Altered pain processing and sensitization in sickle cell disease: a scoping review of quantitative sensory testing findings.

OBJECTIVES: Over 50% of adults living with sickle cell disease (SCD) have chronic pain, but the underlying mechanisms of chronic pain in this population remain unclear. Quantitative sensory testing is an important measurement tool for understanding pain and sensory processing. This scoping review summarizes quantitative sensory testing methodologies used in sickle cell studies and the evidence for central sensitization in this population. METHODS: We conducted a systematic search of PubMed, Embase, and CINAHL to identify studies using quantitative sensory testing in individuals living with sickle cell disease. Search strategies were based on variations of the terms "sickle cell disease," and "quantitative sensory testing." Eligible studies were observational or experimental studies in human participants living with SCD that reported findings and detailed methodology for at least 1 quantitative sensory testing modality. RESULTS: Our search yielded a total of 274 records; 27 of which are included in this scoping review. Of the 27 studies, 17 were original studies (with combined total of 516 adult and 298 pediatric participants), and 10 were secondary or subgroup analyses of these prior studies. Significant variation existed in quantitative sensory testing methodologies across studies, including testing locations, type and intensity of stimuli, and interpretation of findings. Of the identified studies, 22% (2/9 studies) reported sensory abnormalities in mechanical sensitivity and thresholds, 22% (2/9 studies) reported abnormal pressure pain thresholds, 46% (6/13 studies) reported sensory abnormalities in thermal pain thresholds and tolerance (cold and warm), and 50% (2/4 studies) reported abnormalities in temporal summation. CONCLUSION: Future studies should use standardized quantitative sensory testing protocols with consistent and operationalized definitions of sensitization to provide clear insight about pain processing and central sensitization in sickle cell disease.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry.

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26-42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PERSPECTIVE: This study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Precision, integrative medicine for pain management in sickle cell disease.

Sickle cell disease (SCD) is a prevalent and complex inherited pain disorder that can manifest as acute vaso-occlusive crises (VOC) and/or chronic pain. Despite their known risks, opioids are often prescribed routinely and indiscriminately in managing SCD pain, because it is so often severe and debilitating. Integrative medicine strategies, particularly non-opioid therapies, hold promise in safe and effective management of SCD pain. However, the lack of evidence-based methods for managing SCD pain hinders the widespread implementation of non-opioid therapies. In this review, we acknowledge that implementing personalized pain treatment strategies in SCD, which is a guideline-recommended strategy, is currently fraught with limitations. The full implementation of pharmacological and biobehavioral pain approaches targeting mechanistic pain pathways faces challenges due to limited knowledge and limited financial and personnel support. We recommend personalized medicine, pharmacogenomics, and integrative medicine as aspirational strategies for improving pain care in SCD. As an organizing model that is a comprehensive framework for classifying pain subphenotypes and mechanisms in SCD, and for guiding selection of specific strategies, we present evidence updating pain research pioneer Richard Melzack's neuromatrix theory of pain. We advocate for using the updated neuromatrix model to subphenotype individuals with SCD, to better select personalized multimodal treatment strategies, and to identify research gaps fruitful for exploration. We present a fairly complete list of currently used pharmacologic and non-pharmacologic SCD pain therapies, classified by their mechanism of action and by their hypothesized targets in the updated neuromatrix model.

Early Initiation of Sub-Anesthetic Ketamine Infusion in Adults with Vaso-Occlusive Crises Is Associated with Greater Reduction in Sickle Cell Pain Intensity: A Single Center's Experience.

