Systematic review of analgesics and dexamethasone for post-tonsillectomy pain in adults.

BACKGROUND: Intense pain can last several days after tonsillectomy. It is often undertreated and improved analgesic strategies that can be safely used at home are needed. METHODS: We conducted a systematic review and meta-analysis on the effectiveness of systemic medications used for post-tonsillectomy pain in adult and adolescent (13 yr old) patients. Studies were identified from PubMed, the Cochrane Library, and by hand searching reference lists from studies and review articles. Randomised, double-blind, placebo-controlled studies reporting on pain intensity or use of rescue analgesia were included. RESULTS: Twenty-nine randomised controlled trials representing 1816 subjects met the inclusion criteria. Follow-up time was ≤24 h in 15 studies, in which the majority were taking nonsteroidal anti-inflammatory drugs. Thirteen studies were suitable for meta-analysis. In pooled analysis, paracetamol, dexamethasone, and gabapentinoids reduced pain intensity on the day of operation. In individual studies, ketoprofen, ibuprofen, lornoxicam, parecoxib, rofecoxib, indomethacin and dextromethorphan reduced pain intensity, need for rescue analgesics, or both on the day of operation. Oral celecoxib for 2 postoperative weeks or i.v. ketamine on the day of operation were not effective at the studied doses. Dexamethasone in multiple doses provided analgesia beyond 1 postoperative day. Pain was moderate to strong in both study and control groups during the first postoperative week. CONCLUSIONS: Single analgesics and dexamethasone provide only a weak to moderate effect for post-tonsillectomy pain on the day of operation and thus a multimodal analgesic strategy is recommended. Short follow-up times and clinical heterogeneity of studies limit the usefulness of results.

Gabapentin for post-operative pain management - a systematic review with meta-analyses and trial sequential analyses.

BACKGROUND: Perioperative pain treatment often consist of combinations of non-opioid and opioid analgesics, 'multimodal analgesia', in which gabapentin is currently used. The aim was to document beneficial and harmful effects of perioperative gabapentin treatment. METHODS: Randomized clinical trials comparing gabapentin vs. placebo or active placebo in adult surgical patients receiving gabapentin perioperatively were included. This review was conducted using Cochrane standards, trial sequential analysis (TSA), and Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The primary outcomes were 24-h opioid consumption and incidence of serious adverse events (SAE). RESULTS: One hundred and thirty-two trials with 9498 patients were included. Thirteen trials with low risk of bias reported a reduction in 24-h opioid consumption of 3.1 mg [0.5, 5.6] [corrected]. In the analysis of gabapentin as add-on analgesic to another non-opioid analgesic regimen found a mean reduction in 24-h morphine consumption of 1.2 mg [-0.3, 2.6; TSA-adjusted CI: -0.3, 2.6] in trials with low risk of bias. [corrected]. Nine trials with low risk of bias reported a risk ratio of SAEs of 1.61 [0.91; 2.86; TSA-adjusted CI: 0.57, 4.57]. CONCLUSION: Based on GRADE assessment of the primary outcomes in trials with low risk of bias, the results are low or very low quality of evidence due to imprecision, inconsistency, and in some outcomes indirectness. Firm evidence for use of gabapentin is lacking as clinically relevant beneficial effect of gabapentin may be absent and harm is imminent, especially when added to multimodal analgesia.

Adverse effects of perioperative paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review.

Post-operative pain affects millions of patients worldwide and the post-operative period has high rates of morbidity and mortality. Some of this morbidity may be related to analgesics. The aim of this review was to provide an update of current knowledge of adverse events (AE) associated with the most common perioperative non-opioid analgesics: paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCCs), gabapentinoids and their combinations. The review is based on data from systematic reviews with meta-analyses of analgesic efficacy and/or adverse effects of perioperative non-opioid analgesics, and randomised trials and cohort/retrospective studies. Generally, data on AE are sparse and related to the immediate post-operative period. For paracetamol, the incidence of AEs appears trivial. Data are inconclusive regarding an association of NSAIDs with mortality, cardiovascular events, surgical bleeding and renal impairment. Anastomotic leakage may be associated with NSAID usage. No firm evidence exists for an association of NSAIDs with impaired bone healing. Single-dose GCCs were not significantly related to increased infection rates or delayed wound healing. Gabapentinoid treatment was associated with increased sedation, dizziness and visual disturbances, but the clinical relevance needs clarification. Importantly, data on AEs of combinations of the above analgesics are sparse and inconclusive. Despite the potential adverse events associated with the most commonly applied non-opioid analgesics, including their combinations, reporting of such events is sparse and confined to the immediate perioperative period. Knowledge of benefit and harm related to multimodal pain treatment is deficient and needs clarification in large trials with prolonged observation.

Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review.

In contemporary post-operative pain management, patients are most often treated with combinations of non-opioid analgesics, to enhance pain relief and to reduce opioid requirements and opioid-related adverse effects. A diversity of combinations is currently employed in clinical practice, and no well-documented 'gold standards' exist. The aim of the present topical, narrative review is to provide an update of the evidence for post-operative analgesic efficacy with the most commonly used, systemic non-opioid drugs, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs)/COX-2 antagonists, glucocorticoids, gabapentinoids, and combinations of these. The review is based on data from previous systematic reviews with meta-analyses, investigating effects of non-opioid analgesics on pain, opioid-requirements, and opioid-related adverse effects. Paracetamol, NSAIDs, COX-2 antagonists, and gabapentin reduced 24 h post-operative morphine requirements with 6.3 (95% confidence interval: 3.7 to 9.0) mg, 10.2 (8.7, 11.7) mg, 10.9 (9.1, 12.8) mg, and ≥ 13 mg, respectively, when administered as monotherapy. The opioid-sparing effect of glucocorticoids was less convincing, 2.33 (0.26, 4.39) mg morphine/24 h. Trials of pregabalin > 300 mg/day indicated a morphine-sparing effect of 13.4 (4, 22.8) mg morphine/24 h. Notably, though, the available evidence for additive or synergistic effects of most combination regimens was sparse or lacking. Paracetamol, NSAIDs, selective COX-2 antagonists, and gabapentin all seem to have well-documented, clinically relevant analgesic properties. The analgesic effects of glucocorticoids and pregabalin await further clarification. Combination regimens are sparsely documented and should be further investigated in future studies.

Effect of pain on autonomic nervous system indices derived from photoplethysmography in healthy volunteers.

BACKGROUND: Photoplethysmographic pulse wave amplitude (PPGA) and heart rate (HR) can be used to measure cold, nociception-induced autonomic responses, or both. The aim of our study was to correlate the intensity of experimental pain to changes in physiological variables reflecting the autonomic nervous system response to pain. METHODS: PPGA, HR, and subjective measurements of pain intensity were measured in 29 healthy male volunteers during two heat stimuli (43°C and 48°C) and the cold pressor test (CPT). Surgical pleth index (SPI), autonomic nervous system state (ANSS), and ANSS index (ANSSi) were calculated using PPGA and HR. RESULTS: Pain intensity scores increased on the average by 1.6, 3.5, and 8.1 for the 43°C, 48°C, and CPT stimuli, respectively. The pain intensity scores for all three stimuli groups were significantly different from each other (P<0.001). All three stimuli changed HR, PPGA, SPI, ANSS, and ANSSi values significantly from their respective baseline values (P<0.001 for all). Heat stimuli-induced pain intensity did not correlate with the magnitude of the respective changes in HR, PPGA, SPI, ANSS, and ANSSi. CPT-induced pain intensity correlated with the magnitude of the respective changes in HR, PPGA, SPI, ANSS, and ANSSi. PPGA, ANSSi, ANSS, and SPI differentiated between heat and cold stimuli-induced pain. CONCLUSIONS: All three thermal stimuli produced a significant change in photoplethysmograph-derived parameters. All photoplethysmograph-derived parameters appear to be suitable to study autonomic nervous system activation.

Choosing the unit of measurement counts: the use of oral morphine equivalents in studies of opioid consumption is a useful addition to defined daily doses.

AIM: Defined daily dose (DDD) is the most common measurement unit used in drug consumption studies. The DDD for opioids may not reflect their relative clinical potencies. The aim of this study was to explore whether opioid consumption data may be interpreted differently when adding oral morphine equivalent (OMEQ) dose as a measurement unit compared with using DDD. METHODS: The equianalgesic ratio of each opioid relative to morphine was tabulated. Data on opioid consumption expressed in DDD were converted to OMEQs using the equianalgesic ratios. The opioid consumption was compared in three different study settings: clinical data from an opioid switching study, trends within one country and a comparison between countries. RESULTS: Using DDD, the opioid consumption in Norway between 2004-2008 increased of 6.7%, while the increase was 23.6% using OMEQ. While DDD/1000 inhabitants/day showed that Sweden had the highest consumption of opioids among the Nordic countries, OMEQ/1000 inhabitants/day showed that Denmark had the highest consumption. In the switching study DDD indicated a reduction in analgesic dosing and OMEQ an increase when switching from WHO step II to III. CONCLUSION: OMEQ reflects clinical dosing better than DDD, and can give additional insight into opioid consumption when combined with DDD. Using OMEQ can also lead to different conclusions in opioid consumption studies compared with using DDD alone.

