Christopher Sivert Nielsen

Individual differences in pain sensitivity: Genetic and environmental contributions

&NA; Large individual differences in pain sensitivity present a challenge for medical diagnosis and may be of importance for the development of chronic pain. Variance in pain sensitivity is partially mediated by genetic factors, but the extent of this contribution is uncertain. We examined cold‐pressor pain and contact heat pain in 53 identical (MZ) and 39 fraternal (DZ) twin pairs, and 4 single twins to determine the heritability of the two phenotypes, and the extent to which the same genetic and environmental factors affect both pain modalities. An estimated 60% of the variance in cold‐pressor pain and 26% of the variance in heat pain was genetically mediated. Genetic and environmental factors were only moderately correlated across pain modalities. Genetic factors common to both modalities explained 7% of the variance in cold‐pressor and 3% of the variance in heat pain. Environmental factors common to both modalities explained 5% of variance in cold‐pressor and 8% of the variance in heat pain. The remaining variance was due to factors that were specific to each pain modality. These findings demonstrate that cold‐pressor pain and contact heat pain are mainly distinct phenomena from both a genetic and an environmental standpoint. This may partly explain disparate results in genetic association studies and argues for caution in generalizing genetic findings from one pain modality to another. It also indicates that differences in pain scale usage account for a minor portion of the variance, providing strong support for the validity of subjective pain ratings as measures of experienced pain.

Individual differences in pain sensitivity: measurement, causation, and consequences.

UNLABELLED Not only are some clinical conditions experienced as more painful than others, but the variability in pain ratings of patients with the same disease or trauma is enormous. Available evidence indicates that to a large extent these differences reflect individual differences in pain sensitivity. Pain sensitivity can be estimated only through the use of well-controlled experimental pain stimuli. Such estimates show substantial heritability but equally important environmental effects. The genetic and environmental factors that influence pain sensitivity differ across pain modalities. For example, genetic factors that influence cold pressor pain have little impact on phasic heat pain and visa versa. Individual differences in pain sensitivity can complicate diagnosis, among other reasons because low sensitivity to pain may delay self-referral. Inclusion of patients with reduced pain sensitivity can attenuate treatment effects in clinical trials, unless controlled for. Measures of pain sensitivity are predictive of acute postoperative pain, and there is preliminary evidence that heightened pain sensitivity increases risk for future chronic pain conditions. At this time, however, it is unclear which experimental pain modalities should be used as predictors for future pain conditions. Careful assessment of each individuals pain sensitivity may become invaluable for the prevention, evaluation, and treatment of pain. PERSPECTIVE Large individual differences in pain sensitivity can complicate diagnosis and pain treatment and can confound clinical trials. Pain sensitivity may also be of great importance for the development of clinical pain. Thus, assessment of pain sensitivity may be relevant for the prevention, evaluation, and treatment of acute and chronic pain.

Persistent postsurgical pain in a general population: prevalence and predictors in the Tromsø study.

TOC summary Persistent pain after surgery is common, but prevalence of clinically relevant pain may be overestimated. Sensory abnormalities are associated with pain and more intense pain. ABSTRACT Population‐based data on the prevalence of persistent postsurgical pain are scarce. This study aimed to assess the prevalence of persistent postsurgical pain in a general population and to describe associated physical, social, and psychological factors, including symptoms of nerve injury and sensitization. A cross‐sectional survey was performed in northern Norway with questionnaire items covering surgery, pain, and sensory abnormalities in the area of surgery. Of the 12,982 participants, 24.0% (3111) had undergone one or more surgical procedures during the 3 years preceding the survey. Of these, 2043 had the surgery performed more than 3 months before the investigation. Persistent pain in the area of surgery was reported by 40.4% of the patients (826 of 2043), moderate or severe pain by 18.3% (373 of 2043). Hypoesthesia, hyperesthesia, or both was reported by 24.5% (501 of 2043). There were strong associations between sensory abnormalities and persistent pain, increasingly with higher pain intensities; odds ratios were 2.68 for hypoesthesia and 6.27 for hyperesthesia. Of the 826 individuals reporting persistent pain in the anatomical area of surgery, 51.0% reported chronic pain when questioned without specific reference to the surgery. The present study supports evidence from clinical studies of persistent postsurgical pain, indicating a high prevalence, but reveals large discrepancies in report of pain, depending on the questions asked and the context in which the questions are presented. Strong associations between sensory abnormalities and pain indicate neuropathic mechanisms in a major proportion of cases.

