Randomized controlled trial of intra-articular ketorolac on pain and inflammation after minor arthroscopic knee surgery.

BACKGROUND: Ketorolac is an effective non-steroidal anti-inflammatory drug, commonly used with local anaesthetics as part of local infiltration analgesia protocols following orthopaedic surgery. However, systemic uptake and drug action may be the major mechanism after local infiltration. The aims of this project were to study the effects of a small, systemically ineffective dose of ketorolac given intra-articularly for post-operative pain and also to study synovial inflammatory biomarkers. We investigated whether ketorolac affects pro-inflammatory biomarkers in an in vitro model, as well. METHODS: In this placebo-controlled, blind, randomized study, we analysed intra-articular ketorolac (5 mg) in ambulatory minor knee surgery patients with moderate or severe pain (n = 44). We assessed post-operative pain intensity (n = 44) and analysed microdialysis samples taken from knee synovial tissue every 20 min (n = 34). We also tested cyclooxygenase-independent effects of ketorolac in synovial cells stimulated by prostaglandin E2 and chondroitin sulphate in vitro. RESULTS: Intra-articular ketorolac (5 mg) administration did not reduce pain or synovial pro-inflammatory cytokines CXCL1, IL-8, and MCP-1, 0-120 min after knee arthroscopy. Female gender was a risk factor for moderate or severe pain (relative risk 1.45, 95% confidence interval 1.04-2.01). Paradoxically, ketorolac increased the release of CXCL1 and IL-8 in prostaglandin E2 and chondroitin sulphate-stimulated synovial cells in vitro. CONCLUSION: Ketorolac prescribed at a low dose intra-articularly does not produce any detectable analgesic effect after minor knee surgery.

Pregabalin reduces opioid consumption and hyperalgesia but not pain intensity after laparoscopic donor nephrectomy.

BACKGROUND: Gabapentinoids are increasingly used to reduce acute postoperative pain, opioid consumption and opioid-related adverse effects. We explored the opioid-sparing, analgesic and anti-hyperalgesic effect of perioperative administered pregabalin in laparoscopic living donor nephrectomy. METHODS: In this randomized controlled trial, 80 patients were recruited and randomized to receive pregabalin 150 mg twice daily or placebo on the day of surgery and the first postoperative day as part of a multimodal analgesic regimen. Primary outcome was opioid consumption 0-48 h after surgery. Secondary outcomes were pain intensity at rest and with movement 0-48 h after surgery using the 0-10 Numeric Rating Scale and incisional hyperalgesia measured 24 h post-surgery and at hospital discharge. Further secondary outcomes were adverse effects. Persistent post-surgical pain was registered 6 weeks, 6 and 12 months after surgery. RESULTS: Pregabalin significantly reduced opioid consumption compared with placebo 0-48 h after surgery (median mg [25th, 75th percentile]); 29.0 (22.0-45.5) vs. 41.8 (25.8-63.6) (P = 0.04). Pain intensity 0-48 h after surgery calculated as area under the pain (NRS) vs. time curve was not statistically different between groups at rest (P = 0.12) or with movement (P = 0.21). Pregabalin decreased incisional hyperalgesia 24 h after surgery (median cm [25th, 75th percentile] 8.5 (1.0-18.5) vs. 15.5 (9.5-24.0) (P = 0.02). Nausea (P ≤ 0.01), use of antiemetics (P ≤ 0.01) and pain-related sleep interference (P = 0.02) were reduced with pregabalin. CONCLUSIONS: Perioperative pregabalin added to a multimodal analgesic regimen was opioid-sparing, but made no difference to pain intensity score 0-48 h after surgery. Pregabalin may reduce incisional hyperalgesia on the first day after surgery.

Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia.

