Evaluation of capillary miR-122 as a prognostic biomarker of paracetamol-induced liver toxicity.

INTRODUCTION: Paracetamol (acetaminophen) overdose is a leading cause of acute liver failure in many Western countries. Diagnostic tools for this poisoning may be suboptimal in some cases and new biomarkers have been investigated. We investigated the role of capillary microRNA-122 (miR-122) as a prognostic biomarker of liver injury in the clinical management of patients with paracetamol overdose. METHODS: In a paracetamol overdose patient cohort, miR-122 was measured by quantitative polymerase chain reaction in a blood drop obtained by a finger prick at the end of an antidote cycle treatment with N-acetylcysteine treatment (12 h). Liver injury was defined as serum alanine aminotransferase (ALT) activity > 100 IU/L collected at 10 or 20 h after the start of treatment. Pearson's correlation analyses were performed. RESULTS: In patients with paracetamol overdose, capillary miR-122 was positively correlated with ALT measured at 10 h and at 20 h (r = 0.83, P < 0.0001; r = 0.96, P < 0.0001, respectively). CONCLUSION: This work supports the potential use of capillary miR-122 as a prognostic biomarker of liver injury throughout clinical management of patients with paracetamol overdose. Capillary miR-122 can be measured in a blood drop collected by a finger prick, a minimally invasive diagnostic test for patient stratification.

Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses  per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44-77]) compared to ibuprofen (47 years [IQR: 33-62]), diclofenac (57 years [IQR: 43-71]) and paracetamol (58 years [IQR: 39-75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

The presence of abdominal pain associated with acetaminophen overdose does not predict severity of liver injury.

AIM: Whilst it is known that abdominal pain is a common symptom in patients with acetaminophen overdose, its association with severity of liver injury has not been clearly defined. This study investigates the association between the symptom of abdominal pain on presentation to hospital and the degree of liver injury post-acetaminophen overdose. METHODS: Admissions with acetaminophen poisoning, requiring treatment with acetylcysteine were identified and reviewed from a search of a large Australian tertiary hospital network from February 20th, 2014, to August 30th, 2018. Parameters such as presence of abdominal pain, time post-ingestion and peak ALT were collected. Single acute ingestions, staggered and repeated supratherapeutic ingestions were analysed. RESULTS: 539 cases were identified in the study period, 79% female, with mean age 25 (17-43) years. Patients presenting to the emergency department with abdominal pain post-acetaminophen overdose had a similar risk of developing hepatotoxicity or acute liver injury compared to patients without abdominal pain regardless of time to presentation. Patients presenting <8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (1/46, 2.2%) compared to those without abdominal pain (1/54 [1.9%]; OR = 1.18 [0.07 to 19.4]). Those presenting >8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (13/92, 14.1%) compared to those without abdominal pain (4/35 [11.4%]; OR = 1.28 [0.39 to 4.21]). CONCLUSIONS: The presence of abdominal pain after acetaminophen overdose was not predictive of the development of liver injury in patients receiving acetylcysteine treatment. Further prospective studies are required to confirm this finding. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Pain-related hospitalization and emergency room visit following initial analgesic prescription after outpatient surgery.

PURPOSE: Our study examined the association between outpatient postsurgical analgesic prescription and risk of insufficiently managed pain characterized by pain-associated hospital admission and emergency room (ER) visit. METHODS: Eligible individuals were children 1-17 years of age who filled an incident analgesic following an outpatient surgery during 2013-2018. Pain-associated hospital admission or ER visit were measured within 30 days following the outpatient surgical procedure. A hierarchical multivariable logistic regression model with patients nested under prescribers was fitted to test the association between incident analgesic prescription and risk of having pain-associated hospital admission or ER visit. RESULTS: Of 14 277 children meeting the inclusion criteria, 6224 (43.6%) received an incident opioid and 8053 (56.4%) received an incident non-opioid analgesic prescription respectively. There were a total of 523 (3.7%) children undergoing surgical procedures that had pain-related hospital admissions or ER visits with 5.1% initiated on non-opioid analgesics and 1.8% on opioid analgesics. The multilevel model indicated that initial opioid analgesic recipients were 32% less likely of having a pain-associated hospital admission or ER visit [aOR: 0.68 (95% CI: 0.3-0.8)]. CONCLUSION: Majority of postsurgical patients do not require additional pain management strategies. In the 3.7% of patients requiring additional pain management strategies, those initiated on non-opioid analgesics are more likely to have a pain-associated hospital admission or ER visit compared with their opioid recipient counterparts.

