Alpha2 -receptor agonists as adjuvants for brachial plexus nerve blocks-A systematic review with meta-analyses.

BACKGROUND: We review the efficacy and safety of dexmedetomidine and clonidine as perineural or systemic adjuvants for brachial plexus blocks (BPB). METHODS: We included randomised controlled trials on upper limb surgery with BPBs in adults, comparing dexmedetomidine with clonidine or either drug with placebo. The primary outcome was duration of analgesia. Secondary outcomes included adverse and serious adverse events. The review was conducted using Cochrane standards, trial sequential analyses (TSA) and Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included 101 trials with 6248 patients. Overall, duration of analgesia was prolonged with both clonidine (176 min [TSA adj. 95% CI: 118, 205, p < .00001; 33 trials]) and dexmedetomidine (292 min [TSA adj. 95% CI: 245 329, p < .00001; 53 trials]), but was longer for dexmedetomidine than clonidine (205 min [TSA adj. 95% CI: 157, 254, p < .00001; 19 trials]). Compared with placebo, dexmedetomidine was associated with bradycardia (RR 4.2 [95% CI 2.2, 8.3]), and both clonidine (RR 4.5 [95% CI 1.1, 18.3]) and dexmedetomidine (RR 3.9 [95% CI 2.0, 7.5]) were associated with hypotension. Serious adverse events were mostly related to block technique. GRADE-rated quality of evidence was low or very low. CONCLUSION: Alpha2-receptor agonists used as adjuvants for BPBs lead to a prolonged duration of analgesia, with dexmedetomidine as the most efficient. Alpha2-receptor agonists were associated with increased risk of cardiovascular adverse events. The quality of evidence was low to very low.

Benefits and harm of paracetamol and ibuprofen in combination for post-operative pain: Pre-planned subgroup analyses of the multicenter, randomized PANSAID trial.

BACKGROUND: The "Paracetamol and Ibuprofen in Combination" (PANSAID) trial showed that combining paracetamol and ibuprofen resulted in lower opioid consumption than each drug alone and we did not find an increase in risk of harm when using ibuprofen vs paracetamol. The aim of this subgroup analysis was to investigate the differences in benefits and harms of the interventions in different subgroups. We hypothesized that the intervention effects would differ in subgroups with different risk of pain or adverse events. METHODS: In these pre-planned subgroup analyses of the PANSAID trial population, we assessed subgroup heterogeneity in intervention effects between (a) subgroups (sex, age, use of analgesics, American Society of Anesthesiologists (ASA) score, and type of anesthesia) and morphine consumption, and (b) subgroups (sex, age, use of non-steroidal anti-inflammatory drugs (NSAIDs), and ASA score) and serious adverse events. RESULTS: Test of interaction between age and the pairwise comparison between paracetamol 1 g vs paracetamol 0.5 g + ibuprofen 200 mg (P = .009) suggested lower morphine consumption in patients >65 years. However, post hoc analyses of related outcomes showed no interaction for this pairwise comparison. All other tests of interaction regarding both benefit and harm were not statistically significant. CONCLUSION: These pre-planned subgroup analyses did not suggest that patients in the investigated subgroups benefitted differently from a basic non-opioid analgesic regimen consisting of paracetamol and ibuprofen. Further, there was no evidence of subgroup heterogeneity regarding harm and use of ibuprofen. Because of reduced statistical power in subgroup analyses, we cannot exclude clinically relevant subgroup heterogeneity.

Pain management after total hip arthroplasty at five different Danish hospitals: A prospective, observational cohort study of 501 patients.

