Phenylethanolamine N-methyltransferase gene polymorphisms associate with crisis pain in sickle cell disease patients.

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.

A QST-based Pain Phenotype in Adults With Sickle Cell Disease: Sensitivity and Specificity of Quality Descriptors.

BACKGROUND: We sought to refine a screening measure for discriminating a sensitized or normal sensation pain phenotype among African American adults with sickle cell disease (SCD). OBJECTIVE: To develop scoring schemes based on sensory pain quality descriptors; evaluate their performance on classifying patients with SCD who had sensitization or normal sensation, and compare with scores on the Self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and the Neuropathic Pain Symptom Inventory (NPSI). METHODS: Participants completed PAINReportIt, quantitative sensory testing (QST), S-LANSS, and NPSI. Conventional binary logistic regression and least absolute shrinkage and selection operator (lasso) regression were used to obtain 2 sets of weights resulting in 2 scores: the PR-Logistic (PAINReportIt score weighted by conventional binary logistic regression coefficients) and PR-Lasso (PAINReportIt score weighted by lasso regression coefficients). Performance of the proposed scores and the existing scores were evaluated. RESULTS: Lasso regression resulted in a parsimonious model with non-zero weights assigned to 2 neuropathic descriptors, cold and spreading. We found positive correlations between the PR-Lasso and other scores: S-LANSS (r = 0.22, P < 0.01), NPSI (r = 0.22, P < 0.01), and PR-Logistic (r = 0.35, P < 0.01). The NPSI and PR-Lasso performed similarly at different levels of required specificity and outperformed the S-LANSS and PR-Logistic at the various specificity points. CONCLUSION: The PR-Lasso offers a way to discriminate a SCD pain phenotype.

Randomized clinical trial of computerized PAINRelieveIt® for patients with sickle cell disease: PAINReportIt® and PAINUCope®.

OBJECTIVE: To compare effects of a tailored multimedia education program versus usual-care on barriers to pain management of adult patients with SCD. METHODS: Pretest/posttest randomized controlled trial (RCT) of 228 outpatients with SCD randomized to the tablet-based PAINUCope intervention focused on barriers to pain management, pain, and analgesic adherence or selection of games (control). Outcomes were barriers to pain management, pain, and analgesic adherence. RESULTS: The barriers to pain management and pain scores did not change significantly from pretest to posttest for either condition. Changes in analgesic adherence rates from pretest to posttest were statistically significant for the intervention group (p = .046) but not for the usual care group (p = .419). The group difference was not statistically significant. CONCLUSIONS: This first RCT of a tailored multimedia education intervention with adult patients with SCD did not significantly reduce the outcomes of interest compared to the control group. Findings provide insights for improving intervention delivery and reinforcement of patient behaviors. PRACTICE IMPLICATIONS: Study redesign is warranted with modifications that include theoretical and methodological approaches and patient-centered delivery of the intervention that take advantage of recent technology developments.

Patients and Caregivers Rate the PAINReportIt Wireless Internet-Enabled Tablet as a Method for Reporting Pain During End-of-Life Cancer Care.

BACKGROUND: In several studies, investigators have successfully used an internet-enabled PAINReportIt tablet to allow patients to report their pain to clinicians in real-time, but it is unknown how acceptable this technology is to patients and caregivers when used in their homes. OBJECTIVE: The aims of this study were to examine computer use acceptability scores of patients with end-stage cancer in hospice and their caregivers and to compare the scores for differences by age, gender, race, and computer use experience. INTERVENTION/METHODS: Immediately after using the tablet, 234 hospice patients and 231 caregivers independently completed the Computer Acceptability Scale (maximum scores of 14 for patients and 9 for caregivers). RESULTS: The mean (SD) Computer Acceptability score was 12.2 (1.9) for patients and 8.5 (0.9) for caregivers. Computer Acceptability scores were significantly associated with age and with previous computer use for both patients and caregivers. CONCLUSIONS: This technology was highly acceptable to patients and caregivers for reporting pain in real time to their hospice nurses. IMPLICATIONS FOR PRACTICE: Findings provide encouraging results that are worthy of serious consideration for patients who are in end stages of illness, including older persons and those with minimal computer experience. Increasing availability of technology can provide innovative methods for improving care provided to patients facing significant cancer-related pain even at the end of life.

