Sensory and affective dimensions of phasic pain are indistinguishable in the self-report and psychophysiology of normal laboratory subjects.

This study evaluated the discriminant validity of subjects differentially scaling the sensory and affective dimensions of pain. It sought to determine (1) whether subjects can differentially scale sensory and affective aspects of phasic laboratory pain in the absence of task demand bias that fosters apparent differential scaling; (2) whether psychophysiologic responses to painful stimuli can predict pain report (PR); and (3) whether such responses contribute more to affective than to sensory judgments. Fifty-six men and 44 women repeatedly experienced varied painful electrical fingertip stimuli at low, medium, and high intensities. On half of the trial blocks, subjects made sensory judgments; on the remainder they made affective judgments. Response measures included PR, pupil dilation, heart rate, respiration rate, skin conductance response (SCR), and late near field evoked potentials. Subjects did not rate the stimuli differently when making sensory versus affective judgments. The psychophysiologic variables, principally the SCR, accounted for 44% of the variance in the PR. Psychophysiologic response patterns did not differentiate affective and sensory judgment conditions. Noteworthy sources of individual differences included baseline PR levels and the linear effects of SCR on PR.

Phasic pupil dilation response to noxious stimulation in normal volunteers: relationship to brain evoked potentials and pain report.

Pupillary response to noxious stimulation was investigated in men (n = 11) and women (n = 9). Subjects experienced repeated trials of noxious electrical fingertip stimulation at four intensities, ranging from faint to barely tolerable pain. Measures included pupil dilation response (PDR), pain report (PR), and brain evoked potentials (EPs). The PDR began at 0.33 s and peaked at 1.25 s after the stimulus. Multivariate mixed-effects analyses revealed that (a) the PDR increased significantly in peak amplitude as stimulus intensity increased, (b) EP peaks at 150 and 250 ms differed significantly in both amplitude and latency across stimulus intensity, and (c) PR increased significantly with increasing stimulus intensity. Men demonstrated a significantly greater EP peak amplitude and peak latency at 150 ms than did women. With sex and stimulus intensity effects partialled out, the EP peak latency at 150 ms significantly predicted PR, and EP peak amplitude at 150 ms significantly predicted the PDR peak amplitude.

Differences among patients in opioid self-administration during bone marrow transplantation.

The distinctive features of individual patients, here termed individual differences, are inescapable aspects of day-to-day patient pain management, but classically designed research studies ignore such differences. This paper introduces statistical pattern visualization methodology for the study of complex individual differences in clinical settings. We demonstrate the application of such methods in patients undergoing bone marrow transplantation (BMT) and suffering severe oral mucositis as a consequence of the aggressive BMT preparative regimen. Oral mucositis produces severe pain and patients often require parenteral opioid medication for several weeks. Unfortunately, the opioid can cause side-effects that limit drug use for pain control. Patients differ in severity and duration of oral mucositis, analgesic response to opioids, and side-effects. We identified and classified individual differences in patterns of drug use, pain control and side-effects in 33 BMT patients who received opioid drug via patient-controlled analgesia (PCA) systems for 7 days or more. These systems allowed bolus dosing and also provided a basic level of analgesic protection through continuous drug infusion. Continuous infusion levels increased or decreased in response to patient bolus self-administration. We employed statistical smoothing (moving average) techniques to remove random variation from the individual data sets and created three-way (trivariate) plots of change over time in drug use, pain and an opioid side-effect (impairment of concentration). The patterns apparent in these plots indicated that 24.2% of patients used PCA optimally (increases in drug use associated with reductions in pain and little or no side-effect), an additional 30.3% manifested a potentially optimal pattern limited by side-effect that worsened with dosing, and 36.4% used PCA suboptimally (modest pain control plus side-effects). In addition, for each subject we created a summary measure for the simultaneous change in three variables: the distance of each day's trivariate score from the origin of a three dimensional plot. This summary measure correlated significantly with the changing severity of patients' oral mucositis over time (r = 0.502). This study demonstrates how interactive graphic techniques can provide a basis for examining changes over time among multiple, correlated variables associated with a single individual. It illustrates the application of such techniques and demonstrates that individual subject data sets merit examination in cases where clinical data reflect human performance.

Hydromorphone analgesia after intravenous bolus administration.

