Parecoxib, propacetamol, and their combination for analgesia after total hip arthroplasty: a randomized non-inferiority trial.

BACKGROUND: This study assessed non-inferiority of parecoxib vs. combination parecoxib+propacetamol and compared the opioid-sparing effects of parecoxib, propacetamol, and parecoxib+propacetamol vs. placebo after total hip arthroplasty. METHODS: In this randomized, placebo-controlled, parallel-group, non-inferiority study, patients received one of four IV treatments after surgery: parecoxib 40 mg bid (n = 72); propacetamol 2 g qid (n = 71); parecoxib 40 mg bid plus propacetamol 2 g qid (n = 72); or placebo (n = 38) with supplemental IV patient-controlled analgesia (morphine). Patients and investigators were blinded to treatment. Pain intensity at rest and with movement was assessed regularly, together with functional recovery (modified Brief Pain Inventory-Short Form) and opioid-related side effects (Opioid-Related Symptom Distress Scale) questionnaires up to 48 h. RESULTS: After 24 h, cumulative morphine consumption was reduced by 59.8% (P < 0.001), 38.9% (P < 0.001), and 26.8% (P = 0.005) in the parecoxib+propacetamol, parecoxib, and propacetamol groups, respectively, compared with placebo. Parecoxib did not meet criteria for non-inferiority to parecoxib+propacetamol. Parecoxib+propacetamol and parecoxib significantly reduced least-squares mean pain intensity scores at rest and with movement compared with propacetamol (P < 0.05). One day after surgery, parecoxib+propacetamol significantly reduced opioid-related symptom distress and decreased pain interference with function compared with propacetamol or placebo. CONCLUSION: Parecoxib and parecoxib+propacetamol provided significant opioid-sparing efficacy compared with placebo; non-inferiority of parecoxib to parecoxib+propacetamol was not demonstrated. Opioid-sparing efficacy was accompanied by significant reductions in pain intensity on movement, improved functional outcome, and less opioid-related symptom distress. Study medications were well tolerated.

Evidence-based management of postoperative pain in adults undergoing open inguinal hernia surgery.

BACKGROUND: Open inguinal hernia repair is associated with moderate postoperative pain, but optimal analgesia remains controversial. The aim of this systematic review was to evaluate the available literature on the management of pain after open hernia surgery. METHODS: Randomized studies, in English, published between January 1966 and March 2009, assessing analgesic and anaesthetic interventions in adult open hernia surgery, and reporting pain scores, were retrieved from the Embase and MEDLINE databases. In addition to published evidence, clinical practice was taken into account to ensure that the recommendations had clinical validity. RESULTS: Of the 334 randomized studies identified, 79 were included. Quantitative analysis suggested that regional anaesthesia was superior to general anaesthesia for reducing postoperative pain. Spinal anaesthesia was associated with a higher incidence of urinary retention and increased time to home-readiness compared with regional anaesthesia. CONCLUSION: Field block with, or without wound infiltration, either as a sole anaesthetic/analgesic technique or as an adjunct to general anaesthesia, is recommended to reduce postoperative pain. Continuous local anaesthetic infusion of a surgical wound provides a longer duration of analgesia. Conventional non-steroidal anti-inflammatory drugs or cyclo-oxygenase 2-selective inhibitors in combination with paracetamol, administered in time to provide sufficient analgesia in the early recovery phase, are optimal. In addition, weak opioids are recommended for moderate pain, and strong opioids for severe pain, on request.

Frey's syndrome after elective thyroidectomy: a case report.

This case report documents the case of a 41-year-old Caucasian woman who developed a Frey's syndrome after elective thyroidectomy. This patient developed a sudden redness on one side of the face in the recovery room after a total thyroidectomy under general anaesthesia. All other vital signs of the patient remained normal. There were no signs of infection. After a few hours the symptoms disappeared without any treatment. Frey's syndrome is a disorder characterised by unilateral flushing or sweating of the facial skin. This syndrome can occur after parotidectomy or after trauma, injury or inflammation of the parotid, the submandibular glands, or of cervical and thoracic parts of the sympathetic trunk. Frey's syndrome normally results from aberrant regeneration of auriculotemporal nerve fibers to sweat glands in the skin. This case describes a self-limiting Frey' s syndrome after irritation of the cervical portion of the truncus sympathicus following total thyroidectomy.