Sensitivities to Thermal and Mechanical Stimuli: Adults With Sickle Cell Disease Compared to Healthy, Pain-Free African American Controls.

Evidence supports, but is inconclusive that sensitization contributes to chronic pain in some adults with sickle cell disease (SCD). We determined the prevalence of pain sensitization among adults with SCD pain compared with pain-free healthy adults. In a cross sectional, single session study of 186 African American outpatients with SCD pain (age 18-74 years, 59% female) and 124 healthy age, gender, and race matched control subjects (age 18-69 years, 49% female), we compared responses to standard thermal (Medoc TSA II) and mechanical stimuli (von Frey filaments). Although we observed no significant differences in thermal thresholds between controls and patients, patients with SCD had lower pain thresholds to mechanical stimuli and reported higher pain intensity scores to all thermal and mechanical stimuli at a non-painful body site. Compared with controls, about twice as many patients with SCD showed sensitization: 12% versus 23% at the anterior forearm site (P = .02), and 16% versus 32% across 3 tested sites (P = .004). Among patients with SCD, 18% exhibited some element of central sensitization. Findings indicate that persistent allodynia and hyperalgesia can be part of the SCD pain experience and should be considered when selecting therapies for SCD pain. PERSPECTIVE: Compared with matched healthy controls, quantitative sensory testing in adults with pain and sickle cell disease (SCD) demonstrates higher prevalence of sensitization, including central sensitization. The findings of allodynia and hyperalgesia may indicate neuropathic pain and could contribute to a paradigm shift in assessment and treatment of SCD pain.

Thermal and mechanical quantitative sensory testing values among healthy African American adults.

PURPOSE: Only a few studies have reported quantitative sensory testing (QST) reference values for healthy African Americans, and those studies are limited in sample size and age of participants. The study purpose was to characterize QST values in healthy, pain-free African American adults and older adults whose prior pain experiences and psychological status were also measured. We examined the QST values for differences by sex, age, and body test site. PATIENTS AND METHODS: A cross-sectional sample of 124 pain-free African American adults (age 18-69 years, 49% female) completed demographic and self-reported pain, fatigue and psychosocial measures. QST was performed to obtain thermal and mechanical responses and associated pain intensity levels. RESULTS: We found thermal detection values at the anterior forearm were (29.2 °C±1.6) for cool detection (CD) and (34.5 °C±1.2) for warm detection (WD). At that site the sample had cold pain threshold (CPTh) (26.3 °C±5.0), heat pain threshold (HPTh) (37.8 °C±3.6), and mechanical pain thresholds (MPTH) (16.7±22.2 grams of force, gF). There was a significant between sex difference for WD, with women being more sensitive (q=0.027). Lower body sites were less sensitive than upper body sites across all thermal modalities (q<0.003), but not for the mechanical modality. CONCLUSION: The QST values from this protocol at the anterior forearm indicate that the healthy African American adults had average thermal pain thresholds close to the temperature of adaptation and average MPTh under 20 gF. Differences in responses to thermal and mechanical stimuli for upper verses lower body were consistent with prior research.

Relationship of Pain Quality Descriptors and Quantitative Sensory Testing: Sickle Cell Disease.

