Analgesia to acidosis: metabolic acidosis due to chronic acetaminophen (paracetamol) use.

This case describes a rare occurrence of high anion gap metabolic acidosis due to chronic acetaminophen (paracetamol) usage, which can be confirmed by measuring 5-oxoproline (pyroglutamate), an organic acid metabolite. As acetaminophen is an extremely common drug prescribed in both inpatient and outpatient settings, a high degree of clinical suspicion is required to isolate it as the aetiology for metabolic acidosis. Management includes discontinuation of acetaminophen use and at times the supplementation of oral bicarbonate. Metabolic acidosis due to a high anion gap is commonly described by the mnemonic 'MUDPILES' in daily practice. A newer mnemonic, 'GOLD MARK' is proposed to be a more inclusive tool to assist in determining the cause of high anion gap metabolic acidosis, especially with such cases being reported.

Acute liver failure.

ABSTRACT: Acute liver failure, commonly caused by acetaminophen overdose, is associated with numerous systemic complications including cerebral edema, hypotension, acute kidney injury, and infection. Management is primarily supportive, with an emphasis on excellent neurocritical care. Although some antidotes and targeted treatments exist, the only definitive treatment remains orthotopic liver transplant.

Clinical validation of a fast-acting acetaminophen: a randomized, active and placebo controlled dental pain study.

OBJECTIVES: To address the need for faster pain relief of over-the-counter (OTC) analgesic users, a novel drug delivery technology was developed to achieve faster absorption of orally administered acetaminophen with the goal of delivering earlier onset of pain relief. Previous development studies suggested that a 1000 mg dose of this fast-acting acetaminophen (FA-acetaminophen) formulation provided faster absorption and onset of action versus, commercially available OTC fast-acting analgesics, 1000 mg of extra-strength acetaminophen (ES-acetaminophen) or 400 mg of liquid-filled ibuprofen capsules (LG-ibuprofen). This study was designed as the definitive trial evaluating the onset of pain relief of FA-acetaminophen versus these same OTC comparators. METHODS: This single-dose, randomized, double-blind, placebo- and active-controlled clinical trial compared analgesic onset, overall efficacy, and safety of FA-acetaminophen 1000 mg, ES-acetaminophen 1000 mg, LG-ibuprofen 400 mg, and placebo over 4 h in a postsurgical dental pain model. Following removal of 3 to 4 impacted third molars, 664 subjects with moderate-to-severe pain were randomized in a 4:4:2:1 ratio to FA-acetaminophen (249), ES-acetaminophen (232), LG-ibuprofen (124), or placebo (59). Mean age was 18.9 years; 45.5% were male; 57.5% had severe baseline pain intensity. Subjects stopped a first stopwatch if/when they had perceptible pain relief and a second stopwatch if/when their pain relief became meaningful to them. Pain intensity difference (PID) and pain relief (PAR) were obtained using an 11-point numerical rating scale. FINDINGS: FA-acetaminophen 1000 mg had faster median time to onset of pain relief (15.7 min) compared to ES-acetaminophen 1000 mg (20.2 min, p = 0.035), LG-ibuprofen 400 mg (23.2 min, p < 0.001), and placebo (non-estimable), statistically greater mean PAR and PID scores than other treatment groups at 15 and 30 min, and a statistically greater percentage of subjects with confirmed perceptible pain relief at 15 and 20 min. At 25 min, FA-acetaminophen 1000 mg had a statistically significantly greater percentage of subjects with confirmed perceptible pain relief than LG-ibuprofen 400 mg and placebo. No clinically significant adverse events were reported. CONCLUSIONS: This study supports previous studies, demonstrating faster onset of analgesia with FA-acetaminophen 1000 mg compared to OTC ES-acetaminophen 1000 mg and OTC LG-ibuprofen 400 mg. CLINICALTRIALS.GOV IDENTIFIER: NCT03224403 https://clinicaltrials.gov/ct2/show/NCT03224403.

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.

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.

Paracetamol versus ibuprofen in treating episodic tension-type headache: a systematic review and network meta-analysis.