Twin studies of pain

Twin studies provide a method for estimating the heritability of phenotypes and for examining genetic and environmental relationships between phenotypes. We conducted a systematic review of twin studies of pain, including both clinical and experimental pain phenotypes. Fifty‐six papers were included, whereof 52 addressed clinical phenotypes. Of the most comprehensively studied phenotypes, available data indicates heritability around 50% for migraine, tension‐type headache and chronic widespread pain, around 35% for back and neck pain, and around 25% for irritable bowel syndrome. However, differences in phenotype definitions make these results somewhat uncertain. All clinical studies relied on dichotomous outcomes and none used pain intensity as continuous phenotype. This is a major weakness of the reviewed studies and gives reason to question their validity with respect to pain mechanisms. Experimental pain studies indicate large differences in heritability across pain modalities. Whereas there is evidence for substantial common genetic risk across many clinical pain conditions, different experimental pain phenotypes appear to be associated with different genetic factors. Recommendations for future research include inclusion of pain intensity scaling and number of pain sites in phenotyping. Furthermore, studies examining the genetic relationships between pain phenotypes, in particular between clinical and experimental phenotypes, should be prioritized.

Characterizing individual differences in heat-pain sensitivity

Abstract Heat induced pain has been shown to follow a positively accelerating power function for groups of subjects, yet the extent to which this applies to individual subjects is unknown. Statistical methods were developed for assessing the goodness of fit and reliability of the power function for data from individual subjects with the aim of using such functions for characterizing individual differences in heat‐pain sensitivity. 175 subjects rated ascending and random series of contact heat stimuli with visual analogue scales for pain intensity (VAS‐I) and unpleasantness (VAS‐A). Curve fitting showed excellent model fit. Substitution of model estimates in place of observed VAS scores produced minimal bias in group means, about 0.3 VAS units in the ascending series and 1.0 in the random series, on a 0–100 scale. Individual power function exponents were considerably higher for the ascending than for the random series and somewhat higher for VAS‐A than for VAS‐I (means: ascending VAS‐I=9.04, VAS‐A=9.80; random VAS‐I=4.95, VAS‐A=5.67). The reliability of VAS estimates was high (≧.93), and for the ascending series it remained so when extrapolating 4 °C beyond the empirical range. Exponent reliability was high for the ascending series (VAS‐I=.92; VAS‐A=.91), but considerably lower for the random series (VAS‐I=.69; VAS‐A=.71). Individual differences constituted 60% of the total variance in pain ratings, whereas stimulus temperature accounted for only 40%. This finding underscores the importance of taking individual differences into account when performing pain studies.

ERP indicators of disturbed attention in mild closed head injury: A frontal lobe syndrome?

The purpose of the study was to examine the hypothesis that distractibility is a fundamental characteristic of mild closed head injury (MHI). The claim that cognitive symptoms in MHI are due to a mild type of frontotemporal injury was also investigated. Cognitive event-related potentials (ERPs), accuracy and reaction time to target stimuli in a dichotic listening paradigm, and neuropsychological test results were studied in patients with MHI (N = 15), patients with verified frontal lobe damage (N = 10), and healthy controls (N = 13). Information processing reflecting target detection (N2, P3b) and sustained selective attention (processing negativity) was studied. The MHI and frontal patients did not differ on behavioral measures, except that the MHI group had significantly longer reaction times to target stimuli in the ERP task. Both patient groups had deviant ERPs compared with controls, but their ERP patterns differed in important respects. Contrary to expectations, the MHI patients had the most abnormal ERPs. They showed significantly smaller N2 and Nd amplitudes than frontal patients and controls, indicating that the mediating cognitive mechanisms were not equivalent in MHI and frontal injury. The data suggest that MHI patients allocated less processing resources to the task than either the control subjects or the patients with frontal lobe damage.

Sleep and pain sensitivity in adults.

Abstract Sleep problems and pain are major public health concerns, but the nature of the association between the 2 conditions is inadequately studied. The aim of this study was to determine whether a range of sleep measures is associated with experimental increased pain sensitivity. A cross-sectional large population-based study from 2007 to 2008, the Tromsø 6 study, provided data from 10,412 participants (age: mean [SD], 58 [13] years; 54% women). Self-reported sleep measures provided information on sleep duration, sleep onset latency (SOL), and sleep efficiency, as well as frequency and severity of insomnia. The main outcome measure was pain sensitivity tests, including assessment of cold-pressor pain tolerance. We found that all sleep parameters, except sleep duration, were significantly associated with reduced pain tolerance. Both the frequency and severity of insomnia, in addition to SOL and sleep efficiency, were associated with pain sensitivity in a dose–response manner. Adjusting for demographics and psychological distress reduced the strengths of the hazard ratios, but most associations remained significant in the fully adjusted models. There was also a synergistic interaction effect on pain tolerance when combining insomnia and chronic pain. We conclude that sleep problems significantly increase the risk for reduced pain tolerance. Because comorbid sleep problems and pain have been linked to elevated disability, the need to improve sleep among patients with chronic pain, and vice versa, should be an important agenda for future research.

