Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty: The PANSAID Randomized Clinical Trial.

Importance: Multimodal postoperative analgesia is widely used but lacks evidence of benefit. Objective: Investigate beneficial and harmful effects of 4 nonopioid analgesics regimens. Design, Setting, and Participants: Randomized, blinded, placebo-controlled, 4-group trial in 6 Danish hospitals with 90-day follow-up that included 556 patients undergoing total hip arthroplasty (THA) from December 2015 to October 2017. Final date of follow-up was January 1, 2018. Interventions: Participants were randomized to receive paracetamol (acetaminophen) 1000 mg plus ibuprofen 400 mg (n = 136; PCM + IBU), paracetamol 1000 mg plus matched placebo (n = 142; PCM), ibuprofen 400 mg plus matched placebo (n = 141; IBU), or half-strength paracetamol 500 mg plus ibuprofen 200 mg (n = 140; HS-PCM + IBU) orally every 6 hours for 24 hours postoperatively, starting 1 hour before surgery. Main Outcomes and Measures: Two co-primary outcomes: 24-hour morphine consumption using patient-controlled analgesia in pairwise comparisons between the 4 groups (multiplicity-adjusted thresholds for statistical significance, P < .0042; minimal clinically important difference, 10 mg), and proportion of patients with 1 or more serious adverse events (SAEs) within 90 days (multiplicity-adjusted thresholds for statistical significance, P < .025). Results: Among 559 randomized participants (mean age, 67 years; 277 [50%] women), 556 (99.5%) completed the trial and were included in the analysis. Median 24-hour morphine consumption was 20 mg (99.6% CI, 0-148) in the PCM + IBU group, 36 mg (99.6% CI, 0-166) for PCM alone, 26 mg (99.6% CI, 2-139) for IBU alone, and 28 mg (99.6% CI, 2-145) for HS-PCM + IBU. The median difference in morphine consumption between the PCM + IBU group vs PCM alone was 16 mg (99.6% CI, 6.5 to 24; P < .001); for the PCM-alone group vs HS-PCM + IBU, 8 mg (99.6% CI, -1 to 14; P = .001); and for the PCM + IBU group vs IBU alone, 6 mg (99.6% CI, -2 to 16; P = .002). The difference in morphine consumption was not statistically significant for the PCM + IBU group vs HS-PCM + IBU (8 mg [99.6% CI, -2 to 16]; P = .005) or for the PCM-alone group vs IBU alone (10 mg [99.6% CI, -2 to 16]; P = .004) after adjustment for multiple comparisons and 2 co-primary outcomes. There was no significant difference between the IBU-alone group vs HS-PCM + IBU (2 mg [99.6% CI, -10 to 7]; P = .81). The proportion of patients with SAEs in groups receiving IBU was 15%, and in the PCM-alone group, was 11%. The relative risk of SAE was 1.44 (97.5% CI, 0.79 to 2.64; P = .18). Conclusions and Relevance: Among patients undergoing THA, paracetamol plus ibuprofen significantly reduced morphine consumption compared with paracetamol alone in the first 24 hours after surgery; there was no statistically significant increase in SAEs in the pooled groups receiving ibuprofen alone vs with paracetamol alone. However, the combination did not result in a clinically important improvement over ibuprofen alone, suggesting that ibuprofen alone may be a reasonable option for early postoperative oral analgesia. Trial Registration: ClinicalTrials.gov Identifier: NCT02571361.

Gabapentin in procedure-specific postoperative pain management - preplanned subgroup analyses from a systematic review with meta-analyses and trial sequential analyses.

