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Our inability to measure pain effectively is a major barrier to progress in pain research and advancement in clinical interventions for pain. Historically, the mind-body dichotomy has constrained our thinking about pain and its quantification. One line of work has pursued pain as the sensory end product of nociception: pain is the realization of signals of tissue injury arriving at the cortex. At the other extreme, some clinicians contend that pain is ''what the patient says it is''. In other words, it is a purely mental and entirely subjective phenomenon. Research on functional brain imaging, psychophysiological research and recent neurophysiological research on animal models provide confluent evidence that both of these positions are misleading oversimplifications. Pain is the emergent product of massive, parallel, distributed processing in the brain that engages structures involved in emotion and cognition as well as in sensation. To advance pain measurement, our research team has examined Sokolov's defense response in human subjects experiencing repeated, brief painful electrical shocks delivered to a fingertip through a tiny electrode. Sokolov proposed that threatening events elicit a hypothalamically-orchestrated pattern of arousal that prepares the organism to cope with threat. Measures of sympathetic nervous system arousal and brain evoked potentials in our subjects reveal a stable pattern of this sort when we subject the data to structural equation modeling. When subjects undergo equally intense shocks delivered through a large electrode, they experience a strong vibration-like, unpleasant sensation that causes discomfort but not nociception. The non-painful shock elicits broad levels of arousal equal to those obtained with painful shocks in subjects, but structural equation modeling demonstrates that such arousal does not conform to the defense response pattern. Moreover, multivariate measures of sympathetic arousal and evoked potentials can discriminate painful from non-painful stimuli more accurately than can subjective pain reports. These observations suggest that pain may have a unique psychophysiological signature. More importantly, perhaps, this approach suggests that the combination of psychophysiological research and multivariate statistics provides an avenue for advancing pain research outside of the mind-body dichotomy.

Pain is an important focus for consciousness research because it is an avenue for exploring somatic awareness, emotion, and the genesis of subjectivity. In principle, pain is awareness of tissue trauma, but pain can occur in the absence of identifiable injury, and sometimes substantive tissue injury produces no pain. The purpose of this paper is to help bridge pain research and consciousness studies. It reviews the basic sensory neurophysiology associated with tissue injury, including transduction, transmission, modulation, and central representation. In addition, it highlights the central mechanisms for the emotional aspects of pain, demonstrating the physiological link between tissue trauma and mechanisms of emotional arousal. Finally, we discuss several current issues in the field of pain research that bear on central issues in consciousness studies, such as sickness and sense of self., (Copyright 1999 Academic Press.)

Pain is a perceived threat or damage to one's biological integrity. Suffering is the perception of serious threat or damage to the self, and it emerges when a discrepancy develops between what one expected of one's self and what one does or is. Some patients who experience sustained unrelieved pain suffer because pain changes who they are. At a physiological level, chronic pain promotes an extended and destructive stress response characterised by neuroendocrine dysregulation, fatigue, dysphoria, myalgia, and impaired mental and physical performance. This constellation of discomforts and functional limitations can foster negative thinking and create a vicious cycle of stress and disability. The idea that one's pain is uncontrollable in itself leads to stress. Patients suffer when this cycle renders them incapable of sustaining productive work, a normal family life, and supportive social interactions. Although patients suffer for many reasons, the physician can contribute substantially to the prevention or relief of suffering by controlling pain. Suffering is a nebulous concept for most physicians, and its relation to pain is unclear. This review offers a medically useful concept of suffering that distinguishes it from pain, accounts for the contributory relation of pain to suffering by describing pain as a stressor, and explores the implications of these ideas for the care of patients.

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.

Hypnotic analgesia remains an enigma. Recent neuroscience studies demonstrate that widespread distributed processing occurs in the brains of individuals experiencing pain. Emerging research and theory on the mechanisms of consciousness, along with this evidence, suggest that a constructivist framework may facilitate both pain research and the study of hypnosis. The authors propose that the brain constructs elements of pain experience (pain schemata) and embeds them in ongoing consciousness. The contents of immediate consciousness feed back to nonconscious, parallel distributed processes to help shape the character of future moments of consciousness. Hypnotic suggestion may interact with such processing through feedback mechanisms that prime associations and memories and thus shape the formation of future experience.

