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NCT Number: NCT07682558

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

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

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Key information

Conditions

Cancer Pain Cancer Palliative Care Neurologic Manifestations Pain Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

About this study

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 patient's 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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Metamizole

Drug

Metamizole 4 g/d as: 2 capsules of 500 mg Metamizole each (1000 mg) taken 4 x daily orally.

Ibuprofen

Drug

Ibuprofen 1.2 g/d as: 2 capsules of 150 mg Ibuprofen each (300 mg) taken 4 x daily orally

Placebo

Other

Placebo 0 g/d as: 2 capsules containing inactive substance (mannitol) taken 4 x daily orally.

Primary outcomes

  1. Change in cancer pain

    Time frame: up to 5 days

    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); The NRS ranges from 0 ("no pain") to 10 ("pain as bad as the patient can imagine")

Secondary outcomes

  1. Assessment of equivalence of metamizole and ibuprofen in analgesic potency regarding the pain intensity

    Time frame: up to 5 days

    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.

  2. Worst pain in the past 24 hours by NRS

    Time frame: up to 8 days

    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 the patient can imagine"). It will also be assessed at End of Study Visit (EOS).

  3. Least pain in the past 24 hours by NRS

    Time frame: up to 8 days

    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 the patient can imagine"). It will also be assessed at EOS.

  4. Daily differences in pain intensity measured by NRS

    Time frame: up to 7 days

    This outcome will be assessed daily from day 3 to day 7 to investigate efficacy over the course of time. The NRS ranges from 0 ("no pain") to 10 ("pain as bad as the patient can imagine")

  5. Patient's Individual Primary Goal (IPG) achieved

    Time frame: 8 days

    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 a 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).

  6. Personal Symptom Goal (PSG) achieved

    Time frame: up to 7 days

    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 the patient can imagine").

  7. Time to pain control [in days]

    Time frame: up to 7 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.

  8. Patient Global Impression of Pain Change (PGIC) by verbal rating scale (VRS)

    Time frame: day 8

    A 7-option rating-of-change scale to assess participant-reported response to pain therapy using a VRS ("very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse").

  9. ≥30% reduction in daily average pain (Yes/No)

    Time frame: up to 7 days

    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).

  10. Burden through interference of pain with general activity by NRS

    Time frame: up to 8 days

    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.

  11. Burden through interference of pain with mood by NRS

    Time frame: up to 8 days

    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.

  12. Number of opioid rescue medications per day

    Time frame: up to 8 days

    The daily number of IROs (Immediate Release Opioids) will be assessed.

  13. Morphine Equivalent Daily Dose (MEDD) (in mg) calculated by compound, dose and application route of IROs (Immediate Release Opioid) and EROs (Extended-release Opioids)

    Time frame: up to 7 days

    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 equianalgesic dosing.

  14. Number of pain episodes

    Time frame: up to 8 days

    This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS.

  15. Duration [in minutes] of pain episodes

    Time frame: up to 8 days

    This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS.

Other outcomes

  1. Number of patients with ≥30% reduction in pain

    Time frame: up to 7 days

    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)

  2. Adherence to protocol and IMP intake

    Time frame: up to 7 days

    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.

  3. Number of participants that opened the capsules

    Time frame: up to 8 days

    Administration assessed daily as "Capsules opened: Yes/No".

  4. Number of participants that received the IMP through an enteral tube

    Time frame: up to 8 days

    Assessed daily as "Administration through enteral tube": Yes/No, if "capsules opened: Yes"

  5. Continuation of non-opioid treatment

    Time frame: up to 8 days

    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.

  6. Differences in treatment response based on CRP (C-reactive protein) status at baseline

    Time frame: Baseline and day 8

    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).

  7. Changes in symptoms at EOS compared to baseline

    Time frame: up to 8 days

    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.

  8. Changes in performance status (ECOG) at EOS compared to baseline

    Time frame: up to 8 days

    Using the ECOG (Eastern Cooperative Oncology Group) performance status. It describes a patient's level of functioning based on the ability to perform self-care, daily activities, and physical activities (e.g., walking and working). 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.

  9. Changes in activity levels at EOS compared to baseline

    Time frame: up to 8 days

    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).

  10. Accuracy of participant treatment guess

    Time frame: up to 8 days

    (Correct vs incorrect vs unsure) based on comparison with actual treatment allocation

  11. Incidence of (serious) adverse events ((S)AEs)

    Time frame: up to 8 days

  12. Type and duration of (S)AEs

    Time frame: up to 8 days

  13. 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

    Time frame: up to 8 days

  14. Number of dropouts due to clinically relevant decrease in leukocyte count (≥50% from baseline) attributed to metamizole

    Time frame: up to 8 days

Study contacts

Contact information is provided by the study sponsor or research team.

Christopher Böhlke, Prof. Dr.

CONTACT

[email protected]

+41 61 265 25 25,

Sponsors and collaborators

Lead sponsor

University Hospital, Basel, Switzerland

Other

Collaborators

  • Swiss GO Trial Group
  • Swiss National Science Foundation

Registry information

Official study title

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

Acronym: NoDoubt

Important dates

Study start
2026
Primary completion
2029
Study completion
2029
First posted
Jul 6, 2026
Registry last updated
Jul 7, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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