BACKGROUND: It has been argued that postoperative pain treatment should be "procedure-specific", since different analgesics may have specific effects dependent on the surgical procedure. The aim of the present subgroup analysis was to compare the beneficial and harmful effects of perioperative gabapentin treatment in different surgical procedures. METHODS: Relevant databases were searched for randomized clinical trials (RCTs) comparing gabapentin versus placebo. Two authors independently screened titles and abstracts, extracted data and assessed risk of bias. The primary outcomes were differences in 24-h morphine consumption, and serious adverse events (SAE) between surgical procedures. These subgroup analyses were predefined in a PRISMA compliant systematic review registered at PROSPERO (ID: CRD42013006538). It was predefined that conclusions should primarily be based on trials classified as overall low risk of bias. RESULTS: Seventy-four RCTs with 5645 patients were included, assessing benefit and harm in cholecystectomy, hysterectomy, mastectomy, and arthroplasty surgery, spinal surgery, and thoracic surgery. Only eight of 74 trials were classified as overall low risk of bias limiting our ability to conclude on the estimates in most meta-analyses. The differences between surgical procedures in these trials were not statistically significant when tested for subgroup differences. Fifteen trials with 1377 patients reported a total of 59 SAEs, most of which were observed in the thoracic surgery group. CONCLUSION: Both beneficial and harmful effects in these subgroup analyses were influenced by bias and insufficient data, limiting conclusions. With these limitations, we could not adequately test for differences in beneficial or harmful outcomes between six surgical subgroups undergoing perioperative gabapentin treatment.

The Effect of Local Anesthetic Volume Within the Adductor Canal on Quadriceps Femoris Function Evaluated by Electromyography: A Randomized, Observer- and Subject-Blinded, Placebo-Controlled Study in Volunteers.

BACKGROUND: Single-injection adductor canal block (ACB) provides analgesia after knee surgery. Which nerves that are blocked by an ACB and what influence-if any-local anesthetic volume has on the effects remain undetermined. We hypothesized that effects on the nerve to the vastus medialis muscle (which besides being a motor nerve innervates portions of the knee) are volume-dependent. METHODS: In this assessor- and subject-blinded randomized trial, 20 volunteers were included. On 3 separate days, subjects received an ACB with different volumes (10, 20, and 30 mL) of lidocaine 1%. In addition, they received a femoral nerve block and a placebo ACB. The effect on the vastus medialis (primary endpoint) and the vastus lateralis was evaluated using noninvasive electromyography (EMG). Quadriceps femoris muscle strength was evaluated using a dynamometer. RESULTS: There was a statistically significant difference in EMG response from the vastus medialis, dependent on volume. Thirty-five percent (95% confidence interval [CI], 18-57) of the subjects had an affected vastus medialis after an ACB with 10 mL compared with 84% (95% CI, 62-94) following 20 mL (P = 0.03) and 100% (95% CI, 84-100) when 30 mL was used (P = 0.0001). No statistically significant differences were found between volume and effect on the vastus lateralis (P = 0.81) or in muscle strength (P = 0.15). CONCLUSIONS: For ACB, there is a positive correlation between local anesthetic volume and effect on the vastus medialis muscle. Despite the rather large differences in EMG recordings, there were no statistically significant differences in quadriceps femoris muscle strength. Subsequent clinical studies comparing different volumes in a surgical setting, powered to show differences not only in analgesic efficacy, but also in adverse events, are required.

The Isolated Effect of Adductor Canal Block on Quadriceps Femoris Muscle Strength After Total Knee Arthroplasty: A Triple-Blinded, Randomized, Placebo-Controlled Trial with Individual Patient Analysis.

BACKGROUND: Using peripheral nerve block after total knee arthroplasty (TKA), without impeding mobility, is challenging. We hypothesized that the analgesic effect of adductor canal block (ACB) could increase the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle after TKA. METHODS: We included 64 patients on the first postoperative day. Group A received an ACB with 30 mL ropivacaine 0.75% at t0 and with 30 mL saline 60 minutes later (t60). Group B received the treatment in the opposite order. The primary end point was the difference between groups in MVIC at t60, expressed as a percentage of postoperative preblock values. In this manner, the effect of the ACB could be isolated from the detrimental effect on muscle strength caused by the surgery. Secondary end points were differences between groups in mobility and pain scores. We planned a subgroup analysis dividing patients according to preblock pain scores during knee flexion. RESULTS: At t60, MVIC was higher in group A, with a median of 170% (95% confidence interval [CI], 147-231) of preblock values compared with 93% (95% CI, 82-98) in group B (P < 0.0001). No statistically significant differences were found in the Timed Up and Go (TUG) test. Three patients lost the ability to perform the TUG test in group A. At t60, differences in visual analog scale pain were in favor of group A; 12 mm (95% CI, 6-18) at rest, 14 mm (95% CI, 5-22) during knee flexion, and 18 mm (95% CI, 10-26) during the TUG test. CONCLUSIONS: ACB improves quadriceps femoris muscle strength, but whether this translates into enhanced mobility is not clearly supported by this study.