Intrathecal lidocaine elevates prostaglandin E2 levels in cerebrospinal fluid: a microdialysis study in freely moving rats.

BACKGROUND: In this study, we have investigated whether intrathecal (i.t.) lidocaine administration is accompanied with changes of cerebrospinal fluid (CSF) prostaglandin E(2) (PGE(2)) levels. METHODS: Rats were anaesthetized for i.t. implantation of a triple-lumen spinal loop dialysis catheter. CSF changes in PGE(2) after i.t. injection of saline, 400, or 1000 microg of lidocaine were measured. The impact of i.t. pretreatment with 5 microg MK801 (N-methyl-D-aspartate glutamate antagonist) or 10 microg SC76309A (COX-2 inhibitor) was also investigated. CSF dialysates for measurement of PGE(2) were collected for 4 h. During the whole procedure, motor and sensory blocks were evaluated. A separate group receiving i.t. lidocaine 400 microg (without dialysate sampling) was assessed for mechanical (Von Frey) and radiant heat pain. RESULTS: PGE(2) levels increased to 400% of baseline and remained elevated for 90-120 min after i.t. lidocaine at both doses. Pretreatment with SC76309A and MK801 attenuated this increase. A 40 min period of enhanced pain response was observed after Von Frey filament stimulation during and after sensory and motor block recovery. CONCLUSIONS: I.T. lidocaine (400 or 1000 microg) increases PGE(2) levels in the CSF for 90-120 min along with a transient period of mechanical hyperalgesia after sensory and motor block recovery.

A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty.

The PROSPECT Working Group, a collaboration of anaesthetists and surgeons, conducts systematic reviews of postoperative pain management for different surgical procedures (http://www.postoppain.org). Evidence-based consensus recommendations for the effective management of postoperative pain are then developed from these systematic reviews, incorporating clinical practice observations, and transferable evidence from other relevant procedures. We present the results of a systematic review of pain and other outcomes following analgesic, anaesthetic and surgical interventions for total knee arthroplasty (TKA). The evidence from this review supports the use of general anaesthesia combined with a femoral nerve block for surgery and postoperative analgesia, or alternatively spinal anaesthesia with local anaesthetic plus spinal morphine. The primary technique, together with cooling and compression techniques, should be supplemented with paracetamol and conventional non-steroidal anti-inflammatory drugs or COX-2-selective inhibitors, plus intravenous strong opioids (high-intensity pain) or weak opioids (moderate- to low-intensity pain).

Propofol.

The hypnotic agent propofol has pharmacokinetic characteristics that allow for rapid onset and offset of drug effect and fast elimination from the body. Elderly patients show a greater sensitivity to the hypnotic effect of propofol. The drug is extensively metabolized in the liver through the cytochrome P450 system and glucuronidation, with potential for drug interaction. Propofol does not cause significant inotropic depression at clinically relevant concentrations. But in vitro, propofol impairs isotonic relaxation of the heart and decreases free cytosolic Ca(2+) concentrations in myocardial cells. In animal models, the cardioprotective effects of propofol derive in part from its antioxidant and free radical scavenging properties. Propofol decreases cerebral blood flow and cerebral metabolic rate dose-dependently. The neuroprotective effect of propofol in animal models is attributed to its antioxidant property, the potentiation of gamma-aminobutyric acid type A (GABA(A))-mediated inhibition of synaptic transmission, and the inhibition of glutamate release. Subhypnotic doses of propofol induce sedative, amnestic, and anxiolytic effects in a dose-dependent fashion. Propofol impairs ventilation with a considerable effect on the control of ventilation and central chemoreceptor sensitivity. Propofol reduces the ventilatory response to hypercapnia and the ventilatory adaptation to hypoxia, even at subanesthetic doses. The drug potentiates hypoxic pulmonary vasoconstriction, an effect caused by inhibition of K(+) (ATP)-mediated pulmonary vasodilatation. Most of the pharmacological actions of propofol result from interaction with the GABA(A) receptor or with calcium channels. Propofol prolongs inhibitory postsynaptic currents mediated by GABA(A) receptors, indicating that its effects are associated with enhanced inhibitory synaptic transmission, but propofol also influences presynaptic mechanisms of GABAergic transmission. Propofol modulates various aspects of the host's inflammatory response. It decreases secretion of proinflammatory cytokines, alters the expression of nitric oxide, impairs monocyte and neutrophil functions, and has potent, dose-dependent radical scavenging activity similar to the endogenous antioxidant vitamin E.

