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1.  Sex Differences in the Association Between Cortisol Concentrations and Laboratory Pain Responses in Healthy Children 
Gender medicine  2009;6(Suppl 2):193-207.
Background
Research in adult populations has highlighted sex differences in cortisol concentrations and laboratory pain responses, with men exhibiting higher cortisol concentrations and reduced pain responses compared with women. Yet, less is known about the relationship of cortisol concentrations to pain in children.
Objective
This study examined associations between sex, cortisol, and pain responses to laboratory pain tasks in children.
Methods
Salivary cortisol samples from subjects aged 8 to 18 years were obtained at baseline after entering the laboratory (SCb), after the completion of all pain tasks (SC1), and at the end of the session (SC2), 20 minutes later. Blood cortisol samples were also taken after completion of the pain tasks (BC1) and at the end of the session (BC2), 20 minutes later. Subjects completed 3 counterbalanced laboratory pain tasks: pressure, heat, and cold pressor tasks. Pain measures included pain tolerance, and self-reported pain intensity and unpleasantness for all 3 tasks.
Results
The study included 235 healthy children and adolescents (119 boys, 116 girls; mean age, 12.7 years; range, 8–18 years; 109 [46.4%] were in early puberty; 94 [40.0%] white). Salivary and blood cortisol levels were highly correlated with each other. Salivary cortisol levels for the total sample and for boys and girls declined significantly from SCb to SC1 (P < 0.01), although there were no significant changes from SC1 to SC2. No significant sex differences in salivary or blood cortisol levels were evident at any assessment point. Separate examination of the cortisol–laboratory pain response relationships by sex (controlling for age and time of day) suggested different sex-specific patterns. Higher cortisol levels were associated with lower pain reactivity (ie, increased pressure tolerance) among boys compared with girls at SC1, SC2, and BC1 (SC1: r = 0.338, P = 0.003; SC2: r = 0.271, P = 0.020; and BC1: r = 0.261, P = 0.026). However, higher cortisol levels were related to higher pain response (ie, increased cold intensity [BC2: r = 0.229, P = 0.048] and unpleasantness [BC1: r = 0.237, P = 0.041]) in girls compared with boys.
Conclusions
These findings suggest important sex differences in cortisol–pain relationships in children and adolescents. Cortisol levels were positively associated with increased pain tolerance in boys and increased pain sensitivity in girls.
doi:10.1016/j.genm.2009.03.001
PMCID: PMC3486740  PMID: 19406369
pain; children; cortisol; sex differences
2.  Parent and child anxiety sensitivity: Relationship to children’s experimental pain responsivity 
Anxiety sensitivity (AS) or fear of anxiety sensations has been linked to childhood learning history for somatic symptoms, suggesting that parental AS may impact children’s responses to pain. Using structural equation modeling (SEM), we tested a conceptual model in which parent AS predicted child AS, which in turn predicted a hypothesized latent construct consisting of children’s pain intensity ratings for three laboratory pain tasks (cold pressor, thermal heat and pressure). This conceptual model was tested in 211 non-clinical parent-child pairs (104 girls, mean age = 12.4 years; 178 mothers). Our model was supported in girls only indicating that the sex of the child moderated the hypothesized relationships. Thus, parent AS was related to child laboratory pain intensity via its contribution to child AS in girls but not in boys. In girls, 42% of the effect of parent AS on laboratory pain intensity was explained via child AS. In boys, there was no clear link between parent AS and child AS, although child AS was predictive of experimental pain intensity across sex. Our results are consistent with the notion that parent AS may operate via healthy girls’ own fear of anxiety symptoms to influence their responses to laboratory pain stimuli.
Perspective-The present study highlights sex differences in the links among parent and child anxiety sensitivity (AS; fear of anxiety sensations) and children’s experimental pain responses. Among girls, childhood learning history related to somatic symptoms may be a particularly salient factor in the development of AS and pain responsivity.
doi:10.1016/j.jpain.2005.12.004
PMCID: PMC1540407  PMID: 16632321
anxiety sensitivity; laboratory pain; children; adolescents; parent; sex differences
3.  Experimental pain responses in children with chronic pain and in healthy children: How do they differ? 
BACKGROUND:
Extant research comparing laboratory pain responses of children with chronic pain with healthy controls is mixed, with some studies indicating lower pain responsivity for controls and others showing no differences. Few studies have included different pain modalities or assessment protocols.
OBJECTIVES:
To compare pain responses among 26 children (18 girls) with chronic pain and matched controls (mean age 14.8 years), to laboratory tasks involving thermal heat, pressure and cold pain. Responses to cold pain were assessed using two different protocols: an initial trial of unspecified duration and a second trial of specified duration.
METHODS:
Four trials of pressure pain and of thermal heat pain stimuli, all of unspecified duration, were administered, as well as the two cold pain trials. Heart rate and blood pressure were assessed at baseline and after completion of the pain tasks.
RESULTS:
Pain tolerance and pain intensity did not differ between children with chronic pain and controls for the unspecified trials. For the specified cold pressor trial, 92% of children with chronic pain completed the entire trial compared with only 61.5% of controls. Children with chronic pain exhibited a trend toward higher baseline and postsession heart rate and reported more anxiety and depression symptoms compared with control children.
CONCLUSIONS:
Contextual factors related to the fixed trial may have exerted a greater influence on pain tolerance in children with chronic pain relative to controls. Children with chronic pain demonstrated a tendency toward increased arousal in anticipation of and following pain induction compared with controls.
PMCID: PMC3393051  PMID: 22518373
Acute pain; Cold pressor task; Laboratory pain; Pain intensity; Pressure pain; Thermal heat pain
4.  Pain catastrophizing, physiological indexes, and chronic pain severity: tests of mediation and moderation models 
Journal of behavioral medicine  2008;31(2):105-114.
Catastrophizing about pain is related to elevated pain severity and poor adjustment among chronic pain patients, but few physiological mechanisms by which pain catastrophizing maintains and exacerbates pain have been explored. We hypothesized that resting levels of lower paraspinal muscle tension and/or lower paraspinal and cardiovascular reactivity to emotional arousal may: (a) mediate links between pain catastrophizing and chronic pain intensity; (b) moderate these links such that only patients described by certain combinations of pain catastrophizing and physiological indexes would report pronounced chronic pain. Chronic low back pain patients (N = 97) participated in anger recall and sadness recall interviews while lower paraspinal and trapezius EMG and systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were recorded. Mediation models were not supported. However, pain catastrophizing significantly interacted with resting lower paraspinal muscle tension to predict pain severity such that high catastrophizers with high resting lower paraspinal tension reported the greatest pain. Pain catastrophizing also interacted with SBP, DBP and HR reactivity to affect pain such that high catastrophizers who showed low cardiovascular reactivity to the interviews reported the greatest pain. Results support a multi-variable profile approach to identifying pain catastrophizers at greatest risk for pain severity by virtue of resting muscle tension and cardiovascular stress function.
doi:10.1007/s10865-007-9138-z
PMCID: PMC4180106  PMID: 18158618
Pain catastrophizing; Chronic pain severity; Lower paraspinal muscle tension; Cardiovascular reactivity; Profile approach
5.  Pubertal status moderates the association between mother and child laboratory pain tolerance 
BACKGROUND:
There is limited information regarding the relationship between parent and child responses to laboratory pain induction in the absence of experimental manipulation.