BACKGROUND: The available literature does not present a "gold standard" for post-operative pain treatment after total hip arthroplasty (THA). The aim of this prospective observational study was to explore and document post-operative pain treatment, including outcomes, in a large cohort of patients undergoing THA at five different Danish hospitals. METHODS: This prospective, multicentre, observational cohort study of 501 THA patients was performed at five different hospitals in the Capital Region and at the Region Zealand in Denmark, from April 2014 to April 2016. The study had two co-primary outcomes: Pain during mobilisation at 6 hours post-operatively (numeric rating scale [NRS] [0-10]) and morphine consumption 0-24 hours post-operatively. RESULTS: A large variety of analgesic treatments were used at the included hospitals and none of the hospitals used the same non-opioid basic analgesic regimen. For all patients at all hospitals, the NRS-pain level during mobilisation at 6 hours was 5 (3-6), (median [interquartile range]) and the 24-hour intravenous morphine (eqv) consumption was 25 mg (18-35). Although some statistically significant differences between hospitals were found for morphine use, no non-opioid analgesic regimen demonstrated consistent clinically relevant superior efficacy. In general, pain levels at rest were low to moderate and pain during mobilisation was moderate. CONCLUSIONS: Analgesic treatment routines differed between hospitals. Pain levels, however, did not differ substantially and were in general low at rest and moderate during mobilisation. No non-opioid analgesic treatment demonstrated consistent analgesic superiority.

Adductor Canal Block With Continuous Infusion Versus Intermittent Boluses and Morphine Consumption: A Randomized, Blinded, Controlled Clinical Trial.

BACKGROUND: Based on the assumption that relatively large volumes of local anesthetic optimize an adductor canal block (ACB), we theorized that an ACB administered as repeated boluses would improve analgesia without compromising mobility, compared with a continuous infusion. METHODS: We performed a randomized, blinded, controlled study, including patients scheduled for total knee arthroplasty with spinal anesthesia. Patients received 0.2% ropivacaine via a catheter in the adductor canal administered as either repeated intermittent boluses (21 mL/3 h) or continuous infusion (7 mL/h). The primary outcome was total (postoperative day [POD], 0-2) opioid consumption (mg), administered as patient-controlled analgesia. Pain, ambulation, and quadriceps muscle strength were secondary outcomes. RESULTS: We randomized 110 patients, of whom 107 were analyzed. Total opioid consumption (POD, 0-2) was a median (range) of 23 mg (0-139) in the bolus group and 26 mg (3-120) in the infusion group (estimated median difference, 4 mg; 95% confidence interval [CI], -13 to 5; P = .29). Linear mixed-model analyses revealed no difference in pain during knee flexion (mean difference, 2.6 mm; 95% CI, -2.9 to 8.0) or at rest (mean difference, 1.7 mm; 95% CI, -1.5 to 4.9). Patients in the bolus group had improved quadriceps sparing on POD 2 (median difference, 7.4%; 95% CI, 0.5%-15.5%). However, this difference was not present on POD 1 or reflected in the ambulation tests (P > .05). CONCLUSIONS: Changing the mode of administration for an ACB from continuous infusion to repeated intermittent boluses did not decrease opioid consumption, pain, nor mobility.

Does Dexmedetomidine Have a Perineural Mechanism of Action When Used as an Adjuvant to Ropivacaine?: A Paired, Blinded, Randomized Trial in Healthy Volunteers.