Etomidate and other non-barbiturates.

It is today generally accepted that anesthetics act by binding directly to sensitive target proteins. For certain intravenous anesthetics, such as propofol, barbiturates, and etomidate, the major target for anesthetic effect has been identified as the gamma-aminobutyric acid type A (GABA(A)) receptor, with particular subunits playing a crucial role. Etomidate, an intravenous imidazole general anesthetic, is thought to produce anesthesia by modulating or activating ionotropic Cl(-)-permeable GABA(A) receptors. For the less potent steroid anesthetic agents the picture is less clear, although a relatively small number of targets have been identified as being the most likely candidates. In this review, we summarize the most relevant clinical and experimental pharmacological properties of these intravenous anesthetics, the molecular targets mediating other endpoints of the anesthetic state in vivo, and the work that led to the identification of the GABA(A) receptor as the key target for etomidate and aminosteroids.

A procedure-specific systematic review and consensus recommendations for postoperative analgesia following laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy has advantages over the open procedure for postoperative pain. However, a systematic review of postoperative pain management in this procedure has not been conducted. METHODS: A systematic review was conducted according to the guidelines of the Cochrane Collaboration. Randomized studies examining the effect of medical or surgical interventions on linear pain scores in patients undergoing laparoscopic cholecystectomy were included. Qualitative and quantitative analyses were performed. Recommendations for patient care were derived from review of these data, evidence from other relevant procedures, and clinical practice observations collated by the Delphi method among the authors. RESULTS: Sixty-nine randomized trials were included and 77 reports were excluded. Recommendations are provided for preoperative analgesia, anesthetic and operative techniques, and intraoperative and postoperative analgesia. CONCLUSIONS: A step-up approach to the management of postoperative pain following laparoscopic cholecystectomy is recommended. This approach has been designed to provide adequate analgesia while minimizing exposure to adverse events.

Formalin-induced spinal glutamate release in freely moving rats: comparison of two spinal microdialysis approaches.

Two different spinal microdialysis approaches using either a linear tissue probe (LM-3) or a loop probe were explored on freely-moving rats to investigate the basal and formalin-evoked release of glutamate (Glu) in the spinal dorsal horn or in the cerebrospinal fluid (CSF). Adult male Wistar rats were implanted either with a LM-3 probe transversely through the spinal dorsal horn or with a loop probe in the CSF. After 24 hours recovery, microdialysis was initiated with perfusion of modified Ringer's solution at a flow rate of 5 microliters/min and the basal Glu concentrations were sampled for 1 hour. The effects of altering the microdialysis flow rate and perfusion solution on basal Glu release were next investigated. Following the injection of 50 microliters of formalin 5% into the hind paw, 10-min samples were collected for 90 min. The baseline levels of Glu were 0.82 +/- 0.09 microM with LM-3 probes and 5.96 +/- 0.22 microM with the loop probes. Decreasing the flow rate from 5 to 2 microliters/min increased extracellular Glu concentrations by 222.7 +/- 7.3%, whereas perfusion with artificial CSF reduced baseline Glu by 61.5 +/- 9.5% with LM-3 probes. Injection of formalin induced a short-lasting but significant increase of Glu with a similar profile and time course when using either of the microdialysis approaches. In conclusion, microdialysis in the dorsal horn or in the CSF are both effective techniques to assess the alterations in Glu release following peripheral nociceptive input. The loop probe technique in CSF is more reproducible for routine investigation of drug effects, whereas the microdialysis of the dorsal horn provides a useful tool to precisely locate where the release of the neurotransmitters occurs.