BACKGROUND: The aim of this study was to examine if gradual withdrawal of remifentanil infusion prevented opioid-induced hyperalgesia (OIH) as opposed to abrupt withdrawal. OIH duration was also evaluated. METHODS: Nineteen volunteers were enrolled in this randomized, double-blinded, placebo-controlled, crossover study. All went through three sessions: abrupt or gradual withdrawal of remifentanil infusion and placebo. Remifentanil was administered at 2.5 ng ml(-1) for 30 min before abrupt withdrawal or gradual withdrawal by 0.6 ng ml(-1) every five min. Pain was assessed at baseline, during infusion, 45-50 min and 105-110 min after end of infusions using the heat pain test (HPT) and the cold pressor test (CPT). RESULTS: The HPT 45 min after infusion indicated OIH development in the abrupt withdrawal session with higher pain scores compared with the gradual withdrawal and placebo sessions (both P<0.01. Marginal mean scores: placebo 2.90; abrupt 3.39; gradual 2.88), but no OIH after gradual withdrawal compared with placebo (P=0.93). In the CPT 50 min after end of infusion there was OIH in both remifentanil sessions compared with placebo (gradual P=0.01, abrupt P<0.01. Marginal mean scores: placebo 4.56; abrupt 5.25; gradual 5.04). There were no differences between the three sessions 105-110 min after infusion. CONCLUSIONS: We found no development of OIH after gradual withdrawal of remifentanil infusion in the HPT. After abrupt withdrawal OIH was present in the HPT. In the CPT there was OIH after both gradual and abrupt withdrawal of infusion. The duration of OIH was less than 105 min for both pain modalities. CLINICAL TRIAL REGISTRATION: NCT 01702389. EudraCT number 2011-002734-39.

Persistent post-surgical pain and signs of nerve injury: the Tromsø Study.

BACKGROUND: The contribution of nerve lesions and neuropathic pain to persistent post-surgical pain (PPSP) is poorly established. The aim of this study was to assess the association between PPSP and symptoms and signs of possible nerve injury in an unselected surgical sample. METHODS: Eighty-one individuals with and without persistent pain after surgical procedures, were recruited from a cross-sectional study. Follow-up examination with questionnaires and quantitative sensory testing was performed 15-32 months later (21-64 months after surgery). RESULTS: The median rating of maximum pain intensity among individuals with PPSP decreased from numerical rating scale 4/10 at baseline to 2/10 at follow-up, but considerable changes occurred in both directions. Individuals with PPSP at follow-up were significantly more likely to self-report sensory abnormalities than those without PPSP; however, results from sensory testing did not differ significantly between the groups. Self-report of sensory disturbances at the site of surgery was associated with increased warm detection thresholds and tactile pain thresholds. Among individuals with PPSP, 61% had positive findings on sensory testing, suggesting probable neuropathic pain. CONCLUSION: In this study, associations between self-reported symptoms and PPSP were stronger than associations between self-reported symptoms and results of psychophysical tests. Fluctuations in pain intensity together with wide ranges for normal variability in sensory functions, hampers detection of significant group differences. Methodological aspects of quantitative sensory testing applied in a mixed clinical sample are discussed.

The incidence of delirium in Norwegian intensive care units; deep sedation makes assessment difficult.

BACKGROUND: Delirium in critically ill patients is associated with increased length of hospital stay, mortality and costs, and may lead to long-term cognitive impairment. It is often overlooked by clinicians if structured observation is not performed routinely. A national Norwegian survey reported that systematic screening and assessment of delirium were never or seldom performed. The purpose of this study was to test the usefulness of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and to describe the incidence of delirium in critically ill patients at two Norwegian hospitals. METHODS: We conducted a two-site, prospective, descriptive study including patients between 18 and 80 years, intubated or mask ventilated at admission, with an ICU stay > 48 h. The CAM-ICU was scored three times daily. In addition, illness severity, sedation level, pain assessment, drug use and other treatment factors were systematically assessed. RESULTS: Total ICU stays of 139 patients were studied and covered 958 patient days. The incidence of delirium was 23%. Thirty per cent of the patients representing 407 patient days were unable to be assessed at any assessment, mainly due to deep sedation. The patients were delirium and coma free in 45.9% of total days. CONCLUSION: Of the patients, 23% were classed as delirious (CAM-ICU positive) at least once during their stay. The CAM-ICU was difficult to use in patients with sedation so deep that they hardly gave eye contact and responded only weakly to verbal stimulation. Focusing on less sedation and further modifications to the CAM-ICU may benefit ICU patients in the future.

Analgesia and sedation of mechanically ventilated patients - a national survey of clinical practice.