Effect of Total Dose of Lidocaine on Duration of Adductor Canal Block, Assessed by Different Test Methods: A Report of Two Blinded, Randomized, Crossover Studies in Healthy Volunteers.

BACKGROUND: The binary aims of this study were to investigate the effect of total dose of lidocaine on duration of an adductor canal block (ACB) and to validate different methods used to assess nerve blocks. METHODS: We performed 2 blinded, randomized, controlled crossover trials, including healthy, young men. In study 1, 14 subjects received 4 ACBs with saline and 40, 80, and 160 mg lidocaine. In study 2, 14 new subjects received 2 ACBs with 100 and 300 mg lidocaine. We kept volume constant at 20 mL for all blocks, only altering concentration. ACB duration was assessed every hour postblock using mechanical (primary outcome) and temperature discrimination; warmth and heat pain detection thresholds; pain during heat stimulation; and tolerance to electrical current in the saphenous distribution. Finally, we measured quadriceps femoris muscle strength (clinical trial registration: NCT02172729). RESULTS: In study 1, block duration assessed by mechanical discrimination differed significantly when comparing the 40-mg dose with the 80-mg dose (mean difference, 1.15 hours; 99% confidence interval [CI], 0.38-2.09 hours) and with the 160-mg dose (mean difference, 0.92 ours; 99% CI, 0.17-1.62). However, there was no difference between the 80-mg and 160-mg doses (mean difference, -0.23 hour; 99% CI, -1.12 to 0.46 hours). Neither for the secondary outcomes were there any differences between the 80- and 160-mg doses (99% CI including 0). Because of 38% (5/13) failed blocks in the 40-mg group, we decided to perform study 2. In study 2, all but 1 test showed no difference in duration despite a 3-fold increase in dose. The temperature discrimination test showed 100% sensitivity and specificity for differentiating between the presence and absence of block and was the only test with scores >90% for both parameters. CONCLUSIONS: We did not find evidence that increasing the total dose of lidocaine may prolong duration of an ACB. The temperature discrimination test was the only test with scores >90% for both specificity and sensitivity.

The effect of preoperative dexamethasone on pain 1 year after lumbar disc surgery: a follow-up study.

BACKGROUND: It has been hypothesized that dexamethasone can inhibit persistent postoperative pain, but data on humans is lacking and results from animal studies are conflicting. We explored the effect of 16 mg dexamethasone IV administered preoperatively on persistent pain 1 year after lumbar discectomy. METHODS: This is a prospective 1-year follow-up on a single-centre, randomized, and blinded trial exploring the analgesic effect of 16 mg IV dexamethasone or placebo after lumbar discectomy. One year follow-up was a written questionnaire including back and leg pain (VAS 0-100 mm), Short Form 36 survey (SF-36), EuroQol 5D (EQ-5D), OSWESTRY Low Back Pain Questionnaire, duration of sick leave, working capability, contentment with surgical result. RESULTS: Response rate was 71% (55 patients) in the dexamethasone group, 58% (44 patients) in the placebo group. Leg pain (VAS) was significantly lower in the placebo group compared to the dexamethasone group: 17 (95% CI 10-26) vs 26 (95% CI 19-33) mm, respectively (mean difference 9 mm (95% CI -1 to 0), (P = 0.03). No difference regarding back pain. The placebo group reported significantly more improvement of leg pain and were significantly more satisfied with the surgical result. Patients in the dexamethasone group reported significantly higher pain levels in EQ-5D- and Oswestry questionnaires. No difference in the SF-36 survey or daily analgesic consumption. CONCLUSIONS: We found significantly higher pain levels in the dexamethasone group compared to placebo 1 year after lumbar disc surgery. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT01953978 ). Registered 26 Sep 2013.

