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J Lötsch

Publications and source records attributed to J Lötsch.

15 recordsLinked to original sources
PubMed1998

Effects of nasal-airway volume and body temperature on intranasal chemosensitivity.

Interrelations between intranasal detection sensitivity for odor (H2S) and pain (CO2), nasal-airway volume (acoustic rhinometry), and body temperature were studied in young, healthy men across the diurnal cycle. The results showed a weak but statistically significant negative correlation between nasal volume and odor threshold and a weak but positive correlation between body temperature and odor threshold.

Adult↗
PubMed1998

Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration.

BACKGROUND: Morphine-6-beta-glucuronide is a primary morphine metabolite with potent opioid action. However, its low and slow brain permeability eventually prevents its central opioid effects after short-term intravenous administration. Research is needed to establish whether morphine-6-beta-glucuronide qualifies as an analgesic; this study provides the pharmacokinetic bases for such studies. METHODS: Plasma concentration-time data of morphine-6-beta-glucuronide and morphine obtained from 20 healthy volunteers after short-term intravenous administration of either morphine-6-beta-glucuronide or morphine were described by a biexponential disposition curve. Disposition parameters of morphine-6-beta-glucuronide and morphine were estimated by nonlinear regression, and basic pharmacokinetic parameters (clearance, volume of distribution at steady state, and mean disposition residence time) were derived. A new model of metabolite kinetics was applied, and the disposition parameters of morphine and morphine-6-beta-glucuronide were then used to fit the plasma concentration-time profile of morphine-6-beta-glucuronide formed from morphine. Thereby the fraction of morphine metabolized to morphine-6-beta-glucuronide and the mean transit time of morphine across the site of metabolism were estimated. RESULTS: The extent and time course of morphine-6-beta-glucuronide formation from morphine could be well described by a parametric model, with a fraction of morphine metabolized to morphine-6-beta-glucuronide of 7.55% +/- 1.24% and a mean metabolic transit time for morphine to morphine-6-beta-glucuronide of 0.28 +/- 0.21 hour. The underlying disposition of morphine and morphine-6-beta-glucuronide was characterized by clearance (morphine clearance, 32.7 +/- 6 ml.min-1.kg-1, morphine-6-beta-glucuronide clearance, 2.2 +/- 0.4 ml.min-1.kg-1), volume of distribution at steady state (morphine, 1.8 +/- 0.3 L.hr-1; morphine-6-beta-glucuronide, 0.12 +/- 0.02 L.hr-1), and mean disposition residence time (morphine, 1.8 +/- 0.4 hours; morphine-6-beta-glucuronide, 1.7 +/- 0.4 hours). CONCLUSIONS: The time course of morphine-6-beta-glucuronide formation kinetics was analyzed with use of the information on the disposition kinetics of both morphine and preformed morphine-6-beta-glucuronide, which was obtained by separate data fits. The transformation of morphine to morphine-6-beta-glucuronide could be described by two parameters characterizing the extent and delay of metabolite formation. The results of this study will serve as pharmacokinetic bases of future investigations of morphine-6-beta-glucuronide in human beings.

Adult↗
PubMed1997

The negative mucosal potential: separating central and peripheral effects of NSAIDs in man.

OBJECTIVE: We wanted to test whether assessment of both a central pain-related signal (chemo-somatosensory evoked potential, CSSEP) and a concomitantly recorded peripheral signal (negative mucosal potential, NMP) allows for separation of central and peripheral effects of NSAIDs. For this purpose, experimental conditions were created in which NSAIDs had previously been observed to produce effects on phasic and tonic pain by either central or peripheral mechanisms. METHODS: According to a double-blind, randomised, controlled, threefold cross-over design, 18 healthy subjects (11 males, 7 females; mean age 26 years) received either placebo, 400 mg ibuprofen, or 800 mg ibuprofen. Phasic pain was applied by means of short pulses of CO2 to the nasal mucosa (stimulus duration 500 ms, interval approximately 60 s), and tonic pain was induced in the nasal cavity by means of dry air of controlled temperature, humidity and flow rate (22 degrees C, 0% relative humidity, 145 ml.s-1). Both CSSEPs as central and NMPs as peripheral correlates of pain were obtained in response to the CO2 stimuli. Additionally, the subjects rated the intensity of both phasic and tonic pain by means of visual analogue scales. RESULTS: As described earlier, administration of ibuprofen was followed by a decrease in tonic pain but-relative to placebo-an increase in correlates of phasic pain, indicating a specific effect of ibuprofen on the interaction between the pain stimuli under these special experimental conditions. Based on the similar behaviour of CSSEP and NMP, it was concluded that the pharmacological process underlying this phenomenon was localised in the periphery. By means of the simultaneous recording of interrelated peripheral and central electrophysiologic correlates of nociception, it was possible to separate central and peripheral effects of an NSAID. The major advantage of this pain model is the possibility of obtaining peripheral pain-related activity directly using a non-invasive technique in humans.