OBJECTIVES:
To assess the association between responses to cold and pressure pain tasks in 133 nonclinical mothers and children (mean age 13.0 years; 70 girls), and the moderating effects of child sex and pubertal status on these mother-child relationships.
METHODS:
Mothers and children independently completed the cold and pressure pain tasks. Multiple linear regression analyses examined the association between mothers’ and children’s laboratory pain responses. The moderating effects of child sex and pubertal status were tested in the linear models by examining the interaction among mother laboratory pain responses, and child sex and pubertal status.
RESULTS:
Mothers’ cold pain anticipatory anxiety and pressure pain intensity were associated with children’s pressure pain anticipatory anxiety. Mothers’ pressure pain tolerance was associated with children’s pain tolerance for both the cold and pressure pain tasks. Mothers’ cold pain tolerance was associated with children’s pressure pain tolerance. Pubertal status moderated two of the three significant mother-child pain tolerance relationships, such that the associations held for early pubertal but not for late pubertal children. Sex did not moderate mother-child pain associations.
CONCLUSIONS:
The results indicate that mother-child pain relationships are centred primarily on pain avoidance behaviour, particularly among prepubertal children. These findings may inform interventions focused on pain behaviours, with a particular emphasis on mothers of prepubertal children, to reduce acute pain responses in their children.
PMCID: PMC3938339  PMID: 24367794
Adolescents; Children; Cold pressor task; Experimental pain; Parents
6.  Asians Differ from non-Hispanic Whites in Experimental Pain Sensitivity 
This study examined differences between Asians and non-Hispanic Whites (Whites) in pain sensitivity, and its relationship to mean arterial pressure (MAP) and heart rate (HR). In 30 Whites (50% female) and 30 Asians (50% female), experimental pain sensitivity was assessed with a hand cold pressor task, yielding measures of pain threshold, tolerance, intensity, and unpleasantness. Mean arterial pressure and HR measurements taken at rest and in response to speech stress were assessed. Perceived stress, anxiety, perfectionism, parental criticism, parental expectations and depressive symptoms were also measured. The results indicated that for the cold pain test, Asians demonstrated significantly lower pain threshold and tolerance levels than Whites. Although no ethnic differences were seen for MAP or HR responses to stress, for whites higher stress MAP levels were correlated with reduced pain sensitivity, while for Asians higher baseline and stress HR levels were correlated with reduced pain sensitivity. Asians reported higher parental expectations and greater parental criticism than Whites. For Asians only, higher levels of perfectionism were related to more depressive symptoms, anxiety and perceived stress. These results indicate that Asian Americans are more sensitive to experimental pain than Whites and suggest ethnic differences in endogenous pain regulatory mechanisms (e.g. MAP and HR). The results may also have implications for understanding ethnic differences in clinical pain.
doi:10.1016/j.ejpain.2010.11.016
PMCID: PMC3165029  PMID: 21561793
pain sensitivity; ethnic differences; Asians; blood pressure; heart rate; perfectionism
7.  Heart rate variability as a biomarker for autonomic nervous system response differences between children with chronic pain and healthy control children 
Journal of Pain Research  2013;6:449-457.
Studies in adults have demonstrated a relationship between lowered heart rate variability (HRV) and poor health. However, less is known about the role of autonomic arousal in children’s well-being. The aim of the current study was to examine resting HRV in children with chronic pain compared to healthy control children and, further, to examine children’s HRV following a series of acute experimental pain tasks in both groups. Participants included 104 healthy control children and 48 children with chronic pain aged 8–17 years. The laboratory session involved a 5-minute baseline electrocardiogram followed by four pain induction tasks: evoked pressure, cold pressor, focal pressure, and a conditioned pain modulation task. After the tasks were complete, a 5-minute post-task electrocardiogram recording was taken. Spectral analysis was used to capture high-frequency normalized power and the ratio of low-to-high frequency band power, signifying cardiac vagal tone and sympathetic balance, respectively. Results revealed that children with chronic pain had significantly lower resting HRV (signified by low high-frequency normalized power and high ratio of low-to-high frequency band power) compared to healthy children; moreover, a significant interaction between groups and time revealed that children with chronic pain displayed a static HRV response to the pain session compared to healthy children, whose HRV was reduced concomitant with the pain session. These findings suggest that children with chronic pain may have a sustained stress response with minimal variability in response to new acute pain stressors.
doi:10.2147/JPR.S43849
PMCID: PMC3684221  PMID: 23788839
laboratory pain; pediatric pain; cold pressor; experimental pain; childhood pain; stress task
8.  Self-reported pain and disability outcomes from an endogenous model of muscular back pain 
Background
Our purpose was to develop an induced musculoskeletal pain model of acute low back pain and examine the relationship among pain, disability and fear in this model.
Methods
Delayed onset muscle soreness was induced in 52 healthy volunteers (23 women, 17 men; average age 22.4 years; average BMI 24.3) using fatiguing trunk extension exercise. Measures of pain intensity, unpleasantness, and location, and disability, were tracked for one week after exercise.
Results
Pain intensity ranged from 0 to 68 with 57.5% of participants reporting peak pain at 24 hours and 32.5% reporting this at 48 hours. The majority of participants reported pain in the low back with 33% also reporting pain in the legs. The ratio of unpleasantness to intensity indicated that the sensation was considered more unpleasant than intense. Statistical differences were noted in levels of reported disability between participants with and without leg pain.
Pain intensity at 24 hours was correlated with pain unpleasantness, pain area and disability. Also, fear of pain was associated with pain intensity and unpleasantness. Disability was predicted by sex, presence of leg pain, and pain intensity; however, the largest amount of variance was explained by pain intensity (27% of a total 40%). The second model, predicting pain intensity only included fear of pain and explained less than 10% of the variance in pain intensity.
Conclusions
Our results demonstrate a significant association between pain and disability in this model in young adults. However, the model is most applicable to patients with lower levels of pain and disability. Future work should include older adults to improve the external validity of this model.
doi:10.1186/1471-2474-12-35
PMCID: PMC3042990  PMID: 21288349
9.  Relationships among Anxious Symptomatology, Anxiety Sensitivity and Laboratory Pain Responsivity in Children 
Cognitive behaviour therapy  2006;35(4):207-215.