Is heat pain detection threshold associated with the area of secondary hyperalgesia following brief thermal sensitization? A study of healthy volunteers - design and detailed plan of analysis.

BACKGROUND: Several factors are believed to influence the development and experience of pain. Human clinical pain models are central tools, in the investigation of basic physiologic pain responses, and can be applied in patients as well as in healthy volunteers. Each clinical pain model investigates different aspects of the human pain response. Brief thermal sensitization induces a mild burn injury, resulting in development of primary hyperalgesia at the site of stimulation, and secondary hyperalgesia surrounding the site of stimulation. Central sensitization is believed to play an important role in the development of secondary hyperalgesia; however, a possible association of secondary hyperalgesia following brief thermal sensitization and other heat pain models remains unknown. Our aim with this study is to investigate how close the heat pain detection threshold is associated with the size of the area of secondary hyperalgesia induced by the clinical heat pain model: Brief thermal sensitization. METHODS AND DESIGN: We aim to include 120 healthy participants. The participants will be tested on two separate study days with the following procedures: i) Brief thermal sensitization, ii) heat pain detection threshold and iii) pain during thermal stimulation. Additionally, the participants will be tested with the Pain Catastrophizing Scale and Hospital Anxiety and Depression Scale questionnaires. We conducted statistical simulations based on data from our previous study, to estimate an empirical power of 99.9 % with α of 0.05. We define that an R(2) < 0.25 and predictive intervals larger than +/-150 cm(2) are indications of a weak association. DISCUSSION: The area of secondary hyperalgesia may serve as a quantitative measure of the central sensitization induced by cutaneous heat stimulation, and thus may be a biomarker of an individual's pain sensitivity. The number of studies investigating secondary hyperalgesia is growing; however basic knowledge of the physiologic aspects of secondary hyperalgesia in humans is still incomplete. We therefore find it interesting to investigate if HPDT, a known quantitative sensory test, is associated with areas of secondary hyperalgesia following brief thermal sensitization TRIAL REGISTRATION: Clinicaltrials.gov (Identifier: NCT02527395 ). Danish Research Ethics Committee (Identifier: H-8-2014-012). Danish Data Protection Agency (Identifier: 30-1436).

Intraoperative S-ketamine for the reduction of opioid consumption and pain one year after spine surgery: A randomized clinical trial of opioid-dependent patients.

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-centre, randomized, blinded trial of 147 patients. INTERVENTION: Perioperative S-ketamine bolus 0.5 mg/kg followed by S-ketamine 0.25 mg kg-1  hr-1 infusion or placebo. MAIN OUTCOMES: Analgesic use, pain (visual analogue scale 0-100 mm [VAS]) and labour 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 versus 20 (0-62) mg, (p = 0.02), and fewer patients had a daily use of any analgesics in the ketamine group versus placebo group, 42% (95% CI 23-61) versus 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, labour market attachment was better in the ketamine group, (p = 0.02). CONCLUSION: Intraoperative ketamine may reduce analgesic use, pain, and improve labour market attachment one year after spine surgery in a chronic opioid-dependent population. SIGNIFICANCE: This randomized clinical trial shows that intraoperative ketamine may reduce opioid use and pain and improve labour market attachment one year after spine surgery in an opioid-dependent population.

Brain resting-state connectivity in the development of secondary hyperalgesia in healthy men.

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.

Heat pain detection threshold is associated with the area of secondary hyperalgesia following brief thermal sensitization: a study of healthy male volunteers.

