Imipramine reduces experimental pain.

In a homogeneous sample of 20 healthy male students, the analgesic effects of the tricyclic antidepressant imipramine (100 mg) were compared to those of the narcotic meperidine (150 mg) and a further tricyclic compound with assumed analgesic properties (fluradoline, 450 mg). Drugs were orally administered, using a placebo controlled, double-blind repeated measures Latin Square design. Phasic pain was induced by intracutaneous electrical shocks with random intensities and interstimulus intervals. Each stimulus block consisted of 80 stimuli and lasted for 20 min. Pain estimates, somatosensory evoked cerebral potentials (SSEPs) and power spectral density of the electroencephalogram (EEG) were measured under each drug condition. Under placebo, pain ratings and SSEP amplitudes were constant within the entire session lasting for approximately 4 h. Meperidine analgesia was evident within 30 min of drug application, reaching a maximum after about 90 min. Imipramine produced a comparable degree of pain reduction, however, with a delay of 2 h. Under both drugs, the decrease in pain ratings was accompanied by decreased amplitudes of the late components of the SSEP, as well as by a reduction in alpha activity and an enhancement of slow EEG waves. Effects of fluradoline on experimental pain could not be affirmed. These findings are discussed in terms of pain relief and decrease in vigilance.

Effects of acetaminophen and antipyrine on non-inflammatory pain and EEG activity.

Antinociceptive effects of the 2 (each 1000 mg, orally) non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen (paracetamol) and antipyrine (phenazone) were investigated with a non-inflammatory experimental pain model in 32 healthy volunteers. Phasic pain was induced by intracutaneously applied brief electrical pulses (20 msec). Pain ratings, cerebral potentials and the EEG delta power were measured in response to the stimuli. Unspecific effects upon the vigilance system were evaluated by spontaneous EEG, auditory evoked potentials and reaction times. The investigation was performed as a placebo-controlled, double-blind crossover study. Blood samples were taken to monitor the plasma concentrations of the active agents. Ninety minutes after medication the 2 NSAIDs produced similar effects upon all pain-relevant target variables, although the mean plasma concentration of antipyrine (15 micrograms/ml) was approximately twice that of acetaminophen (7.5 microgram/ml). Both NSAIDs reduced pain ratings by 6%, late cerebral potentials by 19%, and stimulus-induced delta power of the EEG by 21%. The antipyrine effects emerged earlier, in agreement with its faster kinetics. Both NSAIDs could be differentiated by their effects upon spontaneous EEG activity. Whereas acetaminophen mainly enhanced the power in the theta range, antipyrine predominantly depressed the alpha frequencies. None of the drugs influenced auditory evoked potentials and reaction times. The central effects of acetaminophen and antipyrine are discussed with respect to antinociception and decrease in vigilance.

Antagonism between tilidine and naloxone on cerebral potentials and pain ratings in man.

The effects of the opioid tilidine and the opiate antagonist naloxone on somatosensory evoked potentials (SSEP) and pain ratings (E), elicited by electrical skin stimuli with randomized intensities, were investigated for different, orally administered tilidine and naloxone combinations in a double-blind Latin square design in 15 healthy humans. A high correlation between SSEP amplitudes and E was found for all treatments investigated. Tilidine (100 mg) decreased both SSEP amplitudes and E by about 25% compared to the placebo. No significant differences were found between the analgesic effects of tilidine and TN8 (tilidine 100 mg; naloxone 8 mg). The effects of both treatments were significantly different from those of the naloxone, placebo and TN32 treatments (tilidine 100 mg; naloxone 32 mg), indicating a marked naloxone-induced reversal of tilidine analgesia. Naloxone (32 mg) increased the SSEP amplitudes. No naloxone-induced hyperalgesia was seen in the pain ratings.

Effects of menthol and cold on histamine-induced itch and skin reactions in man.

