Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Jul 1.
Published in final edited form as: J Pain. 2012 May 24;13(7):656–665. doi: 10.1016/j.jpain.2012.04.001

Sensitization to Acute Procedural Pain in Pediatric Sickle Cell Disease: Modulation by Painful Vaso-occlusive Episodes, Age, and Endothelin-1

Alyssa M Schlenz 1, Catherine B McClellan 1, Teresa RM Mark 2, Alvin D McKelvy 2, Eve Puffer 1, Carla W Roberts 3, Sarah M Sweitzer 2, Jeffrey C Schatz 1
PMCID: PMC3389141  NIHMSID: NIHMS370772  PMID: 22633685

Abstract

The impact of pain early in life is a salient issue for sickle cell disease (SCD), a genetic condition characterized by painful vaso-occlusive episodes (VOEs) that can begin in the first year of life and persist into adulthood. This study examined the effects of age and pain history (age of onset and frequency of recent VOEs) on acute procedural pain in children with SCD. Endothelin-1, a vaso-active peptide released during VOEs and acute tissue injury, and its precursor, Big Endothelin, were explored as markers of pain sensitization and vaso-occlusion. Sixty-one children with SCD (ages 2 to 18) underwent venipuncture at routine health visits. Procedural pain was assessed via child- and caregiver-reports and observational distress. Pain history was assessed using retrospective chart review. Three primary results were found: 1) younger age was associated with greater procedural pain across pain outcomes, 2) higher frequency of VOEs was associated with greater procedural pain based on observational distress (regardless of age), and 3) age was found to moderate the relationship between VOEs and procedural pain for child-reported pain and observational distress for children five years of age and older. Associations between the endothelin variables and pain prior to venipuncture were also observed.

Keywords: sickle cell disease, procedural pain, sensitization, early pain, endothelin-1

Introduction

The impact of early and repeated childhood pain on future pain experiences has been studied in several pediatric populations aside from sickle cell disease (SCD) 11, 20, 21, 25, 27, 37, 43, 46–49, 54, 55, 57. Pain sensitization in childhood is a complex phenomenon, dependent on the type of painful insult 2, the developmental stage of the child 13, and the child’s cumulative experience with pain 48. Longitudinal and retrospective studies suggest that painful experiences occurring in infancy may sensitize children to future painful experiences 20, 46, 47, 54. Beyond infancy, accumulating literature suggests that severe or frequent childhood pain can increase the risk for adult chronic pain 21, 24–27. Additionally, clinical literature suggests that children with chronic pain may exhibit increased pain sensitivity between attacks 57 as well as attentional bias to painful stimuli 55, 56. With regard to pain from medical procedures, research also suggests greater sensitivity to procedural pain in younger versus older children 4, 13, 45, 48.

Childhood pain is a salient issue for sickle cell disease (SCD), a genetic condition in which unpredictable painful vaso-occlusive episodes (VOEs) may begin in the first year of life and persist into adulthood 38, 39, 44. Children with SCD also encounter pain via frequent medical procedures, including additional immunizations, venipunctures at routine health visits, and IV starts 1. Understanding the impact of childhood pain in SCD is important for informing appropriate pain management for both VOEs and acute procedural pain.

Several chemical mediators have been implicated in sensitization that occurs in childhood, many of which have been derived from adult studies and animal models of peripheral and central sensitization 13. Of these mediators, endothelin-1 (ET-1) is the most potent vasoconstrictor identified and is also involved in pain signaling 28. ET-1 is cleaved by endothelin converting enzyme from the precursor Big Endothelin (Big ET), which has 140 times less vaso-activity 29. ET-1 is released during acute tissue injury and has been strongly implicated in central sensitization, the process by which acute pain is amplified and can transition into a chronic state28. ET-1 has also been demonstrated to induce behavioral sensitization in an animal model of pediatric pain, suggesting its potential importance in mediating sensitization that occurs in childhood 35, 36. In SCD, ET-1 has been implicated in the initiation and maintenance of VOEs 17, 18, 30, 41. Thus, investigations of ET-1 in patients with SCD may have implications for understanding sensitization as well as pain specific to SCD.

In the present study, the first aim was to examine the effects of pain history (age of onset and frequency of recent VOEs) on acute procedural pain in children with SCD and to determine the role of age in moderating this effect. The first aim had two hypotheses: (A) an early onset of VOEs (prior to age two) would be predictive of greater procedural pain and (B) an age by pain history interaction, whereby a higher frequency of recent VOEs would be associated with greater procedural pain in younger versus older children. Hypotheses for Aim One were derived from previous studies that have emphasized early childhood as a vulnerable period for sensitization and by research suggesting greater sensitivity to procedural pain in younger versus older children 13, 45, 46, 48. We predicted that the specific combination of younger age and vaso-occlusive pain history would be associated with heightened pain. Support for these hypotheses would suggest a sensitization effect of VOEs early in life. The second aim was to explore relationships between ET-1, procedural pain, and pain history. For the second aim, hypotheses were as follows: higher plasma levels of ET-1 and Big ET would be associated with an early onset of pain, a higher frequency of recent VOEs, and higher ratings of baseline and procedural pain.

Materials and Methods

Participants

All protocols were approved by the Institutional Review Board of Palmetto Richland Hospital, which provides approval concomitantly with the University of South Carolina. All participants were recruited from a Hematology Clinic located in Columbia, South Carolina over a 9-month period. Participants were 61 children and adolescents with SCD ranging in age from two to 18 years receiving routine venipuncture as part of hematological health maintenance visits. We focused recruiting efforts on developmental periods that could be more directly compared to existing rodent studies 35, 36. Children between the ages of 10 and 12 were not recruited for this study due to concerns about the transition between pre- and post-pubescence. Venipuncture was chosen as the painful stimulus because children with SCD receive routine blood draws via venipuncture at clinic visits. This was a predictable pain experience conducted with fairly standardized procedures at the clinic (i.e., no significant procedural differences for younger versus older children). Infants were not recruited due to the rarity with which they receive venipuncture at this center. Consent was obtained from caregivers for all children and verbal assent was obtained from all participants over the age of 12 years. Exclusionary criteria for this study were history of overt stroke or consumption of opioid pain medication within the previous 7 days. Children who could not participate due to opioid pain medication participated at a subsequent routine clinic visit.