Unrelieved pain has been cited as an important reason why cancer patients may seek to hasten their deaths. We interviewed 48 patients with painful metastatic cancer to ascertain their interest in various active and passive modes of hastening death. Ninety percent of these patients supported the general right of terminally ill patients to passive modes of hastening death and 80% supported the right to active modes such as assisted suicide and euthanasia. If they developed severe pain that could not be relieved, 80% would instruct their physician write a "do not attempt resuscitation" order, 40%-50% would want to receive suicide information or a lethal prescription from their physician, and 34% would request a lethal injection from their physician. Current pain and depression levels were not associated with interest in hastening death, but current somatic symptom burden was significantly associated with this interest.

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.

A morphine to hydromorphone equivalence ratio of 7:1 has become the accepted standard, but evidence supporting it comes from single dose studies performed before the advent of patient controlled analgesia (PCA). We compared morphine and hydromorphone use with PCA in bone marrow transplantation patients who required opioids for the control of severe oral mucositis over several days or weeks. An exploratory analysis of clinical records from 102 patients (981 patient days) who used PCA opioids for varying periods of up to 50 days suggested a morphine to hydromorphone use ratio of 3:1. To clarify this observation, we studied a subset of patients under matched conditions. During a 7 day window in which mean oral mucositis severity did not vary across drug use groups and pain scores did not vary over time, patients in both groups gave equal pain relief satisfaction scores. Thirty-six patients who used morphine and 21 who used hydromorphone contributed data on pain, satisfaction with pain control, and drug consumption. We observed an average morphine/hydromorphone ratio of 3:1. This differs markedly from historical single dose studies used in published dose equivalency recommendations implying that other equivalency ratios in clinical use may be inappropriate.

We report 2 years' experience managing 39 preteen (ages 4-12 years) children with patient-controlled analgesia (PCA) for pain associated with bone marrow transplantation (BMT). We prescribed morphine or hydromorphone PCA (starting bolus 20 micrograms/kg morphine or 2 micrograms/kg hydromorphone) with or without continuous infusion (CI), for a period of 6-74 days. The duration of PCA use (median 19 days) depended upon severity of mucositis or other painful conditions. The peak morphine use was on the 11th day after BMT. We prescribed CI opioids in addition to PCA, either at night or around the clock, in 52% of patients. Ninety-five percent of children successfully mastered PCA to control pain associated with BMT. We observed no instances of drug misuse, parental tampering, accidental overdose, or difficulty weaning from opioids. We conclude that opioid PCA, with or without CI, over several days or weeks is safe and effective for preteen children suffering BMT-related pain.

Pain is a complex, multidimensional perception with affective as well as sensory features. In part, it is a somatically focused negative emotion resembling perceived threat. Suffering refers to a perceived threat to the integrity of the self, helplessness in the face of that threat, and exhaustion of psychosocial and personal resources for coping. The concepts of pain and suffering therefore share negative emotion as a common ground. Examination of the central physiological mechanisms underlying pain, negative emotional arousal, and stress helps clarify the physiological basis of suffering and the causal influences of persistent pain and other stressors. Central mechanisms involve both limbic processing of aversive stimulation and disturbance of the hypothalamo-pituitary-adreno-cortical axis with consequent biological disequilibrium. The palliative care specialist can address suffering proactively as well as reactively by treating potentially chronic pain and symptoms aggressively and promoting the psychosocial well-being of the patient at every opportunity.

