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).

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.

Self-perceived readiness to perform at the attending level following surgical specialist training in Denmark.

INTRODUCTION: Great effort has been invested in improving the educational aspect of the Danish five-year national surgical residency programme. Among other initiatives, an updated logbook containing specific objectives was implemented in 2015. The effect of current and prior educational efforts has not previously been studied. In the present study, we aim to investigate the role of supervision in the national surgical residency programme and the self-perceived readiness to undertake the role of a specialist doctor in gastrointestinal surgery in a cohort of gastrointestinal surgeons graduating in 2012 and 2013. METHODS: A retrospective study was conducted, and questionnaires matching the categories from the American Accreditation Council for Graduate Medical Education were distributed to all Danish surgical residents graduating from the national surgery residency programme in 2012 or 2013. RESULTS: A total of 30 graduated residents (55%) responded to the Danish survey. Among those, 14 (47%) felt ready to be a specialist in surgery. A total of 25 (83%) answered that increased supervision would have increased their selfperceived competencies to serve as a surgical specialist. Self -perceived readiness was significantly associated with level of supervision during surgical training (p = 0.02), whereas no association with operative volume could be established. CONCLUSIONS: A worryingly high number of graduates did not feel ready to undertake their role as a gastrointestinal surgical specialist. Adequate supervision seems to play a crucial role in education. FUNDING: none. TRIAL REGISTRATION: not relevant.

Postoperative pain treatment after total knee arthroplasty: A systematic review.

INTRODUCTION: The aim of this systematic review was to document efficacy, safety and quality of evidence of analgesic interventions after total knee arthroplasty (TKA). METHODS: This PRISMA-compliant and PROSPERO-registered review includes all-language randomized controlled trials of medication-based analgesic interventions after TKA. Bias was evaluated according to Cochrane methodology. Outcomes were opioid consumption (primary), pain scores at rest and during mobilization, adverse events, and length of stay. Interventions investigated in three or more trials were meta-analysed. Outcomes were evaluated using forest plots, Grading of Recommendations Assessment, Development and Evaluation (GRADE), L'Abbe Plots and trial sequential analysis. RESULTS: The included 113 trials, investigating 37 different analgesic interventions, were characterized by unclear/high risk of bias, low assay sensitivity and considerable differences in pain assessment tools, basic analgesic regimens, and reporting of adverse events. In meta-analyses single and continuous femoral nerve block (FNB), intrathecal morphine, local infiltration analgesia, intraarticular injection of local anaesthetics, non-steroidal anti-inflammatory drugs, and gabapentinoids demonstrated significant analgesic effects. The 24-hour morphine-sparing effects ranged from 4.2 mg (CI: 1.3, 7.2; intraarticular local anaesthetics), to 16.6 mg (CI: 11.2, 22; single FNB). Pain relieving effects at rest at 6 hours ranged from 4 mm (CI: -10, 2; gabapentinoids), to 19 mm (CI: 8, 31; single FNB), and at 24 hours from 3 mm (CI: -2, 8; gabapentinoids), to 16 mm (CI: 8, 23; continuous FNB). GRADE-rated quality of evidence was generally low. CONCLUSION: A low quality of evidence, small sample sizes and heterogeneity of trial designs prohibit designation of an optimal procedure-specific analgesic regimen after TKA.

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.

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.].

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).

Limited evidence for intranasal fentanyl in the emergency department and the prehospital setting--a systematic review.

INTRODUCTION: The intranasal (IN) mode of application may be a valuable asset in non-invasive pain management. Fentanyl demonstrates pharmacokinetic and pharmacodynamic properties that are desirable in the management of acute pain, and IN fentanyl may be of value in the prehospital setting. The aim of this systematic review was to evaluate the current evidence for the use of IN fentanyl in the emergency department (ED) and prehospital setting. METHOD: Reports of trials of IN fentanyl in (ED) and prehospital treatment of pain were systematically sought using the PubMed database, Embase, Google scholar, the Cochrane database and the Cumulative Index to Nursing and Allied Health Literature. RESULTS: Twelve studies of IN fentanyl in the (ED) and prehospital setting were included in the final analysis. In the ED, analgesic non-inferiority and superiority were demonstrated when comparing IN fentanyl with intravenous (IV) and intramuscular morphine, respectively. Non-blinded, non-controlled studies demonstrated an analgesic effect of IN fentanyl in patients with moderate and severe pain. In the prehospital setting, both analgesic inferiority and non-inferiority were demonstrated when IN fentanyl was compared with IV morphine. Finally, a significant analgesic effect of IN fentanyl was demonstrated when IN fentanyl was compared with methoxyflurane. CONCLUSION: Only limited quality evidence exists for the efficacy of IN fentanyl in the ED and in the prehospital setting, and more double-blinded, randomised, controlled trials are urgently needed to validate the use of IN fentanyl in this context.

Suboptimal pain treatment after craniotomy.

INTRODUCTION: Only few studies have investigated pain, nausea, sedation and analgesic strategies in post-craniotomy patients. The aim of this observational study was to explore pain, nausea, sedation and analgesic procedures after craniotomy, and to evaluate the quality of current analgesic therapy administered to post-craniotomy patients. MATERIAL AND METHODS: A total of 59 patients undergoing supratentorial or infratentorial craniotomy were included over a three-month period. The intensity of pain, nausea and sedation was evaluated at 1, 2, 4, 8 and 24 h after extubation. Post-operative analgesic consumption at 0-48 h after extubation was noted. Post-operative morphine consumption in relation to gender, surgical procedure, administration of preoperative steroids and application of surgical drains was evaluated. RESULTS: Fifty patients completed the study. After the first post-operative hour, 56% suffered from moderate-to-severe pain, which decreased to 38% at 24 h post-operatively. Patients receiving preoperative steroids experienced significantly less pain than patients who did not receive preoperative steroids (p = 0.04). The mean post-operative morphine consumption 0-48 h post-operatively was 28.8 mg (± 23.6 mg). Only 52% of the patients received the planned amount of acetaminophen of 4,000 mg/day. CONCLUSION: Pain following craniotomy is moderate to severe in a substantial number of patients. The quality of the analgesic treatment leaves room for improvement. Administration of preoperative steroids may reduce post-craniotomy pain. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.