Of the 65 families approached, four families refused to participate, citing insufficient available time (2 caregivers), unwillingness to have the procedure captured on videotape (1 caregiver), and no reason (1 caregiver). Of the 61 families who were part of this study, 50 children had adequate plasma recovery to allow for endothelin analysis. Participant and caregiver demographics for the overall sample and the subset of children whose plasma was used for the endothelin analysis are provided in Table 1.

Table 1.

Demographics of Full Study and Endothelin Study Subset

Sample Full Study Sample Endothelin Study Subset
N 61 50
Age M = 9.48 M = 9.81
(SD = 8.93) (SD = 4.88)
Gender
Male 32 26
Female 29 24
Caregiver
Mother 55 45
Father 4 3
Other 2 2
Race/Ethnicity
African-American 60 49
Latino 1 1
SCD Subtype
HbSS 39 29
HbSC 9 8
HbSβ0 Thal. 6 6
HbSβ+ Thal. 7 7
Number of Sticks
1 56 45
2 5 5
Pain History
Pain onset >3yrs 18 16
Pain onset <3yrs 43 34
Open in a new tab

One child was born prematurely, a condition that has been found to impact later pain reactivity in previous studies 2, 11, 48. The exclusion of this child did not change the pattern of results of the study and this child was retained in the statistical analysis. Similarly, surgical procedures have also been found to impact later pain sensitivity 37, 48. Twenty-one children had a history of surgical procedures according to medical records, including splenectomy (n = 2), cholecystectomy (n = 6), and tonsillectomy and/or adenoidectomy (n = 16) (some children had multiple surgical procedures). There were no statistically significant differences between children with and without a surgical history for child-reported pain (t (44) = −1.49, p = .143), caregiver-reported pain (t (56) = −0.43, p = .673), and observational distress (t (56) = 1.21, p = .233).

Measures

Background Information Questionnaire

Caregivers completed a questionnaire to provide demographic information and the child’s age during his/her first VOE.

Child-Reported Pain Ratings

Child reports of baseline (prior to venipuncture) and procedural pain were obtained for children 5-years-old and older using a Wong-Baker Faces scale 59. The Faces scale is a reliable scale with six cartoon faces and numbers ranging from 0 to 10 used as anchors. Research indicates that the Faces scale is also the preferred method of assessing pain in African-American children 31.

Caregiver-Reported Pain Ratings

Caregiver proxy report of child baseline (prior to venipuncture) and procedural pain were obtained using a Visual Analog Scale (VAS). VASs are 100-mm horizontal lines with anchors of no pain and worst pain possible. Research has demonstrated VASs to be a valid method of pain assessment preferable to Likert type scales due to a more even distribution of scores 34. In pediatric populations, caregiver ratings using the VAS scale have yielded excellent convergent validity with child reports of pain (r = .72, p < .001) 52.

Observational Measure of Distress

The modified version of the Observational Scale of Behavioral Distress (m-OSBD) was used to evaluate videotaped recordings of child behavior during venipuncture. The OSBD has demonstrated adequate internal consistency and convergent validity with other ratings of distress 12, 23. Research has shown that the original OSBD procedures do not provide significantly greater validity than those of the m-OSBD 23.

The m-OSBD assesses the presence or absence of 11 behavioral indicators of procedural distress (information seeking, crying, screaming, physical restraint, verbal resistance, seeking emotional support, verbal pain, flail, verbal fear, muscular rigidity, and nervous behavior) during three phases of the procedure. Procedure phases include: (a) baseline (from the time the child sits in the chair to the time that the tourniquet is applied or the site is cleaned), (b) procedural (from the start of the skin cleaning/tourniquet application to the time when the needle is withdrawn), and (c) post-procedural (from the time that the needle is withdrawn to when the child leaves the chair or two minutes post-procedure, whichever comes first). Ratings from the baseline and procedural phases were used to test hypotheses in the present study.

Two undergraduate coders were trained to 95% inter-rater agreement using practice tapes. Following this training, inter-rater reliabilities for the m-OSBD were calculated for 30% of all videotaped observations and weekly review sessions were held to prevent coder drift. Percent agreement ranged from 93–100% agreement across the 11 behaviors, indicating excellent reliability. Researchers have recommended using percent agreement over Kappa to evaluate inter-rater agreement for low frequency behaviors 10, 51.

Pain History Variables

A review of patients’ medical records was completed to obtain information on children’s pain history (age of onset and frequency of recent VOEs). Releases were obtained to access medical records from healthcare providers other than the study site. Chart reviews were done by an individual experienced in collecting medical record data who was blind to all other study measures.

Age of VOE onset was collected from caregiver report and verified via medical record review. The correlation between caregiver and medical record data was r = .97. Eight patients had no history of VOEs. Pain onset was dummy-coded into two groups: those with an early onset of VOEs (i.e., before two years of age; n = 43) versus those with a late onset or no onset of VOEs (i.e., after two years of age or no VOEs to date; n = 18). Two years of age was chosen as the cut-off as studies have demonstrated sensitization effects from painful events that occur before this age 43, 54. Frequency of recent VOEs (over the past 24 months) was measured based on the number of hospitalizations for pain, emergency department visits for pain, and outpatient health care contacts for VOEs documented in the medical chart. This approach is commonly used to measure pain frequency in studies of SCD 5, 38. These three measures of VOEs were highly inter-correlated and had a Cronbach’s alpha of .75 when treated as items on a scale, suggesting that all three forms of health care contact were similarly capturing the same construct (i.e., vaso-occlusive pain).

Procedures

Participants who met eligibility criteria were identified through a review of the medical charts of scheduled patients. Caregivers whose child met the inclusion criteria were presented with basic study information by the attending hematologist (C.W.R.). Caregivers who indicated interest in learning more about the study were directed to a research assistant in the waiting room of the laboratory who explained the purpose of the study as a way for the medical community to gain a greater understanding of venipuncture pain and SCD pain. After completing consent and assent process, the research assistant instructed caregivers and participants in the use of the VAS and Faces pain scales and clarified any questions participants had regarding these scales. Participants then completed the pre-venipuncture forms (Background Information Questionnaire, caregiver and child reports of baseline pain) and consent(s) for medical records release.

To minimize the disturbance to the clinic routine, the research assistant used a remote control to start video-recording the procedure before the child entered the room and stopped the recording after the child exited. Due to equipment malfunction, videotaped observations were not obtained for three participants. Fourteen children were unable to report on procedural pain because they were under the age of 5. One child and three caregivers did not report on the child’s procedural pain due to experimenter error. Upon return to the laboratory waiting room, participants completed the post-venipuncture measures (child and caregiver post-procedural pain ratings). Children and caregivers received a $5 gift card each as compensation for their participation.