The effects of cooling and topical application of menthol on histamine-induced itch, wheal and flare reactions of the left lower arm were investigated in a threefold cross-over design with 15 healthy male volunteers. Lowering skin temperature by cooling from 32.8 +/- 0.3 degrees C to 29.7 +/- 0.5 degrees C reduced itch intensity from 260 +/- 47 units to 55 +/- 12 units (visual analogue scale) and flare diameters from 39.0 +/- 2.0 mm to 30.2 +/- 1.8 mm; wheal reactions were not affected. A similar reduction in itch was found under menthol (42 +/- 14 units) although skin temperature was not decreased. These findings suggest a central inhibitory effect of cold sensitive A-delta fibre activation on itch.

Response plasticity of pain evoked reactions in man.

Pain estimation (E), evoked cerebral potential (EP), electrooculogram (EOG), electromyogram of withdrawal reflex activity (EMG) and skin conductance reaction (SCR) were measured in response to electrical skin stimuli in 11 male volunteers (age 21-31 years). Constant current stimuli (20 msec; 2, 3, 6, 10 mA) were applied to a finger tip (averaged pain threshold at 5.1 mA). Interstimulus intervals (20-40 sec) and stimulus intensities were delivered in quasi-randomized order, each intensity appearing 40 times per session. Four sessions were repeated with intervals of two days between sessions. With randomized stimulus intensities, power spectral density functions of the prestimulus EEG indicated a stable non-specific arousal level between and within sessions. Under these conditions no significant response plasticity was found for E and EP, not in the prepain or the pain range, and also not between or within sessions. In contrast, the amplitudes of EOG, EMG and SCR decreased drastically with time, especially between the first and second session, and between the first 10 and second 10 stimuli of equal intensity in each session. EP and E remained highly correlated in repeated sessions. A EOG-EP contamination could be ruled out because of their different time course to repeated stimuli.

Correlations between histamine-induced wheal, flare and itch.

Correlations between the skin reactions wheal and flare and the subjectively reported degree of itch were investigated in response to 1% histamine, intradermally applied by standardized skin prick and by iontophoresis. Experiments were performed with 15 male volunteers using a threefold repeated measures design (skin prick, and iontophoresis with 0.13 mA for 10 s and with 2.0 mA for 10 s). Skin reactions (perpendicular diameters) were determined at the time of their maximum (10 min). Itch was rated on a computerized visual analogue scale which was anchored upon the individual scratch threshold. Most effective in producing itch was the skin prick which caused strong sensations markedly above the scratch threshold during the entire period of measurement (30 min), whereas iontophoresis induced only transient itch sensations. On the other hand, the largest wheals were generated by iontophoresis of both intensities (mean 10 or 14 mm vs 6 mm with skin prick). The higher current induced higher itch, wheal and flare responses, but after eliminating this effect of stimulus intensity, no correlations were found. In contrast, skin prick-induced flare reactions varied with the degree of itch above the scratch threshold (r = 0.56; P < 0.01). Repeated measurements showed a higher stability for the itch reaction with skin prick compared with iontophoresis. It is hypothesized that in iontophoresis the brief (10-s) histamine bolus passed the most superficial pruritoceptive C fibres too quickly to induce long-lasting itch sensations, whereas the skin prick caused a deposit at the dermal-epidermal junction releasing histamine during the entire time of measurement. Consequently, both the C fibre-mediated itch and the axon reflex flare were more pronounced with the skin prick, and the wheal resulting from a permeability increase in the postcapillary venule walls was an independent phenomenon.

A sensitive method to evaluate effects of analgesics in man.

In recent papers (8, 12, 13) it has been shown that the analysis of event related brain potentials has become a powerful tool in attempts to quantify pain experience in man. However, the following conditions have to be fulfilled when cerebral potentials are used to measure experimentally induced pain, as well as pain relief under pharmacological treatments: 1) randomization of stimulus intensities to minimize effects of habituation within and between sessions (3), 2) randomization of interstimulus intervals with a minimum distance of about 15 seconds to avoid overlapping effects, and 3) control of the power spectral density of brain activity immediately before the stimulus is applied. In searching for pain related cerebral potentials a principal component analysis was utilized. The grand mean of all evoked potentials (analysis period 500 ms) was built, and the brain potentials were decomposed into basic waveforms for the different experimental conditions (painful-nonpainful; different kinds of skin stimuli). Two components were found as correlates of the painfulness in a sample of 8 healthy untreated subjects (4). In order to demonstrate the usefulness and sensitivity of the here described methods to quantify analgesic effects in man, the opioide tilidine and the opiate antagonist naloxone were orally administered in different combinations. In detail, the 5 treatments: tilidine (100 mg), naloxone (32 mg), tilidine (100 mg) + naloxone (8 mg), tilidine (100 mg) + naloxone (32 mg), and placebo, were given double blind (3 replications of 5 X 5 Latin squares) in 15 healthy subjects, each participating in 5 sessions with exactly 3 days intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