BACKGROUND: Dexmedetomidine used as an adjuvant to local anesthetics may prolong the duration of peripheral nerve blocks. Whether this is mediated by a perineural or systemic mechanism remains unknown. The authors hypothesized that dexmedetomidine has a peripheral mechanism of action. METHODS: The authors conducted a randomized, paired, triple-blind trial in healthy volunteers. All received bilateral saphenous nerve blocks with 20 ml ropivacaine, 0.5%, plus 1 ml dexmedetomidine, 100 µg/ml, in one thigh and 20 ml ropivacaine 0.5% plus 1 ml saline in the other thigh. The primary outcome measure was the duration of block assessed by temperature sensation (alcohol swab). The secondary outcome measure was the duration of block assessed by pinprick, pain during tonic heat stimulation, warmth detection threshold, and heat pain detection threshold. RESULTS: All 21 enrolled volunteers completed the trial. The mean duration of block assessed by temperature sensation in the leg receiving ropivacaine plus dexmedetomidine was 22 h (95% CI, 21 to 24) compared to 20 h (95% CI, 19 to 21) in the leg receiving ropivacaine plus placebo with a mean difference of 2 h (95% CI, 1 to 3; P = 0.001). The duration of block was also significantly longer in the leg receiving dexmedetomidine when assessed by pinprick, pain during tonic heat stimulation, and warmth detection threshold but not heat pain detection threshold. One participant experienced numbness in an area in the leg receiving dexmedetomidine. CONCLUSIONS: Dexmedetomidine prolongs the duration of a saphenous nerve block by a peripheral mechanism when controlling for systemic effects but not necessarily to a clinically relevant extent.

Postoperative Treatment of Pain after Hip Fracture in Elderly Patients with Dementia.

BACKGROUND/AIMS: Prior studies have shown that patients with dementia are at risk of receiving insufficient treatment for pain after a hip fracture. We therefore hypothesized that elderly hip fracture patients with dementia received less postoperative pain treatment than those without dementia. METHOD: All patients (age ≥65 years) who had been operated on for a hip fracture in the Copenhagen University Hospital region in 2009 were included. Data about analgesic use for the first 72 h after surgery were acquired from the hospitals' electronic medication system and linked with information about dementia, comorbidity, and prior drug use. RESULTS: A total of 1,507 patients were included, of which 296 (19.6%) suffered from dementia. Both groups were equally likely to receive paracetamol and opioids. Patients with dementia received lower doses of oral morphine equivalents during the first [dementia vs. no dementia: 29.0 (26.4-31.8) vs. 34.7 (33.1-36.4) mg, p = 0.001] and second [27.8 (25.4-30.5) vs. 31.2 (29.9-32.4) mg, p = 0.019] but not on the third postoperative day (p = 0.10). CONCLUSION: The lower doses of opioids may reflect uncertainty about how to treat pain patients with dementia. Further guidance is needed, as inadequate treatment of pain may have adverse consequences.

Transversus abdominis plane block after laparoscopic colonic resection in cancer patients: A randomised clinical trial.

BACKGROUND: A key point in pathways for optimal rehabilitation and enhanced recovery is an effective postoperative multimodal pain treatment regimen. OBJECTIVE: To investigate the analgesic effects of transversus abdominis plane (TAP) block in conjunction with paracetamol and ibuprofen in patients undergoing laparoscopic colonic resection. DESIGN: Randomised placebo-controlled double-blind study. SETTING: Herlev University Hospital, Copenhagen, Denmark, from March 2010 to February 2013. PATIENTS: Eighty adult patients scheduled for elective laparoscopic colectomy. INTERVENTIONS: Bilateral TAP block with 20 ml of either ropivacaine or isotonic saline. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) pain scores (0 to 100 mm) while coughing at 6 h after surgery (primary outcome). Secondary outcomes were area under the curve pain scores (2 to 24 h) at rest and while coughing, 24-h morphine consumption and incidence of nausea and vomiting. RESULTS: VAS pain scores at 6 h while coughing was not different between groups (median, interquartile range), TAP, 27 (11 to 45) mm vs. placebo, 33 (20 to 49) mm (P = 0.20). Total 24-h morphine consumption was reduced in the TAP block group vs. placebo group, 30 (15 to 41) mg vs. 43 (30 to 67) mg, respectively (P = 0.008). This difference was most pronounced in the first postoperative hours. The remaining outcomes did not differ between groups. CONCLUSION: TAP block used in combination with paracetamol and ibuprofen did not reduce pain after laparoscopic colonic surgery. However, we found a 30% reduction in opioid use, most marked in the early postoperative period. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01418144).

Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study.