Comparing the efficacy of intravenous morphine versus ibuprofen or the combination of ibuprofen and acetaminophen in patients with closed limb fractures: a randomized clinical trial.

INTRODUCTION: This study aims to investigate the effectiveness of intravenous ibuprofen or intravenous ibuprofen plus acetaminophen compared to intravenous morphine in patients with closed extremity fractures. METHODS: A triple-blinded randomized clinical trial was conducted at a tertiary trauma center in Iran. Adult patients between 15 and 60 years old with closed, isolated limb fractures and a pain intensity of at least 6/10 on the visual analog scale (VAS) were eligible. Patients with specific conditions or contraindications were not included. Participants were randomly assigned to receive intravenous ibuprofen, intravenous ibuprofen plus acetaminophen, or intravenous morphine. Pain scores were assessed using the visual analog scale at baseline and 5, 15, 30, and 60 min after drug administration. The primary outcome measure was the pain score reduction after one hour. RESULTS: Out of 388 trauma patients screened, 158 were included in the analysis. There were no significant differences in age or sex distribution among the three groups. The pain scores decreased significantly in all groups after 5 min, with the morphine group showing the lowest pain score at 15 min. The maximum effect of ibuprofen was observed after 30 min, while the ibuprofen-acetaminophen combination maintained its effect after 60 min. One hour after injection, pain score reduction in the ibuprofen-acetaminophen group was significantly more than in the other two groups, and pain score reduction in the ibuprofen group was significantly more than in the morphine group. CONCLUSION: The study findings suggest that ibuprofen and its combination with acetaminophen have similar or better analgesic effects compared to morphine in patients with closed extremity fractures. Although morphine initially provided the greatest pain relief, its effect diminished over time. In contrast, ibuprofen and the ibuprofen-acetaminophen combination maintained their analgesic effects for a longer duration. The combination therapy demonstrated the most sustained pain reduction. The study highlights the potential of non-opioid analgesics in fracture pain management and emphasizes the importance of initiation of these medications as first line analgesic for patients with fractures. These findings support the growing trend of exploring non-opioid analgesics in pain management. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05630222 (Tue, Nov 29, 2022). The manuscript adheres to CONSORT guidelines.

Dual Antagonism of α9α10 nAChR and GABAB Receptor-Coupled CaV2.2 Channels by an Analgesic αO-Conotoxin Analogue.

Pain severely affects the physical and mental health of patients. The need to develop nonopioid analgesic drugs to meet medical demands is urgent. In this study, we designed a truncated analogue of αO-conotoxin, named GeX-2, based on disulfide-bond deletion and sequence truncation. GeX-2 retained the potency of its parent peptide at the human α9α10 nAChR and exhibited potent inhibitory activity at CaV2.2 channels via activation of the GABAB receptor (GABABR). Importantly, GeX-2 significantly alleviated pain in the rat model of chronic constriction injury. The dual inhibition of GeX-2 at both α9α10 nAChRs and CaV2.2 channels is speculated to synergistically mediate the potent analgesic effects. Results from site-directed mutagenesis assay and computational modeling suggest that GeX-2 preferentially interacts with the α10(+)α10(-) binding site of α9α10 nAChR and favorably binds to the top region of the GABABR2 subunit. The study offers vital insights into the molecular action mechanism of GeX-2, demonstrating its potential as a novel nonopioid analgesic.

Sex Differences in Opioid Administration After Cardiac Surgery.

OBJECTIVES: To assess whether there are sex-based differences in the administration of opioid analgesic drugs among inpatients after cardiac surgery. DESIGN: A retrospective cohort study. SETTING: At a tertiary academic referral center. PARTICIPANTS: Adult patients who underwent cardiac surgery from 2014 to 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the cumulative oral morphine equivalent dose (OMED) for the postoperative admission. Secondary outcomes were the daily difference in OMED and the administration of nonopioid analgesics. The authors developed multivariate regression models controlling for known confounders, including weight and length of stay. A total of 3,822 patients (1,032 women and 2,790 men) were included. The mean cumulative OMED was 139 mg for women and 180 mg for men, and this difference remained significant after adjustment for confounders (adjusted mean difference [aMD], -33.21 mg; 95% CI, -47.05 to -19.36 mg; p < 0.001). The cumulative OMED was significantly lower in female patients on postoperative days 1 to 5, with the greatest disparity observed on day 5 (aMD, -89.83 mg; 95% CI, -155.9 to -23.80 mg; p = 0.009). By contrast, women were more likely to receive a gabapentinoid (odds ratio, 1.91; 95% CI, 1.42-2.58; p < 0.001). The authors found no association between patient sex and the administration of other nonopioid analgesics or specific types of opioid analgesics. The authors found no association between patient sex and pain scores recorded within the first 48 hours after extubation, or the number of opioids administered in close proximity to pain assessments. CONCLUSIONS: Female sex was associated with significantly lower amounts of opioids administered after cardiac surgery.

