Nefopam pharmacokinetics in patients with end-stage renal disease.
BACKGROUND
Treatment of intense postoperative pain in patients with end-stage renal disease (ESRD) is a recurrent problem for anesthesiologists because of the risk of accumulation of numerous molecules and their metabolites. Nefopam is a potent analgesic metabolized by the liver and weakly eliminated intact in urine that may offer advantages for use in patients with ESRD because it lacks respiratory-depressive effects. However, the effects of renal failure on nefopam disposition have never been investigated.


METHODS
We studied 12 ESRD patients (creatinine clearance < 20 mL/min, mean age 57 ± 13 years) having surgery under general anesthesia to create or repair an arteriovenous fistula. Postoperatively, after complete recovery from anesthesia, each patient received a single 20-mg dose of nefopam IV over 30 minutes. Nefopam and desmethyl-nefopam concentrations in plasma samples obtained over 48 hours were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameter values obtained were compared with those of 12 healthy 50- to 60-year-old volunteers who also received a single 20-mg nefopam infusion over 30 minutes using a population pharmacokinetic approach.


RESULTS
Healthy volunteers and ESRD patients had comparable demographic characteristics. In comparison with those volunteers, ESRD patients had a lower volume of central compartment (115 and 53 L vs. 264 L for patients not yet hemodialyzed and on chronic hemodialysis, respectively; P < 0.001) and lower mean nefopam clearance (37.0 and 27.3 L/h vs. 52.9 L/h, P < 0.001), resulting in higher mean nefopam peak concentration (121 and 223 ng/mL vs. 61 ng/mL, P < 0.001).


CONCLUSIONS
Nefopam distribution and elimination are altered in patients with ESRD, resulting in heightened exposure. To avoid too-high concentration peaks, it is suggested that the daily nefopam dose be reduced by 50%.
Mimoz
Olivier
O
Réanimation Chirurgicale Polyvalente, CHU de Poitiers, Poitiers, France. o.mimoz@chu-poitiers.fr
Chauvet
Stéphane
S
Grégoire
Nicolas
N
Marchand
Sandrine
S
Le Guern
Marie-Emmanuelle
ME
Saleh
Ashraf
A
Couet
William
W
Debaene
Bertrand
B
Levy
René H
RH
D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D001711:Biotransformation; D002853:Chromatography, Liquid; D005260:Female; D005602:France; D006801:Humans; D007262:Infusions, Intravenous; D007676:Kidney Failure, Chronic / Q000097:blood / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009340:Nefopam / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D010149:Postoperative Pain / Q000209:etiology / Q000517:prevention & control*; D006435:Renal Dialysis; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
D018712:Analgesics, Non-Narcotic; C080262:N-desmethylnefopam; D009340:Nefopam