INTRODUCTION: The area of secondary hyperalgesia following brief thermal sensitization (BTS) of the skin and heat pain detection thresholds (HPDT) may both have predictive abilities in regards to pain sensitivity and clinical pain states. The association between HPDT and secondary hyperalgesia, however, remains unsettled, and the dissimilarities in physiologic properties suggest that they may represent 2 distinctively different pain entities. The aim of this study was to investigate the association between HPDT and BTS-induced secondary hyperalgesia. METHODS: A sample of 121 healthy male participants was included and tested on 2 separate study days with BTS (45°C, 3 minutes), HPDT, and pain during thermal stimulation (45°C, 1 minute). Areas of secondary hyperalgesia were quantified after monofilament pinprick stimulation. The pain catastrophizing scale (PCS) and hospital anxiety and depression scale (HADS) were also applied. RESULTS: A significant association between HPDT and the size of the area of secondary hyperalgesia (p<0.0001) was found. The expected change in area of secondary hyperalgesia due to a 1-degree increase in HPDT was estimated to be -27.38 cm2, 95% confidence interval (CI) of -37.77 to -16.98 cm2, with an R2 of 0.19. Likewise, a significant association between HADS-depression subscore and area of secondary hyperalgesia (p=0.046) was found, with an estimated expected change in secondary hyperalgesia to a 1-point increase in HADS-depression subscore of 11 cm2, 95% CI (0.19-21.82), and with R2 of 0.03. We found no significant associations between secondary hyperalgesia area and PCS score or pain during thermal stimulation. CONCLUSION: HPDT and the area of secondary hyperalgesia after BTS are significantly associated; however, with an R2 of only 19%, HPDT only offers a modest explanation of the inter-participant variation in the size of the secondary hyperalgesia area elicited by BTS.

Clonidine used as a perineural adjuvant to ropivacaine, does not prolong the duration of sensory block when controlling for systemic effects: A paired, blinded, randomized trial in healthy volunteers.

BACKGROUND: Clonidine used as an adjuvant to ropivacaine have been shown to prolong the duration of peripheral nerve blocks. The mechanism of action remains unclear. We hypothesized, that clonidine used as an adjuvant to ropivacaine extends the duration of an adductor canal block (ACB) by a peripheral mechanism, compared to ropivacaine alone when controlling for systemic effects. METHODS: We conducted a paired, blinded, randomized trial in healthy volunteers. Participants received bilateral ACBs containing 20 ml ropivacaine 0.5% + 1 ml clonidine 150µg/ml in one leg and 20 ml ropivacaine 0.5% + 1 ml saline in the other leg. The primary outcome measure was duration of sensory block assessed by temperature sensation (alcohol swab). Secondary outcome measures were duration of sensory block assessed by: pinprick, maximum pain during tonic heat stimulation, warmth detection threshold and heat pain detection threshold. RESULTS: We enrolled 21 volunteers and all completed the trial. There was no difference in duration of sensory block assessed with an alcohol swab: Mean duration in the leg receiving ropivacaine + clonidine was 19.4h (SD 2.7) compared to 19.3h (SD 2.4) in the leg receiving ropivacaine + placebo with a mean difference of 0.1h (95% CI: -1.0 to 1.3), P = 0.83. No differences in block duration were detected when assessed by: Pinprick, mean difference 0.0 h (95% CI: -1.3 to 1.3), maximum pain during tonic heat stimulation, mean difference -0.7 h (95% CI: -2.1 to 0.8), warmth detection threshold, mean difference -0.1 h (95% CI: -1.8 to 1.6) or heat pain detection threshold, mean difference -0.2 h (95% CI: -1.7 to 1.4). CONCLUSIONS: Administering clonidine perineurally as an adjuvant to ropivacaine in an ACB did not prolong the duration of sensory block in a setup controlling for systemic effects of clonidine.

Intraoperative ketamine reduces immediate postoperative opioid consumption after spinal fusion surgery in chronic pain patients with opioid dependency: a randomized, blinded trial.

Perioperative handling of surgical patients with opioid dependency represents an important clinical problem. Animal studies suggest that ketamine attenuates central sensitization and hyperalgesia and thereby reduces postoperative opioid tolerance. We hypothesized that intraoperative ketamine would reduce immediate postoperative opioid consumption compared with placebo in chronic pain patients with opioid dependency undergoing lumbar spinal fusion surgery. Primary outcome was morphine consumption 0 to 24 hours postoperatively. Secondary outcomes were acute pain at rest and during mobilization 2 to 24 hours postoperatively (visual analogue scale), adverse events, and persistent pain 6 months postoperatively. One hundred fifty patients were randomly assigned to intraoperative S-ketamine bolus 0.5 mg/kg and infusion 0.25 mg·kg·h or placebo. Postoperatively, patients received their usual opioids, paracetamol and IV patient-controlled analgesia with morphine. In the final analyses, 147 patients were included. Patient-controlled analgesia IV morphine consumption 0 to 24 hours postoperatively was significantly reduced in the ketamine group compared with the placebo group: 79 (47) vs 121 (53) mg IV, mean difference 42 mg (95% confidence interval -59 to -25), P < 0.001. Sedation was significantly reduced in the ketamine group 6 and 24 hours postoperatively. There were no significant differences regarding acute pain, nausea, vomiting, hallucinations, or nightmares. Back pain at 6 months postoperatively compared with preoperative pain was significantly more improved in the ketamine group compared with the placebo group, P = 0.005. In conclusion, intraoperative ketamine significantly reduced morphine consumption 0 to 24 hours after lumbar fusion surgery in opioid-dependent patients. The trend regarding less persistent pain 6 months postoperatively needs further investigation.