Comparison of intravenous ibuprofen and paracetamol for peri-operative analgesia in paediatric day care tonsillectomy.

OBJECTIVE: To determine the effectiveness of intravenous ibuprofen and acetaminophen as perioperative analgesics in paediatric patients undergoing day- care tonsillectomy with general anaesthesia. METHODS: The quasi-experimental stud y was conduc ted at the Ana esthe sia D epartment of Pa k Emirates M ilitary Hospital, Rawalpindi , Pak ist an, from July 20 21 to June 2022, and comp rised paediatric pa t ients aged 5-12 yea r s undergoing day- care tonsil lec tomy with gen era l anaesthesia. The sub jec ts were divid ed into two equa l groups. Patients in Group I received intravenous ibuprofen 7mg/kg and patients in Group P received intravenous paracetamol 10mg/kg im media t ely after induction of anaesthesi a. All patients recei ved standard general anaesthesia with endotracheal intubation. The primary outcome measured was revised faces pain score immediately after recovery and at the time of discharge 6 hours later. Adverse events were also noted. Data was analysed using SPSS 26. RESULTS: Of the 100 patients, there were 50(50%) in Group I; 21(42%) boys and 29(58%) girls with mean age 7.82±1.903 years. The remaining 50(50%) subjects were in Group P; 25(50%) boys and 25(50%) girls with mean age 7.68±1.812 years. At baseline, 44(88%) patients in Group I and 42(84%) in Group P reported no pain, while 6(12%) and 8(16%) patients in the two groups, respectively, reported pain (p=0.56). At discharge, 35(70%) patients in Group I and 18(36%) in Group P reported no pain (p<0.001). Adverse events were not significantly different between the groups (p>0.05). CONCLUSIONS: I ntravenous ibuprofen was found to b e a superior pain-killer than intravenous paracetamol for perioperative care of paediatric patients in day- care tonsillectomy.

Cannabidiol as an Alternative Analgesic for Acute Dental Pain.

Odontogenic pain can be debilitating, and nonopioid analgesic options are limited. This randomized placebo-controlled clinical trial aimed to assess the effectiveness and safety of cannabidiol (CBD) as an analgesic for patients with emergency acute dental pain. Sixty-one patients with moderate to severe toothache were randomized into 3 groups: CBD10 (CBD 10 mg/kg), CBD20 (CBD 20 mg/kg), and placebo. We administered a single dose of respective oral solution and monitored the subjects for 3 h. The primary outcome measure was the numerical pain differences using a visual analog scale (VAS) from baseline within and among the groups. Secondary outcome measures included ordinal pain intensity differences, the onset of significant pain relief, maximum pain relief, changes in bite force within and among the groups, psychoactive effects, mood changes, and other adverse events. Both CBD groups resulted in significant VAS pain reduction compared to their baseline and the placebo group, with a maximum median VAS pain reduction of 73% from baseline pain at the 180-min time point (P < 0.05). CBD20 experienced a faster onset of significant pain relief than CBD10 (15 versus 30 min after drug administration), and both groups reached maximum pain relief at 180-min. Number needed to treat was 3.1 for CBD10 and 2.4 for CBD20. Intragroup comparisons showed a significant increase in bite forces in both CBD groups (P < 0.05) but not in the placebo group (P > 0.05). CBD20 resulted in a significant difference in mean percent bite force change in the 90- and 180-min time points compared to the placebo group (P < 0.05). Compared to placebo, sedation, diarrhea, and abdominal pain were significantly associated with the CBD groups (P < 0.05). There were no other significant psychoactive or mood change effects. This randomized trial provides the first clinical evidence that oral CBD can be an effective and safe analgesic for dental pain.

The association of intraoperative opioid dose with postanesthesia care unit outcomes in children: a retrospective study.