This report examines the relationship of plasma drug concentration to analgesic effect following bolus doses of alfentanil, fentanyl and morphine and assesses individual differences in analgesic response among volunteers. We predicted that the 3 opioids would yield disparate analgesic profiles because their physicochemical and pharmacokinetic characteristics differ. Ten healthy volunteers received intravenous bolus doses of either alfentanil, fentanyl, morphine or normal saline on different days. We stimulated their teeth electrically and measured brain evoked potential (EP) and pain report (PR) repeatedly over 2 h to assess analgesic effect. Concurrently, we drew 18 blood samples to assess opioid plasma concentrations during the test period. The relationship between opioid plasma concentration and analgesic effect was well defined for alfentanil but ambiguous for morphine. Fentanyl exhibited a marked hysteresis. We observed noteworthy individual differences in analgesic response with all 3 drugs but these differences were greatest for morphine and least for alfentanil. Inter- and intrasubject variability in analgesic response across drugs is related to the physicochemical properties of the drugs tested.

Pain threshold for electrical stimulation of healthy, unfilled teeth was studied in young and elderly women. Using the methodology of Sensory Decision Theory, ability to discriminate between suprathreshold shocks (d') and response bias were also assessed. No difference in threshold was observed betweeen the young and elderly groups. The elderly women were poorer at discriminating between suprathreshold shocks than the young women. These results were interpreted to reflect the integrity of highthreshold dental pulp afferents in the elderly and a central nervous system deficit on the part of the elderly for discriminating between such shocks. Significant age differences in response bias were also observed. Elderly subjects were biased against reporting shock as very faint pain compared to the young subjects and they restricted the range of their criteria across the six-point rating scale.

The technology for patient intravenous self-administration of morphine has been successfully implemented in postoperative and other clinical settings and can be used with terminal patients who experience pain. The question of whether patients who use such instrumentation will be vulnerable to over-medication or development of addiction has not been addressed. This report reviews two competing theories that bear upon this question and tests their predictions about self-administration of morphine for pain relief using data obtained from patients in a bone marrow transplant unit. The first, Opponent Process Theory, predicts escalating drug use and the development of addictive behavior in patients who self-administer morphine. The second, Control Theory, predicts that patients will self-regulate pain effectively by administering morphine without developing problems of medication abuse or addiction. Patients self-administering morphine for 2 weeks were compared to controls who received the drug via routine staff-controlled continuous infusion procedures. Self-administering patients used significantly less morphine than controls and still achieved the same amount of pain control; moreover, they terminated drug use sooner than controls. The predictions based upon Opponent Process Theory were not supported in these marrow transplant patients, but Control Theory accounted well for the outcomes. These results support the assumption that self-administration of opioids in a medical setting does not put patients at risk for over-medication or addiction.

We studied the time course and intensity of pain of multiple bone marrow aspirations in 30 healthy adult marrow donors receiving acetaminophen with codeine for analgesia immediately after marrow harvesting for allogeneic bone marrow transplantation. Upon discharge, donors were supplied with acetaminophen (315 mg) plus codeine (30 mg) tablets and instructed to use one or two tablets up to every 4 h as needed for pain control. Donors used analgesic medication for a mean (+/- SE) of 3.3 +/- 0.5 days (range = 1-13 days) and reported less than complete pain relief. Subjects reported more pain at time of medication than between doses, indicating that the analgesic was at least partially effective. Male donors tended to report more pain and use more analgesic than did females. We conclude that donors self-regulate their analgesic usage to achieve maximal relief and that incomplete relief with acetaminophen plus codeine may be due to limited efficacy of this analgesic preparation. Our findings suggest that donor pain management may be improved by use of more powerful analgesics.

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.

The effects of lidocaine 2% infiltration on the brain-evoked potential elicited by painful dental stimulation were observed in human subjects. Both the evoked potential wave form and the subjective pain were eliminated by the local anesthetic in 10 volunteers, whereas saline infiltration under identical conditions in 10 others had no effect. These results support our other observations which indicate that brain-evoked potentials recorded during painful dental stimulation are a reliable physiologic correlate of human pain.

Responses to electrical stimulation of the tooth pulp were obtained in both baseline and test sessions for subjects receiving acupuncture, 33 per cent nitrous oxide, or control conditions. A signal-detection analysis across sessions showed that both treatment groups demonstrated reduced sensitivity to stimulation, and increases in bias against reporting strong stimuli as painful. (Key words: Acupuncture; Anesthetics, gases, nitrous oxide; Measurement techniques, sensory decision theory; Pain, sensory decision theory).

