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Acetaminophen (APAP) in humans has robust effects with a high therapeutic index in altering postoperative and inflammatory pain states in clinical and experimental pain paradigms with no known abuse potential. This review considers the literature reflecting the preclinical actions of acetaminophen in a variety of pain models. Significant observations arising from this review are as follows: 1) acetaminophen has little effect upon acute nociceptive thresholds; 2) acetaminophen robustly reduces facilitated states as generated by mechanical and thermal hyperalgesic end points in mouse and rat models of carrageenan and complete Freund's adjuvant evoked inflammation; 3) an antihyperalgesic effect is observed in models of facilitated processing with minimal inflammation (eg, phase II intraplantar formalin); and 4) potent anti-hyperpathic effects on the thermal hyperalgesia, mechanical and cold allodynia, allodynic thresholds in rat and mouse models of polyneuropathy and mononeuropathies and bone cancer pain. These results reflect a surprisingly robust drug effect upon a variety of facilitated states that clearly translate into a wide range of efficacy in preclinical models and to important end points in human therapy. The specific systems upon which acetaminophen may act based on targeted delivery suggest both a spinal and a supraspinal action. Review of current targets for this molecule excludes a role of cyclooxygenase inhibitor but includes effects that may be mediated through metabolites acting on the TRPV1 channel, or by effect upon cannabinoid and serotonin signaling. These findings suggest that the mode of action of acetaminophen, a drug with a long therapeutic history of utilization, has surprisingly robust effects on a variety of pain states in clinical patients and in preclinical models with a good therapeutic index, but in spite of its extensive use, its mechanisms of action are yet poorly understood.

Abstract licence: CC BY-NC

Objectives . The aim of this study was to determine the effectiveness of preoperative administration of single-dose of paracetamol-codeine, in the relieving of acute postoperative pain after the surgical removal of an impacted mandibular third molar. Materials and Methods . The study cohort consisted of 32 Caucasian outpatients, giving a total of 64 bilateral symmetrical impacted mandibles. Patients were randomized in two experimental groups to receive a preoperative oral dose of paracetamol-codeine (analgesic group) or a placebo (placebo group) at the first and second surgeries. Study participants were asked to record pain intensity scores during the operation and the next 2 days, the time of the first request for rescue analgesic, and the total number of postoperative-supplement paracetamol-codeine tablets. Results . The pain intensity score on the first day was significantly lower in the analgesic group than in the placebo group <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mo stretchy="false">(</mml:mo><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn fontstyle="italic">0.001</mml:mn><mml:mo stretchy="false">)</mml:mo></mml:math>. The time to using rescue therapy was significantly longer in the analgesic group than in the placebo group <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mo stretchy="false">(</mml:mo><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle="italic">0.004</mml:mn><mml:mo stretchy="false">)</mml:mo></mml:math>. The number of paracetamol-codeine tablets used postoperatively did not differ between the analgesic and placebo groups <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mo stretchy="false">(</mml:mo><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle="italic">0.104</mml:mn><mml:mo stretchy="false">)</mml:mo></mml:math>. Conclusions . Preoperative paracetamol-codeine is effective in providing immediate postoperative pain control after third molar surgery and in delaying the initial onset of pain. This trial is registered with ClinicalTrials.gov Identifier (Registration Number): NCT03049878 .

Abstract licence: CC BY

Two different multivariate techniques have been applied for the quantitative analysis of caffeine, codeine, paracetamol and p-aminophenol (PAP) in quaternary mixture, namely, Partial Least Squares (PLS-1) and Artificial Neural Networks (ANN). For suitable analysis, a calibration set of 25 mixtures with various ratios of the drugs and PAP impurity were established using a 4-factor 5-level experimental design. The most meaningful wavelengths for the chemometric models were chosen using Genetic Algorithm (GA) as a variable selection technique. By using an independent validation set, the validity of the proposed methods was evaluated. A comparative study was established between the three multivariate models (PLS-1, GA-PLS and GA-ANN). The comparison between the various models revealed that the GA-ANN model was superior at resolving the highly overlapped spectra of this quaternary combination. The drugs were successfully quantified in their pharmaceutical dosage form utilizing the GA-ANN models.

Abstract licence: CC BY