Tramadol (with or without acetaminophen) efficacy and harm: Systematic review and meta-analysis

To evaluate the efficacy and safety of tramadol (with or without acetaminophen) in adult pain management compared with nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and acetaminophen alone.

Studies were identified through a search of the entire Ovid MEDLINE database, the Ovid MEDLINE Epub Ahead of Print database, Embase, and Evidence-Based Medicine Reviews (Cochrane Central Register of Controlled Trials) from 1946 to August 19, 2022.

Included studies comprised double-blind, randomized controlled trials (RCTs) of oral tramadol (with or without acetaminophen) compared with opioids, NSAIDs, or acetaminophen for treatment of acute or chronic pain that reported at least 1 of 11 outcomes: total adverse events (AEs), fatal serious AEs (SAEs), nonfatal SAEs, patient withdrawals from the study due to AEs (WDAEs), total study withdrawals, measures of dependence or addiction, quality of life, functional improvement, 30% or more pain reduction, 50% or more pain reduction, and rescue medication use. Overall, 3184 articles were screened and 37 RCTs (21 opioid, 15 NSAID, 1 acetaminophen; N=7156; length 1 hour to 12 weeks) were included. Trials were critically appraised and assessed using the Cochrane risk of bias tool for randomized trials 1.0. Meta-analyzed outcomes were reported as risk ratios (with 95% confidence intervals [CIs]).

Compared with opioids, tramadol with or without acetaminophen did not significantly differ in efficacy based on 50% or more or 30% or more reduction in pain or in any harm outcomes (nonfatal SAEs [risk ratio (RR)=1.35, 95% CI 0.43 to 4.20]; WDAEs [RR=0.99, 95% CI 0.80 to 1.22]; total withdrawals [RR=0.93, 95% CI 0.78 to 1.11]; or total AEs [RR=0.97, 95% CI 0.89 to 1.05]). Compared with NSAIDs, tramadol with or without acetaminophen was less likely to achieve a 30% or more reduction in pain (RR=0.82, 95% CI 0.76 to 0.90), and was more likely to result in WDAEs (RR=2.86, 95% CI 2.23 to 3.66), total withdrawals (RR=1.68, 95% CI 1.47 to 1.93), and total AEs (RR=1.37, 95% CI 1.28 to 1.47). Evidence was insufficient for meta-analysis of fatal SAEs, drug dependence or addiction, quality of life, functional improvement, or use of rescue medications.

Tramadol with or without acetaminophen did not differ significantly from other opioids, and was less effective and more poorly tolerated than NSAIDs. Short study duration, small sample size, extensive patient exclusion, and inconsistency in outcome reporting limit the scientific validity of conclusions.