Information processing deficits in head injury assessed with ERPs reflecting early and late processing stages

ERPs provide informative measures of slowed information processing in head injury. While several studies have reported changes in long latency ERPs (N2, P3) in head injury, the data on early ERP components related to attention selection are inconclusive. The problem may be partly methodological because the standard oddball paradigm does not give an adequate basis for discriminating components contributing to the N1 and P2 waveforms. Following a suggestion by Garcia-Larrea et al. [10: Garcia-Larrea L, Lukasziewicz A-C, Maugière F. Revisiting the oddball paradigm. Non-target vs neutral stimuli and the evaluation of ERP attention effects. Neuropsychologia 1992;30:723-741] we used an extended oddball paradigm to study measures of early processing (N1-average, P250) as well as conventional cognitive ERPs (N1, P2, N2, P3) in a group of head injured patients and controls. We found evidence of deficits in early processing of neutral and non-target stimuli in the patient group, and interpret the findings as an indication that the patients are less efficient in terminating processing of irrelevant stimuli. The results further indicate that processing deviations affect both target and non-target stimuli in the oddball paradigm and thus the allocation of attention in the task as a whole.

ERP indices of resource allocation difficulties in mild head injury.

This study examined the hypothesis that distractibility is a characteristic sequela of mild closed head injury (MHI). The Minnesota Multiphasic Personality Inventory (MMPI-2) was used to study whether comorbid stress-related symptoms are associated with behavioral and electrophysiological indexes of attention. Event-related potentials (ERPs) and performance (reaction time, accuracy) were studied in patients with MHI (n = 20), patients with frontal lesions (n = 14), and healthy controls (n = 20) during a three-tone oddball task. Participants were instructed to detect rare target (2000 Hz) tones, and to withhold responding to equally rare distractor (500 Hz) tones and frequently occurring standard (1000 Hz) tones. All groups distinguished the two classes of deviants as indicated by the larger P3 amplitude to target relative to distractor tones. This indicates that the group with MHI was capable of differential allocation of attentional resources to target and non-target events. However, impaired performance and attenuated ERP amplitudes to both classes of deviants relative to patients with frontal lesions and controls, suggest limited availability, or expenditure of the resources needed for adequate task performance. In the group with MHI, both P3 amplitude and reaction time (RT) were significantly related to subjectively reported distress. The difference in RT disappeared, whereas the P3 amplitude differences between the patient groups remained when adjusting for level of distress.

Increased pain sensitivity among adults reporting irritable bowel syndrome symptoms in a large population-based study

Summary Irritable bowel syndrome is associated with increased pain sensitivity in the general population, independent of sex, age, comorbid chronic pain, and psychological distress. ABSTRACT The aim of this study was to examine whether irritable bowel syndrome (IBS) is associated with increased somatic pain sensitivity in a large population‐based sample and to test whether this association was independent of sex, age, comorbid chronic pain, and psychological distress. Pain sensitivity tests included assessment of heat‐pain threshold (N = 4054) and pressure‐pain threshold (N = 4689) and of cold‐pressor pain intensity and tolerance (N = 10,487). Cox regression and analysis of variance (ANOVA) were used to assess the relationship between IBS and pain sensitivity in stepwise multivariate models. The prevalence of IBS symptoms meeting the ROME II criteria was 5.3%. Compared with control subjects, IBS cases had reduced cold‐pressor tolerance (hazard ratio = 1.4, P < .01), increased cold‐pressor pain intensity ratings (z‐score = +0.20, P < 0.01), and lower heat‐pain thresholds (z‐score = –0.20, P < 0.01), after adjusting for sex and age. These results were only slightly attenuated and remained significant when controlling for comorbid chronic pain and psychological distress. Results for pressure‐pain threshold were not significant. Heat‐ and cold‐pressor pain sensitivity was greatest for the IBS reporting severe chronic abdominal pain, indicating that hyperalgesia in IBS is related to degree of clinical pain rather than to the diagnosis per se. Because all pain tests were all carried out on the upper extremities, our findings indicate the presence of widespread hyperalgesia in IBS, which may be a contributing factor to the high rate of comorbid pain seen in this patient group.