Efficacy of Non-opioid Drugs in Addition to Opioid Therapy for Cancer Pain Management (NoDoubt)

Efficacy of Non-opioid Drugs in Addition to Opioid Therapy for Cancer Pain Management: a Double-blind, Randomized, Three Arm, Placebo Controlled Trial Assessing the Key Non-opioids Dipyrone (Metamizole) and Ibuprofen

The investigators investigate the efficacy of non-opioid analgesics compared to placebo together with opioid therapy for cancer pain management.

Study Overview

• Status: Not yet recruiting
• Conditions: Cancer Pain; Cancer Palliative Care
• Intervention / Treatment: Drug: Metamizole; Drug: Ibuprofen; Other: Placebo

Detailed Description

Pain in cancer is common and can be very debilitating. Approximately half of all people with a tumor experience moderate to severe pain during the course of their cancer. Nevertheless, pain management is often difficult because there are not yet enough reliable studies for some medications, especially when used in addition to opioids.

Therefore, the NoDoubt study is investigating whether metamizole and/or ibuprofen - compared to a placebo - in addition to opioids provide better pain relief for cancer patients. The main goal is to reduce pain intensity. The study also examines whether the need for opioids can be reduced. The results could help to establish a clear and standardized practice for the treatment of cancer pain in the future, thus leading to improved care for cancer patients.

• Study Type: Interventional
• Enrollment (Estimated): 318
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Christopher Böhlke, Prof. Dr.; Phone Number: +41 61 265 25 25,; Email: christopher.boehlke@unibas.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel
    • Contact: Christopher Böhlke, Prof. Dr.; Phone Number: +41 61 265 25 25; Email: christopher.boehlke@unibas.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Inpatient setting (discharge possible, if patient returns for End of Study Visit)
• Diagnosis of metastatic or locally advanced cancer
• Cancer pain as defined by IASP (International Association for the Study of Pain)
• Cancer pain therapy with opioids indicated for pain management or start thereof at baseline (drug, dose, and route at treating physician's discretion)
• Average daily pain intensity ≥ 3 on NRS (Numeric Rating Scale)
• Ability to swallow oral medication
• Informed Consent as documented by signature

Exclusion Criteria:

• History of allergy or allergy-like symptoms (bronchospasm, urticaria or severe cutaneous adverse reactions (SCARs)) or hypersensitivity to dipyrone (or other pyrazolones or pyrazolidines) or ibuprofen (or other Non-steroidal anti-inflammatory drug incl. acetylsalicylic acid)
• Moderate to severe renal insufficiency (creatinine-eGFR (estimated Glomerular Filtration Rate) <45 ml/min)
• Severe heart failure (New York Heart Association class III-IV)
• Severe hepatic impairment (liver cirrhosis with ascites) or hepatic porphyria
• History of agranulocytosis induced by dipyrone (or other pyrazolones or pyrazolidines)
• Active gastric and/or duodenal ulcers or bleeding
• History of recurrent gastric and/or duodenal ulcers or gastrointestinal bleeding (≥2 distinct episodes of proven ulceration or bleeding) or increased tendency to bleeding
• Third trimester of pregnancy
• Breastfeeding
• G6PD deficiency
• Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
• Intrathecal or epidural opioids or local or regional anesthetic therapy
• Additional second opioid for co-analgesic effects or other reasons (e.g., methadone, buprenorphine)
• Initiation of therapy with transdermal therapeutic system (TTS) opioid <48 hours before start of IMP
• Use of non-opioids with long half-life (i.e., acemetacin, celecoxib, etodolac, etoricoxib, ketorolac, naproxen, piroxicam, tenoxicam)
• Pain unrelated to cancer (e.g. chronic non-cancer pain [CNCP], postoperative, particularly following coronary artery or cardiopulmonary bypass surgery)
• Inability to follow study procedures or adhere to protocol (e.g., due to language problems, psychological disorders, dementia)
• Inability to abstain from other non-opioids (apart from IMP (Investigational Medicinal Product)) during study participation
• Participation in any interventional study targeted at pain management
• Participant is a family member or employee of the investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Opioid + Metamizole	Drug: Metamizole; Metamizole 4 g/d as: 2 capsules of 500 mg Metamizole each (1000 mg) taken 4 x daily orally.
Experimental: Opioid + Ibuprofen	Drug: Ibuprofen; Ibuprofen 1.2 g/d as: 2 capsules of 150 mg Ibuprofen each (300 mg) taken 4 x daily orally
Placebo Comparator: Opioid + Placebo	Other: Placebo; Placebo 0 g/d as: 2 capsules containing inactive substance (mannitol) taken 4 x daily orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cancer pain	The primary outcome will help to determine whether adding metamizole (dipyrone) or ibuprofen to opioids is more effective than adding placebo in reducing average daily pain intensity (primary outcome) in cancer patients. - Average of 5-day average daily patient reported pain assessed on days 3 to 7 by numeric rating scale (NRS)	up to 5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of equivalence of metamizole and ibuprofen in analgesic potency regarding the pain intensity	Our main secondary outcome will help to investigate whether metamizole and ibuprofen demonstrate similar analgesic potency (are equivalent) regarding the pain intensity. For assessment of equivalence, Average of 5-day average daily patient reported pain assessed on days 3 to 7 by numeric rating scale will be used.	up to 5 days
Worst pain in the past 24 hours by NRS	This outcome will be assessed at baseline and daily from day 3 to 7 using item 3 of the BPI-SF (Brief Pain Inventory - Short Form). The NRS ranges from 0 ("no pain") to 10 ("pain as bad as you can imagine"). It will also be assessed at End of Study Visit (EOS).	up to 8 days
Least pain in the past 24 hours by NRS	This outcome will be assessed at baseline and daily from day 3 to 7 using item 4 of the BPI-SF. The NRS ranges from 0 ("no pain") to 10 ("pain as bad as you can imagine"). It will also be assessed at EOS.	up to 8 days
Daily differences in pain intensity measured by NRS	This outcome will be assessed daily from day 3 to day 7 to investigate efficacy over the course of time.	up to 7 days
Patient's Individual Primary Goal (IPG) achieved	The IPG will be specified at baseline and whether it has been achieved or not will be assessed at EOS based on the specified IPG at baseline. The IPG reflects variation between individuals' analgesic goals and further individualize symptom assessment by allowing each patient to specify their primary goal regarding the amelioration of the main issue as asked at baseline (i.e., patient's most important item from this list: average pain, pain interference with mood or activity, number or duration of pain episodes, worst pain, other).	8 days
Personal Symptom Goal (PSG) achieved	The PSG will be specified at baseline (NRS 0-10) and whether it has been achieved or not will be assessed daily from day 3 to 7. Patients are asked at baseline "At what level would you feel comfortable with this symptom?" to identify the maximal symptom intensity they would consider comfortable on the NRS ranging from 0 ("no pain") to 10 ("pain as bad as you can imagine").	up to 7 days
Time to pain control [in days]	Time until minimal clinically important difference (MCID) of 1 is achieved; Time until PSG is achieved MCID and PSG achieved (Yes/No) will be assessed daily from day 3 to 7.	up to 7 days
Patient Global Impression of Pain Change (PGIC) by verbal rating scale (VRS)	A 7-option rating-of-change scale to assess participants' ratings of their response to pain therapy on a VRS ("very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse").	day 8
≥30% reduction in daily average pain (Yes/No)	This outcome will be assessed based on the average of daily patient reported pain intensity by NRS at baseline (BL-pain) compared to the daily average pain on the last day of the intervention period (day 7).	up to 7 days