Endothelin Analysis by ELISA

At the end of the blood draw, an additional 2 ml of blood was collected from each patient into an EDTA vacutainer tube. The tubes were placed on ice for plasma isolation within 30 minutes of blood collection. The vial was centrifuged at 1000 G for 10 minutes at 4 °C. Following centrifugation the plasma was removed from the vial and stored at −80 °C until all samples were collected for endothelin analysis by enzyme-linked immunosorbent assay (ELISA). ELISA kits for ET (1-21) (Cat no. BI-20052) and the precursor Big ET (Cat no. BI-20082) were purchased from ALPCO Immunoassays (Salem, NH). ELISAs were prepared in triplicate according to the ALPCO protocols. Using Prism 4.0 (GraphPad Software Inc., San Diego, CA), a standard curve was generated from the standards of each kit and used to obtain the sample concentrations from each of the plasma samples.

Statistical Analysis

Pain History

All data were analyzed using SPSS, Version 17.0 (SPSS, Inc., Chicago, IL). A multiple linear regression approach was used to evaluate the effects of age and pain history (age of onset and frequency of recent VOEs) on procedural pain. Before analyzing the data, violations of the assumptions of regression were assessed. All three of the measures of pain (child-reported, caregiver-reported, and observational) were log-transformed due to a significant positive skew in the distribution that did not conform to the assumption of normality. Additionally, pain responses to venipuncture were calculated through standardized residual scores by using linear regression to remove variability in venipuncture pain that could be predicted from baseline (pre-venipuncture) ratings. This procedure was conducted based on previous findings by the authors, which suggested that baseline levels of pain prior to venipuncture accounted for higher ratings of pain during the venipuncture 32. Residual scores were calculated by using the log-transformed value for the pain rating immediately after the venipuncture (or during the venipuncture for observational distress) as the dependent variable and the log-transformed value for the baseline pain rating as the independent variable in a simple bivariate regression.

Each log-transformed residual score for pain ratings was the dependent variable (child report, caregiver proxy report, observational distress ratings) in the regression. Prior to running the regressions, simple t-tests were used to rule out gender differences in pain ratings. In the first step of the regression, age of onset (dummy coded with 0 as early pain onset and 1 as late or no pain onset), recent VOEs (continuous variable), and age (as a continuous variable) were included as independent variables. Interaction effects were tested in the second step of the model.

We had unequal numbers of ratings for child-reported pain versus caregiver-reported pain and observational distress due to some children being too young to complete the self-report measure. Thus, results will be presented twice, once for the subsample of children five years and older, who had all three ratings, and again for caregiver report and observational distress using the whole sample of children. This presentation may allow for a better comparison of results.

Endothelin-1

For descriptive purposes, we examined gender and age differences in ET-1 and Big ET using t-tests and correlations, respectively. Pearson correlations were used to evaluate relationships between endothelin variables, pain history variables, and procedural pain, except if potential outlier values were distorting the correlation value (in which case Spearman correlations were used). The ELISA for ET-1 produced seven values that exceeded the highest standard of the assay. These samples were assigned the highest measurable standard value of 10 pg/mL. Using this approach resulted in an abnormal distribution of scores, with several outlying values. Thus, a Spearman rank-order correlation approach was used, which is considered to be a more conservative procedure compared to Pearson correlation in the face of multiple outliers. For Big ET, the distribution was normal and Pearson correlations were used. Relationships between levels of ET-1, Big ET, pain history (age of onset and recent VOEs), baseline pain, and procedural pain were assessed. Baseline ratings were used to evaluate whether ET-1 and Big ET were related to existing pain prior to the venipuncture. The log-transformed baseline pain ratings were used due to the more normal distribution. For procedural pain, the residual log-transformed values that adjusted for baseline ratings were used as these adjusted scores were considered the more pure measure of pain specific to the venipuncture stimulus.

Results

Results for pain history are presented for children ages five years and older, who had all three ratings, and for the whole sample of children with caregiver report and observational distress ratings. Mean procedural pain and distress ratings by age (without log-transformation and no adjustment for baseline pain) are provided in Table 2. Results from the multiple linear regressions are provided in Table 3.

Table 2.

Child, Caregiver, and Observational Procedural Pain Ratings by Age

Age Child-Reported Pain Caregiver-Reported Pain Observational Distress
M (SD), n M (SD), n M (SD), n
2 to 4 yrs - 40.46 (35.39), n = 13 46.79 (46.16), n =14
5 to 6 yrs 4.44 (3.84), n = 9 20.22 (18.98), n = 9 9.89 (13.91), n = 9
7 to 9 yrs 3.14 (3.01), n = 14 24.00 (24.87), n = 14 4.83 (9.89), n = 12
13 to 14 yrs 2.92 (2.66), n = 13 24.75 (25.74), n = 12 3.93 (11.27), n = 14
15 to 18 yrs 1.40 (1.35), n =10 7.70 (9.52), n = 10 0.78 (1.39), n = 9
 # VOEs in previous M = 8.93 M = 9.02
 24 months (SD = 10.41) (SD = 10.42)
Open in a new tab

Note. This table demonstrates a general decreasing trend for pain ratings with increasing age across child, caregiver, and observational ratings.

Table 3.

Hierarchical Regression Models Predicting Procedural Pain and Distress

Variable Cumulative R2 B SE β R2 Change
Results for Children Five Years and Older
Child Report of Pain (n = 46)
 Step 1 .12 .12
  VOE Onset .04 .33 .02
  Recent VOEs .03 .02 .35†
  Age −.09 .04 −.34*
 Step 2 .23 .11
  Age X Recent VOEs −.01 .00 −.41*
Caregiver Report of Pain (n =44)
 Step 1 .15 .15
  VOE Onset .58 .34 .27†
  Recent VOEs .00 .02 −.01
  Age −.06 .04 −.23
 Step 2 .15 .00
  Age X Recent VOEs .00 .00 .00
Observational Distress (n = 43)
 Step 1 .22 .22
  VOE onset −.14 .27 −.07
  Recent VOEs .04 .01 .54**
  Age −.09 .03 −.40**
 Step 2 .33 .11
  Age X Recent VOEs −.01 .00 −.42*
Results for All Children
Caregiver Report of Pain (n =58)
 Step 1 .17 .17
  VOE Onset .54 .29 .24†
  Recent VOEs .00 .02 .02
  Age −.06 .03 −.30*
 Step 2 .17 .00
  Age X Recent VOEs .00 .00 −.04
Observational Distress (n = 58)
 Step 1 .38 .38
  VOE onset .05 .25 .02
  Recent VOEs .03 .01 .27*
  Age −.14 .02 −.69**
 Step 2 .39 .01
  Age X Recent VOEs .00 .00 −.12
Open in a new tab

Note. Pain and distress ratings (dependent variables) are log-transformed residual scores that were adjusted for baseline levels of pain prior to venipuncture.