Adult↗
PubMed1997

Chronobiology of nasal chemosensitivity: do odor or trigeminal pain thresholds follow a circadian rhythm?

Odor and trigeminal pain thresholds were studied four times each at 24:00, 04:00, 08:00, 12:00, 16:00 and 20:00 h in randomized order on different days in five healthy male volunteers. No circadian rhythm of olfactory or trigeminal thresholds were observed. However, the variability of odor, but not pain thresholds, increased from 04:00 h (thresholds between 0.4 and 1.2 p.p.m.) to 16:00 h (thresholds between 0.1 and 2 p.p.m.). It is hypothesized that environmental influences contribute to this increase in variance.

Adult↗
PubMed1997

Lack of analgesic activity of morphine-6-glucuronide after short-term intravenous administration in healthy volunteers.

BACKGROUND: The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an opioid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine. METHODS: In a placebo-controlled, sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of M-6-G identical to and two and three times higher than those measured after administration of morphine. Morphine and M-6-G were administered as an intravenous bolus followed by infusion over 4 h. Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg x kg(-1) x h(-1). Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg x kg(-1) x h(-1). Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg x kg(-1) x h(-1). Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg x kg(-1) x h(-1) for 4 h. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F was a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide. RESULTS: Morphine significantly reduced subjective and objective pain correlates compared with placebo. In contrast, M-6-G produced no statistically significant effects. The addition of M-6-G to morphine did not increase the effects of morphine. Morphine produced significantly more side effects than M-6-G. CONCLUSION: After short-term intravenous administration at doses that produce plasma concentrations of M-6-G similar to those seen after administration of morphine, M-6-G had no analgesic effects in the present placebo-controlled study in healthy volunteers.

Adult↗
PubMed1997

Antinociceptive effects of the kappa-opioid receptor agonist RP 60180 compared with pentazocine in an experimental human pain model.

Agonists at kappa-opioid receptors may preserve the analgesic properties of mu-opioidergic agonists while avoiding their major adverse effects. The present study was aimed to investigate the antinociceptive effects of the new kappa-opioid receptor agonist RP 60180. An experimental pain model was used based on specific pain stimuli and event-related potentials. Effects of RP 60180 were compared to placebo and to pentazocine that served as positive control. Twenty healthy male volunteers participated in a placebo-controlled, randomized, double-blind, five-way cross-over study. Single peroral doses of RP 60180 (0.1, 0.5, and 1.0 mg), pentazocine (50 mg), and placebo were administered. Pain was induced by means of short pulses of gaseous CO2 applied to the nasal mucosa. In response to these stimuli, chemo-somatosensory event-related potentials (CSSERP) and pain ratings were recorded. Maximum antinociceptive effects were observed 2 h after the administration of 1.0 mg of RP 60180 and 50 mg of pentazocine. This was shortly after RP 60180 had reached the maximum plasma concentration and when highest plasma concentrations of pentazocine were measured. Both RP 60180 and pentazocine reduced pain-related CSSERP amplitudes by approximately 40% at this time. Pentazocine tended to produce more side effects. These results indicate the potential therapeutic value of kappa-agonist analgesics.

Adult↗
PubMed1996

Analgesic effects of propyphenazone in comparison to its combination with caffeine.

OBJECTIVE: The aim of the study was to investigate whether the analgesic effect of propyphenazone (PROP) was increased when it was administered in combination with caffeine (CAFF). METHODS: For assessment of analgesia a model was chosen based on chemo-somatosensory event-related potentials (CSSERP) elicited by stimulation of the nasal mucosa. Twenty healthy volunteers participated in the experiments. The study followed a placebo-controlled, randomised, double-blind, 5-fold cross-over design. Each of the 5 medications (400 mg PROP, 600 mg PROP, 400 mg PROP + 100 mg CAFF, 600 mg PROP + 150 mg CAFF, placebo) was orally administered. Experiments were separated by at least 5 days. In addition to assessment of CSSERP, subjects estimated the intensity of the stimulus. Drug effects unrelated to nociception were monitored, and in addition, the plasma levels of PROP were also analysed. RESULTS: While 400 mg PROP did not significantly reduce the amplitude of CSSERP in comparison to placebo, all other medications produced a significant decrease in amplitudes. For both dosages of PROP, there was a significant amplification of the antinociceptive effect of PROP by CAFF, as indicated by the decrease in CSSERP amplitude. A significant effect of the factor "drug" was also found in the spontaneous EEG, indicating an arousal reaction after CAFF. No significant differences between plasma levels of PROP were found when applied either alone or in combination with CAFF. CONCLUSION: The significant increase in the antinociceptive effect of PROP when administered together with caffeine appears to be related either to amplification of PROP's antinociceptive actions by CAFF or an atinociceptive effect of CAFF itself.

