Efficacy of Paracetamol in Addition to Morphine to Improve Analgesia in the Emergency Department (ParaMoED)

Efficacy of Paracetamol in Addition to Morphine to Improve Analgesia in the Emergency Department: a Multicenter, Randomized, Double-blind, Placebo-controlled Trial

The purpose of this study is to test the additional effect of paracetamol in combination with morphine for analgesia, respectively to test/confirm an opioid sparing effect due to the additional use of Paracetamol, as well as the reduction of adverse drug reactions of morphine.

Study Overview

• Status: Completed
• Conditions: Analgesia
• Intervention / Treatment: Drug: Paracetamol; Drug: Morphine; Drug: Placebo

Detailed Description

Paracetamol (acetaminophen) is widely used around the world for mild to moderate pain in all age groups. Prescription at the emergency department is very common and some studies suggest the use in alternative of Morphine, at least in the renal colic.

Morphine has also a complex analgesic effect due to inhibition of µ Receptors in the central nervous system and in the dorsal horn of the spinal cord. Morphine (like other opioids) is accepted as a cornerstone of acute pain management in the emergency department. However, occurrence of adverse drug reactions is up to 25%, mainly nausea and drowsiness.

The use of paracetamol in addition to morphine showed in a meta-analysis in the post-operative setting an opioid sparing effect of 20% over the first postoperative 24 hours, but did not change the incidence of morphine-related adverse effects in the postoperative period. An additive effect was showed of the two medicaments in another Study measuring the median effective analgesic dose (ED50).

The purpose of this study is to test the additional effect of paracetamol in combination with morphine for analgesia, respectively to test/confirm an opioid sparing effect due to the additional use of Paracetamol, as well as the to reduction of adverse drug reactions of morphine.

The study is a multicenter, randomized, double-blind, placebo-controlled. We randomize patients with pain-score >=4 on a pain Scala of 0-10 Points (numeric rating scale) in two group, one with paracetamol, one with placebo to investigate the (additive) effect of paracetamol in combination with morphine. The treatment team and the patients will be blinded to the administration. The study design is outlined to confirm the result of previous studies who stated a 20% reduction of morphine doses when combined with paracetamol. Study duration for each patient would be 240 min.

• Study Type: Interventional
• Enrollment (Actual): 222
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Sankt Gallen, Switzerland, 9007
    • Kantonsspital St.Gallen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with pain with Pain-score is more or equal than four in a numeric rating scale from zero to ten (i.e. indication for a treatment with morphine)
• Age over 18
• Signed informed consent. In case, patient is not able to sign the informed consent due to pain, at least verbal consent has to be provided. After pain relief, written informed consent with data and time has to be obtained

Exclusion Criteria:

• Analgesia in the past last 6 hours prior to visit at the emergency department
• Current Analgesia with long-acting/extended-release drugs
• Current Analgesia with opioids
• Chronic pain syndrome
• Contraindication for either paracetamol or morphine
• Patient's refusal of paracetamol or morphine treatment
• Pregnancy or Breastfeeding
• GCS < 13
• SpO2 < 90% with a maximum of 4 L/Min O2
• Systolic Blood Pressure < 90 mmHg
• "Fast Track"/Notfallpraxis patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Paracetamol; Paracetamol 1 g (100 mL) IV + Morphine 0.1 mg/kg IV (repeatable in Doses of 0.05 mg/kg), 100 patients over 4 hours	Drug: Paracetamol; s. above; Other Names: Paracetamol Sintetica; Drug: Morphine; s. above; Other Names: Morphine Sintetica
PLACEBO_COMPARATOR: Placebo; Placebo (NaCl 0.9% 100 mL IV) + Morphine 0.1 mg/kg IV (repeatable in Doses of 0.05 mg/kg), 100 patients over 4 hours	Drug: Morphine; s. above; Other Names: Morphine Sintetica; Drug: Placebo; s. above; Other Names: NaCl 0.9%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assessment of the total dose of morphine till pain < 4 on the NRS (0-10) after the first infusion of paracetamol or placebo.	up to 4 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
Assessment of time interval of pain < 4 on the NRS (after been achieved)	up to 4 hours
Total dose of morphine within the first 4 hours after the first infusion of paracetamol or Placebo.	up to 4 hours
Prevalence of morphine adverse reactions within the first 4 hours after infusion of paracetamol or placebo	up to 4 hours, respectively in case of serious adverse events up to recovery time of the patient

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Dose of Morphine based on adverse events	A maximal Dose of opioids has been defined in our daily practice and in several guidelines with a precise number (e.g. 20 mg/4 h). In this trial we will use instead a maximal Dose defined with clinical criteria (GCS < 13, SpO2 < 90% with 4 L/min O2, uncontrolled vomiting). Assessment intended as occurrence of adverse events of the application of a such algorithms will be outcome of interest (not a secondary outcome because absence of a control group)	up to 4 hours

Collaborators and Investigators

• Sponsor: Bruno Minotti

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 2, 2019
• Primary Completion (ACTUAL): October 15, 2020
• Study Completion (ACTUAL): October 15, 2020

Study Registration Dates

• First Submitted: February 14, 2019
• First Submitted That Met QC Criteria: February 14, 2019
• First Posted (ACTUAL): February 18, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 19, 2020
• Last Update Submitted That Met QC Criteria: October 15, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Morphine; Paracetamol
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Emergencies; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Analgesics, Opioid; Narcotics; Acetaminophen; Morphine
• Other Study ID Numbers: CTU17.014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No