OBJECTIVES: Recurrent, severely painful episodes, known as vaso-occlusive crises (VOCs) are the hallmark of sickle cell disease (SCD) and the primary reason for hospitalization. Opioids have been the gold standard for VOC treatment without significant improvement pain outcomes. To aid analgesia and combat opioid related adverse effects (ORAEs), some SCD clinicians have trialed infusions of sub-anesthetic ketamine along with opioids to treat VOCs. In this retrospective analysis, we compared adult SCD patients who received early vs late adjunctive sub-anesthetic ketamine infusions for VOCs. METHODS: We identified adult SCD patients (age 18-50 years) who presented to Duke University with a VOC and received sub-anesthetic ketamine infusions from July 2015 to June 2019. We assessed both daily opioid consumption (measured as oral morphine milligram equivalents (MME)) and self-reported 0-10 numeric pain ratings (NPR) at 1, 2, and 3 days after infusion initiation, as well as 1 day after discontinuation. RESULTS: A total of 56 patients were identified with a median age of 30 years. Compared to late administration, early infusion of sub-anesthetic ketamine was associated with a 24.5% (P = .0003) and 25.9% (P = .0006) reduction, respectively, in median NPR at 1 day and 2 days after infusion initiation but did not persist at 3 days following initiation of the infusion. A statistically significant reduction in MME was not observed. CONCLUSIONS: In a nonrandomized study of sickle cell patients with VOCs, early sub-anesthetic ketamine infusion led to greater reduction in subjective pain intensity than late initiation of the infusion. Randomized studies should further explore whether early vs late ketamine infusion improves management of acute SCD pain.

Moving Toward a Multimodal Analgesic Regimen for Acute Sickle Cell Pain with Non-Opioid Analgesic Adjuncts: A Narrative Review.

Purpose of Review: Sickle cell disease (SCD) is an inherited hemoglobinopathy with potential life-threatening complications that affect millions of people worldwide. Severe and disabling acute pain, referred to as a vaso-occlusive crisis (VOC), is a fundamental symptom of the disease and the primary driver for acute care visits and hospitalizations. Despite the publication of guidelines for VOC management over the past decade, management of VOCs remains unsatisfactory for patients and providers. Recent Findings: Acute SCD pain includes pain secondary to VOCs and other forms of acute pain. Distinguishing VOC from non-VOC pain may be challenging for both patients and clinicians. Further, although opioids have been the gold-standard for VOC pain management for decades, the current highest standard of care for all acute pain is a multimodal approach that is less dependent on opioids, and, instead incorporates analgesics and adjuvants from different mechanistic pathways. In this narrative review, we focus on a multimodal pharmacologic approach for acute SCD pain management and explore the evidence for existing non-opioid pharmacological adjuncts. Moreover, we present an explanatory model of pain, which is not only novel in its application to SCD pain but also captures the multidimensional nature of the SCD pain experience and supports the need for such a multimodal approach. This model also highlights opportunities for new investigative and therapeutic targets - both pharmacological and non-pharmacological. Summary: Multimodal pain regimens that are less dependent on opioids are urgently needed to improve acute pain outcomes for individuals with SCD. The proposed explanatory model for SCD pain offers novel opportunities to improve acute pain management for SCD patients.

Telehealth acceptability and opioid prescribing patterns of providers of painful chronic diseases during the COVID-19 pandemic: A survey of sickle cell providers.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) has led to a rapid transition to telehealth services. It is unclear how subspecialists managing painful chronic diseases-such as sickle cell disease (SCD), an inherited hemoglobinopathy with significant disparities in access and outcomes-have viewed the transition to tele-health or altered their pain management practices. This study elicits the views of sickle cell providers regarding their transition to telehealth and their opioid prescribing patterns during the COVID-19 pandemic. DESIGN: An anonymous online survey was sent to eligible sickle cell providers. SETTING: Comprehensive sickle cell centers and/or clinics across the United States. PARTICIPANTS: Physicians and advanced practice providers providing care to SCD patients. MAIN OUTCOME MEASURES: Respondents answered questions regarding their (1) views of telehealth compared to in-person encounters and (2) opioid prescribing practices during the early months of the pandemic. RESULTS: Of the 130 eligible participants, 53 respondents from 35 different sickle cell centers completed at least 90 percent of the survey. Respondents reported a significant increase in telehealth encounters for routine and acute appointments (mean difference and standard deviation: 57.6 ± 31.9 percent, p < 0.001 and 24.4 ± 34.1 percent, p < 0.001, respectively) since COVID-19. The overwhelming majority of respondents reported no changes in their opioid prescribing patterns since COVID-19, despite increased telehealth use. Only a minority copre-scribed naloxone as a risk mitigation strategy. CONCLUSION: The rapid uptake of telehealth has not suppressed ambulatory providers' prescribing of opioids for SCD. Studies assessing the impact of the COVID-19 pandemic and telehealth on opioid prescribing practices in other painful chronic diseases are needed to ensure health equity for vulnerable pain patients.