BACKGROUND: Chronic pain in adults with sickle cell disease (SCD) may be the result of altered processing in the central nervous system, as indicated by quantitative sensory testing (QST). Sensory pain quality descriptors on the McGill Pain Questionnaire (MPQ) are indicators of typical or altered pain mechanisms but have not been validated with QST-derived classifications. OBJECTIVES: The specific aim of this study was to identify the sensory pain quality descriptors that are associated with the QST-derived normal or sensitized classifications. We expected to find that sets of sensory pain quality descriptors would discriminate the classifications. METHODS: A cross-sectional quantitative study of existing data from 186 adults of African ancestry with SCD. Variables included MPQ descriptors, patient demographic data, and QST-derived classifications. RESULTS: The participants were classified as central sensitization (n = 33), mixed sensitization (n = 23), and normal sensation. Sensory pain quality descriptors that differed statistically between mixed sensitization and central sensation compared to normal sensitization included cold (p = .01) and spreading (p = .01). Aching (p = .01) and throbbing (p = .01) differed statistically between central sensitization compared with mixed sensitization and normal sensation. Beating (p = .01) differed statistically between mixed sensitization compared with central sensitization and normal sensation. No set of sensory pain quality descriptors differed statistically between QST classifications. DISCUSSION: Our study is the first to examine the association between MPQ sensory pain quality descriptors and QST-derived classifications in adults with SCD. Our findings provide the basis for the development of a MPQ subscale with potential as a mechanism-based screening tool for neuropathic pain.

Transient receptor potential polymorphism and haplotype associate with crisis pain in sickle cell disease.

AIM: Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients. METHODS: Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain. RESULTS & CONCLUSION: We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.

Opioid doses and acute care utilization outcomes for adults with sickle cell disease: ED versus acute care unit.

BACKGROUND: Acute care units (ACUs) with focused sickle cell disease (SCD) care have been shown to effectively address pain and limit hospitalizations compared to emergency departments (ED), the reason for differences in admission rates is understudied. Our aim was compare effects of usual care for adult SCD pain in ACU and ED on opioid doses and discharge pain ratings, hospital admission rates and lengths of stay. METHODS: In a retrospective, comparative cohort, single academic tertiary center study, 148 adults with sickle cell pain received care in the ED, ACU or both. From the medical records we documented opioid doses, unit discharge pain ratings, hospital admission rates, and lengths of stay. FINDINGS: Pain on admission to the ED averaged 8.7±1.5 and to the ACU averaged 8.0±1.6. The average pain on discharge from the ED was 6.4±3.0 and for the ACU was 4.5±2.5. 70% of the 144 ED visits resulted in hospital admissions as compared to 37% of the 73 ACU visits. Admissions from the ED or ACU had similar inpatient lengths of stay. Significant differences between ED and ACU in first opioid dose and hourly opioid dose were noted. CONCLUSIONS: Applying guidelines for higher dosing of opioids for acute painful episodes in adults with SCD in ACU was associated with improved pain outcomes and decreased hospitalizations, compared to ED. Adoption of this approach for SCD pain in ED may result in improved outcomes, including a decrease in hospital admissions.

Derivatives of furanditerpenes from Pterodon genus: Pharmacological studies disclose their potential as chronic pain relief in mice.

Pterodon genus fruits are commercially available at the Brazilian medicinal market used in folk medicine due to their anti-inflammatory, analgesic, and anti-rheumatic effects. Previous studies demonstrated that furanditerpenes possessing vouacapan skeleton, isolated from Pterodon genus, possess expressive antinociceptive activities, with promising moiety for the development of new analgesic products. The antinociceptive properties of compounds 6α,7ß-6α-hidroxivouacapan-7ß-17ß-lactone (HVL) and 6α-oxovouacapan-7ß-17ß-lactone (OVL), semi-synthetic analogues of furanditerpenes previously reported as analgesic agents were evaluated on animal experimental models (Spindola et al., 2010, 2011). The chemical-induced pain methods used in the present work, demonstrated for the first time that both compounds HVL and OVL have potential as important templates for the development of chronic pain control drugs. The main findings of this work were that both compounds were: effective in the writhing test; reduced paw edema in the carrageenan test; effective in the inflammatory phase of the formalin test corroborating their activity against inflammatory pain conditions; effective on reducing pain through the stimulation of vanilloid receptors sensible to capsaicin (an important pathway for chronic pain maintenance); reduced the pain stimulus caused by PGE2 injection (a pathway involved in chronic pain hypersensitivity); effective on decreasing mechanical allodynia in the CFA-model, demonstrating their potential use against chronic pain disorders.