Combinations of transcutaneous electrical stimulation (TES) and inhalation of nitrous oxide with oxygen have been used for surgical pain control and this report explored the possible synergism of these two treatments. During painful dental stimulation, 18 subjects gave pain reports while event-related potentials were recorded at vertex. Electrical stimulation was delivered bilaterally at the LI-4 acupuncture points on the hands at 20 Hz, mean = 9.65 mA intensity. Inhalation treatment was nitrous oxide 33% with oxygen. Testing was done on two days to permit evaluation of each treatment alone and their combination. Treatment sequence was counterbalanced. Base-to-peak amplitude and peak latency scores were derived for the event-related potentials under each testing condition. Both stimulation and inhalation treatments altered event-related potential scores and pain report. The combination treatment was significantly more effective than stimulation alone but was not significantly more effective than nitrous oxide alone. Nitrous oxide with oxygen alone reduced peak amplitude at 250 ms and 350 ms, as well as pain report. It increased peak latency at 100 ms. Transcutaneous electrical stimulation alone decreased peak amplitude and latency at 150 ms and increased peak latency at 350 ms. Decreased peak amplitude at 250 ms and increased peak latency at 150 ms were observed when inhalation was added to stimulation, and there was also a significant reduction in pain report. Nine control subjects were studied to demonstrate that analgesic changes were not due to repeated testing. These outcomes demonstrated no synergism between the stimulation and inhalation treatments. The data suggest that nitrous oxide blocks the effects of electrical stimulation at LI-4.

Long-latency evoked potentials (EPs) (50-400 msec) have been obtained from humans during both noxious stimulation of tooth and cutaneous sites in studies of pain and analgesic states. This study investigated whether EPs elicited by tooth and lip stimulation differed in peak latency and whether EPs obtained during painful cutaneous stimulation showed increasing peak latency values with increased conduction distance. Twelve volunteers received painful electrical stimulation at four sites: tooth, lip, thumb, and toe in counterbalanced orders. Evoked potentials recorded at vertex were summation averaged over 128 trials. Multivariate stepwise discriminate analysis was used to determine whether any of the peak latencies of the event-related potentials differed across stimulation sites. No significant latency differences were observed across lip, thumb or toe at any of the major peaks. Since peaks of these EPs did not vary in latency with conduction distance, they appear to reflect processing at higher levels rather than sensory transmission. The negative 140 msec peak of the dental waveform occurred significantly later than the same peak at cutaneous sites.

The practice and theoretical basis of pain measurement is reviewed and critically examined in the areas of animal research, human subjects laboratory investigation and clinical study. The advantages and limitations of both physiological and behavioral methods are discussed in each area, and subjective report procedures are evaluated in human laboratory and clinical areas. The need for procedures that bridge these areas is emphasized and specific issues are identified. Progress in the technology of pain measurement over recent decades is reviewed and directions for future work are suggested.

This contribution reviews the practical applications of evoked potentials (EPs) in the evaluation of experimental studies on analgesic intervention in humans. It is also intended as an introduction to EP methodology, its possibilities, and its limitations, for all fellow researchers working in other fields.

Painful stimulation of tooth pulp and of the maxillary gingiva was undertaken in 16 volunteers. Short-latency evoked potentials (15-50 msec) were recorded over 800 trials in each case at F3-P3 of F4-P4, and the resultant averaged wave forms were compared. The gingival wave was distinct in all subjects and could be averaged across subjects while the dental waves were either noise or very inconsistent over subjects. Averaging of the dental wave forms across subjects yielded an uninterpretable result. It was clear that dental evoked potentials could not be recorded at the sites. These findings could be explained by either or both of two hypotheses: dental afferents are predominantly small fiber, nociceptive end organs that conduct more slowly than soft tissue afferents whereas gingival stimulation activates both large and small fiber populations; and dental representation in somatosensory cortex is different and phylogenetically more primitive than that of neighboring soft tissue. Therefore, the location of the generator sites in cortex and the orientation of the dipole may be different for dental than for gingival wave forms.