Preparation and in-vitro release rate of fentanyl-cyclodextrin complexes for prolonged action in epidural analgesia.

Fentanyl was complexed with cyclodextrin derivatives with the intention to obtain parenteral solutions able to provide prolonged analgesia following epidural administration. Three cylodextrins (CDs) suitable for parenteral use were used: hydroxypropyl-beta-cyclodextrin (HP-beta-CD), sulfobutylether-beta-cyclodextrin (SBE-7-beta-CD), and maltosyl-beta-cyclodextrin (malt-beta-CD). Analysis of fentanyl was done with HPLC-UV. The inclusion capacity of HP-beta-CD was determined from phase-solubility diagrams at pH 6.5, 7.2 and 8.0, and those of SBE-7-beta-CD and of malt-beta-CD at pH 8.0. Solubility of fentanyl increased linearly (i) as a function of the CD concentration, and (ii) with decreasing pH. Complexation was highest with HP-beta-CD and malt-beta-CD, much higher than with SBE-7-beta-CD, with stability constants at pH 8.0 of 801, 729 and 1309 M(-1), respectively. The CD concentration was calculated to obtain a fentanyl-CD formulation, with the desired amount free fentanyl as loading dose in solution and the rest complexed with CD, as reservoir for prolonged action. A suitable membrane and a release-rate apparatus were selected for in-vitro release-rate studies. Best results were obtained with Spectrapor membranes and a home-made release-rate apparatus. Release rate was evaluated in static and dynamic conditions. For both modes, the release rate of fentanyl decreased as a function of CD concentration, due to complex formation of fentanyl, which suggests the possibility to provide prolonged pharmacodynamic effects in vivo.

Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery.

BACKGROUND: Ketorolac is approved for the relief of postoperative pain but concerns have been raised over a possible risk of serious adverse effects and death. Two regulatory reviews in Europe on the safety of ketorolac found the data were inconclusive and lacked comparison with other non-steroidal anti-inflammatory drugs. The aim of this study was to compare the risk of serious adverse effects with ketorolac vs diclofenac or ketoprofen in adult patients after elective major surgery. METHODS: This prospective, randomized multicentre trial evaluated the risks of death, increased surgical site bleeding, gastrointestinal bleeding, acute renal failure, and allergic reactions, with ketorolac vs diclofenac or ketoprofen administered according to their approved parenteral and oral dose and duration of treatment. Patients were followed for 30 days after surgery. RESULTS: A total of 11,245 patients completed the trial at 49 European hospitals. Of these, 5634 patients received ketorolac and 5611 patients received one of the comparators. 155 patients (1.38%) had a serious adverse outcome, with 19 deaths (0. 17%), 117 patients with surgical site bleeding (1.04%), 12 patients with allergic reactions (0.12%), 10 patients with acute renal failure (0.09%), and four patients with gastrointestinal bleeding (0.04%). There were no differences between ketorolac and ketoprofen or diclofenac. Postoperative anticoagulants increased the risk of surgical site bleeding equally with ketorolac (odds ratio=2.65, 95% CI=1.51-4.67) and the comparators (odds ratio=3.58, 95% CI=1.93-6.70). Other risk factors for serious adverse outcomes were age, ASA score, and some types of surgery (plastic/ear, nose and throat, gynaecology, and urology). CONCLUSION: We conclude that ketorolac is as safe as ketoprofen and diclofenac for the treatment of pain after major surgery.