Administration, Oral↗
PubMed1996

Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers.

Steady-state pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) after intravenous administration of either morphine or M-6-G were determined in healthy volunteers. With a dosing regimen calculated on the basis of data obtained in a first series of experiments in four subjects (morphine: intravenous loading dose of 0.24 mg/kg for 5 minutes and an intravenous infusion of 0.069 mg.kg-1.hr-1 for 4 hours; M-6-G: loading dose of 0.011 mg/kg for 5 minutes and an infusion of 0.006 mg.kg-1.hr-1 for 4 hours), it was possible to yield plasma concentrations of morphine and M-6-G in another four subjects close to predefined targeted levels (35 and 45.5 ng/ml morphine and M-6-G, respectively). This dosing regimen may be used in further pharmacodynamic studies to compare the analgesic effects of morphine and M-6-G. In addition, metabolite kinetics of M-6-G were calculated as a function of time with use of a linear systems approach to the estimation of rate and fraction of morphine glucuronidation to M-6-G.

Adult↗
PubMed1996

Loss of olfactory function leads to a decrease of trigeminal sensitivity.

Healthy controls were compared to patients with decreased olfactory sensitivity (n = 32) to investigate interactions between the olfactory and trigeminal systems. Amplitudes of chemo-somatosensory event-related potentials in response to suprathreshold trigeminal stimuli (CO2) were found to be smaller in patients (P < 0.05) indicating a decrease of trigeminally mediated sensations.

Action Potentials↗
PubMed1995

Effects of flurbiprofen enantiomers on pain-related chemo-somatosensory evoked potentials in human subjects.

1. The aim of the study was to investigate the analgesic effects of flurbiprofen enantiomers using an experimental pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjective pain ratings. 2. Healthy female volunteers (n = 16, age 23-36 years) participated in a placebo-controlled, randomised, double-blind, four-way crossover study. Single doses of (S)-flurbiprofen (50 mg), (R)-flurbiprofen (50 and 100 mg) and placebo were administered orally. Measurements were taken before and 2 h after administration of the medications. During each measurement, 32 painful stimuli of gaseous carbon dioxide (200 ms duration, interval approximately 30 s) of two concentrations (60 and 65% CO2 v/v) were applied to the right nostril. EEG was recorded from five positions and CSSERP were obtained in response to the painful CO2- stimuli. Additionally, subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale (VAS). 3. The CSSERP-amplitude P2, a measure of analgesic effect, decreased after administration of both (R)- and (S)-flurbiprofen, while it increased after placebo. This was statistically significant at recording positions C4 (P < 0.01) and Fz (P < 0.05). The analgesia-related decreases in evoked potential produced by (R)-flurbiprofen were dose-dependent. Comparing similar doses of (R)- and (S)-flurbiprofen, the decrease in CSSERP-amplitudes produced by the (S)-enantiomer was somewhat more pronounced, indicating a higher analgesic potency. 4. The present data indicate that both enantiomers of flurbiprofen produce analgesic effects. Since (R)-flurbiprofen caused only little toxicity in rats as compared with the (S)-enantiomer or the racemic compound, a reduction of the quantitatively most important side effects in the gastrointestinal tract might be achieved by employing (R)-flurbiprofen in pain therapy.

Adult↗
PubMed1995

Effects of azapropazone on pain-related brain activity in human subjects.

1. The dose-related effects of azapropazone on (i) event-related and spontaneous EEG-activity and (ii) the subjects' pain ratings were investigated using an experimental human pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjects' pain ratings. 2. Healthy subjects (n = 20) participated in a placebo-controlled, randomized, double-blind, four-way cross-over study. Single doses of azapropazone (300 mg, 600 mg and 1200 mg) and placebo were administered intravenously. Each experiment consisted of five sessions (before and 1, 2, 4 and 8 h after administration of the medication). Each session lasted for approximately 40 min. In the first 20 min, pain was induced by short CO2-stimuli presented to the right nostril (phasic pain; interstimulus interval 30 s) and EEG was recorded from five positions. CSSERPs were obtained in response to painful CO2-stimuli. In the following 20 min period, tonic pain was induced by a constant stream of dry air introduced in the left nostril. Subjects rated the intensity of both phasic and tonic pain by means of a visual analogue scale. Additionally, a frequency analysis of the spontaneous EEG was performed. 3. Azapropazone reduced the pain-related CSSERP-amplitudes at frontal and parietal recording positions. This topographical pattern was observed in previous studies with opioids, while NSAIDs such as flurbiprofen and ketoprofen exerted effects at frontal and central positions. In contrast to other NSAIDs, administration of azapropazone resulted in a reduction of the frequency bands alpha 1, delta and theta of the spontaneous EEG. At the subjective level, analgesic effects of azapropazone were observed in the ratings of tonic pain. 4. Analgesic properties of azapropazone were demonstrated in man. The topographical pattern of the changes in the CSSERPs and the effects on EEG background activity suggest a central component of the analgesic action of azapropazone.

