A Simultaneous Mixed-Effects Pharmacokinetic Model for Nefopam, N-desmethylnefopam, and Nefopam N-Oxide in Human Plasma and Urine.

BACKGROUND AND OBJECTIVE: Nefopam is a non-opioid, non-steroidal, central analgesic thought to act via multiple mechanisms including potent inhibition of serotonin-norepinephrine reuptake and modulation of voltage-sensitive calcium and sodium channels. There has been a resurgence in its use for postoperative pain and neuropathic pain. Dosing route-dependent metabolism and clinical effects have been described following intravenous and oral nefopam. N-desmethylnefopam and nefopam N-oxide are metabolites of clinical interest. We sought to develop a joint pharmacokinetic model to simultaneously describe the plasma and urinary pharmacokinetics of nefopam and the two metabolites following an oral pharmacological dose of [14C]-nefopam to healthy volunteers, and to estimate inter-individual variability in their pharmacokinetics. METHODS: Pharmacokinetic data for the parent and metabolites were analyzed simultaneously using NONMEM® (nonlinear mixed-effect modeling) v7.3. The modeling process evaluated, in part, one- and two-compartment linear pharmacokinetic models for nefopam and a single compartment for each of the two metabolites. Pathways for presystemic metabolism of both metabolites were explored. RESULTS: The final structural model simultaneously described the plasma and urinary pharmacokinetics of nefopam and the two metabolites. It consists of a central compartment for nefopam and for each of the two metabolites, as well as a peripheral compartment for the parent, and the associated urine compartments. The rapid formation and appearance of the N-oxide in plasma, characterized by concentrations that peak earlier than the parent, could be described by presystemic formation in the gastrointestinal tract. CONCLUSIONS: A descriptive, robust and predictive parent-metabolite model has been developed using a population mixed-effects approach to characterize the pharmacokinetics of nefopam and its metabolites simultaneously in healthy subjects following oral administration of nefopam. The model may be used for dose selection, analysis of sparse data, identification of intrinsic and extrinsic factors, and to model the clinical effects of each analyte.

The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised, single-dose, crossover open-label study.

PURPOSE: Nefopam is a widely available analgesic for the management of pain. The aim of this study was to reveal the effect of regional hyperthermia of the abdominal area on the pharmacokinetics of nefopam. MATERIALS AND METHODS: A randomised, single-dose, crossover, open-label study was conducted to reveal the effect of hyperthermia using modulated electro-hyperthermia on the pharmacokinetics of nefopam. The pharmacokinetics of orally administered nefopam without hyperthermia was studied in 12 healthy volunteers and then 7 days later they were treated with nefopam plus modulated electro-hyperthermia to the abdominal area for 1 h. Blood samples were collected up to 24 h after the drug administration. From the blood concentration-time curve, the maxinum plasma concentration (C(max)), time to C(max) (T(max)) and the area under the curve (AUC) were obtained. The safety and tolerability of these treatments were also assessed. RESULTS: The geometric mean ratios (GMRs) ((nefopam + modulated electro-hyperthermia)/nefopam) and the associated 90% confidence intervals (CIs) for C(max), AUC(last) and AUC(inf) were 1.2804 (1.1155∼1.4696), 1.0512 (0.9555∼1.1566) and 1.0612 (0.9528∼1.1819), respectively. The increase in C(max) was statistically significant, and T(max) was significantly shortened. CONCLUSIONS: The significant increase in C(max) and decrease in T(max) indicated that modulated electro-hyperthermia increased the absorption of the orally administered nefopam, thereby transitionally increasing the blood concentration of the drug. The AUC is an important parameter that contributes to the therapeutic effect of drugs. The lack of significant change in AUC suggests that modulated electro-hyperthermia may increases the absorption of orally administered drugs without increasing the systemic adverse effect of the drugs.

Nefopam Hydrochloride: A Fatal Overdose.