Existing laboratory-based research in adult samples has suggested that anxiety sensitivity (AS) increases an individual’s propensity to experience pain-related anxiety which in turn enhances pain responsivity. Such relationships have not been examined in younger populations. Thus, the present study used structural equation modeling (SEM) to test a conceptual model in which AS would evidence an indirect relationship with pain intensity via its contribution to state-specific anticipatory anxiety in relation to a variety of laboratory pain tasks (cold pressor, thermal heat, and pressure pain) in 234 healthy children (116 girls; mean age = 12.6 years, range = 8–18 years). The model further hypothesized that existing anxious symptomatology would demonstrate a direct relationship with pain intensity. Results of the SEM supported the proposed conceptual model with the total indirect effect of AS accounting for 29% of the variance in laboratory pain intensity via its effects on pain-related anticipatory anxiety. AS did not however, evidence a direct relationship with pain intensity. Anxious symptomatology on the other hand, demonstrated a significant direct effect on pain intensity, accounting for 15% of variance. The combined effects of AS, anxiety symptoms, and anticipatory anxiety together explained 62% of the variance in pain intensity. These relationships did not differ for boys and girls indicating no moderating effect of sex in the proposed model. The present results support the potential benefit of assessing both AS and anxiety symptoms in children prior to undergoing painful stimulation.
doi:10.1080/16506070600898272
PMCID: PMC1783843  PMID: 17189238
children; adolescents; anxiety; anxiety sensitivity; laboratory pain; experimental pain; pain intensity
10.  How Well Do Clinical Pain Assessment Tools Reflect Pain in Infants? 
PLoS Medicine  2008;5(6):e129.
Background
Pain in infancy is poorly understood, and medical staff often have difficulty assessing whether an infant is in pain. Current pain assessment tools rely on behavioural and physiological measures, such as change in facial expression, which may not accurately reflect pain experience. Our ability to measure cortical pain responses in young infants gives us the first opportunity to evaluate pain assessment tools with respect to the sensory input and establish whether the resultant pain scores reflect cortical pain processing.
Methods and Findings
Cortical haemodynamic activity was measured in infants, aged 25–43 wk postmenstrual, using near-infrared spectroscopy following a clinically required heel lance and compared to the magnitude of the premature infant pain profile (PIPP) score in the same infant to the same stimulus (n = 12, 33 test occasions). Overall, there was good correlation between the PIPP score and the level of cortical activity (regression coefficient = 0.72, 95% confidence interval [CI] limits 0.32–1.11, p = 0.001; correlation coefficient = 0.57). Of the different PIPP components, facial expression correlated best with cortical activity (regression coefficient = 1.26, 95% CI limits 0.84–1.67, p < 0.0001; correlation coefficient = 0.74) (n = 12, 33 test occasions). Cortical pain responses were still recorded in some infants who did not display a change in facial expression.
Conclusions
While painful stimulation generally evokes parallel cortical and behavioural responses in infants, pain may be processed at the cortical level without producing detectable behavioural changes. As a result, an infant with a low pain score based on behavioural assessment tools alone may not be pain free.
Rebeccah Slater and colleagues show that although painful stimulation generally evokes parallel cortical and behavioral responses in infants, pain may produce cortical responses without detectable behavioral changes.
Editors' Summary
Background.
Pain is a sensory and emotional experience. It is normally triggered by messages transmitted from specialized receptors (nociceptors) in the body to integrative centers in the spinal cord and brainstem and on to the brain, where it undergoes higher sensory and cognitive analysis, allowing the body to respond appropriately to the stimuli. While the experience of pain may be considered to be unpleasant, it is a useful tool in communicating to us and to others that there is something wrong with our bodies. Ultimately, these responses help restrict further damage to the body and start the process of healing.
In a clinical setting, the ability to communicate about pain allows an individual to seek strategies to ease the pain, such as taking analgesics. Being unable to effectively communicate one's experience of pain leaves the individual vulnerable to prolonged suffering. One such vulnerable group is infants.
Ignored and untreated pain in infants has been shown to have immediate and long-term effects as a result of structural and physiological changes within the nervous system. For example, the body responds to untreated pain by increased release of stress hormones, which may be associated with increased morbidity and mortality in the short term. Long-term effects of pain may include altered pain perception, chronic pain syndromes, and somatic complaints such as sleep disturbances, feeding problems, and inability to self-regulate in response to internal and external stressors. It has been proposed that attention deficit disorders, learning disorders, and behavioral problems in later childhood may be linked to repetitive pain in the preterm infant.
Why Was This Study Done?
Until as recently as the 1990s, newborns in some clinical centres underwent surgery with minimal anesthesia. Also, newborns received little or no pain management postoperatively or for painful procedures such as lumbar punctures or circumcisions. Since then, there has been growing awareness amongst clinicians that pain may be experienced from the earliest stages of postnatal life and that inadequate analgesia may lead to the type of long-term consequences mentioned above. However, gauging how much pain infants and young children are experiencing remains a substantial challenge. The researchers in this study wanted to assess the association between cortical pain responses in young infants and currently used tools for the assessment of pain in these infants. These current tools are based on behavioral and physiological measures, such as change in facial expression, and it is possible that these tools do not give an adequate measure of pain especially in infants born preterm.
What Did the Researchers Do and Find?
Twelve clinically stable infants were studied on 33 occasions when they required a heel lance to obtain a blood sample for a clinical reason. The researchers examined the relationship between brain activity and a clinical pain score, calculated using the premature infant pain profile (PIPP) in response to a painful event. Activity in the somatosensory cortex was measured noninvasively by near-infrared spectroscopy, which measures brain regional changes in oxygenated and deoxygenated hemoglobin concentration. The PIPP is a well-established pain score that ascribes a value to infant behavior such as change in facial expression.
They found that changes in brain activity in response to a painful stimulus were related to the PIPP scores. These changes were more strongly linked to the behavioral components of the PIPP, e.g., facial expression, than physiological components, e.g., heart rate. They also found that a positive brain response could occur in the absence of any facial expression.
What Do These Findings Mean?
Behaviors to communicate pain require motor responses to sensory and emotional stimuli. The maturity of this complex system in infants is not clearly understood. The results of this study raise further awareness of the ability of infants to experience pain and highlight the possibility that pain assessment based on behavioral tools alone may underestimate the pain response in infants.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050129.