BACKGROUND: The importance of balanced sedation and pain treatment in intensive care units (ICUs) is evident, but regimes and use of medication differ widely. Previous surveys have focused on the use of various medications and regimes. What has not been explored is the process by which nurses and physicians assess patients' needs and work together toward a defined level of sedation and pain for the ICU patient. The purpose of the study was to determine the use of protocols and medications for sedation and analgesia in Norwegian ICUs and the degree of cooperation between nurses and physicians in using them. METHODS: A national survey was conducted in autumn 2007, using postal self-administered questionnaires. RESULTS: Written pain treatment and sedation protocols were not routinely used in Norwegian ICUs; however, half of the departments titrated sedation according to a scoring system, most commonly the Motor Activity Assessment Score. The most commonly used sedatives were propofol and midazolam, while fentanyl and morphine were the most used analgesics. The majority of respondents were concerned about the side effects of sedation and analgesics, leading to circulatory instability and delayed awakening. Nurses and physicians agreed upon the main indications for sedation: patient tolerance for ventilation, tolerance for medical and nursing interventions, and patient symptoms. CONCLUSIONS: Potential factors which may improve sedation and pain management of mechanically ventilated patients in Norwegian ICUs are more systematic assessments of pain and sedation, and the use of written protocols. Strategies which reduce side effects should be addressed.

Skin pain and skin discomfort is associated with quality of life in patients with psoriasis.

BACKGROUND: Patients with psoriasis commonly report severe sensory skin symptoms, sleep disturbance, psychological distress and impaired health related quality of life (HRQoL). However, the complex associations among these factors are poorly investigated in this patient group. OBJECTIVES: The purpose of this study was to investigate the association between skin pain or skin discomfort and HRQoL, and explore whether sleep disturbance and psychological distress were mediators of these associations. METHODS: A total of 139 psoriasis patients from a university hospital setting participated in this exploratory, cross-sectional study. Data were obtained through interviews and questionnaires (Dermatology Life Quality Index, General Sleep Disturbance Scale, Illness Perception Questionnaire) and analysed using a series of multiple regression analyses. HRQoL was the dependent variable. Independent variables and assumed mediators were entered into the model in a predefined order. RESULTS: Skin pain, skin discomfort, sleep disturbance and psychological distress were significantly associated with HRQoL (all P < 0.05). Sleep disturbance was a partial mediator for the association between skin pain and HRQoL. No such mediation effect was found in terms of psychological distress. The total model explained 40% of the variance in HRQoL. CONCLUSION: In this study, skin pain and skin discomfort were significantly related to HRQoL when controlling for demographic and clinical characteristics. In addition, sleep disturbance mediated the association between skin pain and HRQoL. An understanding of the complex association among physiological and psychological factors, and HRQoL is clinically important in order to provide proper treatment and care of patients with psoriasis.

Percutaneous dilatational tracheotomy in intensive care unit patients with increased bleeding risk or obesity. A prospective analysis of 1000 procedures.

BACKGROUND: Percutaneous dilatational tracheotomy (PT) is safe and cost effective, and has become a routine method in intensive care units (ICU), but safety concerns persist for obese patients and for patients with a high risk of bleeding. In this prospective study of 1000 PTs, we have investigated whether such patient characteristics were associated with an increased procedural risk. METHODS: We prospectively recorded all PTs performed in our ICU from 2001 to 2009. Data on blood transfusion were entered from a central database. The association of risk factors with bleeding and other complications was analysed with logistic regression. RESULTS: The total number of PTs and surgical tracheotomies was 1.454. The median number of days on a ventilator until PT was 6 in 2001, decreasing to 3 in 2009. A procedure-related complication was reported in 17.5%. There was no PT-related mortality. The rate of potentially life-threatening complications was 1.2%. Three patients developed pneumothorax and one of these had circulatory arrest and was successfully resuscitated. Three hundred and twelve patients had one or more units of blood transfused, but only 19 (1.9%) were PT related. Increased INR was the most important risk factor for bleeding [odds ratio (OR) 2.99], followed by low platelets (OR 1.99). The rate of complications in patients with high body mass index was not increased. CONCLUSION: PT is a safe procedure that can be performed with a low complication rate in patients with increased risk of bleeding as well as in obese patients.

