Jørgen B. Dahl’s research while affiliated with Frederiksberg Hospital and other places

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<0.00001; 33 trials)), and dexmedetomidine (292 min (TSA adj. 95% CI: 245,329, P<0.00001; 53 trials), but was longer for dexmedetomidine than clonidine (205 min (TSA adj. 95% CI: 157, 254 P<0.00001; 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 brachial plexus blocks 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.

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 findan increase in risk of harm when using ibuprofen versus paracetamol. The aim of this subgroup analysis was to investigate differences in benefits and harms of the interventions in different subgroups. We hypothesized the intervention effects would differ in subgroups with different risk of pain or adverse events. Methods: In these preplanned subgroup analyses of the PANSAID trial population, we assessed subgroup heterogeneity in intervention effects between 1) subgroups (sex, age, use of analgesics, American Society of Anesthesiologists score, and type of anesthesia) and morphine consumption, and 2) subgroups (sex, age, use of non-steroidal anti-inflammatory drugs, and American Society of Anesthesiologists score) and serious adverse events. Results: Test of interaction between age and the pairwise comparison between paracetamol 1 g versus paracetamol 0.5 g + ibuprofen 200 mg (P=0.009) 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 preplanned subgroup analyses did not suggest that patients in the investigated subgroups benefitteddifferently 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.

Central sensitization is a condition in which there is an abnormal responsiveness to nociceptive stimuli. As such, the process may contribute to the development and maintenance of pain. Factors influencing the propensity for development of central sensitization have been a subject of intense debate and remain elusive. Injury-induced secondary hyperalgesia can be elicited by experimental pain models in humans, and is believed to be a result of central sensitization. Secondary hyperalgesia may thus reflect the individual level of central sensitization. The objective of this study was to investigate possible associations between increasing size of secondary hyperalgesia area and brain connectivity in known resting-state networks. We recruited 121 healthy participants (male, age 22, SD 3.35) who underwent resting-state functional magnetic resonance imaging. Prior to the scan session, areas of secondary hyperalgesia following brief thermal sensitization (3 min. 45 °C heat stimulation) were evaluated in all participants. 115 participants were included in the final analysis. We found a positive correlation (increasing connectivity) with increasing area of secondary hyperalgesia in the sensorimotor- and default mode networks. We also observed a negative correlation (decreasing connectivity) with increasing secondary hyperalgesia area in the sensorimotor-, fronto-parietal-, and default mode networks. Our findings indicate that increasing area of secondary hyperalgesia is associated with increasing and decreasing connectivity in multiple networks, suggesting that differences in the propensity for central sensitization, assessed as secondary hyperalgesia areas, may be expressed as differences in the resting-state central neuronal activity.

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.

Background We tested the joint hypotheses that both perineural and systemic dexmedetomidine prolong the duration of an ulnar nerve block (UNB) compared with ropivacaine alone and that systemic dexmedetomidine is noninferior compared with perineural dexmedetomidine in block prolongation. Methods We performed bilateral UNBs in 22 healthy volunteers on two separate days. On the first day, each arm was randomized to either 4 mL ropivacaine 5 mg/mL+1 mL dexmedetomidine 100 µg/mL (Perineural) or 4 mL ropivacaine 5 mg/mL+1 mL saline (Systemic). On the subsequent treatment day, each arm was randomized to 1 mL of saline plus 4 mL of ropivacaine at either 7.5 mg/mL(HiRopi) or 5 mg/mL (NoDex). The primary outcome measure was the duration of sensory block assessed by mechanical discrimination. Results Mean sensory block duration was longer in both the Perineural (14.4 hours, 95% CI 13.1 to 15.6) and Systemic treatments (9.2 hours, 95% CI 8.6 to 9.8) compared with the NoDex treatment (7.1 hours, 95% CI 6.6 to 7.6) (p<0.0001 for both). Systemic dexmedetomidine was inferior (not noninferior) compared with perineural dexmedetomidine, as the 95% CI of the difference (mean difference 5.2 hour, 95% CI 4.2 to 6.1) exceeded the noninferiority limit of 3.6 hour. Onset time did not differ among the groups. The other test modalities demonstrated similar block durations as the primary outcome. Conclusions Adding dexmedetomidine perineurally to ropivacaine doubles the duration of an UNB. Systemic dexmedetomidine also prolongs the duration of UNB, but has less of an effect compared with the perineural route. Trial registration number NCT03222323 .

