Cancer Pain, Cancer Palliative Care
Conditions
Brief summary
The investigators investigate the efficacy of non-opioid analgesics compared to placebo together with opioid therapy for cancer pain management.
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 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.
Interventions
DRUGMetamizole
Metamizole 4 g/d as: 2 capsules of 500 mg Metamizole each (1000 mg) taken 4 x daily orally.
DRUGIbuprofen
Ibuprofen 1.2 g/d as: 2 capsules of 150 mg Ibuprofen each (300 mg) taken 4 x daily orally
OTHERPlacebo
Placebo 0 g/d as: 2 capsules containing inactive substance (mannitol) taken 4 x daily orally.
Sponsors
University Hospital, Basel, Switzerland
Swiss GO Trial Group
Swiss National Science Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
A multicenter, randomized, double-blind, placebo-controlled, three-armed superiority trial with a 1:1:1 allocation ratio.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in cancer pain | 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
| Measure | Time frame | Description |
|---|---|---|
| Assessment of equivalence of metamizole and ibuprofen in analgesic potency regarding the pain intensity | 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. |
| Worst pain in the past 24 hours by NRS | 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). |
| Least pain in the past 24 hours by NRS | 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. |
| Daily differences in pain intensity measured by NRS | 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") |
| Patient's Individual Primary Goal (IPG) achieved | 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). |
| Personal Symptom Goal (PSG) achieved | 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"). |
| Time to pain control [in days] | up to 7 days | 1. Time until minimal clinically important difference (MCID) of 1 is achieved 2. Time until PSG is achieved MCID and PSG achieved (Yes/No) will be assessed daily from day 3 to 7. |
| Patient Global Impression of Pain Change (PGIC) by verbal rating scale (VRS) | 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"). |
| ≥30% reduction in daily average pain (Yes/No) | 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). |
| Burden through interference of pain with general activity by NRS | 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. |
| Burden through interference of pain with mood by NRS | 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. |
| Number of opioid rescue medications per day | up to 8 days | The daily number of IROs (Immediate Release Opioids) will be assessed. |
| Morphine Equivalent Daily Dose (MEDD) (in mg) calculated by compound, dose and application route of IROs (Immediate Release Opioid) and EROs (Extended-release Opioids) | 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. |
| Number of pain episodes | up to 8 days | This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS. |
| Duration [in minutes] of pain episodes | up to 8 days | This outcome will be assessed at baseline, daily between day 3 and 7. It will also be assessed at EOS. |
Countries
Switzerland
Contacts
CONTACTChristopher Böhlke, Prof. Dr.
PRINCIPAL_INVESTIGATORChristopher Böhlke, Prof. Dr.
University Hospital, Basel, Switzerland
Outcome results
None listed