Important papers on pain in human neonates are discussed in the open access Paediatric Pain Letter with links to original articles
The Institute of Child Health in London has a Web site describing a three-year international project on improving the assessment of pain in hospitalized children, with many useful links
The International Association for the Study of Pain (IASP) provides accurate and up-to-date information and links about pain mechanisms and treatment
doi:10.1371/journal.pmed.0050129
PMCID: PMC2504041  PMID: 18578562
11.  Relationships between Irritable Bowel Syndrome Pain, Skin Temperature Indices of Autonomic Dysregulation, and Sensitivity to Thermal Cutaneous Stimulation 
Pain Research and Treatment  2010;2010:949027.
This study evaluated relationships between irritable bowel syndrome (IBS) pain, sympathetic dysregulation, and thermal pain sensitivity. Eight female patients with diarrhea-predominant IBS and ten healthy female controls were tested for sensitivity to thermal stimulation of the left palm. A new method of response-dependent thermal stimulation was used to maintain pain intensity at a predetermined level (35%) by adjusting thermal stimulus intensity as a function of pain ratings. Clinical pain levels were assessed prior to each testing session. Skin temperatures were recorded before and after pain sensitivity testing. The temperature of palmar skin dropped (1.5°C) when the corresponding location on the opposite hand of control subjects was subjected to prolonged thermal stimulation, but this response was absent for IBS pain patients. The patients also required significantly lower stimulus temperatures than controls to maintain a 35% pain rating. Baseline skin temperatures of patients were significantly correlated with thermode temperatures required to maintain 35% pain ratings. IBS pain intensity was not significantly correlated with skin temperature or pain sensitivity. The method of response-dependent stimulation revealed thermal hyperalgesia and increased sympathetic tone for chronic pain patients, relative to controls. Similarly, a significant correlation between resting skin temperatures and thermal pain sensitivity for IBS but not control subjects indicates that tonic sympathetic activation and a thermal hyperalgesia were generated by the chronic presence of visceral pain. However, lack of a significant relationship between sympathetic tone and ratings of IBS pain casts doubt on propositions that the magnitude of IBS pain is determined by psychological stress.
doi:10.1155/2010/949027
PMCID: PMC3196965  PMID: 22110918
12.  Gender expression, sexual orientation and pain sensitivity in women 
Biological sex is known to have significant effects on pain, with women typically experiencing higher levels of pain compared with men. Although extensive research has been conducted investigating the effects of biological sex on pain, research investigating the effects of gender and sexual orientation is lacking, particularly with regard to women. The authors of this article conducted a study investigating correlations between measures of gender expression and preferred gender expression in a romantic partner in a convenience sample of 172 women, including lesbian and bisexual women as well as heterosexual women.
BACKGROUND:
Despite a growing body of literature investigating sex differences with regard to pain, surprisingly little research has been conducted on the influence of various aspects of self-identity, including gender expression and sexual orientation, on pain sensitivity within each sex, particularly among women. In men, dispositional femininity is linked to greater clinical pain and trait masculinity is associated with higher pain thresholds.
OBJECTIVES:
To examine whether gender expression and sexual orientation are associated with within-sex differences in ischemic pain sensitivity in healthy young women.
METHODS:
A convenience sample of 172 females (mean age 21.4 years; range 18 to 30 years of age; 56.0% white, 89% heterosexual) performed an ischemic pain task in counterbalanced order. Desired levels of dispositional femininity for a preferred romantic partner and self-described levels of personal dispositional femininity were measured.
RESULTS:
Compared with heterosexual women, lesbian and bisexual women reported lower pain intensity ratings early in the discomfort task. Irrespective of sexual orientation, attraction to more feminine romantic partners and dispositional masculinity were correlated with lower pain intensity, and with higher pain thresholds and tolerance levels.
DISCUSSION:
These preliminary findings suggest that within-sex differences in sexual orientation and other aspects of identity, irrespective of biological sex, may be important to consider when examining experimental pain performance and clinical pain experiences.
CONCLUSION:
Larger investigations of the psychophysiological relationships among sexual orientation, gender expression and pain sensitivity are warranted. These findings may have implications for differences in clinical pain sensitivity of lesbian and bisexual women compared with heterosexual women.
PMCID: PMC4028658  PMID: 24575419
Bisexuals; Experimental pain; Gender; Lesbians; Women’s health
13.  A Novel Tool for the Assessment of Pain: Validation in Low Back Pain 
PLoS Medicine  2009;6(4):e1000047.
Joachim Scholz and colleagues develop and validate an assessment tool that distinguishes between radicular and axial low back pain.
Background
Adequate pain assessment is critical for evaluating the efficacy of analgesic treatment in clinical practice and during the development of new therapies. Yet the currently used scores of global pain intensity fail to reflect the diversity of pain manifestations and the complexity of underlying biological mechanisms. We have developed a tool for a standardized assessment of pain-related symptoms and signs that differentiates pain phenotypes independent of etiology.
Methods and Findings
Using a structured interview (16 questions) and a standardized bedside examination (23 tests), we prospectively assessed symptoms and signs in 130 patients with peripheral neuropathic pain caused by diabetic polyneuropathy, postherpetic neuralgia, or radicular low back pain (LBP), and in 57 patients with non-neuropathic (axial) LBP. A hierarchical cluster analysis revealed distinct association patterns of symptoms and signs (pain subtypes) that characterized six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain. Using a classification tree analysis, we identified the most discriminatory assessment items for the identification of pain subtypes. We combined these six interview questions and ten physical tests in a pain assessment tool that we named Standardized Evaluation of Pain (StEP). We validated StEP for the distinction between radicular and axial LBP in an independent group of 137 patients. StEP identified patients with radicular pain with high sensitivity (92%; 95% confidence interval [CI] 83%–97%) and specificity (97%; 95% CI 89%–100%). The diagnostic accuracy of StEP exceeded that of a dedicated screening tool for neuropathic pain and spinal magnetic resonance imaging. In addition, we were able to reproduce subtypes of radicular and axial LBP, underscoring the utility of StEP for discerning distinct constellations of symptoms and signs.
Conclusions
We present a novel method of identifying pain subtypes that we believe reflect underlying pain mechanisms. We demonstrate that this new approach to pain assessment helps separate radicular from axial back pain. Beyond diagnostic utility, a standardized differentiation of pain subtypes that is independent of disease etiology may offer a unique opportunity to improve targeted analgesic treatment.
Editors' Summary
Background
Pain, although unpleasant, is essential for survival. Whenever the body is damaged, nerve cells detecting the injury send an electrical message via the spinal cord to the brain and, as a result, action is taken to prevent further damage. Usually pain is short-lived, but sometimes it continues for weeks, months, or years. Long-lasting (chronic) pain can be caused by an ongoing, often inflammatory condition (for example, arthritis) or by damage to the nervous system itself—experts call this “neuropathic” pain. Damage to the brain or spinal cord causes central neuropathic pain; damage to the nerves that convey information from distant parts of the body to the spinal cord causes peripheral neuropathic pain. One example of peripheral neuropathic pain is “radicular” low back pain (also called sciatica). This is pain that radiates from the back into the legs. By contrast, axial back pain (the most common type of low back pain) is confined to the lower back and is non-neuropathic.
