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

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

Detailed Description
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Chronic pain cancer 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. Between the on-site visits, patients will be followed up by phone calls on day 3 (±1d) and day 10 (±1d). 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.

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

Conditions
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Pain

Intervention / Treatment
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* Drug: Placebo
* Drug: Paracetamol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female cancer 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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: drowsiness |  | During whole study (days 1-14) | 
| 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 |