Paratracheal placement of orotracheal tube: a complication when aborting percutaneous tracheotomy.

Percutaneous dilatational tracheotomies (PT) are commonly performed in the ICU. The procedure carries the risk of complications, among them severe events as loss of airway or pneumothorax. In this case report we describe complications related to a PT procedure in the ICU. The procedure was performed with a single dilator kit, and by visual guidance of a bronchoscope. Because of difficulties with the insertion of the tracheal cannula, the procedure was aborted, and the endotracheal tube (ET) reinserted. After placement of the ET, subcutaneous emphysema emerged. Upon digital exploration in the tracheotomy incision the tube was found to exit from the trachea, the tube-tip being situated para-tracheally. The tube position was corrected using a finger in the incision, and the patient could again be ventilated. Poor visual conditions may occur during PT because of bleeding. Importantly, there is a risk for the ET to exit an incision in the trachea when reintubating during a PT procedure, or after decannulation. This can be prevented using digital occlusion of the tracheal opening.

Dexamethasone has additive effect when combined with ondansetron and droperidol for treatment of established PONV.

BACKGROUND: Prophylactic dexamethasone, ondansetron and droperidol have a documented effect on post-operative nausea and vomiting (PONV). Still, there is a lack of studies investigating the effect of adding dexamethasone to ondansetron and droperidol in order to treat established PONV. METHODS: In this double-blind randomised, controlled trial, we compared triple prophylaxis for PONV consisting of dexamethasone 8 mg intravenous (IV), ondansetron 4 mg IV and droperidol 0.625 mg IV (n = 157) with placebo (n = 156) given before gynaecological day-case surgery. Subsequently, in those having PONV despite triple prophylaxis or placebo, a dose of ondansetron and droperidol plus dexamethasone was compared with the combination of ondansetron and droperidol. RESULTS: Triple prophylaxis reduced acute PONV (0-6 h) (P = 0.0003) and post-discharge PONV (6-24 h) (P = 0.001) when compared with placebo. Among those suffering from PONV despite placebo or active prophylaxis (n = 80), adding dexamethasone to ondansetron and droperidol reduced acute PONV (0-6 h) (P = 0.025) as well as post-discharge nausea (6-24 h) (P = 0.04) compared with duo treatment comprising ondansetron and droperidol. In those reporting PONV despite prophylaxis (n = 12), the treatment comprising ondansetron and droperidol, with or without dexamethasone, gave a 91.7% reduction in acute PONV and an 83.6% reduction in post-discharge PONV. CONCLUSION: Treatment of established PONV comprising ondansetron and droperidol, with or without dexamethasone, reduced PONV in both treatment groups. In those reporting PONV without active prophylaxis, the addition of dexamethasone resulted in a significant amplification of the PONV-reducing [corrected] effects of ondansetron and droperidol.

Haemodynamic effects of repeated doses of oxytocin during Caesarean delivery in healthy parturients.

BACKGROUND: The haemodynamic effects of oxytocin 5 u have been described previously, but still some authors attribute these effects to the delivery itself. We studied the haemodynamic effects of two repeated doses of oxytocin i.v. in 20 healthy women during spinal anaesthesia for Caesarean delivery. METHODS: Data were obtained from a randomized controlled study of 80 pregnant women undergoing an elective Caesarean section. All women had an arterial line inserted, and LidCOPlus was used for measuring cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR). RESULTS: Twenty women required a second bolus of oxytocin 5 u. Both the first and the second doses produced clinically and statistically significant haemodynamic changes, but the haemodynamic changes induced by the second dose were smaller than after the first dose. The mean maximal change in CO after the first and second doses were 94% (CI 70-117) and 42% (CI 33-52), respectively (P<0.0001), and for systolic arterial pressure 31% (CI 27-35) and 23% (CI 20-27), respectively (P=0.003). CONCLUSIONS: An initial bolus of oxytocin 5 u produced prominent haemodynamic changes, whereas a second bolus produced smaller changes. This could be due to desensitization of endothelial oxytocin receptors.

Understanding international differences in terminology for delirium and other types of acute brain dysfunction in critically ill patients.

