{
  "abstract": "Introduction The analgesic and antipyretic paracetamol (acetaminophen) is generally considered safe in therapeutic doses. The most important toxic effect is hepatotoxicity after supratherapeutic doses or in the presence of risk factors (eg, malnutrition, alcoholism). According to the WHO analgesic ladder, a combination of a non-opioid analgesic such as paracetamol with a strong opioid is recommended as step III treatment of patients with chronic pain, despite limited evidence for this approach. The main aim of this study is to test the hypothesis that paracetamol does not provide clinically relevant benefits when added to strong opioids in patients with chronic pain.Methods and analysis Investigator-initiated, randomised, double-blind, placebo-controlled, non-inferiority trial at two Swiss hospitals. A total of 140 patients with chronic pain requiring strong opioids and paracetamol ≥1.5 g/day for at least 7 days will be enrolled and randomised to either continued combination treatment or strong opioid plus placebo. In the first study phase (days 1–7), patients receive identically looking capsules containing either paracetamol at the exact dose previously used or a placebo. During a second study phase (days 7–14), all patients stop the blinded study medication (paracetamol and placebo) with follow-up to day 14. Adherence will be assessed by pill count and measurement of paracetamol and opioid serum concentrations. Patients are instructed to use a pain diary daily during the whole study. The primary outcome is the average pain score on day 7 using a 10 cm visual analogue scale (VAS). A difference between groups of ≤8 mm will be considered clinically irrelevant. Secondary outcomes will include VAS pain score on day 14, number of opioid rescue doses used, subjective ratings of overall feeling of well-being, quality of life, nausea/vomiting, drowsiness and constipation, and other adverse events, and potential effects of study drug concentrations and opioid receptor and cytochrome P450 (CYP) genotypes on the observed differences.Ethics and dissemination The study was approved by the Ethics Committee (Ethikkommission Bern, reference number 2021-01518) and the Swiss Agency for Therapeutic Products (Swissmedic, reference number 701286). Results will be published in open-access policy peer-reviewed journals. The study is funded by the Swiss National Science Foundation (grant number 32 003B_201072).Trial registration number NCT05088876.",
  "authors": [
    {
      "affiliations": [
        "Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland",
        "Graduate School for Health Sciences, University of Bern, Bern, Switzerland"
      ],
      "name": "Christina Kotoula"
    },
    {
      "affiliations": [
        "Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland",
        "Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland"
      ],
      "name": "Maria M Wertli"
    },
    {
      "affiliations": [
        "Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"
      ],
      "name": "Konrad Streitberger"
    },
    {
      "affiliations": [
        "Center of Oncology/Hematology, Cantonal Hospital Baden, Baden, Switzerland",
        "Medical Faculty, University of Basel, Basel, Switzerland"
      ],
      "name": "Sacha I Rothschild"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland",
        "Functioning Information Reference Lab, Swiss Paraplegic Research, Nottwil, Switzerland"
      ],
      "name": "Andreas Limacher"
    },
    {
      "affiliations": [
        "Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"
      ],
      "name": "Felix Hammann"
    },
    {
      "affiliations": [
        "Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Stephan Krähenbühl"
    },
    {
      "affiliations": [
        "Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"
      ],
      "name": "Manuel Haschke"
    },
    {
      "affiliations": [
        "Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland"
      ],
      "name": "Evangelia Liakoni"
    }
  ],
  "title": "Efficacy of paracetamol added to WHO step III opioids in chronic pain control: study protocol for a randomised, double-blind, placebo-controlled, non-inferiority, multicentre study in Switzerland",
  "uid": "a5460bd0-ae93-58a4-987e-750f5e20e1c3"
}