MEG and EEG show different sensitivity to myogenic artifacts.

Simultaneous measurements of EEG, MEG and EMG were performed during randomized blocks with higher and lower muscular stress in comparison to baseline condition. Power spectral density PSD was analyzed separately for five intervals (theta, delta, alpha, beta, gamma). During increased muscular stress, a significant increase could be observed in most bands of EEG while MEG showed no significant changes. Topography of maximum effects for the EEG render cortical generators implausible and point instead to myogenic sources. This was confirmed by correlating changes in EEG with those in EMG. During reduced muscular stress, only gamma activity of the MEG showed significant amplitude reduction. Modeling myogenic activity, its portion could be estimated to be approximately 10 percent in the spontaneous MEG brain signal.

Principal component analysis of pain-related cerebral potentials to mechanical and electrical stimulation in man.

Single trial event-related cerebral potentials (ERPs) in response to skin stimuli of various intensities and qualities in man were investigated in respect to their nociceptive information content. Electrical constant current stimuli (20 msec, 2 - 8 mA) and mechanical force controlled stimuli (20 msec, 0.8 - 3.2 N) were applied to the tip of the left middle finger. Four intensities of each stimulus quality were given, each intensity appearing 40 times in standardized randomized order. EEG segments (between 5 sec before and 500 msec after stimulus onset) were subjected to computer analysis. ERP wave form was shown to depend upon the amount of alpha waves in the prestimulus EEG. For analysis, only subjects with low power in the alpha band were selected. Principal component analysis was applied to all single trial ERPs measured using the variance-covariance matrix of association. Six principal components (PCs) were extracted accounting for about 90% of total variance. Five of the extracted PCs had well located loading maxima: PC1 (50 - 80 msec), PC4 (140 - 160 msec), PC3 (200 - 250 msec), PC4 (280 - 360 msec), PC5 (400 - 500 msec); PC6 appeared polyphasic. Analysis of variance of the mean PC scores revealed that one PC (PC1) discriminated between quality, and 4 PCs (PC1 - PC4) between quantity of stimulation. Eliminating effects of stimulus intensity resulted in two PCs (PC2, PC4) which distinguished exclusively between non-pain and pain. PCA applied to disjunctive subsets of ERPs, corresponding to the different experimental conditions, yielded practically identical sets of PCs, such that no specific ERP component emerged when pain was reported.

Laser evoked brain potentials in response to painful trigeminal nerve activation.

Long latency brain potentials were evoked by infrared laser stimuli (LEPs) applied to the right forehead in order to activate the thinnest cutaneous A-delta afferents of the upper branch of the trigeminal nerve thus inducing a painful sensation. Ten healthy male subjects participated in 4 identical subsequent sessions, one week apart, receiving 4 blocks of 40 stimuli each. This way the individual trigeminal LEPs, as well as their inter- and intraindividual reliability were determined. Five major components could be identified, denoted by polarity and peak latencies: N150, P230, N300, P360, N480. The LEP waveforms were found to be highly stable within subjects, peak latencies varied by less than 5%. Great variation in waveform appeared amongst subjects, peak latencies varied by more than 15%. The last two components exhibited the largest variability and were not identified in all subjects.

Central analgesic effects of acetylsalicylic acid in healthy men.