BACKGROUND: Delirium (acute brain dysfunction) is a potentially life threatening disturbance in brain function that frequently occurs in critically ill patients. While this area of brain dysfunction in critical care is rapidly advancing, striking limitations in use of terminology related to delirium internationally are hindering cross-talk and collaborative research. In the English literature, synonyms of delirium such as the Intensive Care Unit syndrome, acute brain dysfunction, acute brain failure, psychosis, confusion, and encephalopathy are widely used. This often leads to scientific "confusion" regarding published data and methodology within studies, which is further exacerbated by organizational, cultural and language barriers. OBJECTIVE: We undertook this multinational effort to identify conflicts in terminology and phenomenology of delirium to facilitate communication across medical disciplines and languages. METHODS: The evaluation of the terminology used for acute brain dysfunction was determined conducting communications with 24 authors from academic communities throughout countries/regions that speak the 13 variants of the Romanic languages included into this manuscript. RESULTS: In the 13 languages utilizing Romanic characters, included in this report, we identified the following terms used to define major types of acute brain dysfunction: coma, delirium, delirio, delirium tremens, délire, confusion mentale, delir, delier, Durchgangs-Syndrom, acute verwardheid, intensiv-psykose, IVA-psykos, IVA-syndrom, akutt konfusion/forvirring. Interestingly two terms are very consistent: 100 % of the selected languages use the term coma or koma to describe patients unresponsive to verbal and/or physical stimuli, and 100% use delirium tremens to define delirium due to alcohol withdrawal. Conversely, only 54% use the term delirium to indicate the disorder as defined by the DSM-IV as an acute change in mental status, inattention, disorganized thinking and altered level of consciousness. CONCLUSIONS: Attempts towards standardization in terminology, or at least awareness of differences across languages and specialties, will help cross-talk among clinicians and researchers.

Assessment of pain.

UNLABELLED: Valid and reliable assessment of pain is essential for both clinical trials and effective pain management. The nature of pain makes objective measurement impossible. Acute pain can be reliably assessed, both at rest (important for comfort) and during movement (important for function and risk of postoperative complications), with one-dimensional tools such as numeric rating scales or visual analogue scales. Both these are more powerful in detecting changes in pain intensity than a verbal categorical rating scale. In acute pain trials, assessment of baseline pain must ensure sufficient pain intensity for the trial to detect meaningful treatment effects. Chronic pain assessment and its impact on physical, emotional, and social functions require multidimensional qualitative tools and health-related quality of life instruments. Several disease- and patient-specific functional scales are useful, such as the Western Ontario and MacMaster Universities for osteoarthritis, and several neuropathic pain screening tools. The Initiative on METHODS: Measurement, and Pain Assessment in Clinical Trials recommendations for outcome measurements of chronic pain trials are also useful for routine assessment. Cancer pain assessment is complicated by a number of other bodily and mental symptoms such as fatigue and depression, all affecting quality of life. It is noteworthy that quality of life reported by chronic pain patients can be as much affected as that of terminal cancer patients. Any assessment of pain must take into account other factors, such as cognitive impairment or dementia, and assessment tools validated in the specific patient groups being studied.

Pain and disability 1 year after knee arthroscopic procedures.

BACKGROUND: Persistent chronic pain after surgery is a major health care problem. Its prevalence after knee arthroscopy is unknown. We conducted a follow-up of knee arthroscopy patients. The aims were to estimate the prevalence of pain at rest and during activity 1 year after knee arthroscopy. METHODS: One hundred patients with moderate or severe acute pain after knee arthroscopy were included in one of two randomized-controlled pain trials. A questionnaire was mailed to all the patients 1 year after inclusion. RESULTS: The prevalence of pain at rest 1 year after surgery [numeric rating scale (NRS) 0-10 grade >/=1] was 30% (95% CI 17-47) in women and 29% (95% CI 17-46) in men. Four of 33 female (10%) and three of 34 male patients (9%) experienced pain intensities at rest of NRS>4, and the number of patients who had experienced NRS>4 during activities were 7 (21%) and 4 (11%), respectively. Age above 50 years was positively correlated to persistent pain. The number of patients who reported a reduced activity of daily living (ADL) due to pain (NRS>4) was 14 of 33 (42%, 95% CI 28-56%) in female and five of 34 (15%, 95% CI 5-25%) in male patients (P=0.03). Age above 50 years was positively correlated to impaired ADL function due to knee pain. CONCLUSIONS: Persistent pain after knee arthroscopy may be a significant health care problem. Age and female gender are independent risk factors for pain and disability 1 year after surgery.

