Efficacy of Nonopioid Analgesics (Acetaminophen and NSAIDs) Used Alone or in Combination with Opioids for Cancer Pain: Latest Updates on the Evidence Supporting the Guidelines

Cancer pain significantly impairs patients’ quality of life. Although the World Health Organization recommends nonopioid analgesics for pain management in this context, previous systematic reviews have been limited to the qualitative synthesis of oral formulations published up to 2017. To address these limitations and update the clinical guidelines of the Japanese Society of Palliative Medicine (JSPM), we conducted a comprehensive review and a meta-analysis including intravenous formulations with the latest evidence through 2025. We included relevant studies published before 2018 that were cited in the clinical guidelines of JSPM (2020, 3rd edition). Additionally, we searched CENTRAL, PubMed, and ICHUSHI for relevant randomized controlled trials published between January 2018 and December 2025. These combined data were used for an integrated meta-analysis. The review’s primary outcome was pain relief. Effect sizes were evaluated using Hedges’ g. We included five studies for acetaminophen ( n = 253) and 17 for nonsteroidal anti-inflammatory drugs (NSAIDs) ( n = 1493). Acetaminophen coadministered with opioids did not show a statistically significant effect on pain relief (Hedges’ g = 0.18; 95% confidence intervals [CI]: −0.08–0.44). In contrast, the combination of NSAIDs and opioids demonstrated a medium and significant effect compared to opioids alone (Hedges’ g = 0.58; 95% CI: 0.07–1.09). However, considerable heterogeneity was observed in the NSAID combination group ( I 2 = 82%), and five of the seven studies were judged to have a high risk of bias. This study summarizes the evidence regarding the use of nonopioid analgesics. While a robust effect of acetaminophen coadministered with opioids was not demonstrated, NSAIDs combined with opioids showed a potentially beneficial pooled effect on pain relief; however, the certainty of the evidence was very low and the findings should be interpreted cautiously. Further high-quality research is warranted to confirm these effects and to optimize personalized pain management strategies.