STUDY OBJECTIVE: Initial out-of-hospital analgesia is sometimes hampered by difficulties in achieving intravenous access or lack of skills in administering intravenous opioids. We study the safety profile and apparent analgesic effect of intranasal fentanyl in the out-of-hospital setting. METHODS: In this prospective observational study, we administered intranasal fentanyl in the out-of-hospital setting to adults and children older than 8 years with severe pain resulting from orthopedic conditions, abdominal pain, or acute coronary syndrome refractory to nitroglycerin spray. Patients received 1 to 3 doses of either 50 or 100 µg, and the ambulance crew recorded adverse effects and numeric rating scale (0 to 10) pain scores before and after treatment. RESULTS: Our 903 evaluable patients received a mean cumulative fentanyl dose of 114 µg (range 50 to 300 µg). There were no serious adverse effects and no use of naloxone. Thirty-six patients (4%) experienced mild adverse effects: mild hypotension, nausea, vomiting, vertigo, abdominal pain, rash, or decrease of Glasgow Coma Scale score to 14. The median reduction in pain score was 3 (interquartile range 2 to 5) after fentanyl administration. CONCLUSION: The out-of-hospital administration of intranasal fentanyl in doses of 50 to 100 µg is safe and appears effective.

Variation in postoperative non-steroidal anti-inflammatory analgesic use after colorectal surgery: a database analysis.

BACKGROUND: Non-steroid anti-inflammatory drugs (NSAIDs) have been proposed as part of a multimodal postoperative analgesia in patients operated for colorectal cancer. However, whether these drugs are prescribed and taken by the patients have not been evaluated. The aim of this study was to quantify the postoperative use of NSAIDs in these patients. METHODS: Data from patients operated for colorectal cancer between January 1, 2006 and December 31, 2009 were collected from the Danish Colorectal Cancer Group's (DCCG) prospective database. From the electronically registered medical records, data for the use of the two NSAIDs diclofenac and ibuprofen were recorded. The data from six colorectal departments in eastern Denmark were compared. RESULTS: Of the 2,754 patients analyzed overall, 40.6% received NSAIDs as part of their analgesic treatment. The percentage of the patients receiving NSAIDs, receiving a pre-defined dosage as a minimum and receiving NSAIDs as p.r.n. medication, and the type of NSAID were significantly different both between department and within departments. The median dose of ibuprofen and diclofenac were 1200 mg (400-2,400 mg) and 100 mg (50-200 mg), respectively. CONCLUSIONS: The large variation between and within the departments points to an inconsistency in the use of multimodal post-operative pain treatments. This may be a result of insufficient evidence on procedure specific pain treatments and possibly a lack of compliance to existing guidelines. High-quality large-scale studies are warranted to form the basis for guidelines for postoperative analgesic treatment.

Adductor canal block versus femoral nerve block and quadriceps strength: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers.

BACKGROUND: The authors hypothesized that the adductor canal block (ACB), a predominant sensory blockade, reduces quadriceps strength compared with placebo (primary endpoint, area under the curve, 0.5-6 h), but less than the femoral nerve block (FNB; secondary endpoint). Other secondary endpoints were adductor strength and ability to ambulate. METHODS: The authors enrolled healthy young men into this double blind, placebo-controlled, randomized, crossover study. On two separate study days, subjects received either ACB or FNB with ropivacaine, and placebo in the opposite limb. Strength was assessed as maximum voluntary isometric contraction for quadriceps and adductor muscles. In addition, subjects performed three standardized ambulation tests. Clinicaltrials.gov Identifier: NCT01449097. RESULTS: Twelve subjects were randomized, 11 analyzed. Quadriceps strength (area under the curve, 0.5-6 h) was significantly reduced when comparing ACB with placebo (5.0 ± 1.0 vs. 5.9 ± 0.6, P = 0.02, CI: -1.5 to -0.2), FNB with placebo (P = 0.0004), and when comparing FNB with ACB (P = 0.002). The mean reduction from baseline was 8% with ACB and 49% with FNB. The only statistically significant difference in adductor strength was between placebo and FNB (P = 0.007). Performance in all mobilization tests was reduced after an FNB compared with an ACB (P < 0.05). CONCLUSIONS: As compared with placebo ACB statistically significantly reduced quadriceps strength, but the reduction was only 8% from baseline. ACB preserved quadriceps strength and ability to ambulate better than FNB did. Future studies are needed to compare the analgesic effect of the ACB with the FNB in a clinical setting.