Background We aimed to explore the effect of intraoperative S‐ketamine on analgesic consumption and pain one year after spine surgery in chronic opioid dependent patients undergoing spinal fusion surgery. Methods Single center, randomized, blinded trial of 147 patients. Intervention: Perioperative S‐ketamine bolus 0.5 mg/kg followed by S‐ketamine 0.25 mg·kg⁻¹·h⁻¹ infusion or placebo. Main outcomes: Analgesic use, pain (visual analogue scale 0–100 mm (VAS)) and labor market attachment one year after surgery assessed by written questionnaires. Results Response rate was 67%. One year after surgery the daily use of oral morphine equivalents was lower in the ketamine group versus the placebo group: 0 (0 – 20) mg vs 20 (0 – 62) mg, (P = 0.02), and fewer patients had a daily use of any analgesics in the ketamine group vs placebo group, 42% (95% CI 23–61) vs 74% (95% CI 58–87), (P = 0.04). Mobilization pain was lower in the ketamine group compared to the placebo group: Median difference 17 mm (95% CI ‐30 to ‐3), (P = 0.02). Pain at rest was lower in the ketamine group compared to the placebo group with median difference: 13 mm (95% CI ‐23 to ‐3), (P = 0.01). Further, labor market attachment was better in the ketamine group, (P = 0.02). Conclusion Intraoperative ketamine may reduce analgesic use, pain, and improve labor market attachment one year after spine surgery in a chronic opioid dependent population. This article is protected by copyright. All rights reserved.

Introduction Central sensitization plays a pivotal role in maintenance of pain and is believed to be intricately involved in several chronic pain conditions. One clinical manifestation of central sensitization is secondary hyperalgesia. The degree of secondary hyperalgesia presumably reflects individual levels of central sensitization. The objective of this study was to investigate the association between areas of secondary hyperalgesia and volumes of the caudate nuclei and other brain structures involved in pain processing. Materials and methods We recruited 121 healthy male participants; 118 were included in the final analysis. All participants underwent whole brain magnetic resonance imaging (MRI). Prior to MRI, all participants underwent pain testing. Secondary hyperalgesia was induced by brief thermal sensitization. Additionally, we recorded heat pain detection thresholds (HPDT), pain during one minute thermal stimulation (p-TS) and results of the Pain Catastrophizing Scale (PCS) and Hospital Anxiety and Depression score (HADS). Results We found no significant associations between the size of the area of secondary hyperalgesia and the volume of the caudate nuclei or of the following structures: primary somatosensory cortex, anterior and mid cingulate cortex, putamen, nucleus accumbens, globus pallidus, insula and the cerebellum. Likewise, we found no significant associations between the volume of the caudate nuclei and HPDTs, p-TS, PCS and HADS. Conclusions Our findings indicate that the size of the secondary hyperalgesia area is not associated with the volume of brain structures relevant for pain processing, suggesting that the propensity to develop central sensitization, assessed as secondary hyperalgesia, is not correlated to brain structure volume.

CONSORT 2010 checklist. (DOC)

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.

Background: Postoperative analgesic interventions are often tested adjunct to basic non- opioid analgesics in randomized controlled trials (RCTs). Consequently, treatment in control groups, and assay sensitivity, differs between trials. We hypothesized that postoperative opioid requirements and pain intensities varies between different control groups in analgesic trials. Methods: Control groups from RCTs investigating analgesic interventions after total hip and knee arthroplasty were categorized based on standardized basic analgesic treatment. Morphine consumption 0-24h postoperatively, and resting pain scores at 6 and 24 hours for subgroups of basic treatments, were compared with ANOVA. In an additional analysis, we compared pain and opioid requirements in trials where NSAID was administered as an intervention with trial where NSAID was administered in a control group. Results: We included 171 RCTs employing 28 different control groups with large variability in pain scores and opioid requirements. Four types of control groups (comprising 78 trials) were eligi- ble for subgroup comparisons. These subgroups received: 'opioid', 'NSAID+opioid', 'acetamino- phen+opioid', or 'NSAID+acetaminophen+opioid'. Morphine consumption and pain scores varied substantially between these groups, with no consistent superior efficacy in any subgroup. Addi- tionally, trials administering NSAID as an intervention demonstrated lower pain scores and opioid requirements than trials where NSAID was administered in a control group. Conclusions: Analgesic treatment in RCT control groups varies considerably. Control groups receiving various combinations of opioid, NSAID and acetaminophen did not differ consistently in pain and opioid requirements. Pain and opioid requirements were lower in trials administering NSAID as an intervention compared with trials administering NSAID in a control group.