PURPOSE: In children, the relationship between the dose of intraoperative opioid and postoperative outcomes is unclear. We examined the relationship between intraoperative opioid dose and postanesthesia care unit (PACU) pain scores and opioid and antiemetic administrations. METHODS: We performed a single-institution retrospective cohort study. Patients who were aged < 19 yr, had an American Society of Anesthesiologists Physical Status of I-III, were undergoing one of 11 procedures under general anesthesia and without regional anesthesia, and who were admitted to the PACU were included. Patients were analyzed by quartiles of total intraoperative opioid dose using multivariable regression, adjusting for confounders including procedure. An exploratory analysis of opioid-free anesthetics was also performed. RESULTS: Three thousand, seven hundred and thirty-three cases were included, and the mean age of included patients was 8.3 yr. After adjustment, there were no significant differences between the lowest and higher quartiles for first conscious pain score, mean pain score, PACU opioid dose, or PACU length of stay; in addition, estimated differences were small. Patients in higher quartiles were estimated to be more likely to receive antiemetics, significantly so for those in the second quartile. Patients in the lowest quartile received significantly more intraoperative nonopioid analgesics. In the exploratory analysis, no significant difference in PACU pain scores was found in cases without intraoperative opioids. CONCLUSIONS: Children who received lower doses of intraoperative opioids did not have worse PACU pain outcomes but required fewer antiemetics and received greater numbers of nonopioid analgesics intraoperatively. These findings suggest that lower doses of intraoperative opioids may be administered to children as long as other analgesics are used.

RéSUMé: OBJECTIF: Chez les enfants, la relation entre la dose peropératoire d'opioïdes et les issues postopératoires n'est pas claire. Nous avons examiné la relation entre la dose peropératoire d'opioïdes, les scores de douleur en salle de réveil, et les administrations d'opioïdes et d'antiémétiques. MéTHODE: Nous avons réalisé une étude de cohorte rétrospective dans un seul établissement. Nous avons inclus les patient·es âgé·es < 19 ans ayant un statut physique ASA de I-III et bénéficiant de l'une de 11 interventions sous anesthésie générale et sans anesthésie régionale, et qui avaient été admis·es en salle de réveil. Les patient·es ont été analysé·es par quartiles de la dose totale d'opioïdes peropératoires en utilisant une régression multivariée, en ajustant les données pour tenir compte des facteurs de confusion, notamment de l'intervention. Une analyse exploratoire des anesthésiques sans opioïdes a également été réalisée. RéSULTATS: Au total 3733 cas ont été inclus, et l'âge moyen des enfants était de 8,3 ans. Après ajustement, il n'y avait pas de différences significatives entre les quartiles inférieur et supérieur pour le premier score de douleur chez l'enfant conscient·e, le score de douleur moyen, la dose d'opioïdes en salle de réveil ou la durée du séjour en salle de réveil; de plus, les différences estimées étaient faibles. On a estimé que les patient·es des quartiles supérieurs étaient plus susceptibles de recevoir des antiémétiques et ce, de manière significative pour ceux et celles du deuxième quartile. Les patient·es du quartile inférieur ont reçu significativement plus d'analgésiques non opioïdes peropératoires. Dans l'analyse exploratoire, aucune différence significative dans les scores de douleur en salle de réveil n'a été trouvée dans les cas sans opioïdes peropératoires. CONCLUSION: Les enfants qui ont reçu des doses plus faibles d'opioïdes peropératoires n'ont pas eu de pires issues de douleur en salle de réveil, mais ont eu besoin de moins d'antiémétiques et ont reçu un plus grand nombre d'analgésiques non opioïdes en peropératoire. Ces résultats suggèrent que des doses plus faibles d'opioïdes peropératoires peuvent être administrées aux enfants tant que d'autres analgésiques sont utilisés.

Nonopioid Versus Opioid Analgesics After Thyroid and Parathyroid Surgery: A Systematic Review.

OBJECTIVE: To determine whether nonopioid analgesic regimens, taken after discharge for thyroid and parathyroid surgery have noninferior pain outcomes in comparison to opioid analgesic regimens. Secondarily, we sought to determine if nonopioid analgesic regimens decrease the number of opioid medications taken after thyroid and parathyroid surgery, and to assess adverse events associated with opioid versus nonopioid regimens. DATA SOURCES: PubMed, Embase, Cochrane. REVIEW METHODS: A comprehensive search of the literature was performed according to the PRISMA guidelines, and identified 1299 nonduplicate articles for initial review of which 2 randomized controlled trials (RCTs) were identified as meeting all eligibility criteria. Meta-analysis was not conducted due to heterogeneity in the data and statistical analyses. RESULTS: Both RCTs included in this systematic review found no significant differences in postoperative pain scores between individuals discharged with a nonopioid only analgesic regimen compared to analgesic regimen that included oral opioid medications. One study reported significantly increased number of postoperative calls related specifically to pain in the nonopioid arm compared to the opioid arm (15.6% vs. 3.2%, P = .045). CONCLUSION: This systematic review of RCTs revealed a limited number of studies examining nonopioid versus opioid postoperative pain medications among adults who undergo thyroid and parathyroid surgery. Among the 2 RCTs on this topic, there is a shared finding that nonopioid analgesic regimens are noninferior to opioid analgesic regimens in managing postoperative pain after thyroid and parathyroid surgery, supporting the use of nonopioid pain regimens given the risk of opioid dependence associated with prescription opioid medications.