Bilateral transversus abdominis plane (TAP) block with 24 hours ropivacaine infusion via TAP catheters: A randomized trial in healthy volunteers.

BACKGROUND: The analgesic effect of a TAP block has been investigated in various surgical settings. There are however limited information about block level and block duration. Furthermore, there is a lack of information about continuous TAP block after ultrasound-guided posterior TAP blocks.The aim of this double-blind randomized study was therefore to investigate the effect of an ultrasound-guided posterior TAP block with 24 hours local anesthetic infusion via a TAP catheter. METHODS: In this randomized study 8 male volunteers received a bilateral TAP block (20 mLs 0.5% ropivacaine) and were allocated to receive active infusion (ropivacaine 0.2% 5 mL/hr) via a TAP catheter on one side and placebo infusion on the other side. PRIMARY OUTCOME: Dermatomal sensory block involvement after 24 hours evaluated with pinprick. SECONDARY OUTCOMES: Sensory block involvement evaluated with cold test and heat-pain detection thresholds (HPDT) on the abdominal wall. Assessment points: 15 min before block performance and 1, 4, 8, 12 and 24 hours after block performance. RESULTS: The TAP block primarily involved sensory changes in the Th10 to Th12 dermatomes. On the placebo side there was a decrease in extension beginning at 4-8 hours after block performance and with no detectable effect beyond 12 hours. Median number of dermatomes anesthetized (pinprick) at 24 hours after block performance was 1.5 (0-3) on the active side compared with 0 (0-0) on the placebo side (P = 0.039).There were no statistical significant between-side differences in HPDT measurements at 24 hours after block performance. CONCLUSIONS: The spread of sensory block following ultrasound-guided posterior TAP block is partly maintained by a continuous 24 hour ropivacaine infusion through a TAP catheter. TRIAL REGISTRATION: The study was registered at NCT01577940.

A comprehensive multimodal pain treatment reduces opioid consumption after multilevel spine surgery.

PURPOSE: Major spine surgery with multilevel instrumentation is followed by large amount of opioid consumption, significant pain and difficult mobilization in a population of predominantly chronic pain patients. This case-control study investigated if a standardized comprehensive pain and postoperative nausea and vomiting (PONV) treatment protocol would improve pain treatment in this population. METHODS: A new regimen with acetaminophen, NSAIDs, gabapentin, S-ketamine, dexamethasone, ondansetron and epidural local anesthetic infusion or patient controlled analgesia with morphine, was introduced in a post-intervention group of 41 consecutive patients undergoing multilevel (median 10) instrumented spinal fusions and compared with 44 patients in a pre-intervention group. RESULTS: Compared to patients in the pre-intervention group, patients treated according to the new protocol consumed less opioid on postoperative day (POD) 1 (P = 0.024) and 2 (P = 0.048), they were mobilized earlier from bed (P = 0.003) and ambulation was earlier both with and without a walking frame (P = 0.027 and P = 0.027, respectively). Finally, patients following the new protocol experienced low intensities of nausea, sedation and dizziness on POD 1-6. CONCLUSIONS: In this study of patients scheduled for multilevel spine surgery, it was demonstrated that compared to a historic group of patients receiving usual care, a comprehensive and standardized multimodal pain and PONV protocol significantly reduced opioid consumption, improved postoperative mobilization and presented concomitant low levels of nausea, sedation and dizziness.