Pain and pain tolerance in whiplash-associated disorders: A population-based study.

BACKGROUND: Pain is a cardinal symptom in individuals with whiplash-associated disorders (WAD). We aimed to compare pain characteristics between individuals with WAD and individuals reporting chronic pain from other causes, and to determine whether potential differences were accounted for by experimental pain tolerance. METHODS: Data from the 6th Tromsø Study (2007-2008, n = 12,981) were analysed. The number of painful locations was compared between individuals with WAD and individuals reporting chronic pain from other causes using negative binomial regression, pain frequency using multinomial logistic regression and pain intensity using multiple linear regression. Differences in experimental pain tolerance (cold pressor test) were tested using Cox regression; one model compared individuals with WAD to those with chronic pain from other causes, one compared the two groups with chronic pain to individuals without chronic pain. Subsequently, regression models investigating clinical pain characteristics were adjusted for pain tolerance. RESULTS: Of individuals with WAD, 96% also reported other causes for pain. Individuals with WAD reported a higher number of painful locations [median (inter-quartile range): 5 (3.5-7) vs. 3 (2-5), p < 0.001] and higher pain intensity (crude mean difference = 0.78, p < 0.001) than individuals with chronic pain from other causes. Pain tolerance did not differ between these two groups. Compared to individuals without chronic pain, individuals with WAD and individuals with chronic pain from other causes had reduced pain tolerance. CONCLUSIONS: Individuals with WAD report more additional causes of pain, more painful locations and higher pain intensity than individuals with chronic pain from other causes. The increased pain reporting was not accounted for by pain tolerance.

Recommendations on practice of conditioned pain modulation (CPM) testing.

Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results.

Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine--a double-blind, cross-over comparison with alfentanil and placebo.

Cold allodynia and hyperalgesia are frequent clinical findings in patients with neuropathic pain. While there have been several clinical studies showing the involvement of central sensitization mechanisms and N-methyl-D-aspartate (NMDA) receptor activation in mechanical allodynia/hyperalgesia and ongoing pain, the mechanisms of thermal allodynia and hyperalgesia have received less attention. The aim of the present study was to examine the effect of the NMDA-receptor antagonist ketamine on thermal allodynia/hyperalgesia, ongoing pain and mechanical allodynia/hyperalgesia in patients with neuropathic pain (11 patients with post-traumatic neuralgia and one patient with post-herpetic neuralgia). All the patients were known to suffer from severe cold allodynia (cold pain detection threshold (CPDT): 23.8 degrees C, median value). The mu-opioid agonist alfentanil was used as an active control. The study design was double-blind and placebo-controlled and the drugs were administered i.v. (bolus dose and infusion). CPDT in the asymptomatic contralateral area was found to be significantly decreased (cold allodynia) compared to CPDT in site- and age-matched normal controls. Heat pain detection thresholds were found to be normal and no consistent heat hyperalgesia occurred. Alfentanil significantly reduced cold allodynia (by increasing CPDT) in symptomatic area (P=0.0076). Ketamine did not significantly increase the threshold. Significant and marked reductions of hyperalgesia to cold (visual analogue score at threshold value) were seen following both alfentanil (4.5 before, 1.4 after, median value) and ketamine (6.8 before, 0.4 after, median value). Alfentanil and ketamine also significantly reduced ongoing pain and mechanical hyperalgesia. It is concluded that NMDA-receptor mediated central sensitization is involved in cold hyperalgesia, but since CPDT remained unaltered, it is likely that other mechanisms are present.

Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo.

