Recruitment difficulties

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

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.

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

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.