Why Was This Study Done?
Chronic pain is very common—nearly 10% of American adults have frequent back pain, for example—and there are many treatments for it, including rest, regulated exercise (physical therapy), pain-killing drugs (analgesics), and surgery. However, the best treatment for any individual depends on the exact nature of their pain, so it is important to assess their pain carefully before starting treatment. This is usually done by scoring overall pain intensity, but this assessment does not reflect the characteristics of the pain (for example, whether it occurs spontaneously or in response to external stimuli) or the complex biological processes involved in pain generation. An assessment designed to take such factors into account might improve treatment outcomes and could be useful in the development of new therapies. In this study, the researchers develop and test a new, standardized tool for the assessment of chronic pain that, by examining many symptoms and signs, aims to distinguish between pain subtypes.
What Did the Researchers Do and Find?
One hundred thirty patients with several types of peripheral neuropathic pain and 57 patients with non-neuropathic (axial) low back pain completed a structured interview of 16 questions and a standardized bedside examination of 23 tests. Patients were asked, for example, to choose words that described their pain from a list provided by the researchers and to grade the intensity of particular aspects of their pain from zero (no pain) to ten (the maximum imaginable pain). Bedside tests included measurements of responses to light touch, pinprick, and vibration—chronic pain often alters responses to harmless stimuli. Using “hierarchical cluster analysis,” the researchers identified six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain based on the patterns of symptoms and signs revealed by the interviews and physical tests. They then used “classification tree analysis” to identify the six questions and ten physical tests that discriminated best between pain subtypes and combined these items into a tool for a Standardized Evaluation of Pain (StEP). Finally, the researchers asked whether StEP, which took 10–15 minutes, could identify patients with radicular back pain and discriminate them from those with axial back pain in an independent group of 137 patients with chronic low back pain. StEP, they report, accurately diagnosed these two conditions and was well accepted by the patients.
What Do These Findings Mean?
These findings indicate that a standardized assessment of pain-related signs and symptoms can provide a simple, quick diagnostic procedure that distinguishes between radicular (neuropathic) and axial (non-neuropathic) low back pain. This distinction is crucial because these types of back pain are best treated in different ways. In addition, the findings suggest that it might be possible to identify additional pain subtypes using StEP. Because these subtypes may represent conditions in which different pain mechanisms are acting, classifying patients in this way might eventually enable physicians to tailor treatments for chronic pain to the specific needs of individual patients rather than, as at present, largely guessing which of the available treatments is likely to work best.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000047.
This study is further discussed in a PLoS Medicine Perspective by Giorgio Cruccu and and Andrea Truini
The US National Institute of Neurological Disorders and Stroke provides a primer on pain in English and Spanish
In its 2006 report on the health status of the US, the National Center for Health Statistics provides a special feature on the epidemiology of pain, including back pain
The Pain Treatment Topics Web site is a resource, sponsored partly by associations and manufacturers, that provides information on all aspects of pain and its treatment for health care professionals and their patients
Medline Plus provides a brief description of pain and of back pain and links to further information on both topics (in English and Spanish)
The MedlinePlus Medical Encyclopedia also has a page on low back pain (in English and Spanish)
doi:10.1371/journal.pmed.1000047
PMCID: PMC2661253  PMID: 19360087
14.  The Role of Coping and Race in Healthy Children’s Experimental Pain Responses 
Journal of pain management  2008;1(2):151-162.
This study examined the relationship between race, laboratory-based coping strategies and anticipatory anxiety and pain intensity for cold, thermal (heat) and pressure experimental pain tasks. Participants were 123 healthy children and adolescents, including 33 African Americans (51% female; mean age =13.9 years) and 90 Caucasians (50% female; mean age = 12.6 years). Coping in response to the cold task was assessed with the Lab Coping Style interview; based on their interview responses, participants were categorized as ‘attenders’ (i.e., those who focused on the task) vs. ‘distractors’ (i.e., those who distracted themselves during the task). Analysis of covariance (ANCOVA) revealed significant interactions between race (African-American vs. Caucasian) and lab-based coping style after controlling for sex, age and socioeconomic status. African-American children classified as attenders reported less anticipatory anxiety for the cold task and lower pain intensity for the cold, heat and pressure tasks compared to those categorized as distractors. For these pain outcomes, Caucasian children classified as distractors reported less anticipatory anxiety and lower pain intensity relative to those categorized as attenders. The findings point to the moderating effect of coping in the relationship between race and experimental pain sensitivity.
PMCID: PMC2845994  PMID: 20352035
pain; coping; race; children
15.  Relationship of child perceptions of maternal pain to children’s laboratory and nonlaboratory pain 
Previous research has established links between parent and child pain. However, little is known about sex-specific parent-child pain relationships in a nonclinical population. A sample of 186 children aged eight to 18 years (49% female) provided information on maternal and self bodily pain, assessed by asking children about the presence and location of bodily pain experienced. Children also completed three laboratory pain tasks and reported on cold pressor pain intensity, pressure pain intensity and heat pain intensity. The presence of child-reported maternal pain was consistently correlated with daughters’ bodily and laboratory pain, but not with sons’ pain in bivariate analyses. Multivariate analyses controlling for child age and maternal psychological distress indicated that children of mothers with bodily pain reported more total bodily pain sites as well as greater pressure and cold pain intensity, relative to children of mothers without bodily pain. For cold pain intensity, these results differed for boys versus girls, in that daughters reporting maternal pain evidenced significantly higher cold pain intensity compared with daughters not reporting maternal pain. No such differences were found for boys. The findings suggest that children’s perceptions of maternal pain may play a role in influencing children’s own experience of pain, and that maternal pain models may affect boys and girls differently.
PMCID: PMC2642517  PMID: 18592057
Children; Pain; Sex differences; Social learning
16.  Relationship of child perceptions of maternal pain to children's laboratory and non-laboratory pain 
Previous research has established links between parent and child pain. Yet little is known about sex-specific parent-child pain relationships in a non-clinical population. A sample of 186 children aged 8–18 years (49% female) provided information on maternal and self bodily-pain, assessed by asking children about the presence and location of bodily pain experienced. Children also completed three laboratory pain tasks and reported on cold pressor pain intensity, pressure pain intensity and heat pain intensity. The presence of child-reported maternal pain was consistently correlated with daughters’ bodily and laboratory pain, but not with sons’ pain in bivariate analyses. Multivariate analyses controlling for child age and maternal psychological distress indicated that children of mothers with bodily pain reported more total bodily pain sites as well as greater pressure and cold pain intensity, relative to children of mothers without bodily pain. For cold pain intensity, these results differed for boys vs. girls, in that daughters reporting maternal pain evidenced significantly higher cold pain intensity compared to daughters not reporting maternal pain. No such differences were found for boys. The findings suggest that children’s perceptions of maternal pain may play a role in influencing children’s own experience of pain and that maternal pain models may affect boys and girls differently.