Comparison between the cuffed oropharyngeal airway and the laryngeal mask with respect to breathing pattern and capnography.

This study evaluates spontaneous breathing and CO2-monitoring under sevoflurane anesthesia with a cuffed oropharyngeal (COPA) or laryngeal mask (LMA) as airway. Forty patients (ASA I-II) scheduled for varicose vein surgery were given 2 mg.kg-1 propofol for insertion of a COPA or a LMA. Anesthesia was maintained with sevoflurane at 2.5 vol% in 40/60% O2/N2O, while the patients breathed spontaneously. Arterial and end-tidal CO2 partial pressures (PaCO2, PE'CO2), respiratory rate (RR), tidal volume (VT) and expired minute volume (EMV) were recorded at different times before and during the procedure. The dead space (VD) was calculated from the modified Bohr equation. The PaCO2 and the PE'CO2 were generally lower in the LMA group as compared to the COPA group during most of the procedure. EMV was also higher in the LMA group as compared to the COPA group. This difference becomes statistically significant 5 min. before the end of surgery (6.22 +/- 0.34 vs. 5.23 +/- 0.39 L.min-1). RR was consistently higher in the LMA group, while VT and VD were similar. Correlation of PE'CO2 and PaCO2 was 0.87 when measured in the COPA group and 0.88 in the LMA group. The prediction of PaCO2 by PE'CO2 was more sensitive in the LMA group as compared to the COPA group. We conclude that spontaneous breathing is better with the LMA.

Remifentanil and fentanyl during anaesthesia for major abdominal and gynaecological surgery. An open, comparative study of safety and efficacy.

BACKGROUND: and objective This open, multicentre study compared the efficacy and safety of remifentanil with fentanyl during balanced anaesthesia with 0.8% isoflurane (end-tidal concentration) for major abdominal and gynaecological surgery, and the efficacy and safety of remifentanil for pain management in the immediate postoperative period. METHODS: Two-hundred and eighty-six patients were randomized to receive remifentanil 1 microg kg(-1) followed by 0.2 microg kg(-1) min-1 (n=98), remifentanil 2 microg kg(-1) followed by 0.4 microg kg(-1) min(-1) (n=91) or fentanyl 3 microg kg(-1) (n=97) at induction. Thereafter, the study opioids and isoflurane were titrated to effect during the operation. RESULTS: Compared with fentanyl, remifentanil 2 microg kg(-1) followed by 0.4 microg kg(-1) min(-1) reduced the incidence of response to tracheal intubation (30% vs. 13%, P < 0.01), skin incision (33% vs. 4%, P < 0.001) and skin closure (11% vs. 3%, P < 0.05), respectively. Patients receiving remifentanil 1 microg kg(-1) followed by 0.2 microg kg(-1) min(-1) had fewer responses to skin incision than the fentanyl group (12% vs. 33%, P < 0.001), but the incidences of response to tracheal intubation and skin closure were similar. Significantly fewer patients in both remifentanil groups had > or = 1 responses to surgical stress intraoperatively compared with fentanyl (68% and 48% vs. 87%, P < 0.003). The mean isoflurane concentrations required were less in both remifentanil groups compared with the fentanyl group (0.1%, P=0.05). In remifentanil-treated patients, continuation of the infusion at 0.1 microg kg(-1) min(-1) with titration increments of +/- 0.025 microg kg(-1) min(-1) was effective for the management of immediate postoperative pain prior to transfer to morphine analgesia. However, a high proportion of patients experienced at least moderate pain whilst the titration took place. CONCLUSIONS: Anaesthesia combining isoflurane with a continuous infusion of remifentanil was significantly more effective than fentanyl at blunting responses to surgical stimuli. Significantly fewer patients responded to tracheal intubation with remifentanil at 0.4 microg kg(-1) min(-1), supporting the use of a higher initial infusion rate before intubation. Both remifentanil and fentanyl were well-tolerated, with reported adverse events typical of mu-opioid agonists.

