Effect of paracetamol in addition to WHO Step III opioids in chronic cancer pain control - a randomized, placebo-controlled parallel group study

Background: Paracetamol is a centrally acting analgesic and antipyretic with minimal anti-inflammatory properties typically used every 6-8 hours for mild to moderate pain. Although generally considered safe at therapeutic doses, one important adverse effect is hepatotoxicity. In a recent clinical study, >30% of patients treated with therapeutic doses had an alanine aminotransferase increase >3 times the upper limit of normal indicating potential hepatotoxicity also within the recommended dosage. In the 3-step WHO analgesic ladder, paracetamol belongs to step I analgesics (mild pain), and is recommended as baseline analgesic alone or in combination with step II (weak opioids) or step III (strong opioids) analgesics. However, it is unknown whether paracetamol provides sufficient analgesic effect when combined with strong opioids. Objectives: To test the hypothesis that paracetamol does not provide clinically relevant benefits when added to strong opioids that would justify the increased risk of paracetamol-associated adverse effects such as hepatotoxicity.Hypothesis: Blinded withdrawal of paracetamol in patients with chronic cancer pain treated with strong opioids will not exceed a placebo effect and will not decrease pain control. Methods: Double-blind, non-inferiority, randomized, placebo-controlled, parallel-group study. We plan to include 140 cancer patients with chronic pain treated with stable doses (for at least 7 days) of a strong opioid and with =3 g paracetamol daily. Included patients are randomized to one of two treatment arms. In the first study phase (days 1-10), patients will receive identically looking capsules of either paracetamol at the exact dose previously used (group 1) or placebo (group 2). The patients will be instructed not to change their analgesic medication during 10 days after randomization. At day 11 (begin of second study phase), all patients will stop the blinded study medication (paracetamol and placebo) and will be followed up to day 20. During both study phases, in case of uncontrolled pain patients are allowed to take additional rescue doses of opioids. Patients will be followed by phone calls every 3 days and have a final study visit after day 20. Adherence will be assessed by measurement of paracetamol blood levels. Patients will be instructed to use a pain diary to rate their pain using a 100 mm visual analogue scale (VAS) ranging from “no pain at all" to “worst pain you can imagine" twice daily (morning and evening). Primary outcome will be the VAS score (average of morning and evening value) at study day 10. A difference of = 8mm will be considered clinically irrelevant. Secondary outcomes will include VAS pain score at day 20, the number of opioid rescue doses used on each study day, subjective ratings of overall feeling of well-being, quality of life, nausea/vomiting, drowsiness, and constipation, also assessed using VAS scores, and potential effects of drug levels and genotype on the observed differences.Significance: In case of non-inferiority of placebo, the study will have a broad impact on the management of chronic pain patients, both by reducing their pill burden and eliminating the risk of paracetamol-associated (hepato)toxicity.