Pain after orthopaedic surgery: differences in patient reported outcomes in the United States vs internationally. An observational study from the PAIN OUT dataset.

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.

PAIN OUT: the making of an international acute pain registry.

BACKGROUND: About 240 million patients undergo surgery every year, worldwide. Roughly 50% of these patients report clinically significant pain. Numerous barriers impede provision of adequate management. Lack of evidence about appropriateness and effectiveness of interventions is one. A registry can provide such information, eventually facilitating better management. This paper reports the development and feasibility of PAIN OUT, the first international acute pain registry, established with funds from the European Commission, and presents preliminary analysis to illustrate the nature of investigations that registry data make possible. METHODS: On the first postoperative day, 6347 adult patients undergoing orthopaedic or general surgery, in 11 medical centres in Europe and Israel, provided Patient Reported Outcomes (PROs) using a validated questionnaire. Clinical data were abstracted from the patient's chart. RESULTS: Feasibility worked well. Over a period of 1 year, surveyors accrued targeted data sets and entered them into an online browser. Collaborators could receive online feedback comparing their findings about PROs against anonymized findings from other centres. Missing data for the majority of variables were low. Despite considerable variability between institutions, a large number of patients were treated according to the generic, evidence-based recommendations we assessed. However, this was not sufficient to result in acceptable outcomes for the majority of patients. CONCLUSION: The initial development of PAIN OUT has been achieved. From 2013, it continues as a not-for-profit academic project, open to clinicians and researchers worldwide. The International Association for Study of Pain and PAIN OUT will work together to maintain, disseminate and develop the registry.

Feasibility of international data collection and feedback on post-operative pain data: proof of concept.

Post-operative pain exacts a high toll from patients, families, healthcare professionals and healthcare systems worldwide. PAIN-OUT is a research project funded by the European Union's 7th Framework Program designed to develop effective, evidence-based approaches to improve pain management after surgery, including creating a registry for feedback, benchmarking and decision support. In preparation for PAIN-OUT, we conducted a pilot study to evaluate the feasibility of international data collection with feedback to participating sites. Adult orthopaedic or general surgery patients consented to participate between May and October 2008 at 14 collaborating hospitals in 13 countries. Project staff collected patient-reported outcomes and process data from 688 patients and entered the data into an online database. Project staff in 10 institutions met the enrolment criteria of collecting data from at least 50 patients. The completeness and quality of the data, as assessed by rate of missing data, were acceptable; only 2% of process data and 0.06% of patient-reported outcome data were missing. Participating institutions received access to select items as Web-based feedback comparing their outcomes to those of the other sites, presented anonymously. We achieved proof of concept because staff and patients in all 14 sites cooperated well despite marked differences in cultures, nationalities and languages, and a central database management team was able to provide valuable feedback to all.

Pain perception and assessment.

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.

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.

A passion of the soul: an introduction to pain for consciousness researchers.

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.

Requirement of sequences outside the conserved kinase domain of fission yeast Rad3p for checkpoint control.

The fission yeast Rad3p checkpoint protein is a member of the phosphatidylinositol 3-kinase-related family of protein kinases, which includes human ATMp. Mutation of the ATM gene is responsible for the disease ataxia-telangiectasia. The kinase domain of Rad3p has previously been shown to be essential for function. Here, we show that although this domain is necessary, it is not sufficient, because the isolated kinase domain does not have kinase activity in vitro and cannot complement a rad3 deletion strain. Using dominant negative alleles of rad3, we have identified two sites N-terminal to the conserved kinase domain that are essential for Rad3p function. One of these sites is the putative leucine zipper, which is conserved in other phosphatidylinositol 3-kinase-related family members. The other is a novel motif, which may also mediate Rad3p protein-protein interactions.

Suffering: the contributions of persistent pain.

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.

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.

Evidence for a subsurface ocean on Europa.

Ground-based spectroscopy of Jupiter's moon Europa, combined with gravity data, suggests that the satellite has an icy crust roughly 150 km thick and a rocky interior. In addition, images obtained by the Voyager spacecraft revealed that Europa's surface is crossed by numerous intersecting ridges and dark bands (called lineae) and is sparsely cratered, indicating that the terrain is probably significantly younger than that of Ganymede and Callisto. It has been suggested that Europa's thin outer ice shell might be separated from the moon's silicate interior by a liquid water layer, delayed or prevented from freezing by tidal heating; in this model, the lineae could be explained by repetitive tidal deformation of the outer ice shell. However, observational confirmation of a subsurface ocean was largely frustrated by the low resolution (>2 km per pixel) of the Voyager images. Here we present high-resolution (54 m per pixel) Galileo spacecraft images of Europa, in which we find evidence for mobile 'icebergs'. The detailed morphology of the terrain strongly supports the presence of liquid water at shallow depths below the surface, either today or at some time in the past. Moreover, lower-resolution observations of much larger regions suggest that the phenomena reported here are widespread.