The Opioid Analgesic Reduction Study (OARS) Pilot: A Double-Blind Randomized Multicenter Trial.

BACKGROUND: With addiction rates and opioid deaths increasing, health care providers are obligated to help stem the opioid crisis. As limited studies examine the comparative effectiveness of fixed-dose combination nonopioid analgesia to opioid-containing analgesia, a comparative effectiveness study was planned and refined by conducting a pilot study. METHODS: The Opioid Analgesic Reduction Study (OARS) pilot, a stratified, randomized, multisite, double-blind clinical trial, was designed to test technology and procedures to be used in the full OARS trial. Participants engaged in the full protocol, enabling the collection of OARS outcome data. Eligible participants reporting to 1 of 5 sites for partial or full bony impacted mandibular third molar extraction were stratified by biologic sex and randomized to 1 of 2 treatment groups, OPIOID or NONOPIOID. OPIOID participants were provided 20 doses of hydrocodone 5 mg/acetaminophen 300 mg. NONOPIOID participants were provided 20 doses of ibuprofen 400 mg/acetaminophen 500 mg. OARS outcomes data, including pain experience, adverse effects, sleep quality, pain interference, overall satisfaction, and remaining opioid tablets available for diversion, were collected via surveys, electronic medication bottles, eDiary, and activity/sleep monitor. RESULTS: Fifty-three participants were randomized with 50 completing the OARS pilot protocol. Across all outcome pain domains, in all but 1 time period, NONOPIOID was better in managing pain than OPIOID (P < 0.05 level). Other outcomes suggest less pain interference, less adverse events, better sleep quality, better overall satisfaction, and fewer opioid-containing tablets available for diversion. DISCUSSION: Results suggest patients requiring impacted mandibular third molar extraction would benefit from fixed-dose combination nonopioid analgesia. KNOWLEDGE TRANSFER STATEMENT: Study results suggest fixed-dose nonopioid combination ibuprofen 400 mg/acetaminophen 500 mg is superior to opioid-containing analgesic (hydrocodone 5 mg/acetaminophen 500 mg). This knowledge should inform surgeons and patients in the selection of postsurgical analgesia.

Paracetamol (acetaminophen) poisoning: The early years.

Paracetamol (acetaminophen) was marketed in the 1950s as a nonprescription analgesic/antipyretic without any preclinical toxicity studies. It became used increasingly for self-poisoning, particularly in the UK and was belatedly found to cause acute liver damage, which could be fatal. Management of poisoned patients was difficult as maximum abnormalities of liver function were delayed for 3 days or more after an overdose. There was no treatment and the mechanism of hepatotoxicity was not known. The paracetamol half-life was prolonged with liver damage occurring when it exceeded 4 h and the Rumack-Matthew nomogram was an important advance that allowed stratification of patients into separate zones of risk. It is used to guide prognosis and treatment and its predictive value could be increased by combining it with the paracetamol half-life. The problems of a sheep farmer in Australia in the early 1970s led to the discovery of the mechanism of paracetamol hepatotoxicity, and the first effective treatment of overdosage with intravenous (IV) cysteamine. This had unpleasant side effects and administration was difficult. N-acetylcysteine soon became the treatment of choice for paracetamol overdose and given early it was very effective when administered either IV or orally. N-acetylcysteine could cause anaphylactoid reactions, particularly early during IV administration when the concentrations were highest. Simpler and shorter regimes with slower initial rates of infusion have now been introduced with a reduced incidence of these adverse effects. In addition, there has been a move to use larger doses of N-acetylcysteine given over longer periods for patients who are more severely poisoned and those with risk factors. There has been much interest recently in the search for novel biomarkers such as microRNAs, procalcitonin and cyclophilin that promise to have greater specificity and sensitivity than transaminases. Paracetamol-protein adducts predict hepatotoxicity and are specific biomarkers of toxic paracetamol metabolite exposure. Another approach would be measurement of the plasma levels of cysteine and inorganic sulfate. It is 50 years since the first effective treatment for paracetamol poisoning and, apart from liver transplantation, there is still no effective treatment for patients who present late.