Transfer of Tramadol and its Metabolite into Breastmilk

Purpose of the study:  To investigate the transfer of rac-tramadol and its rac-O-desmethyl metabolite into transitional milk, to estimate the absolute and relative infant doses via milk, and to assess unwanted effects in the breastfed infant. Methods:  Tramadol HCl (100 mg six hourly) was administered to 75 breastfeeding mothers for postoperative analgesia on days 2–4 after caesarian section. Three samples of transitional milk and one of plasma were collected over 6–14 h following the 4th dose. Tramadol and O-desmethyltramadol were measured by high performance liquid chromatography. Milk/plasma ratio (M/P) was calculated, and absolute infant dose and relative infant dose were calculated by standard methods. The behavioral characteristics of the exposed breastfed infants and a matched control group of infants not exposed to tramadol were also studied. Results:  Mean (95% CI) M/P was 2.2 (2.0–2.4) for tramadol and 2.8 (2.5–3.1) for O-desmethyltramadol. Average concentrations in milk across a 6 h dose interval at steady-state were 748 (681–815) mcg l−1 for tramadol and 203 (188–217) mcg l−1for O-desmethyltramadol. Estimated absolute and relative infant doses were 112 (102–122) mcg kg−1 day−1 and 30 (28–32) mcg kg−1 day−1, and 2.24 (2.04–2.44)% and 0.64 (0.59–0.69)% for tramadol and O-desmethyltramadol respectively. The exposed infants and control breastfed infants had similar characteristics, including Apgar scores at birth and Neurologic and Adaptive Capacity Scores (NACS) on days 3–4 after birth. Conclusions:  The absolute infant doses for tramadol and its active metabolite combined were around 14% of the child therapeutic dose for tramadol. The combined relative infant dose of 2.88% of the weight-adjusted maternal dose was also low. The similarity of NACS in exposed infants and controls suggests that there were no clinically significant effects on infant well-being. We conclude that short-term maternal use of tramadol during establishment of lactation is safe for the breastfed infant.