Stereoselective pharmacokinetics of ketorolac in children, adolescents and adults.

BACKGROUND: Previous pharmacokinetic studies on racemic ketorolac using nonstereoselective analytical methods have indicated that the plasma clearance of ketorolac is higher and the volume of distribution greater in children than in adults. The aim of this study was to study the stereoselective pharmacokinetics of racemic ketorolac in children, adolescents and adults. METHODS: 18 children (6-11 yrs), 18 adolescents (12-17 yrs) and 18 adults (18-44 yrs) participated in the study. At the end of eye surgery they were given intravenous racemic ketorolac tromethamine 0.5 mg/kg. Plasma samples were assayed for (R)- and (S)-ketorolac with high-pressure liquid chromatography. Clearance (CL), volume of distribution at steady state (Vss) and elimination (Vz) and elimination half-life (t1/2,z) were calculated with standard methods. Incidence of side-effects were recorded. RESULTS: CL, Vss, Vz and t1/2,z were higher (P<0.05) for (S)-ketorolac than for the (R)-enantiomer. Vss of the active (S)-enantiomer was higher in children than in adolescents (P<0.05) and adults (P<0.001) but the values for CL were similar. Due to the higher volume of distribution, t1/2,z was also higher in children than in adults. The pharmacokinetics of the (R)-enantiomer were essentially unaffected by age. CONCLUSION: On a pharmacokinetic basis, the maintenance dose requirements of ketorolac are similar in children, adolescents and adults.

Does propofol reduce vomiting after strabismus surgery in children?

BACKGROUND: Previous studies have indicated that propofol anaesthesia may reduce the incidence of postoperative nausea and vomiting after strabismus surgery in children. This study was designed to investigate the incidence of vomiting after strabismus surgery at two different levels of propofol anaesthesia compared to thiopental/isoflurane anaesthesia. METHODS: Ninety ASA class I or II children, aged 5-14 yrs were randomly assigned to one of three groups: Group T/I (n = 30) induction with 5 mg kg-1 of thiopental and maintenance with isoflurane, group P5 (n = 31) induction with propofol 2 mg kg-1, maintenance with propofol infusion 5 mg kg-1 h-1 or group P10 (n = 29) induction with propofol 2 mg kg-1, maintenance with propofol 10 mg kg-1 h-1. All received glycopyrrolate, vecuronium, fentanyl and controlled ventilation with O2/N2O 30/70. Ketorolac i.v. was given to prevent postoperative pain. If additional analgesia was needed, ibuprofen/acetaminophen or buprenorphine was given according to clinical need. RESULTS: There were no differences between study groups with respect to age, weight, history of previous anaesthesia or emesis after previous anaesthesia, duration of anaesthesia, surgery or sleep after anaesthesia, or number of muscles operated. The incidence of vomiting was 37%, 29% and 28% in groups T/I, P5 and P10, respectively. There were no statistically significant differences between the three groups in the incidence of vomiting. The median age of patients who vomited was 7.5 (range 5.0-13.7) yrs while the median age of the patients who did not vomit was 9.1 (range 5.0-14.0) yrs (P < 0.01). CONCLUSION: In the present study, propofol anaesthesia compared to thiopental/isoflurane anaesthesia did not reduce the incidence of vomiting following strabismus surgery in children.

Clinical pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children.

Pain in childhood has not always been managed as actively as that in adults because of the limited amount of research available to provide guidelines for the management of paediatric pain. However, for many years now the pharmacokinetics and pharmacodynamics of opioid analgesics in infants and children have been studied intensively. Morphine is the standard for opioid analgesics and its pharmacology is the best studied in paediatric patients. During the neonatal period, the volume of distribution (Vd) appears to be smaller in neonates than in adults, but adult values are reached soon after the neonatal period. Although morphine is absorbed both orally and rectally, there is little information on the pharmacokinetics of morphine administered by these routes. The bioavailability of morphine after rectal administration appears to be highly variable. For all the opioid analgesics studied, the elimination of the opioids is slower in neonates than in adults. However, the rate of elimination usually reaches and even exceeds adult values within the first year of life. The high rate of drug metabolism means higher dosage requirements. In regard to the pharmacodynamics of opioid analgesics, infants and children do not appear to be more sensitive to the effects of opioids than adults. Thus, except for the neonatal period, the pharmacokinetics and pharmacodynamics of opioid analgesics are not markedly different from those of adults, and the risk of using opioids in infants and children is not higher.

Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children.

1. Oxycodone hydrochloride (0.1 mg kg-1) was given by intravenous bolus to 18 children after ophthalmic surgery. Plasma was sampled for up to 8 h. Blood pressure, heart rate, peripheral arteriolar oxygen saturation, end-tidal carbon dioxide and halothane concentrations and ventilatory rate were also recorded. 2. Mean (+/- s.d.) values of drug clearance and volume of distribution (Vss) were 15.2 +/- 4.2 ml min-1 kg-1 and 2.1 +/- 0.8 l kg-1. Maximum mean end-tidal carbon dioxide concentration and minimum mean ventilatory rate occurred 8 min after administration of oxycodone but the minimum mean peripheral arteriolar oxygen saturation occurred at 4 min. 3. Oxycodone (0.1 mg kg-1) appears to cause greater ventilatory depression than comparable analgesic doses of other opioids.

Pharmacokinetics of i.v. and rectal pethidine in children undergoing ophthalmic surgery.

We have studied the pharmacokinetics of i.v. and rectal pethidine in 20 children age 4-8 yr undergoing ophthalmic surgery. After i.v. administration, the clearance of pethidine was mean 10.4 (SD 1.7) ml kg-1 min-1, volume of distribution at steady state 2.8 (0.6) litre kg-1 and elimination half-life 3.0 (0.5) h. After rectal administration, plasma pethidine concentrations varied greatly and peak concentrations appeared late, at 147 (44) min. The mean systemic bioavailability after rectal administration was approximately 55%. Because the bioavailability of rectal pethidine varies greatly, this route is not encouraged in the management of acute pain.

Pharmacokinetics and pharmacodynamics of pentazocine in children.

Pharmacokinetics and ventilatory effects of a single intravenous dose of 0.5 mg/kg of pentazocine were studied in ten children aged 4 to 8 years after ophthalmic surgery. Elimination half-life (mean +/- S.D.) was 3.0 +/- 1.5 hr and clearance 21.8 +/- 5.9 ml/min./kg. The values for Vc, Vss and V beta were 0.73 +/- 0.21, 4.0 +/- 1.2 and 5.3 +/- 2.1 l/kg, respectively. The pharmacokinetic parameters were similar to those of adults. After administration of pentazocine decrease in ventilatory rate and oxygen saturation and increase in end-tidal carbon dioxide were relatively fast and steep. Oxygen saturation of four patients decreased below 90% and in one patient the decrease did not recover instantly and additional oxygen was given for 2 min. No patient needed assisted ventilation. Only clinically insignificant changes in heart rate and mean arterial pressure were observed. The duration of analgesia was 164 +/- 59 min. No serious side-effects appeared.

Comparison of the ventilatory effects of morphine and buprenorphine in children.

This study was a prospective, randomized comparison of the ventilatory effects of equianalgesic single-doses of morphine, 100 micrograms/kg, and buprenorphine, 3.0 micrograms/kg, administered intravenously to 20 children (5-8 years of age) after elective ophthalmic surgery. The decrease in ventilatory rate and acute change in the arteriolar oxygen saturation and the increase in end-tidal CO2 levels were statistically significantly greater in magnitude and duration after buprenorphine than after morphine. For both drugs, the time, duration and magnitude of ventilatory changes varied appreciably between individuals. No child had apnea or hypoventilation requiring assistance. The authors conclude that acutely administered buprenorphine depresses ventilation to a greater degree than morphine. The maximal ventilatory effect of buprenorphine occurs later than with morphine, and ventilatory depression after buprenorphine may develop late. For safety, all children given opioids intravenously should be observed until they are fully responsive and ventilatory control has stabilized.

Ventilatory effects of morphine, pethidine and methadone in children.

The ventilatory effects of single i.v. doses of morphine 0.1 mg kg-1, pethidine 0.67 mg kg-1 and methadone 0.1 mg kg-1 were compared after ophthalmic surgery in an open, randomized study in 30 children aged 3-8 yr. Ventilatory changes after each drug had distinctive profiles, with appreciable individual variation. Acutely, the decrease in ventilatory frequency was greater with pethidine and methadone than with morphine. The acute decrease in oxygen saturation was greater with methadone and pethidine than with morphine. Methadone produced a greater and longer lasting increase in end-tidal carbon dioxide and greater decrease in end-tidal oxygen than morphine or pethidine. Changes in end-tidal carbon dioxide and oxygen concentrations and saturation were most transient after pethidine and of longest duration after methadone. No child developed apnoea or hypoventilation requiring assistance.