Comparative Pharmacokinetics and Pharmacodynamics of Intravenous and Oral Nefopam in Healthy Volunteers*

Abstract

To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orallyπplacebo intravenous infusion and placebo orallyπintravenous infusion of 20 mg nefopam with one week interval, in a doubleblind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36∫0.13. The AUC oral /AUC iv ratio of nefopamπdesmethyl-nefopam was 0.62∫0.23. The half-life of nefopam was similar whether administered orally (5.1∫1.3 hr) or intravenously (5.1∫0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6∫3.0 versus 5.1∫1.3 hr, PϽ10ª4 and intravenously: 15.0∫2.4 versus 5.1∫0.6 hr, PϽ10 ª4 ). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug-naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC 0»24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90∫142 versus 35∫84 (PΩ0.27) and 66∫74 versus 46∫54 mm.hr (PΩ0.36), respectively. The AUC 0»24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68∫65 versus 27∫30 (PΩ0.005) and 54∫63 versus 28∫48 mm.hr (PΩ0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.Nefopam is a non-opioid analgesic drug usually administered by intravenous infusion or intramuscular injection for postoperative pain (Calmi et al. 1985;Pandit et al. 1989; Goucke et al. 1990;Guirimand et al. 1990;Moffat et al. 1990). Previous studies in man have shown that 20 mg nefopam reduces daily morphine consumption by 30 % after upper abdominal surgery (McLintock et al. 1988) and by 50% after elective hepatic resection (Mimoz et al. 2001). Results obtained in man on the nociceptive R III reflex suggest that nefopam probably exerts its analgesic action through central (spinal and/or supraspinal) mechanisms. An oral formulation of nefopam is not available in France. Oral administration of intravenous solution of n...

Study of Pharmacokinetics and Comparative Bioavailability of Nefopam 30 mg Tablets in Twelve Fasting Healthy Pakistani Male Young Subjects: Single-Dose, Randomized, Two-Period, Two-Treatment and Two-Way Cross-Over Design

“…The validation showed that the assay was adequate for extraction of nefopam from human plasma and its reliable quantification. Our results were similar to the previous pharmacokinetic study of Aymard et al [2] which reported the following mean pharmacokinetic parameters – C max , AUC 0– ∞, T max – of 48.5 ± 18.9 ng/ml, 377 ± 193 ng·h/ml, 1.73 ± 0.12 h, respectively. However, there was a little difference which could be related to the aldosterone synthase, cytochrome P450 (CYP) 11B2 gene which is the key rate-controlling enzyme in the final steps of aldosterone biosynthesis in the zona glomerulosa cells of human adrenal glands, and its expression is primarily regulated by angiotensin II and serum potassium levels [8].…”

“…All other chemicals were of analytical grade and were used without any alteration. Plasma nefopam was quantified based on a modified HPLC method that was validated before the study [2]. The HPLC conditions were optimized for the column (Eclipse XDB C 18 ; 5 µm, 4.6 × 150 mm, column internal diameter 4.5 mm), mobile phase, and sample preparation.…”

“…The pharmacokinetics and comparative bioavailability of nefopam has been reported [2]. When administered orally, its bioavailability is low most likely due to first-pass metabolism, its peak plasma concentration is achieved within 1–3 h and the terminal half-life is 4.0– 5.1 h [2].…”

“…When administered orally, its bioavailability is low most likely due to first-pass metabolism, its peak plasma concentration is achieved within 1–3 h and the terminal half-life is 4.0– 5.1 h [2]. Neopam is mainly excreted via urinary tract.…”

Nefopam for the prevention of postoperative pain: quantitative systematic review

“…Nefopam undergoes extensive hepatic biotransformation to desmethylnefopam (which seems to be biologically active) and N-oxide-nefopam. 2 Protein binding is 75%, and the major route of elimination (87%) is renal whereas a small part (8%) is excreted in the faeces. Ninety-five per cent of an initial dose is excreted within 5 days, 5% as unchanged substance.…”