Nefopam is a non-opiate analgesic commonly used for the treatment of moderate to severe pain. A case of a 37-year-old male who was found dead in the morning is presented. An autopsy was performed and femoral venous blood, heart blood, urine, and vitreous humor were submitted for toxicological analysis. A general drug screen detected the presence of nefopam, caffeine, nicotine, citalopram, gabapentin, amitriptyline, diazepam and paracetamol in cardiac blood. Nefopam was quantitated by high-performance liquid chromatography with diode-array detection. Nefopam was found at the following concentrations: 13.6 mg/L in unpreserved femoral blood; 14.7 mg/L in preserved (fluoride-oxalate) femoral blood; 21.2 mg/L in unpreserved cardiac blood and 4.5 mg/L in preserved vitreous. Citalopram was present at a concentration of 0.7 mg/L (femoral blood) and 0.9 mg/L (cardiac blood). Ethanol analyzed by headspace gas chromatography (GC-FID) was detected in preserved (fluoride-oxalate) vitreous (14 mg/100 mL) and preserved (fluoride-oxalate) urine 50 mg/100 mL. Death was attributed to atherosclerotic coronary artery disease and therapeutic drug toxicity.

Pharmacokinetics of dexamethasone and nefopam administered alone or in combination using a newly developed prefilled multi-drug injector in rats.

BACKGROUND/AIM: It is significant for patients with traumatic brain injury (TBI) to receive prehospital emergency treatment as early as possible to reduce mortality. Therefore, a new prefilled multi-drug injector was developed to improve the treatment of TBI. Here, we studied the pharmacokinetics of dexamethasone (DXM) and nefopam using the injector to investigate the significance of drug interactions and the necessity of dose adjustment. METHODS: Rats were administered DXM and nefopam intramuscularly alone or in combination using the injector. The concentrations of DXM and nefopam were measured by means of HPLC. The noncompartmental approach was used to calculate pharmacokinetic parameters. RESULTS: All animals appeared to tolerate the injection very well. The maximum concentration 90% confidence interval (CI) of nefopam was in the bioequivalence range when nefopam was co-administered with DXM. However, the AUC 90% CI of nefopam was out of the range. A statistically significant alteration was also observed in the clearance of nefopam. The co-administration exhibited no significant influence on the pharmacokinetic parameters of DXM. CONCLUSIONS: These results indicate that the co-administration of DXM and nefopam using the prefilled multi-drug injector significantly alters some pharmacokinetic parameters of nefopam and has a minor effect on DXM pharmacokinetics.

Compartmental pharmacokinetics of nefopam during mild hypothermia.

BACKGROUND: Nefopam is a non-opioid, non-steroidal, centrally acting analgesic which has an opioid-sparing effect. It also reduces the threshold (triggering core temperature) for shivering without causing sedation or respiratory depression. The drug is therefore useful as both an analgesic and to facilitate induction of therapeutic hypothermia. However, compartmental pharmacokinetics during hypothermia are lacking for nefopam. METHODS: We conducted a prospective, randomized, blinded study in eight volunteers. On two different occasions, one of two nefopam concentrations was administered and more than 30 arterial blood samples were gathered during 12 h. Plasma concentrations were determined using gas chromatography/mass spectrometry to investigate the pharmacokinetics of nefopam with non-linear mixed-effect modelling. RESULTS: A two-compartment mammillary model with moderate inter-individual variability and inter-occasional variability independent of covariates was found to best describe the data [mean (SE): V(1)=24.13 (2.8) litre; V(2)=183.34 (13.5) litre; Cl(el)=0.54 (0.07) litre min(-1); Cl(dist)=2.84 (0.42) litre min(-1)]. CONCLUSIONS: The compartmental data set describing a two-compartment model was determined and could be implemented to drive automated pumps. Thus, work load could be distributed to a pump establishing and maintaining any desired plasma concentration deemed necessary for a treatment with therapeutical hypothermia.

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.

