Reporting rate of adverse drug reactions to the French pharmacovigilance system with three step 2 analgesic drugs: dextropropoxyphene, tramadol and codeine (in combination with paracetamol)

Br J Clin Pharmacol. 2009 Sep;68(3):422-6. doi: 10.1111/j.1365-2125.2009.03472.x.


Aims: Three 'weak' opioid analgesics in association with paracetamol are marketed in France as step 2 analgesics: dextropropoxyphene, tramadol and codeine. These combinations are involved in several adverse drug reactions (ADRs), but no data are available about their comparative reporting rate. The aim was to compare the reporting rate of ADRs between tramadol/paracetamol (TRM+P), codeine/paracetamol (COD+P) and dextropropoxyphene/paracetamol (DXP+P).

Methods: All spontaneous reports submitted to the French Pharmacovigilance Database from 1 January 1987 to 31 December 2006 suspected to be induced by one of the three step 2 analgesic combinations (DXP+P, TRM+P, COD+P) were extracted. Their consumption for the same period was obtained from the French Drug Agency. The number of ADRs, serious ADRs and different organ classes of ADRs were compared according to their consumption. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each variable using DXP+P as reference.

Results: The reporting rate of ADRs was calculated as 24.9/100 000 person-years for DXP+P, 44.5/100 000 person-years for TRM+P and 12.5/100 000 person-years for COD+P. The reporting rate (OR 0.56, 95% CI 0.50, 0.63) and 'seriousness>>' (OR 0.65, 95% CI 0.53, 0.80) of ADRs were significantly higher with TRM+P than with DXP+P. However, hepatobiliary ADRs were significantly more frequent with the DXP+P combination (OR 2.62, 95% CI 1.59, 4.37). In contrast, the reporting rate (OR 1.99, 95% CI 1.82, 2.18) and 'seriousness' (OR 2.64, 95% CI 2.24, 3.11) of ADRs were significantly higher with DXP+P than with COD+P.

Conclusions: Among the three step 2 analgesic combinations, reporting rate and 'seriousness' of ADRs are the highest with TRM+P and the lowest with COD+P. Our study suggests that the safety profile of DXP+P is worst than that of COD+P.

MeSH terms

  • Acetaminophen / adverse effects*
  • Adverse Drug Reaction Reporting Systems / statistics & numerical data*
  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / therapeutic use
  • Codeine / adverse effects*
  • Databases, Factual / statistics & numerical data
  • Dextropropoxyphene / adverse effects*
  • Drug Therapy, Combination
  • France
  • Humans
  • Tramadol / adverse effects*


  • Analgesics, Opioid
  • Acetaminophen
  • Tramadol
  • Dextropropoxyphene
  • Codeine