Nefopam enantiomers: Preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration

Mather, Gary G.; Labroo, Rita; Guern, Marie‐Emmanuelle Le; Lepage, F.; Gillardin, Jean-Marie

doi:10.1002/(sici)1520-636x(2000)12:3<153::aid-chir9>3.0.co;2-v

Cited by 30 publications

(17 citation statements)

References 20 publications

(16 reference statements)

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“…The low bioavailability of nefopam might be caused by poor absorption and/or a high first‐pass. The terminal half‐life of nefopam appears slightly longer in the present study than in the study by Mather et al (2000) (5.1±0.6 versus 4.0±0.7 hr) of a 20 mg intravenous administration. Davies et al (1986) administered 60 mg (two 30 mg capsules) of nefopam by the oral route to healthy males and showed a half‐life of 6.3±1.8 hr.…”

Section: Discussioncontrasting

confidence: 76%

“…Davies et al (1986) administered 60 mg (two 30 mg capsules) of nefopam by the oral route to healthy males and showed a half‐life of 6.3±1.8 hr. The results by Mather et al (2000) might be related to the shorter duration of the study period and /or to the difference between the limits of quantification of analytical methods (3.9 versus 16.2 nmol.l −1 ). This point is indirectly confirmed by the increased half‐life found in the study by Davies et al (1986) which might reflect the larger dose used.…”

Section: Discussionmentioning

confidence: 99%

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

Aymard

Warot

Démolis

et al. 2003

Pharmacology & Toxicology

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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...

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Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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

Aymard

Warot

Démolis

et al. 2003

Pharmacology & Toxicology

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“…The nefopam infusion profile was based on published pharmacokinetic data 38 and was designed to provide a time to peak plasma concentrations of 20 minutes with a mean elimination half-life of 240 minutes. The nefopam infusion profile was based on published pharmacokinetic data 38 and was designed to provide a time to peak plasma concentrations of 20 minutes with a mean elimination half-life of 240 minutes.…”

Section: Protocolmentioning

confidence: 99%

Nefopam and Meperidine Are Infra-Additive on the Shivering Threshold in Humans

Alfonsi

Passard

Guignard

et al. 2014

Anesthesia &Amp; Analgesia

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“…1981. Nefopam is a racemic mixture of its two enantiomers 3 and is a centrally acting non-narcotic analgesic. Its mechanisms of action are not fully understood, but in vitro analysis revealed inhibition of serotonin and norepinephrine reuptake in animal models.…”

mentioning

confidence: 99%

Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery † †Declaration of interest. This work has been sponsored by Biocodex Laboratories, in charge of nefopam (Acupan injectable™) commercialization.

Manoir

Aubrun

Langlois

et al. 2003

British Journal of Anaesthesia

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Nefopam enantiomers: Preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration

Cited by 30 publications

References 20 publications

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

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

Nefopam and Meperidine Are Infra-Additive on the Shivering Threshold in Humans

Randomized prospective study of the analgesic effect of nefopam after orthopaedic surgery † †Declaration of interest. This work has been sponsored by Biocodex Laboratories, in charge of nefopam (Acupan injectable™) commercialization.

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