**

p <. 01

*

p < .05

†

p < .10

Pain History (Children Ages Five Years and Older)

For children five years of age and older, there were no significant gender differences for child-reported pain (t (44) = −.83, p = .41), caregiver-reported pain, (t (43) = − 1.57, p = .12), and observational distress, (t (42) = −.77, p = .44), so this variable was excluded from the regression models. Age of VOE onset was not a significant predictor in any of the regression models.

For child report of procedural pain, the overall regression model was statistically significant (F (4, 41) = 3.04, p = .028). Recent VOEs approached significance (t (45) = 1.98, p = .055), with a higher frequency of recent VOEs associated with greater child-reported pain. Child age was a significant predictor in the model (t (45) = −2.47, p = .018), with younger age associated with greater child-reported pain. The interaction for child age and recent VOEs was also significant (t (45) = −2.38, p = .022). The combination of higher frequency of recent VOEs and younger age was associated with greater child-reported pain.

For caregiver report, the overall regression model was not statistically significant (F (4, 40) = 2.31, p = .091). For observational distress, the overall regression model was statistically significant (F (4, 39) = 4.86, p = .003). Recent VOEs was a significant predictor of distress (t (42) = 3.20, p = .003), with a higher frequency of recent VOEs associated with greater distress. Child age was also a significant predictor of distress (t (42) = −3.01, p = .005), with younger children exhibiting greater distress compared to older children. The interaction for child age and recent VOEs was significant (t (42) = −2.53, p = .015). The combination of higher frequency of recent VOEs and younger age was associated with greater observational distress.

Figure 1 displays the interactions for child-reported pain (A) and observational distress (B) by providing a scatterplot of the relationship between the frequency of recent VOEs and pain outcomes for children by age. In this figure, age is represented in a categorical manner for the purposes of demonstrating the interaction.

Figure 1.

Figure 1

Open in a new tab

Child-reported pain and observational distress during venipuncture are related to recent VOE frequency in an age-dependent manner. Note. This finding was for children ages five years of age and older. Age is represented in a categorical manner for the purposes of demonstrating the interaction effect. For all statistical analyses, age was represented as a continuous variable. Child-reported pain and observational distress are represented in log-transformed standardized residuals (std. res.) that have been adjusted for baseline pain. VOE = painful vaso-occlusive episode

Pain History (All Children)

For the whole sample of children, there were no significant gender differences for caregiver-reported pain (t (56) = −1.34, p = .19) and observational distress, (t (57) = 1.20, p = .24), so this variable was excluded from the regression models. Age of VOE onset was not a significant predictor in any of the regression models.

For caregiver report, the overall regression model was statistically significant (F (4, 53) = 2.67, p = .042). Child age was a significant predictor of pain response (t (57) = −2.15, p = .036), with younger age associated with greater caregiver-reported pain. Recent VOEs did not predict caregiver-reported pain and the interaction of child age and recent VOEs was also not statistically significant in this model.

For observational distress, the overall regression model was statistically significant (F (4, 54) = 8.59, p < .001). Recent VOEs was a significant predictor of distress (t (57) = 2.05, p = .045), with a higher frequency of recent VOEs associated with greater distress. Child age was also a significant predictor of distress (t (57) = −5.84, p < .001), with younger children exhibiting greater distress compared to older children.

Endothelin Plasma Levels

ET-1 and Big ET in plasma was measured by ELISA. ET-1 in plasma ranged from 0.21 to >10.00 pg/mL (M = 2.20, SD = 3.30). Excluding the children whose plasma ET-1 exceeded 10.00 pg/mL resulted in a range of 0.21 to 4.25 pg/mL (M = 0.93, SD = 0.96). Big ET in plasma ranged from 0.00 to 1.57 pg/mL (M = 0.39, SD = 0.30). ET-1 concentrations for males (M = 1.66, SD = 2.68) and females (M = 2.69, SD = 3.77) did not significantly differ (t (1, 48) = −1.09, p =.277). Similarly, Big ET concentrations for males (M = 0.42, SD = 0.37) and females (M = 0.36, SD = 0.22) did not significantly differ (t (1, 47) = .73, p = .472). ET-1 (r = −.17, p = .239) and Big ET (r = −.15, p =.313) were not significantly associated with age.

Table 4 provides correlations for the endothelin variables, baseline pain, procedural pain, and pain history using Spearman and Pearson correlations. ET-1 and Big ET were significantly and positively related (rs = .57, p = < .001) and (r = .33, p = .020). ET-1 was significantly and positively related to child-reported baseline pain (rs = .42, p = .007), with higher plasma ET-1 in children with higher baseline pain ratings. Big ET was significantly and positively related to baseline levels of caregiver-reported pain (r = .35, p = .014) and observational distress (r = .36, p = .014), with higher plasma Big ET in children with greater baseline pain responses prior to venipuncture. In contrast, Big ET was significantly and negatively related to recent VOEs (r = −.29, p = .048), with lower plasma Big ET in children with a higher frequency of recent VOEs.

Table 4.

Correlations between Small ET-1, Big ET, and Pain Outcomes

Variables 1 2 3 4 5 6 7 8 9 10
1. Small ET-1 - .33* .18 .01 .00 .12 .22 .20 −.09 −.09
2. Big ET .57** - .26 .02 .35* .02 .36* .08 .26† −.29*
3. Child Report (Baseline Pain) .42* .25 - .00 .47** .17 .11 .05 .26† −.10
4. Child Report (Procedural Pain) .19 .15 .06 - .25† .33* .06 .45** .04 .05
5. Caregiver Report (Baseline Pain) .18 .18 .43** .36* - .00 −.02 .06 −.06 −.01
6. Caregiver Report (Procedural Pain) .21 .14 .13 .35* .04 - .23 .18 .29* −.19
7. Obs. Distress (Baseline Distress) .23 .31* −.01 .10 .04 .19 - .00 .12 −.23†
8. Obs. Distress (Procedural Distress) .21 .17 .06 .32* −.02 .18 .05 - .00 .05
9. VOE onset .01 .16 .16 .05 −.02 .35** .11 −.02 - −.36**
10. Recent VOEs −.20 −.30* .00 .11 .01 −.13 −.24† −.03 −.43* -
Open in a new tab

Note. The upper off-diagonal displays Pearson correlation results while the lower off-diagonal displays Spearman correlation results. Baseline venipuncture pain and distress ratings were log-transformed. Procedural pain and distress ratings were log-transformed and adjusted for baseline pain ratings.