Episodic plate separation and fracture infill on the surface of Europa. Galileo Imaging Team.

Images obtained by the Voyager spacecraft revealed dark, wedge-shaped bands on Europa that were interpreted as evidence that surface plates, 50-100 km across, moved and rotated relative to each other. This implied that they may be mechanically decoupled from the interior by a layer of warm ice or liquid water. Here we report similar features seen in higher resolution images (420 metres per pixel) obtained by the Galileo spacecraft that reveal new details of wedge-band formation. In particular, the interior of one dark band shows bilateral symmetry of parallel lineaments and pit complexes which indicates that plate separation occurred in discrete episodes from a central axis. The images also show that this style of tectonic activity involved plates < 10 km across. Although this tectonic style superficially resembles aspects of similar activity on Earth, such as sea-floor spreading and the formation of ice leads in polar seas, there are significant differences in the underlying physical mechanisms: the wedge-shaped bands on Europa most probably formed when lower material (ice or water) rose to fill the fractures that widened in response to regional surface stresses.

Hypnotic analgesia: a constructivist framework.

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.

Measurement in pain therapy: is pain relief really the endpoint?

Pain is not an isolated symptom. Severe pain creates fatigue, impairs concentration, compromises mood, degrades sleep and diminishes overall activity level. The goal of intervention for chronic pain must include alleviating the functional impairment that pain produces as well as its discomfort. Evaluating treatment outcome requires: (1) quantification of both pain intensity and pain-related impairment; and (2) review of how the relationship between these variables changes as a function of treatment. Simply tracking pain intensity level as an indicator of pain relief is insufficient and can lead to misinterpretation of the effects of an intervention.

Pain and the choice to hasten death in patients with painful metastatic cancer.

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.

Comparative efficacy of patient-controlled administration of morphine, hydromorphone, or sufentanil for the treatment of oral mucositis pain following bone marrow transplantation.

A total of 119 bone marrow transplant patients suffering from oral mucositis pain were enrolled in a randomized, double-blind, parallel-group trial comparing the efficacy of patient-controlled analgesia with morphine, hydromorphone and sufentanil. Patient ratings of pain and side-effects on visual analog scales were gathered daily from the start of patient-controlled analgesia (PCA) therapy until the discontinuation of opioid treatment either because of resolution of oral mucositis pain, intolerable side-effects, inadequate pain control, or complications related to transplantation. Of the 119 enrolled subjects, 100 met the evaluable criteria of developing oral mucositis and remaining on the study for at least 2 days. Multivariate analysis of the outcome measures indicated that the analgesia achieved in all three opioid groups was nearly equivalent, while measures of side-effects, especially for the combination of sedation, sleep and mood disturbances, were statistically lower in the morphine group than in hydromorphone or sufentanil groups. Patients in the hydromorphone group exhibited the most variability in pain control. Event analysis also indicated significant differences in time to treatment failure between the three groups, with the morphine arm exhibiting clear superiority. The proportion of patients discontinued because of inadequate pain relief was much higher in the sufentanil group (7/36) as compared to the hydromorphone (0/34) or the morphine group (1/30). The daily opioid consumption pattern showed a continual dose escalation during the first week of therapy for all groups, coincident with worsening mucositis. Morphine consumption reached a plateau by day 5, whereas hydromorphone and sufentanil consumption continued to rise until days 7 and 9, respectively. Sufentanil dose requirement increased by approximately 10-fold compared to morphine and hydromorphone, whose requirements increased only 5-fold, suggesting the possibility of development of acute pharmacological tolerance in some patients with this phenylpiperidine opioid. This study provides support for the recommendation that morphine is the opioid of first choice when patient-controlled analgesia is employed for the treatment of severe oropharyngeal pain in bone marrow transplantation (BMT) patients.

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.

rqh1+, a fission yeast gene related to the Bloom's and Werner's syndrome genes, is required for reversible S phase arrest.

In eukaryotic cells, S phase can be reversibly arrested by drugs that inhibit DNA synthesis or DNA damage. Here we show that recovery from such treatments is under genetic control and is defective in fission yeast rqh1 mutants. rqh1+, previously known as hus2+, encodes a putative DNA helicase related to the Escherichia coli RecQ helicase, with particular homology to the gene products of the human BLM and WRN genes and the Saccharomyces cerevisiae SGS1 gene. BLM and WRN are mutated in patients with Bloom's syndrome and Werner's syndrome respectively. Both syndromes are associated with genomic instability and cancer susceptibility. We show that, like BLM and SGS1, rqh1+ is required to prevent recombination and that in fission yeast suppression of inappropriate recombination is essential for reversible S phase arrest.

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.