Acetylsalicylic acid (CAS 50-78-2) (1000 mg orally) was investigated in a non-inflammatory experimental pain model in healthy male volunteers, selected for maximal homogeneity. Phasic pain was induced by intracutaneously applied electrical pulses of constant current. The nociceptive responses measured were, the pain ratings, the cerebral potentials and the EEG delta power in response to the stimuli. In addition, spontaneous EEG, auditory evoked potentials and reaction times were evaluated to determine effects upon the vigilance system. The study was performed in a placebo-controlled, double-blind repeated measures design. Blood samples were taken to monitor the plasma concentrations of the active agents. Acetylsalicylic acid produced clear analgesic effects in all pain relevant target variables. The effects increased with post-medication time, becoming significantly different from placebo 90 min after medication (p less than 0.01). At this time point the pain ratings were reduced by 4%, the pain related cerebral potentials by 15%, and the stimulus induced delta power of the EEG by 20%. These findings suggest a central action of acetylsalicylic acid by attenuation of experimentally induced nociceptive activity. No influences could be observed upon auditory evoked potentials, spontaneous EEG and reaction times. In other words, acetylsalicylic acid did not change vigilance by unspecific alterations of the CNS. The plasma concentration of acetylsalicylic acid reached mean values of 2.5 +/- 2.4 micrograms/ml within 25 min after oral medication, which remained constant during the entire post-medication period of 105 min. In contrast, the concentration of the metabolite salicylic acid increased steadily reaching mean values of 32.0 +/- 16.8 micrograms/ml at the end of the investigated period.(ABSTRACT TRUNCATED AT 250 WORDS)

Pre-stimulus/post-stimulus relations in EEG spectra and their modulations by an opioid and an antidepressant.

Parametric spectral analysis of late cerebral potential components (later than 80 msec) evoked by painful somatosensory stimuli reveals a stimulus-induced increase of power in the low frequencies, delta and theta. This paper investigates the effect kinetics of the opioid meperidine (150 mg, p.o.) and the antidepressant imipramine (100 mg, p.o.) on spontaneous and evoked EEG activity in a placebo-controlled double-blind cross-over study with 20 healthy male subjects. Brief electrical stimuli (5 msec) were intracutaneously applied on the finger tip with randomized intensities above pain threshold and intervals between 10 and 20 sec. Spectra of short (500 msec) pre- and post-stimulus EEG epochs were evaluated using the maximum entropy method (model order 20). The main findings were: (1) The maximum effects of the 2 drugs upon spontaneous and evoked EEG activity were comparable: in the pre-stimulus (spontaneous) EEG both drugs increased the power in the low frequencies and decreased the power in the alpha range. In the post-stimulus (evoked) EEG the drugs decreased the power in all frequency bands. (2) Since in the low frequency range the drugs exhibited contrary effects upon spontaneous and evoked EEG activity, the pre-/post-stimulus relationship of the delta power was found to be the most sensitive measure for monitoring the cerebral bioavailability of the tested drugs. (3) The time courses of development of the effects of the two drugs were different: maximal effects of meperidine were obtained 85-105 min, and of imipramine 190-210 min after medication. The differences in the effect kinetics agreed with the different pharmacodynamics, with time constants for absorption and elimination of 40 min and 240 min for meperidine, and 240 min and 840 min for imipramine. (4) The most important difference between the 2 drugs was the different effect kinetic. Furthermore, in contrast to meperidine the effects of imipramine upon beta activity could not be separated from placebo, either in the spontaneous or in the evoked EEG activity.

[Comparison of the action of 2 effective analgesics. Experimental study: tramadol versus tilidine/naloxone]. / Zwei effektive Analgetika im Wirkungsvergleich. Experimentelle Studie: Tramadol versus Tilidin/Naloxon.

In the present study involving healthy test subjects, tilidin/naloxone (Valoron N; VAL) proved to have an analgesic effect roughly twice as pronounced as that of tramadol (TRA). Moreover, the analgesic effect of VAL showed a significantly more rapid onset than did that of TRA. This finding reflects the difference in rate of action of the active substances. In accordance with these findings, VAL is thus the most powerful analgesic presently available on the German market on simple prescription.

Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumour necrosis factor-alpha) at the dermal-epidermal junction.