**

p < .01

*

p < .05

†

p < .10

Discussion

The impact of childhood pain is a rapidly growing and important area of study 11, 20, 21, 25, 27, 37, 43, 46–49, 54–57. The current study found consistent support for a heightened procedural pain response in younger versus older children with SCD. This study also found preliminary support suggesting that children with frequent, recent VOEs may experience heightened procedural pain and that age may moderate this effect; however, these findings were not observed consistently across all statistical models. Finally, the results suggest relationships between the endothelin system and existing pain prior to venipuncture. Additional work is needed to carefully evaluate and understand the role of development and the endothelin system on sensitization to pain.

The results extend previous findings of age as a correlate of children’s pain responses during medical procedures 4, 45 to African American children with SCD. Child age was the most consistent predictor of procedural pain, with younger children experiencing greater procedural pain than older children across pain outcomes. The only exception to this finding was for caregiver-reported pain for children five years of age and older. Cross-sectional research with children and adolescents has found that younger children exhibit greater procedural pain responses than older children, which may represent differing levels of pain sensitivity across development 4 or a habituation effect to procedural pain over time 22, 45. Age differences could also be the result of developmental differences in coping skills for pain 45 or fewer displays of distress during medical procedures in older versus younger children, the latter of which would be most apparent on caregiver report and observational ratings 16.

Given the consistency of the age effect across pain outcomes, it is unlikely that the age effect simply represents differences in displays of distress. With regard to the habituation hypothesis, a limitation of the present study is the lack of a non-SCD comparison group that would allow for the differentiation of general age-related changes in pain sensitivity versus a specific habituation effect related to pain experience in SCD; however, children with SCD who have frequent experiences of procedural pain may not necessarily habituate over time 45. Future prospective research may delineate the exact developmental processes that produce age differences in response to procedural pain in SCD and other pediatric populations.

Given the vast literature on the adverse consequences of early pain in infancy 2, 13, 43, 46, 48, 50, the finding that age of onset of first VOE did not predict any procedural pain outcome is unexpected. The absence of this association may be the result of methodological limitations in identifying the precise onset of VOEs through the use of retrospective chart review and caregiver report. Retrospective chart reviews can be limited by incomplete documentation, difficulty in interpreting information in the medical chart, and variability in the quality of information 15. Caregiver reports of pain can result in underreporting of pain, especially in younger children 8, 9, 16. Furthermore, in the current study, the chart review and caregiver report only provided documentation of a VOE as a surrogate measure of pain since infants and toddlers are unable to communicate verbally about pain. Future research using a prospective approach may be superior in identifying a precise age of onset to determine the effects of early VOEs on subsequent procedural pain in children with SCD, although differentially identifying fatigue, illness, and pain in toddlers with SCD to measure the precise age of onset remains a significant challenge even in a prospective study.

In contrast, the frequency of recent VOEs was related to greater procedural pain responses for observational distress. Furthermore, the results for children five years of age and older for child-reported pain and observational distress suggest that age may moderate the effects of recent VOEs, such that younger children with frequent VOEs experience greater procedural pain versus older children. This specific finding may suggest a sensitization effect that may be more likely to occur in early childhood, a finding previously reported in other patient populations2,3, 46, 48. Alternatively, it has been suggested that the Wong-Baker Faces scale used for child-reported pain may capture affective aspects of pain in addition to pain per se. Observational ratings have also been noted to capture aspects of affect and pain 23. Thus, it is possible that children’s previous experiences with VOEs are associated with greater affective responses to procedural pain that were captured by our pain measures 8. Additional research is needed to clarify these alternate interpretations of the findings, though we find the sensitization explanation to be consistent with much prior research and a more parsimonious explanation.

The endothelin variables were most consistently related to baseline pain prior to venipuncture. The most probable source of baseline pain in SCD is from vaso-occlusion, though other forms of pain are also possible (e.g., headache pain) 14. In both children and adults, levels of ET-1 tend to be higher during vaso-occlusive events 17, 30, 41. ET-1 tends to parallel the progression and slow resolution of VOEs, with higher levels of ET-1 during the event and a slow return to baseline several weeks later 17. Thus, in the current study, relationships between endothelin variables and vaso-occlusion (captured by baseline pain levels) would be consistent with this literature 17, 30, 41.

Although many correlations did not reach statistical significance for ET-1, the magnitude of several correlations fell around .20. Future studies evaluating ET-1 in children may consider powering the study to detecting effects of this magnitude. It should be noted that the short half-life of ET-1 in plasma makes it difficult to accurately measure dynamic changes across the venipuncture procedure. ET-1 has a half-life of seven minutes 40 and is cleared from plasma following degradation by endopeptidases 6, 7. In the current study, the time it took to draw the vial of blood for our endothelin analysis varied and likely increased inter-patient ET-1 variability.

Lower Big ET expression was observed in children with fewer recent VOEs. This relationship could be related to increased cleavage of big ET to the vaso-active small ET-1, which has a much shorter plasma half-life compared to the precursor big ET 19. Future studies may consider measuring levels of endothelin converting enzyme 29, which would provide additional support for this hypothesis.