Analgesic efficacy of ultrasound-guided adductor canal blockade after arthroscopic anterior cruciate ligament reconstruction: a randomised controlled trial.

CONTEXT: Anterior cruciate ligament (ACL) reconstruction surgery is associated with moderate to severe postoperative pain, which may be ameliorated by peripheral nerve blocks. The adductor canal block (ACB) is an almost exclusively sensory nerve block that has been demonstrated to reduce pain and opioid consumption after major knee surgery. OBJECTIVES: To investigate the analgesic effect of ACB in patients receiving a basic analgesic regimen of paracetamol and ibuprofen after arthroscopic ACL reconstruction under general anaesthesia. DESIGN: Randomised, double-blind, placebo-controlled, parallel groups. SETTING: Day Case Surgery, University of Copenhagen, Glostrup Hospital, Denmark, June 2010 to March 2012. PATIENTS: Fifty patients, aged 18 to 70 years, scheduled for arthroscopic ACL reconstruction. INTERVENTIONS: Patients were randomised to receive ACB with either 30  ml ropivacaine 7.5  mg ml (n = 25) or 30  ml 0.9% saline (n = 24). MAIN OUTCOME MEASURES: Primary outcome was pain score (0 to 100  mm) during standing at 2  h after surgery. Secondary outcomes were pain at rest, during standing and after walking 5 m, opioid consumption and opioid-related side effects for 24  h after surgery. RESULTS: Median (interquartile range) pain scores for the primary outcome were 20 (12 to 36)  mm in the ropivacaine and 20 (10 to 44) mm in the control group (P = 0.84, 95% confidence interval for difference of -9 to 12 mm). No significant differences were observed in any of the secondary outcomes. CONCLUSION: An analgesic regimen with paracetamol and ibuprofen provides acceptable postoperative pain control after arthroscopic ACL reconstruction. ACB did not confer further benefit in our patients. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01212666.

Ultrasound-guided peripheral nerve blockade of the upper extremity.

PURPOSE OF REVIEW: Is ultrasound guidance changing the practice of upper extremity regional anesthesia? This review will aim to describe the findings published in the literature during the previous 18 months. RECENT FINDINGS: In some approaches to brachial plexus blockade, local anesthetic volumes may be reduced without deterioration of analgesic effect. However, even 10 ml of local injected into the interscalene space may result in diaphragmatic paresis. High-resolution ultrasonography has revealed anatomical variations of C5, C6 and C7 nerve roots in almost half of the patients examined, without negative block effectiveness. The addition of dexamethasone may prolong analgesia after single-shot interscalene and supraclavicular blocks. Insertion of brachial plexus perineural catheters using ultrasound guidance can be successful and provides better postoperative analgesia than single-shot blocks for up to 24 h postoperatively. Infraclavicular catheters provide superior analgesia when compared with supraclavicular catheters. Multiple-site injections of local offer no advantage over a single-site injection during an infraclavicular block. Ultrasound guidance compared with neurostimulation may reduce patient discomfort during axillary blocks compared with neurostimulation. Intra-epineural injections are common during an interscalene blockade, but the incidence of neurological injury remains low. There is an ongoing debate on the effectiveness and safety of ultrasound-guided intra-epineurial injections. SUMMARY: Current literature suggests a reduction of the volume of local anesthetics used for ultrasound-guided upper extremity blockades. Dexamethasone may prolong duration of brachial plexus blocks and more frequent use of perineural catheters is encouraged. Controversy over intra-epineurial injections exists and requires additional large-scale studies.

Pain treatment after craniotomy: where is the (procedure-specific) evidence? A qualitative systematic review.

