigorous methodology provides evidence-based information on the equipotence in terms of side effects of opioids administered PCA. However, their use is substantially less now since the concept of multimodal analgesia, local analgesia, and the development of anesthesia without opiates.

Physician rater

Nicely presented study that illuminates a sensitive pain management area. All physicians who deal with the problem must be made aware of this study and its results.
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