Correction: The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers: Inter- and Intra-Individual Variance and Reproducibility.

[This corrects the article DOI: 10.1371/journal.pone.0155284.].

PANSAID - PAracetamol and NSAID in combination: study protocol for a randomised trial.

BACKGROUND: Effective postoperative pain management is essential for the rehabilitation of the surgical patient. No 'gold standard' exists after total hip arthroplasty (THA) and combinations of different nonopioid medications are used with virtually no evidence for additional analgesic efficacy compared to monotherapy. The objective of this trial is to investigate the analgesic effects and safety of paracetamol and ibuprofen alone and in combination in different dosages after THA. METHODS: PANSAID is a placebo-controlled, parallel four-group, multicentre trial with centralised computer-generated allocation sequence and allocation concealment and with varying block size and stratification by site. Blinding of assessor, investigator, caregivers, patients and statisticians. Patients are randomised to four groups: (A) paracetamol 1 g × 4 and ibuprofen 400 mg × 4, (B) paracetamol 1 g × 4 and placebo, (C) placebo and ibuprofen 400 mg × 4 and (D) paracetamol 0.5 g × 4 and ibuprofen 200 mg. The two co-primary outcomes are 24-h consumption of morphine and number of patients with one or more serious adverse events within 90 days after surgery. Secondary outcomes are pain scores during mobilisation and at rest at 6 and 24 h postoperatively, and number of patients with one or more adverse events within 24 h postoperatively. Inclusion criteria are patients scheduled for unilateral, primary THA; age above 18 years; ASA status 1-3; BMI >18 and <40 kg/m2; women must not be pregnant; and provision of informed consent. Exclusion criteria are patients who cannot cooperate with the trial; participation in another trial; patients who cannot understand/speak Danish; daily use of strong opioids; allergy against trial medication; contraindications against ibuprofen; alcohol and/or drug abuse. A total of 556 eligible patients are needed to detect a difference of 10 mg morphine i.v. the first 24 h postoperatively with a standard deviation of 20 mg and a family wise type 1 error rate of 0.025 (two-sided) and a type 2 error rate of 0.10 for the six possible comparisons of the four intervention groups. DISCUSSION: We started recruiting patients in December 2015 and expect to finish in September 2017. Data analysis will be from September 2017 to October 2017 and manuscript submission ultimo 2017. TRIAL REGISTRATION: EudraCT: 2015-002239-16 (12/8-15); ClinicalTrials.gov: NCT02571361 . Registered on 7 October 2015.

PANSAID-PAracetamol and NSAID in combination: detailed statistical analysis plan for a randomised, blinded, parallel, four-group multicentre clinical trial.

BACKGROUND: Effective postoperative pain management is essential for the rehabilitation of the surgical patient. The PANSAID trial evaluates the analgesic effects and safety of the combination of paracetamol and ibuprofen. This paper describes in detail the statistical analysis plan for the primary publication to prevent outcome reporting bias and data-driven analysis results. METHODS/DESIGN: The PANSAID trial is a multicentre, randomised, controlled, parallel, four-group clinical trial comparing the beneficial and harmful effects of different doses and combinations of paracetamol and ibuprofen in patients having total hip arthroplastic surgery. Patients, caregivers, physicians, investigators, and statisticians are blinded to the intervention. The two co-primary outcomes are 24-h consumption of morphine and proportion of patients with one or more serious adverse events within 90 days after surgery. Secondary outcomes are pain scores during mobilisation and at rest at 6 and 24 h postoperatively, and the proportion of patients with one or more adverse events within 24 h postoperatively. DISCUSSION: PANSAID will provide a large trial with low risk of bias regarding benefits and harms of the combination of paracetamol and ibuprofen used in a perioperative setting. TRIAL REGISTRATION: ClinicalTrials.org identifier: NCT02571361 . Registered on 7 October 2015.

