A systematic review and meta-analysis to identify vertical limits for a high-dose opioid therapy

Chronic pain represents the defining and quality-of-life limiting feature in patients with cancer pain (CP) or chronic non-cancer pain (CNCP) and is often treated with opioids. Over time, opioid use is frequently accompanied by necessity of an increasing dose due to pharmacological tolerance and progress of the underlying diseases. The potential side effects were found to correlate with accelerating doses. More recently, the opioid crisis in the United States has drawn attention to the adverse effects and toxicities. Until today it is unclear what high-dose opioid therapy is and guidelines are inconsistent regarding an evidence-based threshold.

This systematic review and meta-analysis aim to determine a threshold for high-dose opioid therapy. A systematic literature search was conducted in 4 databases from earliest publication available until May 2025. Studies were eligible if participants with CP or CNCP were able to self-titrate their opioid dosage to reach a sufficient pain relief.

4305 records were screened. Nineteen included studies with a total of 3111 participants investigating eight different opioids were included. The studies were assessed for risk of bias. Results were synthesised as oral morphine equivalents (OMEs).

The meta-analysis found a weighted mean of 74.7 mg OME per day and the 97.5% percentile corresponded to about 138 mg/d (range 134-139 mg/d) as a "high dose". In CNCP the limit was 78 mg/d (range 74-78 mg/d), whereas in CP it reached 288 mg/d (range 280-289 mg/d; p < 0.01).

Despite the overall moderate risk of bias of the included studies and the heterogeneity in underlying pain conditions, the reference range of typically prescribed dosages in a broad study population could be investigated. These systematically derived thresholds may enhance physicians' awareness in carefully tailoring opioid treatments and thereby contribute to improved pharmacotherapy safety.

CRD42020219256.