OBJECTIVE: To study the pharmacokinetics and comparative bioavailability of nefopam tablets (Acupan®). SUBJECTS AND METHODS: Experimentation of this study was based on a single-dose, two-sequence, cross-over randomized design using 12 fasting healthy Pakistani male young subjects. This validated LC/MS method was applied to a pharmacokinetic and bioavailability study in 12 fasting healthy Pakistani male subjects from the blood samples taken up to 24 h after an oral dose of one tablet of 30 mg nefopam in a double-blind, randomized, cross-over design. RESULTS: The mean maximum plasma concentration (C(max)) for the reference formulation was 60.71 ± 2.36 ng/ml (± SEM) and for test formulation 60.46 ± 1.30 ng/ml (± SEM). The mean time to reach maximum plasma concentration (T(max)) values of reference and test formulations was 1.63 ± 0.13 h (± SEM) and 1.83 ± 0.07 h (± SEM), respectively. The mean ± SEM values of AUC(0-)∞ for the reference and test formulations were 293.01 ± 16.09 ng·h/ml and 307.53 ± 8.99 ng·h/ml, respectively. CONCLUSION: The results showed that both formulations possessed almost the same relative bioavailability and pharmacokinetic parameters.

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%.

The effects of nefopam on the gain and maximum intensity of shivering in healthy volunteers.

BACKGROUND: Mild hypothermia has been shown to improve neurologic outcome after cardiac arrest. Nefopam, a centrally acting, nonsedative analgesic, decreases the threshold of shivering, but not vasoconstriction, and thus might be a suitable drug for induction of therapeutic hypothermia. However, not only the threshold but also the gain and maximum intensity of shivering define the thermoregulatory properties of a drug and thus are clinically important. Therefore, we evaluated the gain and maximum intensity of shivering at 2 different doses of nefopam and placebo. METHODS: Seven healthy volunteers were randomly assigned to 3 study days: (1) control (saline), (2) small-dose nefopam (50 ng/mL), and (3) large-dose nefopam (100 ng/mL). On all study days volunteers were cooled using central venous infusion of cold IV fluid while mean skin temperature was maintained at 31 degrees C. Core temperature was recorded at the tympanic membrane. Threshold, gain, and maximum intensity of shivering were evaluated using oxygen consumption. RESULTS: Both 50 and 100 ng/mL nefopam significantly reduced the shivering threshold as well as the gain of shivering: shivering threshold: 35.6 degrees C + or - 0.2 degrees C (control); 35.2 degrees C + or - 0.3 degrees C (small dose); 34.9 degrees C + or - 0.5 degrees C (large dose), P = 0.004; gain of shivering: 597 + or - 235 mL x min(-1) x degrees C(-1) (control); 438 + or - 178 mL x min(-1) x degrees C(-1) (small dose); 301 + or - 134 mL x min(-1) x degrees C(-1) (large dose), P = 0.028. Maximum intensity of shivering did not differ among the 3 treatments. CONCLUSIONS: Nefopam significantly reduced the gain of shivering. This reduction, in combination with a reduced shivering threshold, will allow clinicians to cool patients even further when therapeutic hypothermia is indicated.

Specific and sensitive analysis of nefopam and its main metabolite desmethyl-nefopam in human plasma by liquid chromatography-ion trap tandem mass spectrometry.

A specific and sensitive liquid chromatography-tandem mass spectrometric (LC-MS-MS) method using an ion trap spectrometer was developed for quantitation of nefopam and desmethyl-nefopam in human plasma. Nefopam, desmethyl-nefopam and the internal standard (ethyl loflazepate) were extracted in a single step with diethyl ether from 1 mL of alkalinized plasma. The mobile phase consisted of acetonitrile with 0.1% formic acid (50:50, v:v). It was delivered at a flow-rate of 0.3 mL/min. The effluent was monitored by MS-MS in positive-ion mode. Ionisation was performed using an electrospray ion source operating at 200 degrees C. Nefopam and desmethyl-nefopam were identified and quantified in full scan MS-MS mode using a homemade MS-MS library. Calibration curves were linear over the concentration range of 0.78-100 ng/mL with determination coefficients >0.996. This method was fast (total run time<6 min), accurate (bias<12.5%), and reproducible (intra- and inter-assay precision<17.5%) with a quantitation limit of 0.78 ng/mL. The high specificity and sensitivity achieved by this method allowed the determination of nefopam and desmethyl-nefopam plasma levels in patients following either intermittent or continuous intravenous administration of nefopam.

