Pain: neuroanatomy, chemical mediators, and clinical implications.

Most pain information begins at simple, naked nerve endings called nociceptors that form a functional pain unit with nearby tissue capillaries and mast cells. Tissue injury causes these nerve terminals to depolarize, an event that is propagated along the entire afferent fiber eventuating in sensory impulses reaching the spinal cord. This firing of primary afferent fibers at the site of tissue injury causes axonal release of vesicles containing neuropeptides such as substance P, which acts in an autocrine and paracrine manner to sensitize the nociceptor and increase its rate of firing. Cellular damage and inflammation increase concentrations of other chemical mediators such as histamine, bradykinin, and prostaglandins in the area surrounding functional pain units. These additional mediators act synergistically to augment the transmission of nociceptive impulses along sensory afferent fibers. Primary fibers travel from the periphery to the dorsal horn where they synapse on secondary neurons and interneurons. When activated, interneurons exert inhibitory influences on further pain signal trafficking. Efferent supraspinal influences, in turn, determine the activity of interneurons by releasing a variety of neurotransmitter substances, thus resulting in a high degree of modulation of nociception within the dorsal horn. Events occurring in the periphery and in the dorsal horn can cause a dissociation of pain perception from the presence or degree of actual tissue injury. These phenomena involve many chemical mediators and receptor systems, and can increase pain experience qualitatively, quantitatively, temporally, and spatially. The complexity and plasticity of the nociceptive system can make clinical management of pain difficult. Undestanding the structure and chemical signals associated with this system can improve the use of existing analgesics and provide targets for development of newer and more specific pain-fighting drugs.

Neuromyopathy in venous insufficiency.

Since July, 1985, the authors have studied 23 patients with history and physical findings of venous insufficiency syndrome (VIS) confirmed by venous pressure, muscle biopsy, ascending and descending venography, electromyography, and nerve conduction velocity studies. Clinically, swelling appears to be the most important symptom, along with high venous pressure, particularly ambulatory venous pressure, correlated with venography findings. Muscle atrophy was present in 18 cases. Electromyography and nerve conduction velocity studies yielded abnormal findings in 20 of 23 cases. The authors suggest that nerve conduction velocity and EMG studies could perhaps be used as noninvasive tests for diagnosis and follow-up of cases with VIS.

Lipid-soluble and water-soluble beta-blockers. Comparison of the central nervous system depressant effect.

The sedative effects of a relatively lipid-soluble and a water-soluble beta-blocker were compared in 20 male hypertensives, 30 to 60 years old. In a blinded, randomized, crossover study, critical flash fusion frequency and computerized Stroop Word Test were used to assess psychomotor function parameters during a drug-free control day and then following 14 days of either metoprolol, 150 mg daily, or atenolol, 100 mg daily, treatment. Both drugs caused subtle but significant reductions in both parameters of sedation (critical flash fusion frequency and computerized Stroop Word Testing). Sedation was significantly related to serum concentrations of both drugs. The maximum drug-induced change was 17.2% +/- 9% for metoprolol and 19.6% +/- 3% for atenolol. The duration of effect was six hours after atenolol and two hours after metoprolol. Blood pressure control for all patients was similar during both treatment phases. These results demonstrate that relative lipid solubility does not reliably predict the neurologic effects of beta-blockers. The intensity of drug-induced sedation was similar, but the water-soluble agent produced a longer duration of sedative activity.

Accumulation and washout kinetics of valproic acid and its active metabolites.

There is growing evidence that the metabolites of valproic acid (VPA) may be pharmacologically active and could contribute to both the therapeutic and toxic effects of the drug. The accumulation and washout kinetics of VPA and its oxidative metabolites were, therefore, examined in five healthy volunteers. Valproic acid (250-mg capsules) was administered bid for 15 days. Blood samples were obtained periodically during the 15 days of drug administration and for seven days following termination of treatment. Urine was also collected over the final dosing interval. Steady-state serum concentrations of VPA were achieved within three to four days of treatment. The accumulation of all metabolites in serum lagged behind that of the parent compound, with the mono-desaturated metabolites accumulating more slowly than the hydroxylated species. Furthermore, the apparent washout half-life of each metabolite was longer than the elimination half-life of VPA. In general, the unsaturated metabolites were eliminated more slowly than the hydroxylated metabolites. The serum and urinary metabolite profiles of VPA observed in the healthy volunteers were comparable with those reported for epileptic patients. The differences in the disposition kinetics of VPA and of its potentially active metabolites may explain the previously observed dissociation between the pharmacokinetics and pharmacodynamics of the drug in epileptic patients.

Attenuation of response to mental stress in patients with essential tremor treated with metoprolol.