The Area of Secondary Hyperalgesia following Heat Stimulation in Healthy Male Volunteers: Inter- and Intra-Individual Variance and Reproducibility.

INTRODUCTION: Clinical pain models can be applied when investigating basic physiologic pain responses in healthy volunteers. Several pain models exist; however, only few have been adequately validated. Our primary aim with this prospective study was to investigate the intra- and inter-individual variation in secondary hyperalgesia elicited by brief thermal sensitization (45°C for 3 min) in healthy volunteers. MATERIAL AND METHODS: Fifty healthy volunteers were included. Areas of secondary hyperalgesia following brief thermal sensitization were investigated by 2 observers on 4 experimental days, with a minimum interval of 7 days. Additionally, heat pain detection threshold and pain during thermal stimulation (45°C for 1 min.), and the psychological tests Pain Catastrophizing Scale and Hospital Anxiety and Depression Score were applied. RESULTS: For areas of secondary hyperalgesia, an intra-observer intra-person correlation of 0.85, 95% CI [0.78, 0.90], an intra-observer inter-person correlation of 0.03, 95% CI [0.00, 0.16], and a coefficient of variation of 0.17, 95% CI [0.14, 0.21] was demonstrated. Four percent of the study population had areas of secondary hyperalgesia both below the 1st and above the 3rd quartile considering all included participants. Heat pain detection threshold predicted area of secondary hyperalgesia with an adjusted R2 of 0.20 (P = 0.0006). CONCLUSIONS: We have demonstrated a low intra-individual, and a high inter-individual variation in thermally induced secondary hyperalgesia. We conclude that brief thermal sensitization produce secondary hyperalgesia with a high level of reproducibility, which can be applied to investigate different phenotypes related to secondary hyperalgesia in healthy volunteers. TRIAL REGISTRATION: clinicaltrials.gov NCT02166164.

Is the Volume of the Caudate Nuclei Associated With Area of Secondary Hyperalgesia? - Protocol for a 3-Tesla MRI Study of Healthy Volunteers.

BACKGROUND: Experience and development of pain may be influenced by a number of physiological, psychological, and psychosocial factors. In a previous study we found differences in neuronal activation to noxious stimulation, and microstructural neuroanatomical differences, when comparing healthy volunteers with differences in size of the area of secondary hyperalgesia following a standardized burn injury. OBJECTIVE: We aim to investigate the degree of association between the volume of pain-relevant structures in the brain and the size of the area of secondary hyperalgesia following brief thermal sensitization. METHODS: The study consists of one experimental day, in which whole-brain magnetic resonance imaging (MRI) scans will be conducted including T1-weighed three-dimensional anatomy scan, diffusion tensor imaging, and resting state functional MRI. Before the experimental day, all included participants will undergo experimental pain testing in a parallel study (Clinicaltrials.gov Identifier: NCT02527395). Results from this experimental pain testing, as well as the size of the area of secondary hyperalgesia from the included participants, will be extracted from this parallel study. RESULTS: The association between the volume of pain-relevant structures in the brain and the area of secondary hyperalgesia will be investigated by linear regression of the estimated best linear unbiased predictors on the individual volumes of the pain relevant brain structures. CONCLUSIONS: We plan to investigate the association between experimental pain testing parameters and the volume, connectivity, and resting state activity of pain-relevant structures in the brain. These results may improve our knowledge of the mechanisms responsible for the development of acute and chronic pain. CLINICALTRIAL: Danish Research Ethics Committee (identifier: H-15010473). Danish Data Protection Agency (identifier: RH-2015-149). Clinicaltrials.gov NCT02567318; http://clinicaltrials.gov/ct2/show/NCT02567318 (Archived by WebCite at http://www.webcitation.org/6i4OtP0Oi).