Effect of route of administration on the pharmacokinetic behavior of enantiomers of nefopam and desmethylnefopam.

Nefopam hydrochloride is a non-narcotic analgesic used parenterally and orally as a racemic mixture for the relief of postoperative pain. However, no information is presently available on the oral kinetics of (+) and (-) nefopam in humans. Also, nefopam is metabolized by N-demethylation but it is not known whether the desmethylnefopam enantiomers (DES1 and DES2) are present in plasma following intravenous (I.V.) or oral administration of parent drug. To address these issues, 24 healthy white male subjects received two treatments using a double-blind, placebo-controlled crossover design: oral administration of 20 mg nefopam hydrochloride solution or a placebo solution on a sugar cube, simultaneously with a continuous infusion of 20 mg nefopam hydrochloride or placebo infusion. A chiral assay using LC-MS was developed for the simultaneous determination of both enantiomers of the parent drug and its metabolite in plasma and urine. Following I.V. administration, the kinetics of (+) and (-) nefopam could be fitted to a bi-exponential equation but exhibited no stereoselectivity. Both enantiomers had large clearances (53.7 and 57.5 L/hr) and volumes of distribution (390 and 381 L) and half-lives around 5 hours. Following oral administration, (+) and (-) nefopam were rapidly absorbed with bioavailabilities of 44% and 42%, respectively, probably due to a first-pass effect. After I.V. administration, the enantiomers of desmethylnefopam exhibited lower concentrations and longer half-lives (20.0 h for DES1 and 25.3 h for DES2) relative to nefopam enantiomers. Following oral administration, desmethylnefopam enantiomers' plasma concentrations peaked earlier and higher than after I.V. administration (P < 0.05). Following I.V. and oral administration, desmethylnefopam enantiomers showed stereoselectivity in AUC and Cmax values. Urinary excretion of parent and metabolite enantiomers was less than 5% of dose. This study shows that desmethylnefopam enantiomers can contribute to the analgesic effect of racemic nefopam only when it is administered orally.

Sensitive determination of nefopam and its metabolite desmethyl-nefopam in human biological fluids by HPLC.

Nefopam (NEF) and desmethyl-nefopam (DMN) were assayed simultaneously in plasma, globule and urine samples using imipramine as internal standard. A liquid-liquid extraction procedure was coupled with a reverse phase high-performance liquid chromatography system. This system requires a mobile phase containing buffer (15 mM KH(2)PO(4) with 5 mM octane sulfonic acid: pH 3.7) and acetonitrile (77:33, v/v) through (flow rate=1.5 ml/min) a C(18) Symmetry column (150x4.6 I.D., 5 micrometer particle size: Waters) and a UV detector set at 210 nm. Internal standard was added to 1 ml of plasma or globule sample or 0.5 ml of urine sample, prior to the extraction under alkaline ambiance with n-hexane. The limits of quantification were 1 and 2 ng/ml for both molecules in plasma and globule, respectively; 5 and 10 ng/ml for NEF and DMN in urine, respectively. The method proved to be accurate and precise: the relative error at three concentrations ranged from -13.0 to +12.3% of the nominal concentration for all molecule and biological fluid; the within-day and between-day precision (relative standard deviation %) ranged from 1.0 to 10.1% for all the molecules and biological fluids. The method was linear between 1 and 60 ng/ml for both molecules in the plasma; 2 and 25 ng/ml for both molecules in the globule; 25 and 250 ng/ml for NEF and 50 and 500 ng/ml for DMN in the urine: correlation coefficients of calibration curves (determined by least-squares regression) of each molecule were higher than 0.992 whatever the biological fluid and during the pre-study and in-study validations. This method was successfully applied to a bio-availability study of NEF in healthy subjects.

Determination of plasma nefopam by liquid chromatography and electrochemical detection.