This study investigated the analgesic effects of three intravenous bolus doses of hydromorphone (10, 20, 40 micrograms/kg) on experimental pain measures in normal humans. Ten healthy male volunteers participated in four study sessions, one for each of the hydromorphone doses as well as a placebo (saline). They received the four treatments in counterbalanced order under double-blind conditions and with study days at least 1 week apart. During each session subjects underwent repeated electrical tooth pulp stimulation at intensities sufficient to elicit a rating of 'strong pain' before drug administration. Subjective pain reports (PRs) and dental evoked potential amplitude measures (EPs) served as analgesic effect indicators. We observed dose-dependent analgesia as measured by both PR (P = 0.009) and EP (P = 0.017). Area under the PR versus time curve as well as the EP versus time curve decreased in a log dose-dependent fashion. Although the peak effect was poorly defined, the onset of analgesia was rapid, within 5 min, and maximum analgesic effect was seen between 10 and 20 min after maximum plasma hydromorphone concentration. However, within sessions we found a poor correspondence between hydromorphone plasma concentration and effect. Compared to pain report data from other human studies done in our laboratory, hydromorphone has a shorter time to peak effect compared to morphine, and overall, hydromorphone hydrochloride is approximately five times as potent as morphine sulfate on a milligram basis.

Effects of combining propofol and alfentanil on ventilation, analgesia, sedation, and emesis in human volunteers.

BACKGROUND: Propofol and alfentanil frequently are administered together for intravenous sedation. This study investigated pharmacokinetic and pharmacodynamic interactions between propofol and alfentanil, at sedative concentrations, with specific regard to effects on ventilation, analgesia, sedation, and nausea. METHODS: Ten male volunteers underwent steady-state infusions on 3 separate days consisting of propofol alone, alfentanil alone, or a combination of the two. Target plasma concentrations for propofol were 150, 300, and 600 ng/ml for 1 h at each concentration; for alfentanil it was 40 ng/ml for 3 h. Assessment included serial measurements of (1) ventilatory function (minute ventilation, carbon dioxide production, end-tidal carbon dioxide, ventilatory response to rebreathing 7% CO2); (2) analgesia (subjective pain report in response to graded finger shock and evoked potential amplitude); (3) sedation (subjective rating, observer scores, and digit symbol substitution test); (4) nausea (visual analog scale, 0-100 mm). RESULTS: During combination treatment, propofol plasma concentration was 22% greater than during propofol alone using replicate infusion schemes (P < 0.009). End-tidal carbon dioxide was unchanged by propofol, and increased equally by alfentanil and alfentanil/propofol combined (delta end-tidal carbon dioxide 7.5 and 6.2 mmHg, respectively). Analgesia with propofol/alfentanil combined was greater than with alfentanil alone. (Pain report decreased 50% by PA vs. 28% for alfentanil, P < 0.05). Sedation was greater with propofol/alfentanil combined than with alfentanil or propofol alone (digit symbol substitution test 30 for propofol/alfentanil combined vs. 57 for alfentanil, and 46 for propofol, P < 0.05). Nausea occurred in 50% of subjects during alfentanil, but in none during propofol/alfentanil combination treatment. CONCLUSIONS: The combination of propofol and alfentanil produced greater sedation and analgesia than that with either drug alone. Propofol offset the emetic effects of alfentanil. Equivalent depression of the carbon dioxide response curve, and elevation of end-tidal carbon dioxide occurred with propofol/alfentanil combined and alfentanil.

A computer-based system for controlling plasma opioid concentration according to patient need for analgesia.

Microprocessor-controlled infusion pumps, which allow a patient to self-administer bolus doses of an analgesic to relieve pain, are becoming commonplace. While these patient-controlled analgesia (PCA) systems overcome the large interpatient variations in pharmacokinetics, they do not provide steady relief from pain since they rely on delivering a drug in small, incremental doses. To overcome this problem, the authors developed an algorithm and computer-pump system that allows patients to control their own plasma concentration of analgesic. This approach uses individually predetermined pharmacokinetic parameters to provide steady plasma opioid concentrations that can be increased or decreased by the patient in line with the need for more pain relief or fewer side effects. The control software uses a novel, recursive algorithm to compute the pump rates necessary to maintain constant plasma drug (e.g. morphine) concentrations at desired values and to reach a new steady concentration in response to patient requests. This report describes the mathematical approach to the problem of control of plasma opioid concentration, the application of this new drug delivery system to management of persistent pain in cancer patients undergoing bone marrow transplantation, and the magnitude of pharmacokinetic variability with morphine in this patient population. Results are presented from individual patients using this adjustable drug delivery system continuously for up to 2 weeks to control pain from oral mucositis.