Secondary hyperalgesia phenotypes exhibit differences in brain activation during noxious stimulation.

Noxious stimulation of the skin with either chemical, electrical or heat stimuli leads to the development of primary hyperalgesia at the site of injury, and to secondary hyperalgesia in normal skin surrounding the injury. Secondary hyperalgesia is inducible in most individuals and is attributed to central neuronal sensitization. Some individuals develop large areas of secondary hyperalgesia (high-sensitization responders), while others develop small areas (low-sensitization responders). The magnitude of each area is reproducible within individuals, and can be regarded as a phenotypic characteristic. To study differences in the propensity to develop central sensitization we examined differences in brain activity and anatomy according to individual phenotypical expression of secondary hyperalgesia by magnetic resonance imaging. Forty healthy volunteers received a first-degree burn-injury (47 °C, 7 min, 9 cm(2)) on the non-dominant lower-leg. Areas of secondary hyperalgesia were assessed 100 min after the injury. We measured neuronal activation by recording blood-oxygen-level-dependent-signals (BOLD-signals) during mechanical noxious stimulation before burn injury and in both primary and secondary hyperalgesia areas after burn-injury. In addition, T1-weighted images were used to measure differences in gray-matter density in cortical and subcortical regions of the brain. We found significant differences in neuronal activity between high- and low-sensitization responders at baseline (before application of the burn-injury) (p < 0.05). After the burn-injury, we found significant differences between responders during noxious stimulation of both primary (p < 0.01) and secondary hyperalgesia (p ≤ 0.04) skin areas. A decreased volume of the right (p = 0.001) and left caudate nucleus (p = 0.01) was detected in high-sensitization responders in comparison to low-sensitization responders. These findings suggest that brain-structure and neuronal activation to noxious stimulation differs according to secondary hyperalgesia phenotype. This indicates differences in central sensitization according to phenotype, which may have predictive value on the susceptibility to development of high-intensity acute and persistent pain.

[Strengths and challenges in connection to the clinical education in anaesthesiology:].

We performed a qualitative interview study regarding perceived strengths and challenges in connection to the clinical curriculum in anaesthesiology. Medical students and the medical specialists in charge of supervising the clinical curriculum pointed out that the primary strengths were that the staff was committed to tutoring, good general structure and possibility to explore basic and more advanced clinical procedures. Challenges were seen in the current lack of cooperation between hospitals and the general lack of knowledge regarding medical students' curriculum. Future processes for better practice sharing between hospitals should be explored.

Insufficient pain management after spine surgery.

INTRODUCTION: A prospective observational quality assurance study was performed at Glostrup Hospital, Denmark, to describe patients undergoing spine surgery with regard to perioperative analgesic management, post-operative pain, opioid consumption and side effects. MATERIAL AND METHODS: Patients eligible for the study were identified consecutively from the operation chart. The following data were registered: post-operative visual analogue (VAS) pain score at rest and during mobilisation, opioid consumption for the first 24 h, other analgesics administered and side effects. RESULTS: A total of 87 patients were included. For instrumented lumbar fusion patients (n = 24), the VAS pain scores at 1, 4 and 24 h after surgery were (median (interquartile range)) 5 (0-7), 2.5 (0-8) and 5.5 (0-9) at rest and 5 (0-8), 3 (0-9) and 7 (3-9) during mobilisation, respectively. The other surgical subgroups generally experienced VAS ≤ 3. For instrumented lumbar fusion, the total 0-24 h consumption of intravenous morphine equivalents was 39.1 (27.5-62.7) mg. Only eight of 87 patients received the entire scheduled standard post-operative pain treatment. Adverse events were rare. CONCLUSION: Most patients experienced acceptable pain levels, but instrumented lumbar fusion leads to moderate to severe pain levels and a relatively high opioid consumption. The scheduled standard pain management protocols were sparsely followed. Challenges exist in post-operative pain management as observed in previous surveys, especially for instrumented lumbar fusion surgery. Future work should focus on optimising treatment plans. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.