Nonsteroidal anti-inflammatory drugs and paracetamol in children.

The cyclooxygenase enzymes produce large amounts of prostaglandins in presence of tissue injury and inflammation. Prostaglandins exert their influence on nerve membrane excitability both at the peripheral site and at the spinal dorsal horn. Their key role in peripheral tissue inflammation and central sensitization warrants their incorporation in pain management strategies for children. As the COX2 isoenzyme is the main target for controlling hyperalgesia, nonsteroidal anti-inflammatory drugs (NSAIDs) with high affinity for this enzyme will provide reliable antihyperalgesic effects. The benefits of NSAIDs for postsurgical pain therapy must be balanced against the risk of postoperative bleeding in children in whom any derangement of hemostasis could adversely affect outcome. If contraindications for NSAID use exist, paracetamol is the alternative. Paracetamol has potent antipyretic and analgesic effects, but no anti-inflammatory effect. The rectal route of administration is notoriously unreliable for eliciting an analgesic effect and the oral route is to be preferred. The dosage of paracetamol must take into account the pharmacokinetic properties of the drug in children. The maximum daily dosage should not be exceeded to avoid excessive production of a hepatotoxic metabolite.

A prospective, open, single blind, randomized study comparing four analgesics in the treatment of peripheral injury in the emergency department.

The efficacy of four analgesics, distinct concerning analgesic power and mechanism of action, was evaluated for pain relief in patients suffering from single peripheral injury. Patients were randomly allocated to receive either propacetamol (the pro-drug of paracetamol) 20 mg/kg i.v., piritramide 0.25 mg/kg i.m., tramadol 1 mg/kg i.v. or diclofenac 1 mg/kg i.v. Pain scores were measured by the patient using the visual analogue scale (VAS) and by an observer using a 4-point verbal rating scale (VRS). Cardiorespiratory variables and side effects were recorded. One hundred and sixty patients were included, 131 completed the study. Groups matched for demography and baseline pain levels. In general pain scores decreased with time. No significant differences were found between groups at any particular time point. VAS scores were significantly (p < 0.02) lower than baseline scores 30 minutes after injection in all treatment groups except for the piritramide group where significance (p < 0.01) was reached after 60 minutes. VRS score analysis showed a similar trend although significances differed. In the piritramide group significantly more side effects were noted than in the other groups (p < 0.05). We conclude that intravenous propacetamol, tramadol and diclofenac are equally efficacious for emergency analgesic treatment of single peripheral trauma.

Isoflurane, desflurane and sevoflurane for carotid endarterectomy.

After carotid endarterectomy under general anaesthesia, the rapid elimination of desflurane and sevoflurane may allow earlier postoperative neurological assessment than after the use of isoflurane. However, desflurane may be associated with tachycardia and hypertension and may therefore increase cardiovascular risk. We investigated haemodynamic and recovery characteristics in patients scheduled for carotid endarterectomy who were anaesthetised with isoflurane, sevoflurane or desflurane. No significant peri-operative differences were noted in cardiac index or ST segment analysis. The times to extubation, movement on command and consciousness were shorter after desflurane and sevoflurane than after isoflurane anaesthesia. Postoperative pain, nausea, vomiting and shivering were similar in the three study groups.

Why should I change my practice of anesthesia? Opioids.

The selection of opioid drugs for anesthesia is often based on empirical judgment such as the selection of opioids with rapid elimination half-life for short surgical procedures (e.g. alfentanil), while opioids with longer elimination half-life (e.g. fentanyl, sufentanil) are used for longer procedures. A better insight in the pharmacokinetic and pharmacodynamic differences between opioids allows a more rational selection of the drug and its dosing scheme, and will contribute to rapid recovery after anesthesia. As opioids are adjuncts to other anesthetic drugs, drug interaction principles should be considered when titrating the opioid administration.