The reported levels of ET-1 and Big ET may be beneficial for future studies evaluating the endothelin system in pediatric SCD. Big ET, in particular, has not been widely studied in relation to VOEs. The average plasma ET-1 level across all of the patients (M = 2.20 pg/mL, SD = 3.30) in the present study was somewhat higher than previously reported in a study of ET-1 in children ages 2 to 15 years with sickle cell anemia, in which the reported mean steady-state levels ranged from 0.37 to 0.65 pg/mL (depending on the child’s hydroxyurea status) and the reported mean level during clinical events was 1.32 pg/mL 30. The higher mean ET-1 level in the present study may have been the result of very high ET-1 levels in a subset of the sample. With the exclusion of these outlying values, levels of ET-1 more closely approximately those of the previous study (M = 0.95 pg/mL, SD = 0.96). A specific, systematic reason for the high ET-1 levels (e.g., recent VOE) in these children could not be identified, but it is likely that they recently experienced some form of painful insult, SCD-related clinical event, or were in the precipitating phase of a VOE. ET-1 levels during VOEs in adults with sickle cell anemia have been reported as high as 130.90 pg/ml with levels remaining elevated at 23.69 pg/ml when examined 1–3 weeks post-crisis 17.

The results of this study should be evaluated with certain limitations in mind. The interaction effect for age and recent VOEs was only observed for the subsample of children five years of age and older. It is surprising that we were unable to replicate this finding for the whole sample, which included children ages two to four. We would anticipate that the youngest children would be most vulnerable to the effects of early pain; however, the results from this study may not generalize to this age range. We did observe a modest correlation between age and pain history (r = .31), such that younger children had fewer recent VOEs versus older children. Only 50% of children under the age of five had documented pain episodes in the medical chart. The limited pain history for children in this age range may have restricted the range of VOEs for younger children, thereby reducing our ability to detect a moderator effect for age on the caregiver and observational pain outcomes for the whole sample of children. Given the relatively small sample size, it is also possible that the current study was underpowered to detect a statistically significant interaction for the caregiver and observational outcomes. The effect sizes for these interactions (see Table 3) were very small, explaining 1% or less of the variance in pain outcomes.

Additionally, the examination of recent VOEs was limited to SCD-related painful events that were captured in the patient’s medical chart. This measurement limits us to only the more severe of SCD-related pain experiences and does not include the vast majority of pain experiences that are often treated at home without requiring medical attention 33, 44. The duration and intensity of these experiences was also not assessed 53. Given that most of these measurement factors work in favor of adding unexplained variance to the analyses, the association of VOEs with the magnitude of the pain response may have been underestimated in the reported results.

In conclusion, this study has implications for children with SCD as well as other pediatric pain conditions that involve recurring episodes of pain 21, 52, 55, 56. First, although many studies focus on the management of VOEs, children with SCD may encounter frequent pain from medical procedures each year 1. The present study suggests that younger children with SCD and those who have experienced recent VOEs may be vulnerable to enhanced pain or a greater affective response to pain during medical procedures. Appropriate procedural pain management should be routine component of health care for children with SCD 42. Second, an emerging body of literature suggests that recurring episodes of pain may impact later pain sensitivity and the risk for developing chronic pain in adulthood 21, 25, 27, 55–57. These studies along with the present findings suggest that early interventions for pain 47 are not only important for improving immediate care for pain, but also for preventing enhanced pain and distress during future pain experiences. Future studies may consider the use of a prospective design, ideally in a larger cohort of patients, to facilitate a better understanding of the impact of prior pain experiences on current pain and to delineate critical or sensitive time points for sensitization during development 20, 54. Additionally, the use of multiple forms of pain measurement, particular those that are less sensitive to the affective components of pain, would be particular useful in demonstrating a sensitization effect.

Perspective.

For children with SCD, the child’s age and recent pain history should be considered in procedural pain management. The endothelin system may be involved in pre-procedure pain, but additional research is needed to understand the role of endothelins in pain sensitization.

Footnotes

Conflicts of Interest

No conflicts of interest are declared by the authors.

Disclosures

This study received support from the following programs: USC School of Medicine Translational Research Grant (SMS, CR); USC School of Medicine Department of Pharmacology, Physiology, and Neuroscience Seed Grant for Translational Research (SMS, JCS); the Pfizer Fellowship in Health Disparities (CBM); the National Institutes of Health (RO1 DA023593 to SMS); and the National Institutes of Health, National Institute of General Medical Sciences (T32 GM081740 to AMS).