A liquid chromatographic method for the determination of plasma nefopam is presented. A combination of liquid- and solid-phase extraction and electrochemical detection gave clean extracts and, hence, a low limit of detection. Calibration curves were linear over at least two orders of magnitude (1-100 ng/ml) making the method suitable for pharmacokinetic studies.

Nefopam excretion in human milk.

Human milk and plasma samples were obtained from five healthy nursing mothers who were taking nefopam hydrochloride (60 mg four-hourly) for post-episiotomy pain. Concentrations of nefopam were quantified in milk and plasma paired samples, taken daily from birth for 5 days, by a specific paired-ion reverse phase h.p.l.c. method. Although nefopam was present in human milk in an equivalent concentration to plasma (milk: plasma ratio 1.2 +/- 0.7, mean +/- s.d.), the likely infant exposure was less than 0.05 mg kg-1 day-1 which, on a body weight basis, would be less than 3% of the maternal dose.

Quantitative determination of nefopam in human plasma, saliva and cerebrospinal fluid by gas-liquid chromatography using a nitrogen-selective detector.

A sensitive and selective gas-liquid chromatographic method for the determination of nefopam in human plasma, saliva and cerebrospinal fluid has been developed. The method includes the selective extraction of nefopam and the internal standard, orphenadrine, from biological fluids by a double extraction procedure. The extracted nefopam and internal standard are analyzed by a gas chromatograph equipped with a 3% OV-17 glass column and a nitrogen-phosphorus flame ionization detector (NPFID) operated in the nitrogen mode. The detector provides the needed high sensitivity and also selectivity due to the inherent characteristics of NPFID to discriminate against non-nitrogen containing materials. Five nanograms nefopam per ml plasma or saliva are routinely quantitated with a 1-ml sample or as little as 2 ng per ml cerebrospinal fluid with a 3-ml sample. The intra-day reproducibilities, expressed as the relative standard deviation, are 5, 2 and 3% at 10, 35 and 75 ng/ml plasma levels, respectively. The accuracies expressed by relative error at these levels are 12, -4 and -2%, respectively. The inter-day reproducibility is demonstrated by the small relative standard, deviation, 2%, of the slopes from ten plasma standard curves run on ten different days. In various clinical studies in humans the method has been successfully applied to the study of single-dose pharmacokinetics of nefopam and the monitoring of nefopam concentrations in saliva and cerebrospinal fluids.

GLC determination of nanogram quantities of a new analgesic, nefopam, in human plasma.

A sensitive and specific method was developed for the quantitative GLC determination of plasma nefopam levels. The method includes a multiple-step solvent extraction of the analgesic drug and the internal mass standard, orphenadrine. The accuracy, expressed as the relative error, was--4,6,6, and 4% at 20, 40, 70, and 130 ng/ml, respectively. The precision, expressed as relative standard deviation, was 17, 7, 3, and 5% at these same concentrations, respectively. Quantitation of nefopam in human plasma is possible down to 20 ng/ml with a 2-ml plasma sample; the sensitivity can be increased by using larger plasma samples. The methods was applied successfully to the determination of plasma nefopam levels in humans in pharmacokinetic studies at therapeutic doses.

Nefopam HCl interaction study with eight other drugs.

A controlled clinical trial was undertaken to determine potential for drug interaction of nefopam HCl, a new analgesic, with eight other widely used compounds. Nefopam HCl was administered in combination with these drugs and placebo to forty-five healthy volunteer subjects in nine groups of five subjects each. Possible drug interactions were detected by the occurrence of side-effects and interference with bioavailability of the new analgesic, also by changes in vital signs or in various laboratory tests. Results indicated no statistically significant differences in these parameters between the nefopam HCl-placebo regimen and the other eight combinations. Despite this, there were substantial clinical differences in the intensity and incidence of side-effects with combinations of codeine, pentazocine and propoxyphene. These differences warrant further study. Serum nefopam HCl levels were significantly higher on Day 3 than on Day 1, indicating no defect in bioavailability due to drug interaction. Overall, results of this study support the feasibility of concomitant use of these eight drugs with nefopam HCl for short treatment periods.