CONTEXT AND OBJECTIVE: Pain following craniotomy has been demonstrated to be frequent and moderate-to-severe in nature. In recent years, the focus on the challenges in treatment of postoperative pain following craniotomy has increased. Fear of using opioids because of their wide array of side-effects has led to the search for alternative analgesic options. The objective of this systematic review was to evaluate current evidence about analgesic therapy following craniotomy. DATA SOURCES: PubMed database, Embase, Cochrane library, Google scholar and the Cumulative Index to Nursing and Allied Health Literature. ELIGIBILITY CRITERIA: Randomised double-blinded placebo-controlled trials (RCTs) with pain or supplemental postoperative analgesic consumption as an endpoint were included in the analysis. RESULTS: A total of 34 RCTs were identified, and nine RCTs were included in the final analysis, with a total of 519 patients (251 control vs. 268 active treatment). Four treatment modalities - scalp infiltration (five RCTs), nerve scalp block (two RCTs), parecoxib (one RCT) and patient-controlled analgesia with morphine (one RCT) - were evaluated. Scalp infiltration with local anaesthetic may provide adequate analgesia in the first few postoperative hours, and nerve scalp block may provide longer lasting analgesia for about 6 h. Morphine was found to reduce total analgesic rescue doses with no significant effect on nausea and no other side-effects. No significant evidence was found to support the use of parecoxib in the treatment of postcraniotomy pain. CONCLUSION: No firm recommendations on analgesic therapy following craniotomy can be given because the number of well performed RCTs is limited and the study populations are very small. However, evidence on scalp infiltration suggests an analgesic effect in the first few postoperative hours. There is an urgent need for well performed RCTs on pain therapy following craniotomy.

Preventive analgesia.

PURPOSE OF REVIEW: This paper will discuss the concepts of pre-emptive and preventive analgesia in acute and persistent postsurgical pain, based on the most recent experimental and clinical literature, with a special focus on injury-induced central sensitization and the development from acute to chronic pain. RECENT FINDINGS: The nature of central sensitization during acute and chronic postsurgical pain share common features, and there may be interactions between acute and persistent postoperative pain. The term 'pre-emptive analgesia' should be abandoned and replaced by the term 'preventive analgesia'. Recent studies of preventive analgesia for persistent postoperative pain are promising. However, clinicians must be aware of the demands for improved design of their clinical studies in order to get more conclusive answers regarding the different avenues for intervention. SUMMARY: The concept of preventive analgesia is still an attractive working hypothesis but with inconclusive results. A plea for better design of clinical studies is forwarded.

Susceptibility to fraud in systematic reviews: lessons from the Reuben case.

BACKGROUND: Dr. Scott Reuben allegedly fabricated data. The authors of the current article examined the impact of Reuben reports on conclusions of systematic reviews. METHODS: The authors searched in ISI Web of Knowledge systematic reviews citing Reuben reports. Systematic reviews were grouped into one of three categories: I, only cited but did not include Reuben reports; II, retrieved and considered, but eventually excluded Reuben reports; III, included Reuben reports. For quantitative systematic reviews (i.e., meta-analyses), a relevant difference was defined as a significant result becoming nonsignificant (or vice versa) by excluding Reuben reports. For qualitative systematic reviews, each author decided independently whether noninclusion of Reuben reports would have changed conclusions. RESULTS: Twenty-five systematic reviews (5 category I, 6 category II, 14 category III) cited 27 Reuben reports (published 1994-2007). Most tested analgesics in surgical patients. One of 6 quantitative category III reviews would have reached different conclusions without Reuben reports. In all 6 (30 subgroup analyses involving Reuben reports), exclusion of Reuben reports never made any difference when the number of patients from Reuben reports was less than 30% of all patients included in the analysis. Of 8 qualitative category III reviews, all authors agreed that one would certainly have reached different conclusions without Reuben reports. For another 4, the authors' judgment was not unanimous. CONCLUSIONS: Carefully performed systematic reviews proved robust against the impact of Reuben reports. Quantitative systematic reviews were vulnerable if the fraudulent data were more than 30% of the total. Qualitative systematic reviews seemed at greater risk than quantitative.