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  • 1.American Academy of Pediatrics. Health supervision for children with sickle cell disease. Pediatrics. 2002;109:526–35. doi: 10.1542/peds.109.3.526. [DOI] [PubMed] [Google Scholar]
  • 2.Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med. 1987;317:1321–9. doi: 10.1056/NEJM198711193172105. [DOI] [PubMed] [Google Scholar]
  • 3.Anand KJ, Johnston CC, Oberlander TF, Taddio A, Lehr VT, Walco GA. Analgesia and local anesthesia during invasive procedures in the neonate. Clin Ther. 2005;27:844–76. doi: 10.1016/j.clinthera.2005.06.018. [DOI] [PubMed] [Google Scholar]
  • 4.Arts SE, Abu-Saad HH, Champion GD, Crawford MR, Fisher RJ, Juniper KH, Ziegler JB. Age-related response to lidocaine-prilocaine (EMLA) emulsion and effect of music distraction on the pain of intravenous cannulation. Pediatrics. 1994;93:797–801. [PubMed] [Google Scholar]
  • 5.Ballas SK, Lieff S, Benjamin LJ, Dampier CD, Heeney MM, Hoppe C, Johnson CS, Rogers ZR, Smith-Whitley K, Wang WC, Telen MJ. Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol. 2009;85:6–13. doi: 10.1002/ajh.21550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bremnes T, Paasche JD, Mehlum A, Sandberg C, Bremnes B, Attramadal H. Regulation and intracellular trafficking pathways of the endothelin receptors. J Biol Chem. 2000;275:17596–604. doi: 10.1074/jbc.M000142200. [DOI] [PubMed] [Google Scholar]
  • 7.Burkhardt M, Barton M, Shaw SG. Receptor- and non-receptor-mediated clearance of big-endothelin and endothelin-1: Differential effects of acute and chronic ETA receptor blockade. J Hypertens. 2000;18:273–9. doi: 10.1097/00004872-200018030-00006. [DOI] [PubMed] [Google Scholar]
  • 8.Chambers CT, Giesbrecht K, Craig KD, Bennett SM, Huntsman E. A comparison of faces scales for the measurement of pediatric pain: Children’s and parents’ ratings. Pain. 1999;83:25–35. doi: 10.1016/s0304-3959(99)00086-x. [DOI] [PubMed] [Google Scholar]
  • 9.Chambers CT, Reid GJ, Craig KD, McGrath PJ, Finley GA. Agreement between child and parent reports of pain. Clin J Pain. 1998;14:336–42. doi: 10.1097/00002508-199812000-00011. [DOI] [PubMed] [Google Scholar]
  • 10.Cicchetti DV, Feinstein AR. High agreement but low kappa: II. Resolving the paradoxes. J Clin Epidemiol. 1990;43:551–8. doi: 10.1016/0895-4356(90)90159-m. [DOI] [PubMed] [Google Scholar]
  • 11.Derbyshire SW, Fitzgerald M. The painful consequences of neonatal nociceptive input. Pain. 2010;150:220–1. doi: 10.1016/j.pain.2010.04.032. [DOI] [PubMed] [Google Scholar]
  • 12.Elliott CH, Jay SM, Woody P. An observation scale for measuring children’s distress during medical procedures. J Pediatr Psychol. 1987;12:543–51. doi: 10.1093/jpepsy/12.4.543. [DOI] [PubMed] [Google Scholar]
  • 13.Fitzgerald M, Howard RF. The Neurobiologic Basis of Pediatric Pain. In: Schechter NL, Berde CB, Yaster M, editors. Pain in Infants, Children, and Adolescents. 2. Lippincott Williams & Wilkins; Philadelphia: 2003. pp. 19–42. [Google Scholar]
  • 14.Fuggle P, Shand PA, Gill LJ, Davies SC. Pain, quality of life, and coping in sickle cell disease. Arch Dis Child. 1996;75:199–203. doi: 10.1136/adc.75.3.199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Gearing RE, Mian IA, Barber J, Ickowicz A. A methodology for conducting retrospective chart review research in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry. 2006;15:126–34. [PMC free article] [PubMed] [Google Scholar]
  • 16.Goodenough B, Champion GD, Laubreaux L, Tibah L, Kampel L. Needle pain severity in children: Does the relationship between self-report and observed behaviour vary as a function of age? Aust J Psychol. 1998;50:1–9. [Google Scholar]
  • 17.Graido-Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood. 1998;92:2551–5. [PubMed] [Google Scholar]
  • 18.Hebbel RP, Osarogiagbon R, Kaul D. The endothelial biology of sickle cell disease: Inflammation and a chronic vasculopathy. Microcirculation. 2004;11:129–151. [PubMed] [Google Scholar]
  • 19.Hemsen A, Ahlborg G, Ottosson-Seeberger A, Lundberg JM. Metabolism of Big endothelin-1 (1-38) and (22-38) in the human circulation in relation to production of endothelin-1 (1-21) Regul Pept. 1995;55:287–97. doi: 10.1016/0167-0115(94)00119-i. [DOI] [PubMed] [Google Scholar]
  • 20.Hermann C, Hohmeister J, Demirakca S, Zohsel K, Flor H. Long-term alteration of pain sensitivity in school-aged children with early pain experiences. Pain. 2006;125:278–85. doi: 10.1016/j.pain.2006.08.026. [DOI] [PubMed] [Google Scholar]
  • 21.Hotopf M, Carr S, Mayou R, Wadsworth M, Wessely S. Why do children have chronic abdominal pain, and what happens to them when they grow up? Population based cohort study. BMJ. 1998;316:1196–200. doi: 10.1136/bmj.316.7139.1196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Jacobsen PB, Manne SL, Gorfinkle K, Schorr O, Rapkin B, Redd WH. Analysis of child and parent behavior during painful medical procedures. Health Psychol. 1990;9:559–76. doi: 10.1037//0278-6133.9.5.559. [DOI] [PubMed] [Google Scholar]
  • 23.Jay SM, Elliott C. Behavioral observation scales for measuring children’s distress: The effects of increased methodological rigor. J Couns Clin Psychol. 1984;52:1106–7. doi: 10.1037//0022-006x.52.6.1106. [DOI] [PubMed] [Google Scholar]
  • 24.Jones GT, Macfarlane GJ. Epidemiology of low back pain in children and adolescents. Arch Dis Child. 2005;90:312–6. doi: 10.1136/adc.2004.056812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Jones GT, Power C, Macfarlane GJ. Adverse events in childhood and chronic widespread pain in adult life: Results from the 1958 British Birth Cohort Study. Pain. 2009;143:92–6. doi: 10.1016/j.pain.2009.02.003. [DOI] [PubMed] [Google Scholar]
  • 26.Jones GT, Silman AJ, Macfarlane GJ. Predicting the onset of widespread body pain among children. Arthritis Rheum. 2003;48:2615–21. doi: 10.1002/art.11221. [DOI] [PubMed] [Google Scholar]
  • 27.Jones GT, Silman AJ, Power C, Macfarlane GJ. Are common symptoms in childhood associated with chronic widespread body pain in adulthood? Results from the 1958 British Birth Cohort Study. Arthritis Rheum. 2007;56:1669–75. doi: 10.1002/art.22587. [DOI] [PubMed] [Google Scholar]
