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Introduction: As the most distressing complication of sickle cell disease (SCD), pain is marked by considerable heterogenicity. In this study we explored the potential association of alcohol dehydrogenase 7 gene ( ADH7 ) polymorphism rs971074 with sickle cell pain. Methods: We analyzed clinical phenotypes and the rs971074 single-nucleotide polymorphism in ADH7 by MassARRAY-iPlex analysis in a cohort of SCD patients. Results: The synonymous rs971074 was significantly associated with both acute and chronic pain in SCD. Patients with the minor T allele(s) recorded significantly more crisis episodes and severe chronic pain symptoms. Conclusion: Our study has identified the rs971074 minor T allele as a genetic biomarker potentially influencing acute and chronic pain. These findings may ultimately help inform strategies to develop precision pain therapies in SCD.

Background: Pain intensity remains a primary focus clinically for sickle cell disease pain assessment despite the fact that pain quality and pain location and distribution are critical for clinical diagnosis and treatment of its etiology. However, in part because of measurement issues, scant evidence is available about pain location or its relationship to intensity and quality in adults with SCD., Aim: Our study aim was to examine sickle cell disease pain location for relationships with pain quality and intensity measured in outpatient and inpatient settings., Methods: We used an existing longitudinal dataset prospectively collected with the valid and reliable tablet-based PAINReportIt Ⓡ . Adults with sickle cell disease (n = 99) reported pain location, intensity, and quality during a routine outpatient clinic visit and again during a subsequent hospitalization. From their digital body outline drawings and using the ImageJ software, we computed the pain-affected body surface area. With Pearson's correlations and paired t tests, we examined relationships between pain-affected body surface area and other pain variables across outpatient and inpatient visits., Results: The mean pain-affected body surface area was 14.4% ± 15.0% of the total body surface area for outpatient visits (min-max: 0.0%-90.2%) and 13.5% ± 14.7% (min-max: 0.0%-73.0%) for inpatient stay. Pain-affected body surface area was positively correlated with pain quality scores for both visits but not significantly correlated with pain intensity at either visit. Compared with the outpatient visit, mean pain intensity for inpatient stay was higher (p < .001); pain quality (p = .12) and pain-affected body surface area (p = .60) did not differ significantly between visits., Conclusions: Unknown is the explanation for pain-affected body surface area association with SCD pain quality but not pain intensity at outpatient and inpatient visits. Additional research is warranted to explore these findings and examine the clinical utility of pain-affected body surface area for chronic sickle cell disease pain and acute sickle cell disease crisis pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Background: Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD., Methods: Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform., Results: Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance., Conclusions: S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner., Competing Interests: The authors have declared that no competing interests exist.

Aim: Phenylethanolamine N- methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.

Individuals with pain from sickle cell disease (SCD) are often treated for nociceptive pain, but recent findings indicate they may also have neuropathic pain. PAIN Report It, a computerized version of the McGill Pain Questionnaire, provides a potential subscale that is the summed number of selected neuropathic pain quality words (PR-NNP), but it lacks construct validity. The study purpose was to ascertain PR-NNP construct validity in adults with SCD and chronic pain. In an outpatient setting, 186 participants completed the PAIN Report It, Neuropathic Pain Symptom Inventory (NPSI), and Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS). PR-NNP was moderately correlated with NPSI ( r = .33, p < .001) and S-LANSS ( r = .40, p < .001). Regression analysis indicated that PR-NNP and pain intensity, but not a nociceptive pain subscale, were significant predictors of NPSI and S-LANSS. Findings support construct validity of PR-NNP, which may be useful as a screening tool for neuropathic pain in patients with SCD.