The response to mental stress in patients with benign essential tremor is an exaggeration of the resting tremor. We have studied the ability of metoprolol tartrate to attenuate specifically the tremorgenic response to mental stress in five patients with essential tremor who were each studied on four occasions. Treatment regimens consisted of 0-, 25-, 50-, and 75-mg doses of metoprolol tartrate, given twice daily for seven- to ten-day periods. Tremor was measured while patients were resting comfortably and then again following mental stress over eight-hour study periods. During the baseline study period, the investigational mental stress consistently exaggerated tremor in each patient. Metoprolol treatment reduced both the resting tremor and tremor following mental activity, but the drug-induced change in the response to mental stress was more pronounced than the drug-induced reduction in resting tremor. The ability of metoprolol to blunt the response to mental stress was associated with serum concentrations of the drug. The time courses of metoprolol serum concentrations were similar to the time course of metoprolol's ability to blunt the response to mental stress. Metoprolol possesses the ability to blunt the tremorgenic response to mental stress in patients with essential tremor, but the duration of this effect lasts less than seven hours after administration of a dose.

The relationship between serum concentrations and central nervous system actions of metoprolol.

The relationship between serum levels of metoprolol, hydroxymetoprolol and changes in psychomotor function as measured by standard reaction time and flash fusion frequency was studied. Blinded subjects were given placebo or 150 mg dose of metoprolol and crossed over on the next study day. Flash fusion frequency, reaction time, and serial blood levels of metoprolol and hydroxymetoprolol were collected. Oral dosing of metoprolol produced no significant changes in reaction time. However, significant decreases in flash fusion frequency were observed from 2 to 6 hours after the dose. Changes in flash fusion frequency were related to levels of metoprolol. Flash fusion frequency changes lagged behind the time course of metoprolol concentrations. The nadir of variance in the metoprolol plus hydroxymetoprolol concentration-effect relationship occurred when potency of hydroxymetoprolol was assumed to be 0.3 of metoprolol. These data suggest that the central nervous system actions of metoprolol are related to metoprolol serum levels and occur at low metoprolol concentrations. However, CNS effects of metoprolol do not intensify at high concentrations. Further CNS activity of hydroxymetoprolol may explain the lag seen in the relationship between concentration and CNS effect.

Metoprolol and alpha-hydroxymetoprolol concentrations and reduction in essential tremor.

The relationship between reductions in essential tremor and concentrations of metoprolol and alpha-hydroxymetoprolol was examined in five patients with essential tremor after treatment with 0, 25, 50, and 75 mg metoprolol twice daily for 7 to 10 days. Serum concentrations of metoprolol and alpha-hydroxymetoprolol were measured simultaneous to serial accelerometry measurements of tremor over 8-hr periods. There was a relationship between degree of tremor reduction and steady-state metoprolol concentration. Time course of the drug and metabolite concentration correlated better with the time course of effect than with the time course of metoprolol concentration alone. Data suggest that the alpha-hydroxymetabolite of metoprolol may contribute to the reduction in essential tremor.

High-performance liquid chromatographic determination of metoprolol and alpha-hydroxymetoprolol concentrations in human serum, urine, and cerebrospinal fluid.

A sensitive and simplified high-performance liquid chromatographic procedure was developed for the simultaneous quantification of metoprolol and alpha-hydroxymetoprolol in human serum, as well as cerebrospinal fluid and urine. Following protein precipitation with trichloroacetic acid, the sample was alkalinized with 1 M NaOH and extracted with dichloromethane. The mobile phase consisted of acetonitrile-water (50:50) containing 0.005 M 1-heptanesulfonic acid in 0.001% acetic acid. Using pronetalol as an internal standard, compounds were quantitated using fluorescence detection at 230 nm with a 300-nm emission filter and 0.02 AUFS. Extraction recovery is approximately 80% for both compounds. The lower limits of detection are 5 ng/mL and 4 ng/mL for metoprolol and alpha-hydroxymetoprolol, respectively.

Biochemical and mood responses predictive of stressful diving performance.

Measures of six self-reported moods (assessed using the Mood Questionnaire), serum cholesterol levels, and serum uric acid (SUA) levels were obtained from 26 divers attending the Saturation Diver Training (SDT) course, the most sophisticated and arduous diving course offered by the U.S. Navy. These measures were correlated with various types of diving activity that occurred during the seven years following graduation from the SDT course. Multiple regression analyses showed that two moods, Fear and Happiness, from the Mood Questionnaire, were independently related to years of subsequent diving experience, while mood Fear and cholesterol levels were associated with total number of dives made during this period. The number of dives made to depths of over 100 feet of sea water was related independently to cholesterol levels and mood Happiness. A high frequency of saturation diving (i.e., dives that last for periods in excess of 12 hours) was found for divers with high SUA levels and low scores on mood Fear. Variations in significant mood and biochemical measures across the different types of diving criteria are discussed in terms of the level of stress involved, prior diving experience, psychological traits including perceived control and achievement motivation, and attitudes formed toward diving during the SDT course.

Biochemical variability in a tem sports situation.

Using 13 members of an amateur softball team during the last seven games of the regular season, associations were determined between overall offensive and defensive performance and levels of serum uric acid (SUA) and cholesterol, and urinary adrenaline and noradrenaline. Skilled players were found to have significantly lower cholesterol and noradrenaline levels than less skilled players whether the games were won or lost. Adrenaline and SUA levels did not differ between the two groups nor between losing or winning outcomes. The elevated cholesterol and noradrenaline levels found among the less skilled players may indicate that although they were stressed by the discrepancy between their expectations and their performance, they nonetheless maintained perceived control over performance because of the social support and reinforcement received from the other players and the coach.