Tension-type headache (TTH) is the most common type of headache worldwide. It is defined and classified according to the International Classification of Headache Disorders. TTH is treated with over-the-counter medications, mostly paracetamol or ibuprofen. The purpose was to assess the effectiveness of paracetamol versus ibuprofen in treating episodic tension-type headache (ETTH) through direct and indirect comparisons of randomized controlled trials (RCTs). We included RCTs comparing paracetamol with a placebo, ibuprofen with a placebo, or paracetamol with ibuprofen for acute ETTH treatment that were published between 1988 and 2022. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and the Web of Science. The Cochrane Collaboration risk of bias tool was used to assess the risk of bias. We identified 14 studies including 6521 people with ETTH. None of the studies had a low risk of bias for all domains; this was most likely due to inadequate reporting and a small sample size. Ibuprofen (odds ratio (OR): 1.73, 95% confidence interval (CI): 1.17-2.56) showed better efficacy than paracetamol (OR: 1.62, 95% CI 1.24-2.13) for pain-free status at 2 h, while paracetamol (OR: 1.42, 95% CI 0.87-2.30) showed better efficacy than ibuprofen (OR: 1.20, 95% CI 0.58-2.48) for pain-free status at 1 h. Paracetamol was associated with the lowest likelihood of rescue medication use (OR: 0.49, 95% CI 0.37-0.65). Ibuprofen was associated with a lower likelihood of the occurrence of any events and gastrointestinal adverse events compared with placebo and paracetamol (OR: 0.95, 95% CI 0.64-1.41 and OR: 0.81, 95% CI 0.44-1.50, respectively). Paracetamol and ibuprofen showed better efficacy than placebo in treating ETTH; there was no statistically significant difference in efficacy between the two drugs. For individuals at a higher risk (like renal insufficiency or risk of GI bleeding), paracetamol may be considered as a preferred option instead of Ibuprofen. Further meta-analyses of head-to-head trials are needed for direct comparisons in the future.PROSPERO registration number: CRD42022340936.

Effect of infusion time of intravenous acetaminophen on blood pressure in the intensive care unit.

OBJECTIVE: To understand the effect of prolonged intravenous acetaminophen infusion on blood pressure. MATERIALS AND METHODS: We retrospectively studied a cohort of intensive care patients receiving initial intravenous acetaminophen. We used propensity score matching to adjust for differences between patients who were classified into two groups: control (acetaminophen infusion for 15 minutes) and prolonged administration (acetaminophen infusion for > 15 minutes). RESULTS: After acetaminophen administration, diastolic blood pressure was unchanged in the control group, and was significantly lower at 30 and 60 minutes in the prolonged administration group. CONCLUSION: Prolonged duration of acetaminophen infusion did not prevent acetaminophen-induced blood pressure reduction.

Over the Counter Pain Medications Used by Adults: A Need for Pharmacist Intervention.

BACKGROUND: The safety of pharmacotherapy for geriatric patients is an essential aspect of the demographic perspective in view of the increasing size of this population. Non-opioid analgesics (NOAs) are among the most popular and often overused over-the-counter medications (OTC). The reasons for drug abuse are common in the geriatric population: musculoskeletal disorders, colds, inflammation and pain of various origins. The popularity of self-medication and the ability to easily access OTC drugs outside the pharmacy creates the danger of their misuse and the incidence of adverse drug reactions (ADRs). The survey included 142 respondents aged 50-90 years. The relationship between the prevalence of ADRs and the NOAs used, age, presence of chronic diseases, and place of purchasing and obtaining information about the mentioned drugs were evaluated. The results of the observations were statistically analyzed using Statistica 13.3. The most commonly used NOAs among the elderly included paracetamol, acetylsalicylic acid (ASA) and ibuprofen. Patients consumed the medications for intractable headaches, toothaches, fevers, colds and joint disorders. Respondents indicated the pharmacy as the main location for purchasing medications, and the physician as the source of information for selecting the therapy. ADRs were reported most frequently to the physician, and less frequently to the pharmacist and nurse. More than one-third of respondents indicated that the physician during the consultation did not take a medical history and did not ask about concomitant diseases. It is necessary to extend pharmaceutical care to geriatric patients that includes advice on adverse drug reactions, especially drug interactions. Due to the popularity of self-medication, and the availability of NOAs, long-term measures should be taken to increase the role of pharmacists in providing effective, safe health care to seniors. We are targeting pharmacists with this survey to draw attention to the problem of the prevalence of selling NOAs to geriatric patients. Pharmacists should educate seniors about the possibility of ADRs and approach patients with polypragmasy and polypharmacy with caution. Pharmaceutical care is an essential aspect in the treatment of geriatric patients, which can contribute to better results in their existing treatment and increase the safety of medication intake. Therefore, it is important to improve the development of pharmaceutical care in Poland in order to enhance patient outcomes.

Adverse drugs reactions to paracetamol and ibuprofen in children: a 5-year report from a pediatric poison control center in Italy.