Background: Pain is the quintessential symptom for individuals suffering from sickle cell disease (SCD). Although the degree of suffering and the cost of treatment are staggering, SCD continues to be grossly understudied, including a lack of data for pain-related genes and prevalence of polymorphisms in this population. This lack of data adds to the inadequacy of pain therapy in this population. Pain genetics investigators have recently examined allele frequencies of single-nucleotide polymorphisms from candidate genes in people who have SCD. One of the genes identified was the arginine vasopressin receptor 1A gene (AVPR1A) and its associated single-nucleotide polymorphism (SNP) rs10877969. Progress in explaining pain-related polymorphisms associated with SCD can be facilitated by understanding the literature. Aim/Design: The purpose of this literature review was to describe mechanisms of the polymorphic gene AVPR1A and the phenotypic variations associated with its SNPs relative to health conditions and pain., Methods: Published studies were included if the research addressed AVPR1A and was a full article in a peer-reviewed journal, in the English language, a human or animal study, and published 2009 to present. Abstracts were included if they were in English and provided information not found in a full article., Results: The results of this review revealed that AVPR1A is associated with behavioral phenotypes, which include pair bonding, autism spectrum disorder, musical aptitude, infidelity, altruism, monogamy, mating, substance abuse, and alcohol preference. In addition, there were associations with pain, stress pain by sex, and sickle cell pain., Conclusion: Summary of this literature could provide insights into future pain research of this SNP in people with SCD., (Copyright © 2018 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Background: Patients with sickle cell disease (SCD) report pain scores that appear greater than those reported in a meta-analysis for patients with cancer, but statistical comparisons of the pain scores from both populations have not been published., Aims: The goal of the study described here was to compare pain outcomes reported by outpatients with cancer or SCD., Design: Descriptive comparative study., Setting: Outpatient oncology or sickle cell clinics., Subjects: The participants were outpatients (N = 415) from three studies: (1) 106 patients with SCD, 93% African-American (referent group); (2) 140 patients with cancer, 90% Caucasian (race discordant); (3) 169 patients with cancer, 20% Caucasian, 65% African-American (race concordant)., Methods: Patients completed the PAINReportIt including pain location, quality, pattern, intensity, expectation, satisfaction, and demographic questions. Analyses included the χ 2 test, analysis of variance, and regression., Results: Outpatients with SCD reported more pain location sites than the race-discordant (p < .001) and race-concordant (p < .001) cancer groups; higher pain quality than the race-discordant (p < .001) and race-concordant (p < .001) groups; and greater pain pattern scores than the race-discordant (p < .001) and race-concordant (p < .001) groups. The race-concordant group reported higher worst pain intensity than the SCD (p < .001) and race-discordant (p = .002) groups. The three groups did not differ significantly on pain expectation (p = .06). Regarding satisfaction with pain level, there was a significant difference between the race-concordant and SCD (p = .006) groups, but not between the race-discordant and SCD (p = .12) groups or between the race-discordant and race-concordant (p = .49) groups., Conclusions: Outpatients with SCD reported three of four sensory pain parameters that were greater than those reported by outpatients with cancer. A better understanding of these differences is pertinent to improving pain outcomes., (Copyright © 2017 American Society for Pain Management Nursing. All rights reserved.)

Aim: Pain is prevalent in sickle cell disease (SCD) patients who display great heterogeneity in pain severity and frequency. Hypothesizing that inflammatory factors are involved in the pathogenesis of SCD pain, we focused on the IL1A C/T polymorphism rs1800587 that is an SNP located in a cis-transcriptional regulatory region., Methods: We genotyped IL1A rs1800587 and performed association studies with phenotype data obtained by a multidimensional pain assessment tool using the PAINReportIt ® Questionnaire., Results: Each T allele was associated with a 3.9 increase in composite pain index score (p = 0.04) as determined by multiple linear regression., Conclusion: IL1A rs1800587 may influence chronic pain in SCD., Competing Interests: Financial & competing interests disclosure This study was supported in part by funds from the Illinois Department of Public Health (IDPH) and grants R01HL124945 and R01HL098141 from the National Heart, Lung, and Blood Institute (NHLBI), NIH. EH Jhun is supported by a predoctoral fellowship from NIDCR (T32DE018381). Y He is a Sickle Cell Scholar (U54HL117658). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the IDPH, NIH, NHLBI, NIDCR or Veteran's Administration. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Pain is a life-long symptom in sickle cell disease (SCD) and a predictor of disease progression and mortality, but little is known about its molecular mechanisms. Here, we characterized pain in a targeted knockin mouse model of SCD (TOW mouse) that exclusively expresses human alleles encoding normal α- and sickle β-globin. TOW mice exhibited ongoing spontaneous pain behavior and increased sensitivity to evoked pain compared with littermate control mice expressing normal human hemoglobins. PKCδ activation was elevated in the superficial laminae of the spinal cord dorsal horn in TOW mice, specifically in GABAergic inhibitory neurons. Functional inhibition and neuron-specific silencing of PKCδ attenuated spontaneous pain, mechanical allodynia, and heat hyperalgesia in TOW mice. Furthermore, we took a hematopoietic stem cell transplantation approach to generating a SCD model in PKCδ-deficient mice. Neither spontaneous pain nor evoked pain was detected in the mice lacking PKCδ despite full establishment of SCD phenotypes. These findings support a critical role of spinal PKCδ in the development of chronic pain in SCD, which may become a potential target for pharmacological interventions.

Background: Recruiting and retaining participants for clinical trials, particularly women and ethnic minorities, are challenging. Few studies, however, examine gender and ethnic differences in research processes. Such information is important for findings to adequately represent the available population., Objective: The study aim was to examine study recruitment processes (referral, eligibility, consent/enrollment) and study retention (completion) for gender and ethnic differences., Methods: A descriptive comparative analysis of data from 2 randomized clinical trials focused on cancer outpatients with pain and/or fatigue. A computerized ResearchTracking software allowed documentation of recruitment and retention effort outcomes., Results: Among the 1464 referred patients, 612 (42%) were eligible for study participation. Lack of ongoing care at the study settings and lack of English skills were the main reasons for ineligibility. There were no gender differences in consent/enrollment or completion rates. Ethnic minority patients were represented proportionally to the available population (13%) and were equally willing to consent/enroll and complete both studies as their white counterparts, if they were eligible., Conclusions: Specific strategies to target language eligibility barriers are necessary to increase minority participation., Implications for Practice: Future studies could include audio-aided tools in their native language to help recruit patients with limited English skills, if the study tools can be validly translated into other languages and are equivalent to English versions. Efforts to educate and garner support of providers could improve enrollment of patients in cancer studies, especially in studies of audio- or video-recorded patient-provider interaction.