PMCID: PMC2642517  PMID: 18592057
pain; sex differences; social learning; children
17.  Perception of Thermal Pain and the Thermal Grill Illusion Is Associated with Polymorphisms in the Serotonin Transporter Gene 
PLoS ONE  2011;6(3):e17752.
Aim
The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 (‘tri-allelic 5-HTTLPR’) genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI.
Results
Thresholds to heat- and cold-pain correlated strongly (rho  = −0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p = 0.02) and cold-pain (p = 0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p = 0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men.
Conclusion/Significance
We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms.
doi:10.1371/journal.pone.0017752
PMCID: PMC3057988  PMID: 21423614
18.  Relationship of Salivary Alpha Amylase and Cortisol to Social Anxiety in Healthy Children Undergoing Laboratory Pain Tasks 
Objective
Salivary alpha amylase (sAA) has been shown to be a sensitive and reliable marker of the autonomic nervous system (ANS) response to stress. A link between sAA, cortisol, and social/evaluative stress has been established in youth, but little is known about these relationships in response to other stressors in children, and how social anxiety might moderate these relationships. The current study explored the associations among sAA and salivary cortisol responses to laboratory pain tasks and self-reported social anxiety symptoms in a sample of healthy children.
Method
Two hundred thirty-one children (114 girls; 49.4%) with a mean age 12.68 years (SD=3.0; range 7–18) participated in the study. Participants completed self-report questionnaires prior to undergoing a series of laboratory pain tasks involving cold, pressure, and heat pain. Saliva samples were collected upon arrival to the laboratory (pre-task), following the completion of the pain tasks (post-task1), and 20 minutes after the completion of the pain tasks (post-task2).
Results
Demographic factors (age, sex, pubertal stage) did not predict either sAA or cortisol levels. However, children reporting higher levels of social anxiety demonstrated significantly higher sAA but not cortisol levels across three salivary collection times, compared to children reporting lower levels of social anxiety. Further, it does not appear that reduced state levels of anxiety before or during the tasks buffer this relationship.
Conclusion
These data highlight the possibility of identifying biomarkers of stress that are consistent across time and developmental stage. sAA appears to be a marker of stress response in children with self-reported social anxiety. There may also be a potentially unique relationship of sAA to stress in this population. In addition, sAA may reflect stable individual differences in levels of ANS arousal and may be a useful biomarker for identifying children at risk for stress.
doi:10.4172/jcalb.1000129
PMCID: PMC4267054  PMID: 25525630
Alpha amylase; Cortisol; Social anxiety; Anxiety; stress; Children; Youth; Pain
19.  A Randomized, Controlled Investigation of Motor Cortex Transcranial Magnetic Stimulation (TMS) Effects on Quantitative Sensory Measures in Healthy Adults: Evaluation of TMS Device Parameters 
The Clinical journal of pain  2011;27(6):486-494.
There is emerging evidence that transcranial magnetic stimulation (TMS) can produce analgesic effects in clinical samples and in healthy adults undergoing experimentally induced pain, and the field of minimally invasive brain stimulation for the management of pain is expanding rapidly. While, motor cortex is the most widely used cortical target for TMS in the management of neuropathic pain, few studies have systematically investigated the analgesic effects of a full range of device parameters to provide initial hints about what stimulation intensities and frequencies are most helpful (or even potentially harmful) to patients. Further, there is considerable inconsistency between studies with respect to laboratory pain measurement procedures, TMS treatment parameters, sophistication of the sham methods, and sample-sizes. The present study employed a sham-controlled, within-subject, cross-over design to examine the effects of five different TMS treatment parameters across several quantitative sensory measures in a sample of healthy adult volunteers. 65 participants underwent quantitative sensory testing procedures pre- and post- 40-minutes of real and sham motor cortex TMS. TMS was delivered at 1Hz 80% resting motor threshold (rMT), 1Hz 100%rMT, 10Hz 80%rMT, 10Hz 100%rMT, or 50Hz triplets at 90% of active motor threshold (intermittent theta-burst). The mean painfulness rating of real TMS stimulation itself was 3.0 (SE=.36) out of 10 and was significantly greater than zero (t(64)=8.17, p<.0001). The sham TMS methods used permitted matching between real and sham TMS-induced scalp sensations and participants were successfully blinded to condition (real versus sham). Findings suggest that the effects of motor cortex TMS on quantitative sensory tests in healthy adults vary across different treatment parameters with the smallest observed effect for intermittent theta-burst stimulation (Cohen's d=0.03) and the largest for 10Hz 100%rMT (d=.34). Overall, TMS was associated with statistically significant effects on warm and cool sensory thresholds, cold pain thresholds, suprathreshold stimulus unpleasantness ratings and wind-up pain. With respect to device parameter effects, higher frequency stimulation appears to be associated with the most analgesic and anti-sensitivity effects with the exception of intermittent theta-burst stimulation. The present findings support several clinical research findings suggesting that higher TMS frequencies tend to be associated with the most clinical benefit in patients with chronic pain.
doi:10.1097/AJP.0b013e31820d2733
PMCID: PMC3111894  PMID: 21415720
transcranial magnetic stimulation; pain; motor cortex; TMS; thermal; theta
20.  Lower Bone Mineral Content in Hypertensive Compared with Normotensive Overweight Latino Children and Adolescents 
American journal of hypertension  2007;20(2):190-196.
Background
In adults, hypertension has been shown to be inversely correlated with bone mineral content (BMC); however, the association between blood pressure (BP) and BMC has not been studied in pediatrics.
Methods
Total body BMC of 187 overweight (mean BMI=28.7 kg/m2) Latino children and adolescents (mean age=11.2 years) were measured using dual-energy x-ray absorptiometry. Seated systolic (SBP) and diastolic (DBP) blood pressure were measured using a standard mercury sphygmomanometer. Hypertension was defined by SBP or DBP above the 90th percentile for height, age, and gender.