Stimulus intensity and inter-stimulus interval effects on pain-related cerebral potentials.

The inter-relationship between stimulus intensity and inter-stimulus interval (ISI) on pain-related evoked vertex potentials was studied. Sixteen subjects were tested with 4 stimulus intensities at 4 different ISIs forming 16 averaged event-related potentials for each subject. Data were analyzed in 2 ways: first by multiple regression analysis of peak-to-peak amplitudes and secondly by single-trial analysis for each subject based on a linear model employing principal component loadings as basis functions, from which were derived separate time-dependent functions describing the contributions of intensity and ISI. Peak-to-peak amplitudes of the averaged waves increased with increases in either intensity of ISI. There were no significant interactions. However, single-trial analysis revealed subtle, but consistent, differences in the peak latencies between stimulus and ISI components, suggesting that the components arise from distinct sources.

Stepwise shortening: evidence and implications.

The observation that sarcomeres shorten in steps has proved controversial. On the one hand, the phenomenon implies that the contractile process cannot be based on a molecular mechanism that behaves in a random manner: The fact that the steps and pauses characterize the kinetics of large volumes of tissue implies that the elements comprising such volumes must stop and pause synchronously. On the other hand, since current contractile models do not anticipate synchronized behavior, there has been considerable speculation that the phenomenon might not be a genuine feature of contraction, but an instrument-based artifact. We present here a review of observations made with four methods that have been brought to bear on the question. All four show discrete, synchronized contractile behavior. The observation of steps with multiple independent methods implies either that each technique harbors its own " gremlin " that generates spurious steps and pauses of a similar nature, or that the phenomenon is genuine. Finally, some consistent properties of the distribution of step size are considered with respect to possible molecular models.

Quantized nature of sarcomere shortening steps.

A new technique providing real-time high-speed measurements of sarcomere length from on-line analysis of the striation image has been developed. This method of measurement is not susceptible to the problems of interpretation encountered in laser diffraction. Sarcomere shortening patterns were obtained, using this method, from single toe fibres of Rana pipiens, and stepwise phenomena similar to those previously reported from laser diffraction were observed. The distribution of step size showed several peaks, the most prominent corresponding to 5.7 nm per half sarcomere.

Stepwise sarcomere shortening: analysis by high-speed cinemicrography.

Sarcomere shortening in striated muscle appears to follow a regionally synchronized staircase-like time course not anticipated in some cross-bridge models. The visualization method used has been criticized as subject to Bragg diffraction effects. Two independent optical methods were used to visualize a muscle during contraction; agreement between the stepwise behavior observed with the two methods suggests that the phenomenon is genuine.

The natural history of "chipping".

The authors present five case histories illustrating controlled use of opiates ("chipping"). Long-term chippers tend to develop consistent social use patterns that permit and also limit use. The authors conclude that controlled use of opiates is possible and that large numbers of people are involved in such use, although they are hard to locate and identify. Controlled users are differentiated from compulsive users more by their development and maintenance of social drug use rituals than by such variables as availability of the drug and personality and family background of the user.

Social sanctions and rituals as a basis for drug abuse prevention.

This paper will report on preliminary findings of an on-going study of "controlled" use of marihuana, psychedelics, and opiates which point to the possibility of minimizing the social costs of illicit drug use via social control. This study, sponsored by The Drug Abuse Council, Inc., a non-profit private foundation, shows that despite the lack of larger cultural support for controlled illicit drug use and other obstacles, users are able to develop and maintain moderate, long-term, nonabusive, i.e., controlled, drug-using patterns. We will show that these patterns are primarily supported by the development of social drug-using situations in which sanctions and rituals permit use while condemning abuse. In the discussion, we will compare the management of controlled use in our sample to the larger culture's handling of alcohol.