We have studied the effects of electrical acupuncture stimulation and transcutaneous electrical stimulation on the ability of human volunteers to perceive pain. Both psychophysical indices and measures of cerebral evoked responses to painful stimuli have been used to demonstrate that these treatments reduce pain perception. A recently completed study showed that the analgesic effects of transcutaneous electrical stimulation can be partly reversed when 0,4 mg of naloxone is injected. This observation suggests that endogenic morphine-like peptides are released in response to low frequency electrical stimulation of the skin.

Effects of inhaling three levels of nitrous oxide in oxygen on event-related brain potentials (ERPs) and pain report were examined in 10 volunteers undergoing painful electrical stimulation of tooth pulp. Previous work by the authors demonstrated that inhalation of nitrous oxide 33 per cent in oxygen, iv injection of 0.1 mg fentanyl, oral administration of 975 mg aspirin, and electrical acupunctural stimulation all reduced ERP amplitudes obtained a vertex during painful tooth pulp stimulation. The authors report here the demonstration of a dose-response relationship between increasing concentrations of nitrous oxide in oxygen and measures of ERP amplitude and pain report. Subjects inhaled room air, nitrous oxide 25 per cent, 37 per cent, and 50 per cent in oxygen while ERPs were recorded and pain reports were given. The procedure was repeated on three separate days with each subject experiencing all levels of treatment on each day. Analyses of variance revealed that both ERP amplitude and pain report significantly decreased as dosage increased, and a significant linear trend was observed for the positive-going ERP wave-form deflection between 160 and 240 ms. Pain report scores decreased significantly (P less than 0.001) and proportionally as dosage increased, but there was not a significant linear trend. Inhalation of nitrous oxide in oxygen increased peak latency for the negative component at 50 ms and the positive component at 90 ms but not for later components. These outcomes demonstrate that amplitude measures of the vertex ERP obtained with dental dolorimetry correlate consistently with pain and analgesia. Simultaneous assessment of brain electrical activity and subjective report appears to be a useful approach for the assessment of analgesia in humans.

Radiant heat stimulation was applied to volunteers and rating scale responses were obtained to assess the analgesic properties of 33 percent nitrous oxide. The methodology of signal detection theory was applied to the data to demonstrate that nitrous oxide reduces both sensitivity to pain and willingness to report pain. This method is superior to threshold estimation for the evaluation of analgesics.

Background: A previous PAIN OUT study found that American orthopaedic-surgical patients rated 'worst pain' higher than did similar European patients. This study aims to confirm these findings in a larger, international patient sample, explore whether risk factors for greater postoperative pain exist disproportionately in the American population, and confirm the findings for one procedure.Methods: Surveyors collected patient reported outcomes (PROs) and perioperative pain management practices using PAIN OUT methodology. Most PROs used 11-point numerical rating scales (0=null, 10=worst possible). Risk factors included: female gender, younger age, high BMI, chronic pain, and opioid use before surgery. Initial analysis used a mixed patient cohort. A secondary analysis used only patients undergoing total knee replacement (TKR). Inference was based primarily on effect size using Cohen's d.Results: 13,770 patients in 13 European and non-European countries (international ) and 564 patients from the United States (US) contributed data on the 1st postoperative day. Three of 11 PROs differed between the cohorts: 'worst pain' {US 7.5 (2.5) vs international 5.6 (2.8); d=0.66 [confidence interval (CI) 0.58-0.75]}; proportion 'receiving information about treatment options' [US 0.86 vs international 0.66; d=0.53 (CI 0.39-0.66)]; reporting adverse effects and their severity [US 0.87 vs international 0.73; d=0.52 (CI 0.38-0.66)]. Risk factors did not differ between the two cohorts. PROs and management patterns in TKR patients were similar to the mixed cohort.Conclusions: Three PROs differed between international and US patients, with higher 'worst pain' for US patients. Neither risk factors, nor patient mix accounted for the observed differences for 'worst pain'.Clinical Trial Registration: NCT 02083835. [ABSTRACT FROM AUTHOR]