Pain assessment in clinical trials: a narrative review.

Pain is a symptom measured in many clinical trials. For pain as an outcome domain, trialists need to choose adequate outcome measure(s), as there are myriad outcome measures for pain to choose from. To ensure consistency and uniformity in clinical trials and systematic reviews, core outcome sets (COS) have been defined; COS includes a predefined minimal list of core outcomes that should be measured within a trial, to ensure their consistency and comparability. COS is defined via consensus procedure, which includes relevant stakeholders such as experts from a specific field and patients. Along with outcomes, outcome measures for each outcome need to be defined to make sure that the outcomes will be measured consistently and uniformly. Hereby we reviewed studies that have examined use of recommended core outcome domains and outcome measures in clinical trials that would be expected to measure pain. Despite the existence of COS and defined core outcome measures (COMs), multiple studies have shown that these are not necessarily used in clinical trials, or in the relevant systematic reviews, which further increases heterogeneity of existing evidence, hinders evidence synthesis and trial comparability, and assessment of comparative effectiveness of interventions. Trialists are encouraged to use COS and COMs when designing clinical trials. Research community is encouraged to design interventions that will help with identifying barriers for using COS and COMs and interventions to foster their uptake. Use of consistent pain outcomes and pain outcome measures is in the interest of patients, research community, healthcare workers and decision-makers. For clinical conditions for which there are no COS and COMs, efforts to design them would be beneficial.

Outcome Domains, Outcome Measures, and Characteristics of Randomized Controlled Trials Testing Nonsurgical Interventions for Osteoarthritis.

OBJECTIVE: Core outcome set (COS) is the minimum set of outcome domains that should be measured and reported in clinical trials. We analyzed outcome domains, prevalence of use of COS published by Outcome Measures in Rheumatology (OMERACT) initiative, outcome measures for outcome domains recommended by OMERACT COS, duration and size of randomized controlled trials (RCT) testing nonsurgical interventions for osteoarthritis (OA). METHODS: We searched PubMed and analyzed RCT about nonsurgical interventions for OA published from June 2012 to June 2017. We extracted data about trial type, use of OMERACT COS, efficacy outcome domains, safety outcome domains, outcome measures used for COS assessment, duration, and sample size. RESULTS: Among 334 analyzed trials, complete OMERACT-recommended COS was used by 14% of trials. Higher median prevalence of using OMERACT COS was found in trials explicitly described as phase III, and trials of pharmacological interventions with followup ≥ 1 year, but both with wide range of COS usage. Trialists used numerous different outcome measures for analyzing core outcome domains: 50 different outcome measures for pain, 74 for physical function, 9 for patient's global assessment, and 5 for imaging. CONCLUSION: Suboptimal use of recommended COS and heterogeneity of outcome measures is reducing quality and comparability of OA trials and hinders conclusions about efficacy and comparative efficacy of nonsurgical interventions. Interventions for improving study design of trials in this field would be beneficial.

Selective reporting bias due to discrepancies between registered and published outcomes in osteoarthritis trials.

Aim: Outcome reporting bias (ORB) occurs when outcomes planned in a study protocol are subsequently not reported or are partially reported. Our aim was to analyze ORB in randomized controlled trials (RCTs) about conservative interventions for osteoarthritis (OA) by comparing registered protocols and published manuscripts, as well as association between study funding type and intervention type, and ORB in those RCTs. Materials & methods: We analyzed RCTs that were published in a peer-review journal and analyzed any type of conservative intervention for treatment of OA in humans that reported in the manuscript registration in a public clinical trial registry and provided unique registration identifier. We extracted data indicating ORB by comparing outcomes in protocol and published article, and characteristics of trials. Results: In 190 (57%) of 334 included RCTs, it was indicated in the manuscript that a trial was registered. In 48% of trials we found discrepancies in number, type or time point of primary efficacy outcome between protocol and manuscript. Significantly less discrepancies in primary efficacy outcomes between protocols and published articles were found in trials funded by a commercial sponsor (p = 0.0062) and trials of pharmacological interventions (p = 0.0016). Conclusion: Trials about conservative therapies for OA have high prevalence of discrepancies between protocol and publication, and frequent ORB. This may mislead readers of published results because it has been shown that ORB can lead to both overestimation and underestimation of effects of interventions, depending on the intervention and outcome. Efforts to prevent nonregistration of protocols and selective reporting are needed.

Outcome domains and pain outcome measures in randomized controlled trials of interventions for postoperative pain in children and adolescents.