BACKGROUND: This study aimed to analyze all the patients who contacted the hospital's pediatric poison control center (PPCC) for exposure to ibuprofen and acetaminophen, in order to assess the incidence of any adverse reactions. METHODS: We retrospectively reported the clinical data of children who accessed the PPCC of the Bambino Gesù Children's Hospital, IRCCS, Rome, from January 1, 2018 to September 30, 2022 due to wrong, accidental or intentional intake of inappropriate doses of acetaminophen and/or ibuprofen. In addition, we compared patients according to the intake of one of the two drugs and reported the trimestral distribution of cases during the study period. RESULTS: A total of 351 patients accessed the PPCC during the study period. The median age was 3.0 years. Most patients were females (57.8%). The most common reason for inappropriate oral intake of paracetamol or ibuprofen was a wrong use or an accidental intake (78.6%), with a fifth of patients taking the drug with suicidal intent (21.1%). According to the PPCC evaluation, most patients were not intoxicated (70.4%). Hospitalization was required for 30.5% of patients. Adverse reactions were reported in 10.5% of cases, with a similar incidence in patients who took paracetamol or ibuprofen. Nausea and vomiting were the most commonly reported adverse reactions. A higher frequency of moderate intoxication was found in patients who took paracetamol compared to ibuprofen (p = 0.001). The likelihood of intoxication was also higher in the paracetamol cohort. A spike of cases was registered at the end of 2021. CONCLUSIONS: We analyze exposures to the two most commonly used pediatric molecules, paracetamol and ibuprofen, to assess the frequency of adverse reactions. We demonstrated that these relatively "safe" drugs may be associated with intoxications and adverse reactions when inappropriately administered.

Opioid sparing effects of intravenous and oral acetaminophen in hip fracture patients: A population-based study.

STUDY OBJECTIVE: Acetaminophen (APAP) and intravenous acetaminophen (IVAPAP) has been proposed as a part of many opioid-sparing multimodal analgesic pathways. The aim of this analysis was to compare the effectiveness of IVAPAP with oral APAP on opioid utilization and opioid-related adverse effects. DESIGN: Retrospective study of population-based database. PATIENTS: The Premier Healthcare database was queried patients undergoing surgery for a primary diagnosis of hip fracture from 2011 to 2019 yielding 245,976 patients. Primary exposure was use of IVAPAP or oral APAP on the day of surgery. INTERVENTIONS: None. MEASUREMENTS: The primary outcome of interest was opioid utilization over the hospital stay, secondary outcomes included opioid-related adverse effects, length, and costs of hospital stay. Mixed effect models measured the association of IVPAP and APAP and outcomes. MAIN RESULTS: In the study population 30.67% (75,445) received at least 1 dose of IVAPAP on the day of surgery. Upon adjusting for relevant covariates, patients who received IVPAP on the day of surgery had slightly higher opioid use standardized by length of hospital stay (2.8% CI: 2%, 3.6%; p < .001), higher hospital cost (2.7% CI: 2.1%, 3.4%), and higher odds of naloxone use (1.18, CI: 1.1, 1.27; p < .001) when compared with patients who received oral APAP. CONCLUSIONS: In this population, IVAPAP use on the day of surgery failed to reduce opioid use or associated opioid related adverse effects when compared with oral APAP. IVAPAP was associated with increased overall costs, opioid requirements, and naloxone use. These results do not support the use of IV over oral APAP routinely for hip fracture surgery patients.

Effect of Standing Intravenous Acetaminophen on Postoperative Opioid Exposure in a Pediatric Cardiac Intensive Care Unit.

This study assessed the association between standing intravenous acetaminophen and opioid exposure after cardiac surgery. Before vs after implementation of a standardized pain pathway, we report decreased opioid exposure, 0.38 milligram per kilogram of morphine equivalents [IQR 0.10-0.81] vs 0.26 milligram per kilogram of morphine equivalents [0.09-0.56] (P = .01) and increased acetaminophen exposure, 3 [2-4] vs 4 [4-5] doses (P < .001).

Decision tree algorithm can determine the outcome of repeated supratherapeutic ingestion (RSTI) exposure to acetaminophen: review of 4500 national poison data system cases.

This study is aimed at establishing the outcome of RSTI exposure to acetaminophen based on a decision tree algorithm for the first time. This study used the National Poison Data System (NPDS) to conduct a six-year retrospective cohort analysis, which included 4522 individuals. The patients had a mean age of 26.75 ± 16.3 years (1-89). 3160 patients (70%) were females. Most patients had intentional exposure to acetaminophen. Almost all the patients had acetaminophen exposure via ingestion. In addition, 400 (8.8%) experienced major outcomes, 1500 (33.2%) experienced moderate outcomes, and 2622 (58%) of the patients experienced mild ones. The decision tree model performed well in the training and test groups. In the test group, the accuracy was 0.813, precision of 0.827, recall being 0.798, specificity 0.898, and an F1 score 0.80. In the training group, accuracy was 0.831, recall was 0.825, precision was 0.837, specificity was 0.90, and F1 score was 0.829. Our results showed that serum liver enzymes being present at elevated levels (Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) greater than 1000 U/L followed by ALT, AST between 100 and 1000 U/L), prothrombin time (PT) prolongation, bilirubin increase, renal failure, confusion, age, hypotension, other coagulopathy (such as partial thromboplastin time (PTT) prolongation), acidosis, and electrolyte abnormality were the effective factors in determining the outcomes in these patients. The decision tree algorithm is a dependable method for establishing the prognosis of patients who have been exposed to RSTI acetaminophen and can be used throughout the patients' hospitalization period.