Burden through interference of pain with general activity by NRS	Will be assessed at baseline and daily from day 3 to 7 using item 9 A ("General activity") of the BPI-SF. The NRS ranges from 0 ("does not interfere") to 10 ("completely interferes"). Both outcomes will also be assessed at EOS.	up to 8 days
Burden through interference of pain with mood by NRS	Will be assessed at baseline and daily from day 3 to 7 using item 9 B ("Mood") of the BPI-SF. The NRS ranges from 0 ("does not interfere") to 10 ("completely interferes"). Both outcomes will also be assessed at EOS.	up to 8 days
Number of opioid rescue medications per day	The daily number of IROs (Immediate Release Opioids) will be assessed.	up to 8 days
Morphine Equivalent Daily Dose (MEDD) (in mg) calculated by compound, dose and application route of IROs (Immediate Release Opioid) and EROs (Extended-release Opioids)	Baseline MEDD and MEDD at EOS will be assessed. This outcome will be assessed daily between day 1 and 7. MEDD is calculated by multiplying the daily dose of the prescribed opioid (if not already morphine) by a compound-specific, route of application-dependent conversion factor. The opioid conversion ratios used to calculate MEDD are based on the literature and practical clinical considerations on equianalgesia.	up to 7 days
Number of pain episodes	This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS.	up to 8 days
Duration [in minutes] of pain episodes	This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS.	up to 8 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with ≥30% reduction in pain	For this outcome, the number of patients achieving ≥30% reduction in pain will be assessed, comparing pain at baseline (BL-pain) to the daily average pain on the last day of the intervention (day 7)	up to 7 days
Adherence to protocol and IMP intake	Discharge during d1-d7 will be assessed (Yes/No), including time to discharge after inclusion, if applicable. IMP intake (i.e., missed doses day d1-d7) will be assessed daily.	up to 7 days
Number of participants that opened the capsules	Administration assessed daily as "Capsules opened: Yes/No".	up to 8 days
Number of participants that received the IMP through an enteral tube	Assessed daily as "Administration through enteral tube": Yes/No, if "capsules opened: Yes"	up to 8 days
Continuation of non-opioid treatment	This will be assessed at EOS based on the clinical decision at physician's discretion (after unblinding). It will be assessed whether the non-opioid is continued, discontinued, switched, or if a (new) non-opioid is initiated. If applicable, the drug and the daily dose (mg/24 h) will be assessed.	up to 8 days
Differences in treatment response based on CRP (C-reactive protein) status at baseline	The CRP measured at baseline will be used to exploratively assess whether treatment response differs according to baseline inflammatory status as measured by CRP (i.e., whether baseline inflammation may act as a potential effect modifier of the observed treatment response).	Baseline and day 8
Changes in symptoms at EOS compared to baseline	Using ESAS (Edmonton Symptom Assessment System): This scale is designed to help assess pain, tiredness, drowsiness, nausea, depression, anxiety, appetite, wellbeing, and shortness of breath. The blank scale can be used to assess "other problems" as needed. Each symptom's severity at the time of assessment is rated from 0 to 10; 0 meaning the symptom is absent and 10 being the worst possible severity.	up to 8 days
Changes in performance status (ECOG) at EOS compared to baseline	Using the ECOG (Eastern Cooperative Oncology Group) performance status. It describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.). The scale runs from 0 to 5, where lower numbers indicate better functioning. However, as 5 indicates death, only 0 to 4 are used for assessment of this outcome.	up to 8 days
Changes in activity levels at EOS compared to baseline	Average activity levels of the past 7 days will be assessed at baseline and at EOS using a NRS (numeric rating scale) ranging from 0 (no activity at all) to 10 (maximum possible activity/the same as in health).	up to 8 days
Accuracy of participant treatment guess	(Correct vs incorrect vs unsure) based on comparison with actual treatment allocation	up to 8 days
Incidence of (serious) adverse events ((S)AEs)		up to 8 days
Type and duration of (S)AEs		up to 8 days
Number of dropouts due to decrease in creatinine-estimated (e)GFR <30 ml/min and/or ≥1.5-fold increase in baseline serum creatinine attributed to ibuprofen		up to 8 days
Number of dropouts due to clinically relevant decrease in leukocyte count (≥50% from baseline) attributed to metamizole		up to 8 days

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Collaborators: Swiss National Science Foundation; Swiss GO Trial Group
• Investigators: Principal Investigator: Christopher Böhlke, Prof. Dr., University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): November 1, 2029
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: June 26, 2026
• First Submitted That Met QC Criteria: June 26, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 26, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cancer Pain; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Carboxylic Acids; Acids, Carbocyclic; Pyrazoles; Phenylpropionates; Pyrazolones; Aminopyrine; Dipyrone; Ibuprofen
• Other Study ID Numbers: 2026-00784; ex23gaertner

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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