BACKGROUND: We analysed outcome domains and pain outcome measures in randomized controlled trials of interventions for postoperative pain management in children and adolescents and compared them to the core outcome set recommended by the Pediatric Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (PedIMMPACT). METHODS: Systematic literature search was conducted in MEDLINE, CDSR, DARE, CINAHL and PsycINFO up to 31 January 2017. One author extracted data and second verified the extraction. Outcome domains and pain outcome measures were analysed and compared with the PedIMMPACT core outcome set. RESULTS: We included 337 trials. Median number of reported outcomes was five (range 1-11) for the included trials and two (range 0-6) for PedIMMPACT. The most commonly analysed PedIMMPACT outcome domains were pain intensity (93%) and "symptoms and adverse events" (83%). The remaining four PedIMMPACT outcomes were present in under 30% of included randomized controlled trials. Proportion of PedIMMPACT outcome domains did not change after the PedIMMPACT was published in 2008. Of the 312 trials that reported pain intensity, 303 (97%) also specified pain assessment tools, in which the most common was the visual analogue scale (24%) followed by the Children's Hospital of Eastern Ontario Pain Scale (18%). CONCLUSION: Analysed trials about interventions for pediatric postoperative pain insufficiently used the recommended core outcome set for acute pain in children. Relevance of the PedIMMPACT core outcome set, as well as the reasons behind its limited uptake, need to be further evaluated. SIGNIFICANCE: Recommended core outcomes have been insufficiently used in randomized controlled trials about postoperative pain in children, which hinders comparability of studies and makes synthesis of evidence difficult.

Authors' lack of awareness and use of core outcome set on postoperative pain in children is hindering comparative effectiveness research.

AIM: To analyze awareness about and acceptability of core outcome set (COS) for pediatric pain recommended by the PedIMMPACT. METHODS: We invited authors of systematic reviews and randomized controlled trials about interventions for postoperative pain in children to participate in a survey. RESULTS: Only a third of surveyed authors of systematic reviews and randomized controlled trials about postoperative pain in children had heard about the PedIMMPACT COS for acute pediatric pain. Problems indicated as preventing them from using the COS were lack of awareness, difficulties with implementation, and lack of resources. CONCLUSION: Further discussions about the adequacy of COS for acute pediatric pain, as well as interventions to increase the uptake of COS may be warranted.

Efficacy and Safety Outcomes in Systematic Reviews of Interventions for Postoperative Pain in Children: Comparison Against the Recommended Core Outcome Set.

Objective: To investigate the range of efficacy and safety outcomes used in systematic reviews (SRs) of randomized controlled trials (RCTs) of interventions for postoperative pain in children and compare them with outcome domains recommended in the Pediatric Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (PedIMMPACT). Methods: Five electronic databases were searched: MEDLINE, Cochrane Database of Systematic Reviews, DARE, CINAHL, and PsycINFO. Two review authors extracted outcome data independently. Efficacy and safety outcomes were extracted and categorized. The type and number of outcomes were analyzed and compared against the outcomes recommended by PedIMMPACT. The study protocol was registered in PROSPERO (CRD42015029654). Results: We included 48 systematic reviews with data from 816 trials. The median number of all outcomes was 4, while the median number of the PedIMMPACT core outcomes was three out of six. The most commonly reported outcome of the PedIMMPACT Core Outcome set (COS) was "symptoms and adverse events," followed by pain intensity, which was reported in 75% of the included SRs. Just over half of the SRs that included a pain intensity outcome also indicated the specific pain assessment tool used in the methods section. Conclusions: Systematic reviews in the field of pediatric pain do not use the recommended COS. Nor do they consistently include pain as an outcome. This makes comparisons of efficacy and safety across interventions very difficult. Future studies should explore whether the authors are aware of the COS and whether the recommended COS is appropriate.

Interventions for postoperative pain in children: An overview of systematic reviews.