Cytokines have been proposed as histamine-independent itch mediators. To investigate this hypothesis, single doses of interleukin-2 (IL-2, 10 MU/mL) and tumour necrosis factor alpha (TNF-alpha, 10 micrograms/mL) were delivered to the epidermis of 10 healthy volunteers with a controlled skin-prick model; 1% histamine and solvent controls were included in a double-blind, randomized crossover design. Itch ratings (computerized visual analogue scale) were obtained every 20 s for 15 min and cutaneous reactions (weal, flare and temperature) were measured. Reactions were also recorded after 2, 24 and 48 h. The mean itch ratings were: histamine 35.5, IL-2 3.3 (both P < 0.01 compared with control), TNF-alpha 1.6 and solvent control 1.75 (not significant). Weal and flare occurred only with histamine. In two volunteers, an inflammatory papule with transient pruritus developed 12-18 h after applying IL-2. In conclusion, IL-2 showed a rapid, low pruritogenic effect, which may be followed by an inflammatory response. TNF-alpha induced no itching in this setting. Skin-prick testing with appropriate doses of potential pruritogens provides a safe and sensitive model for further chemoreceptor studies.

Seroreactivity to Campylobacter jejuni and gangliosides in patients with Guillain-Barré syndrome.

Seroreactivities to Campylobacter jejuni or Campylobacter coli and to the gangliosides GM1 and GD1b were studied by quantitative and immunoglobulin class-specific ELISAs in 42 patients with recent onset of acute Guillain-Barré syndrome (GBS), in 39 patients with positive Campylobacter serology but no neurologic disease, and in 52 healthy blood donors. GBS patients showed positive reactivities to C. jejuni in 57%, 26%, and 2% for IgG, IgA, and IgM, respectively, while blood donors had corresponding values of 6%, 2%, and 4%. IgG, IgA, and IgM reactivities to GM1 were 48%, 78%, and 56% for GBS patients and 4%, 2%, and 4% for blood donors, respectively. Reactivities to GD1b were 77%, 51%, and 15% for the GBS group and 2%, 8%, and 8% for the blood donors, respectively. Patients with positive Campylobacter serology but no neurologic disease also had antibodies to GM1 and GD1b in over half of the cases. Increased titers to C. jejuni closely correlated with increased titers to GM1 and GD1b.

Pentazocine and flupirtine effects on spontaneous and evoked EEG activity.

Somatosensory (SEP), auditory evoked potentials (AEP) and power spectral density of ongoing EEG (PSD) were investigated under different drug conditions: the opioid pentazocine (30 mg), the centrally acting non-narcotic analgesic flupirtine (80 mg) and placebo were administered i.v. in a double-blind cross-over study (intersession interval 7 days) with 20 healthy male subjects. Intracutaneous electrical stimuli were applied to the finger tip with randomized intensities of two- and threefold individual pain threshold. One stimulus block consisted of 80 trials. Mean values of two stimulus blocks per session were analyzed: one block before and one block 30 min after treatment. Pentazocine significantly reduced the peak-to peak amplitude of the late SEP components (N150-P240) from pretreatment to posttreatment blocks, and flupirtine diminished this amplitude to nearly the same degree. With placebo no substantial reduction was found. In contrast to these drug-induced changes in SEP, the AEP components showed no significant alterations after any treatment. The PSD under pentazocine showed a reduction of total power. This effect was mainly due to a reduced power in the alpha band. The PSD under flupirtine showed slight increases in power of theta, alpha and beta activity. Again, under placebo no changes from pretreatment to posttreatment conditions occurred. The difference in EEG change might suggest different sites of action of the two analgesics.

The analgesic efficacy of flupirtine in comparison to pentazocine and placebo assessed by EEG and subjective pain ratings.