  • 28.Khodorova A, Montmayeur J, Strichartz G. Endothelin receptors and pain. J Pain. 2009;10:4–28. doi: 10.1016/j.jpain.2008.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kimura S, Kasuya Y, Sawamura T, Shinimi O, Sugita Y, Yanagisawa M, Goto K, Masaki T. Conversion of big endothelin-1 to 21-residue endothelin-1 is essential for expression of full vasoconstrictor activity: Structure-activity relationships of big endothelin-1. J Cardiovasc Pharmacol. 1989;13(Suppl 5):S5–7. doi: 10.1097/00005344-198900135-00003. discussion S18. [DOI] [PubMed] [Google Scholar]
  • 30.Lapoumeroulie C, Benkerrou M, Odievre MH, Ducrocq R, Brun M, Elion J. Decreased plasma endothelin-1 levels in children with sickle cell disease treated with hydroxyurea. Haematologica. 2005;90:401–3. [PubMed] [Google Scholar]
  • 31.Luffy R, Grove SK. Examining the validity, reliability, and preference of three pediatric pain measurement tools in African-American children. Pediatr Nurs. 2003;29:54–9. [PubMed] [Google Scholar]
  • 32.McClellan CB, Schatz JC, Mark TR, McKelvy A, Puffer E, Roberts CW, Sweitzer SM. Criterion and convergent validity for 4 measures of pain in a pediatric sickle cell disease population. Clin J Pain. 2009;25:146–52. doi: 10.1097/AJP.0b013e3181839ac4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.McClellan CB, Schatz JC, Puffer E, Sanchez CE, Stancil MT, Roberts CW. Use of Handheld Wireless Technology for a Home-based Sickle Cell Pain Management Protocol. J Pediatr Psychol. 2008 doi: 10.1093/jpepsy/jsn121. [DOI] [PubMed] [Google Scholar]
  • 34.McGrath PJ. Pain in Children: Nature, Assessment, and Treatment. Guilford Press; New York: 1990. [Google Scholar]
  • 35.McKelvy AD, Mark TR, Sweitzer SM. Age- and sex-specific nociceptive response to endothelin-1. J Pain. 2007;8:657–66. doi: 10.1016/j.jpain.2007.04.002. [DOI] [PubMed] [Google Scholar]
  • 36.McKelvy AD, Sweitzer SM. Endothelin-1 exposure on postnatal day 7 alters expression of the endothelin B receptor and behavioral sensitivity to endothelin-1 on postnatal day 11. Neurosci Lett. 2009;451:89–93. doi: 10.1016/j.neulet.2008.12.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Peters JW, Schouw R, Anand KJ, van Dijk M, Duivenvoorden HJ, Tibboel D. Does neonatal surgery lead to increased pain sensitivity in later childhood? Pain. 2005;114:444–54. doi: 10.1016/j.pain.2005.01.014. [DOI] [PubMed] [Google Scholar]
  • 38.Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325:11–6. doi: 10.1056/NEJM199107043250103. [DOI] [PubMed] [Google Scholar]
  • 39.Roth-Isigkeit A, Thyen U, Stoven H, Schwarzenberger J, Schmucker P. Pain among children and adolescents: Restrictions in daily living and triggering factors. Pediatrics. 2005;115:e152–62. doi: 10.1542/peds.2004-0682. [DOI] [PubMed] [Google Scholar]
  • 40.Rubin SA, Levin ER. Clinical review 53: The endocrinology of vasoactive peptides: Synthesis to function. J Clin Endocrinol Metab. 1994;78:6–10. doi: 10.1210/jcem.78.1.8288715. [DOI] [PubMed] [Google Scholar]
  • 41.Rybicki AC, Benjamin LJ. Increased levels of endothelin-1 in plasma of sickle cell anemia patients. Blood. 1998;92:2594–6. [PubMed] [Google Scholar]
  • 42.Schechter NL. The Management of Pain in Sickle Cell Disease. In: McGrath PJ, Finley GA, editors. Chronic and Recurrent Pain in Children and Adolescents. IASP Press; Seattle: 1999. pp. 99–114. [Google Scholar]
  • 43.Schmelzle-Lubiecki BM, Campbell KA, Howard RH, Franck L, Fitzgerald M. Long-term consequences of early infant injury and trauma upon somatosensory processing. Eur J Pain. 2007;11:799–809. doi: 10.1016/j.ejpain.2006.12.009. [DOI] [PubMed] [Google Scholar]
  • 44.Shapiro BS, Dinges DF, Orne EC, Bauer N, Reilly LB, Whitehouse WG, Ohene-Frempong K, Orne MT. Home management of sickle cell-related pain in children and adolescents: Natural history and impact on school attendance. Pain. 1995;61:139–44. doi: 10.1016/0304-3959(94)00164-A. [DOI] [PubMed] [Google Scholar]
  • 45.Slifer KJ, Tucker CL, Dahlquist LM. Helping children and caregivers cope with repeated invasive procedures: How are we doing? J Clin Psychol Med Settings. 2002;9:131–151. [Google Scholar]
  • 46.Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain responses during vaccination in boys. Lancet. 1995;345:291–2. doi: 10.1016/s0140-6736(95)90278-3. [DOI] [PubMed] [Google Scholar]
  • 47.Taddio A, Gurguis MG, Koren G. Lidocaine–prilocaine cream versus tetracaine gel for procedural pain in children. Ann Pharmacother. 2002;36:687–92. doi: 10.1345/aph.1A138. [DOI] [PubMed] [Google Scholar]
  • 48.Taddio A, Katz J. The effects of early pain experience in neonates on pain responses in infancy and childhood. Paediatr Drugs. 2005;7:245–57. doi: 10.2165/00148581-200507040-00004. [DOI] [PubMed] [Google Scholar]
  • 49.Taddio A, Shah V, Atenafu E, Katz J. Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants. Pain. 2009;144:43–8. doi: 10.1016/j.pain.2009.02.012. [DOI] [PubMed] [Google Scholar]
  • 50.Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA. 2002;288:857–61. doi: 10.1001/jama.288.7.857. [DOI] [PubMed] [Google Scholar]
  • 51.Uebersax JS. Validity inferences from interobserver agreement. Psychol Bull. 1988;104:405–16. [Google Scholar]
  • 52.Varni JW, Thompson KL, Hanson V. The Varni/Thompson Pediatric Pain Questionnaire. I. Chronic musculoskeletal pain in juvenile rheumatoid arthritis. Pain. 1987;28:27–38. doi: 10.1016/0304-3959(87)91056-6. [DOI] [PubMed] [Google Scholar]
  • 53.von Baeyer CL. Children’s self-reports of pain intensity: Scale selection, limitations and interpretation. Pain Res Manag. 2006;11:157–62. doi: 10.1155/2006/197616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Wollgarten-Hadamek I, Hohmeister J, Demirakca S, Zohsel K, Flor H, Hermann C. Do burn injuries during infancy affect pain and sensory sensitivity in later childhood? Pain. 2009;141:165–72. doi: 10.1016/j.pain.2008.11.008. [DOI] [PubMed] [Google Scholar]
  • 55.Zohsel K, Hohmeister J, Flor H, Hermann C. Altered pain processing in children with migraine: An evoked potential study. Eur J Pain. 2008;12:1090–101. doi: 10.1016/j.ejpain.2008.02.001. [DOI] [PubMed] [Google Scholar]
  • 56.Zohsel K, Hohmeister J, Flor H, Hermann C. Somatic pain sensitivity in children with recurrent abdominal pain. Am J Gastroenterol. 2008;103:1517–23. doi: 10.1111/j.1572-0241.2008.01911.x. [DOI] [PubMed] [Google Scholar]
  • 57.Zohsel K, Hohmeister J, Oelkers-Ax R, Flor H, Hermann C. Quantitative sensory testing in children with migraine: Preliminary evidence for enhanced sensitivity to painful stimuli especially in girls. Pain. 2006;123:10–8. doi: 10.1016/j.pain.2005.12.015. [DOI] [PubMed] [Google Scholar]

RESOURCES