IL1A rs1800587 associates with chronic noncrisis pain in sickle cell disease.

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.

Composite Pain Index: Reliability, Validity, and Sensitivity of a Patient-Reported Outcome for Research.

OBJECTIVE: A single score that represents the multidimensionality of pain would be an innovation for patient-reported outcomes. Our aim was to determine the reliability, validity, and sensitivity of the Composite Pain Index (CPI). DESIGN: Methodological analysis of data from a randomized controlled, pretest/post-test education-based intervention study. SETTING: The study was conducted in outpatient oncology clinics. SUBJECTS: The 176 subjects had pain, were 52 ± 12.5 years on average, 63% were female, and 46% had stage IV cancers. METHODS: We generated the CPI from pain location, intensity, quality, and pattern scores measured with an electronic version of Melzack's McGill Pain Questionnaire. RESULTS: The internal consistency values for the individual scores comprising the CPI were adequate (0.71 baseline, 0.69 post-test). Principal components analysis extracted one factor with an eigenvalue of 2.17 with explained variance of 54% at baseline and replicated the one factor with an eigenvalue of 2.11 at post-test. The factor loadings for location, intensity, quality, and pattern were 0.65, 0.71, 0.85, and 0.71, respectively (baseline), and 0.59, 0.81, 0.84, and 0.63, respectively (post-test). The CPI was sensitive to an education intervention effect. CONCLUSIONS: Findings support the CPI as a score that integrates the multidimensional pain experience in people with cancer. It could be used as a patient-reported outcome measure to quantify the complexity of pain in clinical research and population studies of cancer pain and studied for relevance in other pain populations.

Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease.

Recent evidence of neuropathic pain among adults with sickle cell disease (SCD) reveals a need for adjuvant analgesic treatments for these patients. Ca(2+)/calmodulin protein kinase IIα (CaMKIIα) has a known role in neuropathic pain and trifluoperazine is a potent CaMKIIα inhibitor. The study aim was to determine trifluoperazine's acute effects, primarily on adverse effects and secondarily on pain intensity reduction, in adults with SCD. In a phase I, open-label study of 6 doses of trifluoperazine (0.5, 1, 2, 5, 7.5, 10mg), we obtained 7-hourly and 24-h repeated measures of adverse effects, pain intensity, and supplemental opioid analgesics in 18 adults with SCD (18 hemoglobin SS disease, 15 women, average age 35.8±8.9 years, ranged 23-53) each of whom received a single dose. Data were analyzed with descriptive statistics. Subjects reported moderate to severe sedative effects at 7.5 and 10mg doses, respectively. Eight subjects reported 50% reduction in chronic pain without severe sedation or supplemental opioid analgesics; one of these subjects had dystonia 24.5h after the 10mg dose. The analgesic effect lasted for at least 24h in 3 subjects. Sedation resolved with caffeine and dystonia resolved with diphenhydramine. Adults with SCD experienced minimal adverse effects at doses under 10mg. In this molecular mechanism-driven translational study, trifluoperazine shows promise as an analgesic drug that is worthy of further testing in a randomized controlled study of adults with SCD starting at a dose of 1mg in repeated doses to determine long-term adverse and analgesic effects.

Role for platelet glycoprotein Ib-IX and effects of its inhibition in endotoxemia-induced thrombosis, thrombocytopenia, and mortality.