The aim of this study was to conduct an overview of systematic reviews that summarizes the results about efficacy and safety from randomized controlled trials involving the various strategies used for postoperative pain management in children. We searched the Cochrane Database of Systematic Reviews, CINAHL, Database of Reviews of Effect, Embase, MEDLINE, and PsycINFO from the earliest date to January 24, 2016. This overview included 45 systematic reviews that evaluated interventions for postoperative pain in children. Out of 45 systematic reviews that investigated various interventions for postoperative pain in children, 19 systematic reviews (42%) presented conclusive evidence of efficacy. Positive conclusive evidence was reported in 18 systematic reviews (40%) for the efficacy of diclofenac, ketamine, caudal analgesia, dexmedetomidine, music therapy, corticosteroid, epidural analgesia, paracetamol, and/or nonsteroidal anti-inflammatory drugs and transversus abdominis plane block. Only one systematic review reported conclusive evidence of equal efficacy that involved a comparison of dexmedetomidine vs morphine and fentanyl. Safety of interventions was reported as conclusive in 14 systematic reviews (31%), with positive conclusive evidence for dexmedetomidine, corticosteroid, epidural analgesia, transversus abdominis plane block, and clonidine. Seven systematic reviews reported equal conclusive safety for epidural infusion, diclofenac intravenous vs ketamine added to opioid analgesia, bupivacaine, ketamine, paracetamol, and dexmedetomidine vs intravenous infusions of various opioid analgesics, oral suspension and suppository of diclofenac, only opioid, normal saline, no treatment, placebo, and midazolam. Negative conclusive statement for safety was reported in one systematic review for caudal analgesia vs noncaudal regional analgesia. More than half of systematic reviews included in this overview were rated as having medium methodological quality. Of 45 included systematic reviews, 10 were Cochrane reviews and they had higher methodological quality than non-Cochrane reviews. As evidence concerning efficacy and safety is inconclusive for most of the analyzed interventions, our review points out the need for more rigorous trials concerning pain management in children.

Interventions for Neuropathic Pain: An Overview of Systematic Reviews.

Numerous interventions for neuropathic pain (NeuP) are available, but its treatment remains unsatisfactory. We systematically summarized evidence from systematic reviews (SRs) of randomized controlled trials on interventions for NeuP. Five electronic databases were searched up to March 2015. Study quality was analyzed using A Measurement Tool to Assess Systematic Reviews. The most common interventions in 97 included SRs were pharmacologic (59%) and surgical (15%). The majority of analyzed SRs were of medium quality. More than 50% of conclusions from abstracts on efficacy and approximately 80% on safety were inconclusive. Effective interventions were described for painful diabetic neuropathy (pregabalin, gabapentin, certain tricyclic antidepressants [TCAs], opioids, antidepressants, and anticonvulsants), postherpetic neuralgia (gabapentin, pregabalin, certain TCAs, antidepressants and anticonvulsants, opioids, sodium valproate, topical capsaicin, and lidocaine), lumbar radicular pain (epidural corticosteroids, repetitive transcranial magnetic stimulation [rTMS], and discectomy), cervical radicular pain (rTMS), carpal tunnel syndrome (carpal tunnel release), cubital tunnel syndrome (simple decompression and ulnar nerve transposition), trigeminal neuralgia (carbamazepine, lamotrigine, and pimozide for refractory cases, rTMS), HIV-related neuropathy (topical capsaicin), and central NeuP (certain TCAs, pregabalin, cannabinoids, and rTMS). Evidence about interventions for NeuP is frequently inconclusive or completely lacking. New randomized controlled trials about interventions for NeuP are necessary; they should address safety and use clear diagnostic criteria.

Analysis of perioperative pain management in vascular surgery indicates that practice does not adhere with guidelines: a retrospective cross-sectional study.

BACKGROUND: Inadequate treatment of pain related to surgery may be associated with complications and prolonged recovery time and increased morbidity and mortality rates. We investigated perioperative pain management in vascular surgery and compared it with the relevant guidelines for the treatment of perioperative pain. METHODS: We conducted a retrospective study on 501 patients who underwent vascular surgery at the University Hospital Split, Croatia. We collected the following data from patients' charts: age, gender, premedication, preoperative patient's physical status, type of surgery, duration of surgery and anesthesia, type of anesthesia, postoperative analgesia, and need for intensive care. We examined departmental procedures to assess adherence to guidelines for perioperative pain management. RESULTS: None of the 501 patients' charts recorded information about perioperative pain intensity, 28% of patients did not receive any medication the night before their elective surgical procedures, and 17% of patients did not receive premedication immediately before the procedure. Most patients (66%) did not receive any pain medication in the operating room after surgery. Following surgery, 36% of patients were monitored in the intensive care units, while the rest were released to the ward. Some patients (17%) did not receive any analgesia after surgery. Procedures at the department did not adhere to the current recommendations for perioperative pain management. CONCLUSION: The study indicates that management of surgery-related pain in complex vascular procedures at this hospital did not follow guidelines for the management of acute perioperative pain. Our finding that most patients did not receive appropriate analgesia after vascular surgery leads to the conclusion that the institution would benefit from developing guidelines for the management of acute perioperative pain, which should be applied in all cases.