Paracetamol in Addition to WHO Step III Opioids in Chronic Cancer Pain Control (ParOP)

Paracetamol in Addition to WHO Step III Opioids in Chronic Cancer Pain Control - a Randomized, Double-blind, Placebo-controlled, Non-inferiority Study

Blinded withdrawal of regular co-medication with paracetamol in chronic pain patients under strong opioids on pain control.

Study Overview

• Status: Terminated
• Conditions: Pain
• Intervention / Treatment: Drug: Paracetamol; Drug: Placebo

Detailed Description

Chronic pain patients receiving a strong opioid in combination with paracetamol in a minimum dose of 1.5 g/day will be randomized to receive either paracetamol in the dose already prescribed (group "paracetamol") or an identically looking placebo (group "placebo") using the same schedule during the first study phase (days 1-7). In the second study phase (days 8-14) paracetamol or placebo will be stopped in both arms to assess the effect of pill withdrawal on pain control.

Next to baseline the patients will be instructed to use a pain diary to rate their pain during the study and also document the required opioid rescue doses. Further assessments will include adverse events, subjective ratings of quality of sleep, overall feeling of functioning and quality of life. At the screening visit, patients will also be asked to rate their expected changes in pain relief as a result of co-treatment with paracetamol. At the completion of the study, patients will be asked about their preference and whether, overall, they felt their pain was more poorly controlled during the study.

Adherence will be checked by pill count and measurement of paracetamol blood concentrations. Genotyping of OPRM1, COMT and relevant CYP enzymes and opioid blood concentrations will be assessed as co-variates for pain control.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Baden, Switzerland
    • Kantonsspital Baden
  • Bern, Switzerland
    • Inselspital, Bern University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female patients receiving a WHO step III opioid (i.e. morphine, oxycodone, methadone, fentanyl, hydromorphone, or buprenorphine) in combination with paracetamol (minimum dose 1.5 g/day)
• Age ≥ 18 at screening
• Ability to understand the study procedures and to provide written informed consent
• Stable analgesia before randomisation, defined as no required changes in the analgesic treatment during the previous 7 days

Exclusion Criteria:

• Participation in another interventional trial within 30 days prior to randomisation, with the exception of cancer treatment trials
• Changes of the dosage or start of other (co-)analgesics (e.g. tricyclic antidepressants, neuroleptics, nonsteroidal anti-inflammatory drugs (NSAIDs), dipyrone), within the last 7 days preceding randomisation
• Surgery within the 14 days preceding randomisation or surgery planned within the duration of the study
• Any circumstances, comorbidities or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Blinded withdrawal of regular co-medication with paracetamol
Active Comparator: Paracetamol	Drug: Paracetamol; Paracetamol in the dose already used

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
VAS score (average pain intensity)	Study day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients' expectation regarding pain relief from paracetamol prior to study treatment paracetamol using the Expectation for Treatment Scale (ETS)	Five-item ETS with each item rated on a 4-point scale ranging from 1 to 4 (partially disagree, partially agree, agree and definitely agree)	Prior to study treatment
Average pain using the Brief Pain Inventory (BPI)		On each study day, up to 14 days
Minimum pain using the Brief Pain Inventory (BPI)		On each study day, up to 14 days
Worst pain using the Brief Pain Inventory (BPI)		On each study day, up to 14 days
Current pain using the Brief Pain Inventory (BPI)		On each study day, up to 14 days
Average pain using the Brief Pain Inventory (BPI)		During the last four days of each study phase (days 4-7 und 11-14)
Minimum pain using the Brief Pain Inventory (BPI)		During the last four days of each study phase(days 4-7 und 11-14)
Worst pain using the Brief Pain Inventory (BPI)		During the last four days of each study phase (days 4-7 und 11-14)
Current pain using the Brief Pain Inventory (BPI)		During the last four days of each study phase (days 4-7 und 11-14)
Cumulative dose of rescue medication used		On each study day, up to 14 days
Cumulative dose of rescue medication used		During the last four days of each study phase (days 4-7 und 11-14)
Number of rescue medication used		On each study day, up to 14 days
Number of rescue medication used		During the last four days of each study phase (days 4-7 und 11-14)
Percentage increase in pain compared to baseline		During each study phase (days 1-7 and days 8-14)
Percentage of patients meeting the predefined pain threshold		During each study phase (days 1-7 and days 8-14)
Subjective ratings of quality of sleep using the Brief Pain Inventory (BPI)		At baseline and during each study phase (days 1-7 and days 8-14)
Subjective ratings of quality of life using the EQ-5D-5L questionnaire		At baseline and during each study phase (days 1-7 and days 8-14)
Subjective ratings of functioning using the Brief Pain Inventory (BPI) and the EQ-5D-5L questionnaire		At baseline and during each study phase (days 1-7 and days 8-14)
Question about participant's preference	Study vs. baseline	At day 7 and 14
Participant's impression of change	11-point scale tool between -5 ="very much worse" and +5 ="completely recovered"	At day 7 and 14
Participants' guess regarding their assigned group (verum or placebo)		At day 7 and 14
Assessment of serious adverse events		During each study phase (days 1-7 and days 8-14)
Assessment of specific adverse events: nausea/vomiting		During each study phase (days 1-7 and days 8-14)
Assessment of specific adverse events: appetite		During each study phase (days 1-7 and days 8-14)
Assessment of specific adverse events: constipation		During each study phase (days 1-7 and days 8-14)
Assessment of other adverse events		During each study phase (days 1-7 and days 8-14)
Number of withdrawals from study or treatment		During each study phase (days 1-7 and days 8-14)
Time (days) of stable pain control		During whole study (days 1-14)
Patients' potential to develop hepatotoxicity (investigation of risk factors)		During whole study (days 1-14)
% hours with pain/24h		On each study day, up to 14 days
Assessment of specific adverse events: drowsiness		During each study phase (days 1-7 and days 8-14)

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Evangelia Liakoni, Inselspital, Bern University Hospital

Publications and helpful links

General Publications

• Kotoula C, Wertli MM, Streitberger K, Rothschild SI, Limacher A, Hammann F, Krahenbuhl S, Haschke M, Liakoni E. 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. BMJ Open. 2025 Dec 31;15(12):e107360. doi: 10.1136/bmjopen-2025-107360.

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2024
• Primary Completion (Actual): March 5, 2026
• Study Completion (Actual): March 5, 2026

Study Registration Dates

• First Submitted: October 5, 2021
• First Submitted That Met QC Criteria: October 19, 2021
• First Posted (Actual): October 22, 2021

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Organic Chemicals; Anilides; Amides; Aniline Compounds; Amines; Acetanilides; Acetaminophen
• Other Study ID Numbers: BASEC-ID: 2021-01518

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data that relates to individual, primary publications (and not the whole study database as such) will be deposited in the Bern Open Repository and Information System (BORIS). All efforts will be made to protect privacy and to de-identify the data. Data will be shared on request under the following conditions: A meaningful study question by the requester, outline of the planned analyses, valid methodology, signed data sharing agreement that contains a confidentiality agreement in case of sensitive data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No