Effects of morphine and ketamine (NMDA receptor antagonist) on temporally summated pain ('wind-up-like pain') and spatial aspects of secondary hyperalgesia were investigated in 12 healthy volunteers. Hyperalgesia was produced by a local 1 degree burn injury covering 12.5 cm2 on the medial surface of the calf. Primary hyperalgesia was determined by measuring heat pain detection threshold (HPDT) within the site of injury. Spatial aspects of secondary hyperalgesia present outside the site of injury were quantitated by determination of the areas in which a mechanical punctate (von Frey hair, 50.6 mN), or brush stimuli elicited pain sensation. Temporal aspects of secondary hyperalgesia were determined by repetitively pricking the skin with a standard von Frey hair (834 mN) inducing a 'wind-up-like pain'. Morphine 0.15 mg/kg, ketamine 0.15 mg/kg or placebo (NaCl 0.9%) were administrated i.v. on 3 separate days 50 min after the burn injury in a double-blind, placebo controlled, randomised and cross-over design. In all subjects HPDT was significantly reduced within the injured area compared to the pre-injury threshold (primary hyperalgesia). All subjects developed areas of allodynia and hyperalgesia to punctate stimuli and brush stimuli outside the injured area (secondary hyperalgesia). HPDT was not reduced in the area of secondary hyperalgesia. In 95% of the measurements we found a sudden appearance of pain to repeated pricking with a von Frey hair (834 mN) in the area of secondary hyperalgesia ('wind-up-like pain'). Ketamine significantly reduced the area of secondary hyperalgesia both for punctate and brush stimuli in the first measurement 15 min after injection and eight of the 11 subjects reported that the 'wind-up-like pain' disappeared. On the measurements 45 and 75 min after ketamine injection, secondary hyperalgesia and 'wind-up-like pain' reappeared. Morphine did not significantly change the size of the area of secondary hyperalgesia and did not affect 'wind-up-like pain'. Ketamine or morphine did not change thermal detection thresholds. We conclude that spatial and temporal mechanisms, underlying secondary hyperalgesia, are mediated by glutamatergic transmission via NMDA receptors.

Ibuprofen plus codeine, ibuprofen, and placebo in a single- and multidose cross-over comparison for coxarthrosis pain.

The analgesic efficacy of 200 mg ibuprofen plus 30 mg codeine, 200 mg ibuprofen and placebo was investigated in a new analgesic evaluation model using single- and repeated-dose administration. The study was a double-blind randomized cross-over investigation in 26 coxarthrosis patients with persistent pain. After a washout period of at least 2 days with paracetamol available as rescue analgesic, each of the 3 treatments was administered in a total of 6 doses during 24 h. The hourly pain intensity was recorded on a 100-mm visual analogue scale (VAS) for 8 h after the 1st and the 6th dose. The pretreatment VAS score was 31-37 mm. After the 1st dose the 8-h mean pain intensity values were 25, 27, and 26 mm after ibuprofen plus codeine, ibuprofen, and placebo, respectively. Following another 5 doses every 4 h the corresponding values were 10, 17 and 29 mm. Repeated administration of both active drugs reduced the pain intensity significantly. The analgesic efficacy of ibuprofen plus codeine was significantly superior to that of ibuprofen which was, in turn, superior to that of placebo. In conclusion, analgesic efficacy was better differentiated after repeated-dose than after single-dose administration. The present study design was able to differentiate between 200 mg ibuprofen plus 30 mg codeine and 200 mg ibuprofen alone in a relatively small number of patients.

Local treatment with the N-methyl-D-aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action.

Due to the recent discovery of peripheral N-methyl-D-aspartate (NMDA) (and other glutamate) receptors in animal studies, the NMDA receptor antagonist, ketamine (0.83 mg/ml, 6 ml) or saline was injected s.c. preinjury in 10 healthy volunteers, to study the effect on burn-induced primary and secondary hyperalgesia. On the saline treated leg, all subjects developed primary hyperalgesia and secondary hyperalgesia. On the contralateral leg treated with ketamine, there was a significant reduction of primary hyperalgesia and an inhibition of development of secondary hyperalgesia. In an experimental day 2, lidocaine temporarily blocked the development of primary and secondary hyperalgesia. When saline was injected in the contralateral leg treated with ketamine 1 week previously (n = 6), no zone of secondary hyperalgesia was developed. In contrast, subjects (n = 3) treated with ketamine 2 weeks before, reported development of secondary hyperalgesia following saline, a preliminary indication of a long-lasting peripheral action of ketamine.