OBJECTIVE: Poor prognosis of sepsis is associated with bacterial lipopolysaccharide (LPS)-induced intravascular inflammation, microvascular thrombosis, thrombocytopenia, and disseminated intravascular coagulation. Platelets are critical for thrombosis, and there has been increasing evidence of the importance of platelets in endotoxemia. The platelet adhesion receptor, the glycoprotein Ib-IX complex (GPIb-IX), mediates platelet adhesion to inflammatory vascular endothelium and exposed subendothelium. Thus, we have investigated the role of GPIb-IX in LPS-induced platelet adhesion, thrombosis, and thrombocytopenia. APPROACH AND RESULTS: LPS-induced mortality is significantly decreased in mice expressing a functionally deficient mutant of GPIbα. Furthermore, we have developed a micellar peptide inhibitor, MPαC (C13H27CONH-SIRYSGHpSL), which selectively inhibits the von Willebrand factor -binding function of GPIb-IX and GPIb-IX-mediated platelet adhesion under flow without affecting GPIb-IX-independent platelet activation. MPαC inhibits platelet adhesion to LPS-stimulated endothelial cells in vitro and alleviates LPS-induced thrombosis in glomeruli in mice. Importantly, MPαC reduces mortality in LPS-challenged mice, suggesting a protective effect of this inhibitor during endotoxemia. Interestingly, MPαC, but not the integrin antagonist, Integrilin, alleviated LPS-induced thrombocytopenia. CONCLUSIONS: These data indicate an important role for the platelet adhesion receptor GPIb-IX in LPS-induced thrombosis and thrombocytopenia, and suggest the potential of targeting GPIb as an antiplatelet strategy in managing endotoxemia.

Patient-reported outcomes: descriptors of nociceptive and neuropathic pain and barriers to effective pain management in adult outpatients with sickle cell disease.

Despite frequent episodes of severe recurrent pain in sickle cell disease (SCD), sensory pain in outpatient adults with SCD lacks sufficient characterization. Furthermore, pivotal barriers may interfere with these patients' adherence to prescribed analgesic therapies but have not been studied systematically. We describe sensory pain characteristics, barriers, and analgesic use reported by adults with SCD during routine clinic visits. Patients (N = 145; 67% female, 94% African American) completed measures on a pen-tablet computer. Patients reported an average of 3.6 +/- 2.3 pain sites; mean current pain intensity (3.3 +/- 3.2), least (3.0 +/- 2.7) and worst (4.9 +/- 3.5) pain intensity in 24 hours on a 0 to 10 scale, multiple neuropathic (4.5 +/- 3.4, 8.3% selected none) and nociceptive (6.8 +/- 4.0) pain descriptors, and continuous pain pattern (59%). Their mean pain barriers score was 2.2 +/- 0.9, and 33% were dissatisfied with their pain levels. Only 14% reported taking at least 1 adjuvant drug, 82% were taking nonopioids, 85% step 2 opioids, and 65% step 3 opioids. Patients reported using, on average, 4.9 +/- 2.7 analgesics. Their pain barriers scores were similar to or greater than people with cancer. Importantly, their pain may be both nociceptive and neuropathic, contrary to common expectations that SCD pain is only nociceptive. Few patients, however, took drugs effective for neuropathic pain.

Neurobiological mechanisms of pain in sickle cell disease.

Pain is a frequent complaint of people living with sickle cell disease (SCD); however, the neurobiology of pain in SCD remains poorly understood. Whereas this pain has been thought to be primarily related to visceral and somatic tissue injury subsequent to vaso-occlusion events, emerging evidence from human and animal studies has suggested that a component of SCD pain may be related to neuropathic processes. Significant knowledge has been obtained from studies of molecular and neurobiological mechanisms leading to and maintaining neuropathic pain. Some of the most promising evidence has implicated major roles of protein kinase C and Ca2+/calmodulin-dependent protein kinase II, and their interaction with the N-methyl-D-aspartate receptors and the transient receptor potential vanilloid 1 receptor in the development of neuropathic pain. The latest evidence from our studies suggests that these pathways are important for SCD pain as well. Coupled with emerging animal models of SCD pain, we can now start to elucidate neurobiological mechanisms underlying pain in SCD, which may lead to better understanding and effective therapies.