Adult↗
PubMed1995

Analgesic effects of dihydrocodeine and tramadol when administered either in the morning or evening.

The aim of the study was to investigate the analgesic effects of two opioids [dihydrocodeine (DHC) and tramadol] when administered either in the morning or evening. The experimental technique used is based on chemosomatosensory event-related potentials (CSSERPs) in response to painful chemical stimuli that are applied to the nasal mucosa. Eighteen healthy volunteers participated in the experiments. The study followed a controlled, randomized, double-blind, sixfold, cross-over design. Thus, each of the three medications (90 mg DHC, 50 mg tramadol, or placebo) was perorally administered to all subjects on different days at 08:00 or 20:00 h. Measurements were performed before and 60, 120, 240, and 360 min after administration of the medication. In addition to the assessment of CSSERP, subjects rated the intensity of the stimuli. Moreover, unspecific drug effects were monitored by means of acoustical event-related potentials and the subjects' performance in a video game. The results indicated that the painful intensity of the chemical stimuli strongly increased during evening sessions. In addition, both DHC and tramadol exerted stronger analgesic effects when administered in the evening. Thus, an inflexible scheme of prescription might produce either an increase of pain in the morning due to insufficient analgesia or the unnecessary overdosing of analgesics in the evening.

Acoustic Stimulation↗
PubMed1994

Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.

Plasma concentrations of the enantiomers of flurbiprofen were measured following oral administration of (S)-flurbiprofen 50 mg and (R)-flurbiprofen 50 mg and 100 mg to sixteen healthy subjects. Chiral inversion did not occur to a measurable extent. Significantly higher values of AUC (55.2 +/- 17.0 vs 44.6 +/- 11.2 micrograms ml-1h) elimination half-life (5.6 +/- 1.4 vs 4.0 +/- 1.0 h) and mean residence time (7.5 +/- 1.6 vs 5.7 +/- 1.2 h) were observed after 50 mg (S)-flurbiprofen as compared with 50 mg (R)-flurbiprofen. With the exception of Cmax and AUC values pharmacokinetic data for the 50 mg and the 100 mg dose of (R)-flurbiprofen did not differ significantly. The data are of clinical relevance if (R)-flurbiprofen also has analgesic activity in humans and is to be developed as an analgesic.

Administration, Oral↗
PubMedDate not supplied

No contribution of morphine-6-glucuronide to clinical morphine effects after short-term administration.

The primary metabolite of morphine, morphine-6-beta-glucuronide (M-6-G), is reported to contribute to the effects of morphine. The authors investigated the effects of M-6-G on the central nervous system (CNS) after short-term intravenous (i.v.) administration by employing both electroencephalograph (EEG) power spectra analyses and clinical signs as indicators of opioid effects. Three dosages of M-6-G, one dosage of morphine (bolus 10 mg/70 kg and 3.5 mg/70 kg/hour for 4 hours), a combination of morphine and M-6-G, and placebo were administered to 20 healthy volunteers as i.v. bolus plus i.v. infusion for 4 hours. M-6-G was dosed to produce steady state plasma concentrations that were either identical, 2 times, or 3 times higher than the M-6-G plasma concentrations observed after administration of morphine. The EEG background activity and clinical effects were recorded 3.5 hours after the infusion started. M-6-G failed to produce effects on any of the investigated EEG or clinical parameters at the doses tested. In contrast, morphine produced a significant increase in the alpha 1 and delta power of the EEG. In addition, morphine increased the subjects' ratings of tiredness, sickness, vertigo, and drowsiness, and decreased their level of performance in a tracking task. It was concluded that after short-term i.v. administration, M-6-G does not affect the CNS at the doses tested. Therefore, its contribution to clinical effects of morphine after short-term administration is questionable. The missing CNS effects were probably caused by the slow brain permeability of M-6-G, which in short-term treatment might not attain effective CNS concentrations.

Adult↗