In a placebo-controlled double-blind study the analgesic efficacy of the non-narcotic analgesic flupirtine (80 mg i.v.) was evaluated in comparison with the opioid pentazocine (30 mg i.v.). The variables investigated were the subjects' pain ratings (E), the somatosensory evoked cerebral potentials (SEP), the auditory evoked potentials (AEP) and the power spectral density of the ongoing EEG (PSD). One stimulus block before (PRE) and one stimulus block after (POST) medication were applied. In one stimulus block 80 intracutaneous electrical stimuli of two- and three-fold pain threshold amperage were given in randomized order of intensity and inter-stimulus intervals. Both treatments reduced the subjects' pain ratings significantly, while the placebo values were constant. These effects on pain ratings were in parallel with the SEP changes. The peak-to-peak amplitudes of the late components were significantly diminished by both drugs. Placebo had no effect on this variable. The AEPs remained considerably constant after all three treatments indicating specific drug effect on the pain-related somatosensory pathways. Flupirtine showed effects similar to those of pentazocine in terms of pain relief. The changes in ongoing EEG activity, however, were of a different kind. Pentazocine changed the EEG in an opiate-like manner, while flupirtine increased relative power in the theta and beta range.

Analgesic efficacy of low-dose ketamine. Somatosensory-evoked responses in relation to subjective pain ratings.

BACKGROUND: Low-dose ketamine has been shown to exert analgesic effects. Whether ketamine-induced pain relief may be quantitated by somatosensory evoked cerebral potentials has not been established. METHODS: Thirty healthy volunteers were assigned randomly to one of three groups. Subjects of group 1 (n = 10, control) were given saline as placebo. In groups 2 (n = 10) and 3 (n = 10), intravenous ketamine (0.25 mg. kg-1 and 0.50 mg. kg-1, respectively) was administered. The following variables were recorded at baseline and for 50 min after drug administration: electroencephalographic (EEG) data, somatosensory-evoked late cortical responses (SEP) elicited by intracutaneous stimulation of the fingertip (2-3 fold pain threshold), heart rate, mean arterial blood pressure, and end-tidal PETCO2 via a tight-fitting mask. Electroencephalographic spectral power in selected frequency bands and frequency percentiles were calculated from the spontaneous EEG segment preceding each somatosensory stimulus. Somatosensory-evoked late cortical response parameters were calculated from the respective poststimulus EEG segments. After recording of each EEG response, subjects were asked to rate the individual pain sensation. RESULTS: In group 1, all variables did not change over time. Ketamine administration resulted in dose-dependent decreases in alpha-activity and increases in theta power (group 2: 190%, group 3: 440%). Electroencephalographic changes were not related to changes in pain perception. For the first 30 min after ketamine injection, a dose-dependent decrease of the long-latency N150-P250 somatosensory-evoked late cortical response component was observed (group 2: 15-20%; group 3: 25-30%). Subjective pain ratings were also different between groups, with a higher degree of pain relief in group 3 for the first 30 min. At the end of the observation period, pain relief and the N150-P250 amplitude were comparable in both ketamine groups. CONCLUSIONS: These data indicate that pain relief induced by low-dose ketamine is dose-dependent for the first 30 min after bolus injection. Changes in pain perception may be quantitated by somatosensory-evoked cortical responses. Also, EEG changes are not specific for changes in nociception, but the increase in theta power may reflect the hypnotic effect of low-dose ketamine.

New aspects of itch pathophysiology: component analysis of atopic itch using the 'Eppendorf Itch Questionnaire'.

Itch represents a leading symptom in dermatological practice with many psychophysiological aspects. Instruments for qualitative registration of these central nervous factors and evaluation of therapeutic measures are still missing. We analyzed in detail the subjective itch sensation in 108 patients with acute atopic eczema with a new questionnaire developed in analogy to the McGill pain questionnaire. The descriptors with the highest load in atopic itch and the most frequent reaction patterns in atopic eczema patients were identified. Itch intensity (mean VAS 62%) and eczema severity (SCORAD mean 41 points) showed a different frequency distribution pattern with a correlation of r = 0.33 (p < 0.05). Principal component analysis of the itch questionnaire data was performed and compared with the standardized SCORAD severity index for the patients with atopic eczema. Three main factors of atopic itch explained 58% of the total variance: (1) 'suffering' (correlation with SCORAD, r = 0.6); (2) 'phasic intensity' (correlation with SCORAD, r = 0.4), and (3) 'ecstatic' component (associated with certain active reaction patterns). In conclusion, the complete description of itch has to consider different factors, which may be described on a more general level by three main components. Two of these are correlated with objective criteria of disease activity.