Results
Partial correlations revealed an inverse association between SBP and BMC (r=- 0.24, p=0.02) in boys (n=105); results were non-significant (p=0.27) in girls (n=82). There were no significant correlations between DBP and BMC. When BMI and insulin sensitivity were adjusted for, hypertensive boys (n=21) had lower BMC (1435 versus 1636 g; p=0.03) than normotensive boys (n=84); similarly, hypertensive girls (n=25) had lower BMC (1438 versus 1618 g; p=0.02) than normotensive girls (n=57). In post-pubertal adolescents (Tanner stage 4-5; n= 48), inverse correlations were stronger (r=- 0.40, p=0.007); results were non-significant in pre-pubertal and pubertal children (Tanner stage 1-3; n=139, p=0.57). In post-pubertal girls (n=37), there were no significant correlations (p=0.14); inverse correlations in post-pubertal boys (n=11) became markedly stronger (r= -0.80, p=0.02).
Conclusion
SBP is inversely correlated with BMC in overweight adolescents; additionally, hypertensives have lower adjusted means of BMC than normotensives. These promising new findings suggest that hypertension may be a risk factor for osteopenia in overweight children and adolescents; this risk may be exacerbated in post-pubertal boys.
doi:10.1016/j.amjhyper.2006.07.014
PMCID: PMC1852456  PMID: 17261466
Pediatric; Latino; Bone Mineral Content; Blood Pressure; Osteopenia
21.  Health care utilization for pain in children and adolescents: a prospective study of laboratory and non-laboratory predictors of care-seeking 
Background
Few studies have focused on identifying predictors of medical consultation for pain in healthy children and adolescents.
Objective
This investigation sought to identify parent and child laboratory and non-laboratory predictors of pediatric healthcare utilization for pain problems.
Study group
Participants were 210 healthy children and adolescents (102 girls), aged 8–17 years who took part in a laboratory pain session.
Methods
Three months after the laboratory session, participants were contacted by telephone to ascertain whether they had experienced pain and whether they had seen a healthcare professional for pain. Zero-order correlations among sociodemographics, child laboratory pain responses, parent physical/mental health status and medical consultation for pain were conducted to identify relevant correlates of pediatric healthcare utilization; these correlates were subjected to multivariate analyses.
Results
Bivariate analyses indicated that higher anticipated pain and bother for the cold pressor task, as well as poorer parent physical health status, were associated with pediatric medical consultation for pain, but only among girls. Sequential logistic regression analyses controlling for child age indicated that only parent physical health status, not the laboratory indicators, significantly predicted healthcare consultation for pain among girls. No parent or child correlates of care-seeking for pain emerged for boys.
Conclusion
The findings suggest that parents’ perceived physical health plays a role in determining whether medical care is sought for pain complaints in healthy girls. These results suggest that interventions to assist parents in managing their own physical health problems may lead to reductions in medical consultation for girls’ pain.
PMCID: PMC3246362  PMID: 22191197
pediatric health care; parent health status; parent-child relationship; experimental pain; acute pain
22.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Objective
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Design
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Results
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Conclusions
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
doi:10.1542/peds.2006-0092
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
23.  Child Mortality Estimation: Estimating Sex Differences in Childhood Mortality since the 1970s 
PLoS Medicine  2012;9(8):e1001287.
Cheryl Sawyer uses new methods to generate estimates of sex differences in child mortality which can be used to pinpoint areas where these differences in mortality merit closer examination.
Introduction
Producing estimates of infant (under age 1 y), child (age 1–4 y), and under-five (under age 5 y) mortality rates disaggregated by sex is complicated by problems with data quality and availability. Interpretation of sex differences requires nuanced analysis: girls have a biological advantage against many causes of death that may be eroded if they are disadvantaged in access to resources. Earlier studies found that girls in some regions were not experiencing the survival advantage expected at given levels of mortality. In this paper I generate new estimates of sex differences for the 1970s to the 2000s.
Methods and Findings
Simple fitting methods were applied to male-to-female ratios of infant and under-five mortality rates from vital registration, surveys, and censuses. The sex ratio estimates were used to disaggregate published series of both-sexes mortality rates that were based on a larger number of sources. In many developing countries, I found that sex ratios of mortality have changed in the same direction as historically occurred in developed countries, but typically had a lower degree of female advantage for a given level of mortality. Regional average sex ratios weighted by numbers of births were found to be highly influenced by China and India, the only countries where both infant mortality and overall under-five mortality were estimated to be higher for girls than for boys in the 2000s. For the less developed regions (comprising Africa, Asia excluding Japan, Latin America/Caribbean, and Oceania excluding Australia and New Zealand), on average, boys' under-five mortality in the 2000s was about 2% higher than girls'. A number of countries were found to still experience higher mortality for girls than boys in the 1–4-y age group, with concentrations in southern Asia, northern Africa/western Asia, and western Africa. In the more developed regions (comprising Europe, northern America, Japan, Australia, and New Zealand), I found that the sex ratio of infant mortality peaked in the 1970s or 1980s and declined thereafter.
Conclusions
The methods developed here pinpoint regions and countries where sex differences in mortality merit closer examination to ensure that both sexes are sharing equally in access to health resources. Further study of the distribution of causes of death in different settings will aid the interpretation of differences in survival for boys and girls.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
In 2000, world leaders agreed to eradicate extreme poverty by 2015. To help track progress towards this global commitment, eight Millennium Development Goals (MDGs) were set. MDG 4, which aims to reduce child mortality, calls for a reduction in under-five mortality (the number of children who die before their fifth birthday) to a third of its 1990 level of 12 million by 2015. The under-five mortality rate is also denoted in the literature as U5MR and 5q0. Progress towards MDG 4 has been substantial, but with only three years left to reach it, efforts to strengthen child survival programs are intensifying. Reliable estimates of trends in childhood mortality are pivotal to these efforts. So, since 2004, the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) has used statistical regression models to produce estimates of trends in under-five mortality and infant mortality (death before age one year) from data about childbearing and child survival collected by vital registration systems (records of all births and deaths), household surveys, and censuses.
Why Was This Study Done?
In addition to estimates of overall childhood mortality trends, information about sex-specific childhood mortality trends is desirable to monitor progress towards MDG 4, although the interpretation of trends in the relative mortality of girls and boys is not straightforward. Newborn girls survive better than newborn boys because they are less vulnerable to birth complications and infections and have fewer inherited abnormalities. Thus, the ratio of infant mortality among boys to infant mortality among girls is greater than one, provided both sexes have equal access to food and medical care. Beyond early infancy, girls and boys are similarly vulnerable to infections, so the sex ratio of deaths in the 1–4-year age group is generally lower than that of infant mortality. Notably, as living conditions improve in developing countries, infectious diseases become less important as causes of death. Thus, in the absence of sex-specific differences in the treatment of children, the sex ratio of childhood mortality is expected be greater than one and to increase as overall under-five mortality rates in developing countries decrease. In this study, the researcher evaluated national and regional changes in the sex ratios of childhood mortality since the 1970s to investigate whether girls and boys have equal access to medical care and other resources.
What Did the Researcher Do and Find?
The researcher developed new statistical fitting methods to estimate trends in the sex ratio of mortality for infants and young children for individual countries and world regions. When considering individual countries, the researcher found that for 92 countries in less developed regions, the median sex ratio of under-five mortality increased between the 1970s and the 2000s, in line with the expected changes just described. However, the average sex ratio of under-five mortality for less developed regions, weighted according to the number of births in each country, did not increase between the 1970s and 2000s, at which time the average under-five mortality rate of boys was about 2% higher than that of girls. This discrepancy resulted from India and China—the two most populous developing countries—having sex ratios for both infant and under-five mortality that remained constant or declined over the study period and were below one in the 2000s, a result that indicates excess female mortality. In China, for example, infant mortality was found to be 12% higher for boys than for girls in the 1970s, but 24% lower for boys than for girls in the 2000s. Finally, although in the less developed regions (excluding India and China) girls went from having a slight survival disadvantage at ages 1–4 years in the 1970s, on average, to having a slight advantage in the 2000s, girls remained more likely to die than boys in this age group in several Asian and African countries.
What Do These Findings Mean?
Although the quality of the available data is likely to affect the accuracy of these findings, in most developing countries the ratio of male to female under-five mortality has increased since the 1970s, in parallel with the decrease in overall childhood mortality. Notably, however, in a number of developing countries—including several each in sub-Saharan Africa, northern Africa/western Asia, and southern Asia—girls have higher mortality than boys at ages 1–4 years, and in India and China girls have higher mortality in infancy. Thus, girls are benefitting less than boys from the overall decline in childhood mortality in India, China, and some other developing countries. Further studies are needed to determine the underlying reasons for this observation. Nevertheless, the methods developed here to estimate trends in sex-specific childhood mortality pinpoint countries and regions where greater efforts should be made to ensure that both sexes have equal access to health care and other important resources during early life.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001287.
This paper is part of a collection of papers on Child Mortality Estimation Methods published in PLOS Medicine
The United Nations Childrens Fund works for children's rights, survival, development, and protection around the world; it provides information on Millennium Development Goal 4, and its Childinfo website provides detailed statistics about child survival and health, including a description of the United Nations Inter-agency Group for Child Mortality Estimation; the 2011 UN IGME report Levels & Trends in Child Mortality is available
The World Health Organization also has information about Millennium Development Goal 4 and provides estimates of child mortality rates (some information in several languages)
Further information about the Millennium Development Goals is available
A 2011 report by the United Nations Department of Economic and Social Affairs entitled Sex Differentials in Childhood Mortality is available
doi:10.1371/journal.pmed.1001287
PMCID: PMC3429399  PMID: 22952433
24.  Life style related to blood pressure and body weight in adolescence: Cross sectional data from the Young-HUNT study, Norway 
BMC Public Health  2008;8:111.
Background
The associations between physical activity, unhealthy dietary habits and cigarette smoking and blood pressure, overweight and obesity are well established in adulthood. This is not the case for similar associations in adolescence. Thus, the purpose of this study is to examine how physical activity, smoking status and dietary habits were related to overweight, obesity and blood pressure in a population of Norwegian adolescents.
Methods
Weight, height, systolic (SBP) and diastolic blood pressure (DBP) were measured, and body mass index (BMI) was calculated among 8408 adolescents who participated in a population based study in 1995–97 in the county of Nord-Trøndelag. Internationally accepted cut-off values were used to determine if the adolescents were overweight or obese. The adolescents also completed a detailed questionnaire including dietary habits, physical activity and smoking habits. We calculated adjusted mean blood pressures and odds ratios for being overweight or obese for different exposure categories of life style variables.
Results
Low levels of physically activity were associated with increased odds of being overweight (odds ratio (OR), 1.4; 95% confidence interval (CI), 1.1–1.8 in girls and OR, 2.0; 95% CI, 1.6–2.5 in boys) or obese (girls: OR, 3.1; 95% CI, 1.6–6.0; boys: OR, 3.7; 95% CI, 2.1–6.4). In addition, the least physically active girls had a 1.5 mmHg higher mean DBP compared with the most active (p-trend <0.001), and among boys this difference was 1.0 mmHg (p-trend < 0.001). Smokers were more likely to be obese (OR, 1.6; 95% CI, 1.1–2.5 in girls and 1.4; 95% CI, 0.9–2.1 in boys) compared with non-smokers. Smokers also had lower mean SBP than non-smokers; however, this finding was restricted to smokers with the lowest smoking exposure. Associations between dietary habits and weight status largely disappeared after adjusting for weight losing behaviour.
Conclusion
In this population of adolescents low levels of physical activity were associated with higher mean DBP and higher odds of overweight or obesity. Smoking was also associated with higher odds of overweight and obesity. The paradoxical associations between healthy dietary habits and overweight and obesity are most likely an effect of reverse causality.
doi:10.1186/1471-2458-8-111
PMCID: PMC2375890  PMID: 18400086
25.  Effects of Seasonal Differences in Testosterone and Cortisol Levels on Pain Responses Under Resting and Anxiety Conditions 
Yonsei Medical Journal  2013;55(1):216-223.
Purpose
This study investigated whether hormones and pain perception are associated with exam anxiety, and also whether exam anxiety is affected by seasonal differences in testosterone and cortisol levels.
Materials and Methods
Forty-six healthy males were recruited from a medical college. Anxiety was induced by having participants perform the Objective Structured Clinical Examination. Pressure was applied to the participants to induce pain. Pain thresholds, pain ratings, anxiety ratings, blood pressure, heart rate, salivary testosterone and cortisol levels were measured under resting and anxiety conditions in the spring and summer. Data were collected from 46 participants during the spring (n=25) and summer (n=21).
Results
Pain thresholds and testosterone levels were significantly lower under anxiety than at rest for all participants (n=46), while cortisol levels, pain ratings, and anxiety ratings were significantly higher under anxiety than at rest. In the spring (n=25), testosterone levels were significantly higher at rest than under anxiety, while there was no difference in cortisol levels between resting and anxiety conditions. In the summer (n=21), cortisol levels were significantly higher under anxiety than at rest, while there was no difference in testosterone levels between resting and anxiety conditions. There were no significant seasonal differences in pain and anxiety ratings and pain threshold.
Conclusion
These results indicate that seasonal differences in testosterone and cortisol levels under anxiety and at rest may affect pain responses. These results also suggest that acute clinical pain may be relieved by managing anxiety that is related to a decrease of testosterone in spring and a large increase of cortisol in summer.
doi:10.3349/ymj.2014.55.1.216
PMCID: PMC3874911  PMID: 24339310
Cortisol; testosterone; pain; seasonal differences

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