The Origins and Future of Sentinel: An Early-Warning System for Pandemic Preemption and Response.

While investigating a signal of adaptive evolution in humans at the gene LARGE, we encountered an intriguing finding by Dr. Stefan Kunz that the gene plays a critical role in Lassa virus binding and entry. This led us to pursue field work to test our hypothesis that natural selection acting on LARGE-detected in the Yoruba population of Nigeria-conferred resistance to Lassa Fever in some West African populations. As we delved further, we conjectured that the "emerging" nature of recently discovered diseases like Lassa fever is related to a newfound capacity for detection, rather than a novel viral presence, and that humans have in fact been exposed to the viruses that cause such diseases for much longer than previously suspected. Dr. Stefan Kunz's critical efforts not only laid the groundwork for this discovery, but also inspired and catalyzed a series of events that birthed Sentinel, an ambitious and large-scale pandemic prevention effort in West Africa. Sentinel aims to detect and characterize deadly pathogens before they spread across the globe, through implementation of its three fundamental pillars: Detect, Connect, and Empower. More specifically, Sentinel is designed to detect known and novel infections rapidly, connect and share information in real time to identify emerging threats, and empower the public health community to improve pandemic preparedness and response anywhere in the world. We are proud to dedicate this work to Stefan Kunz, and eagerly invite new collaborators, experts, and others to join us in our efforts.

Predictors of pharmacologic therapy for neonatal opioid withdrawal syndrome: a retrospective analysis of a statewide database.

OBJECTIVE: Identify factors associated with the need for pharmacologic therapy (PT) among opioid exposed newborn (OENs). STUDY DESIGN: Retrospective analysis of a statewide database of OENs from 2017 through 2019. Multivariable mixed-effects logistic regression modeled the association of maternal characteristics, infant characteristics, and family engagement practices on the receipt of PT. RESULTS: Of 2098 OENs, 44.8% required PT for NOWS. Higher odds of PT were associated with in-utero exposure to medication treatment for opioid use disorder (MOUD) and non-prescribed opioids in addition to MOUD; nicotine, benzodiazepines, SSRIs; male; out-born infants and mother's ineligibility to provide breast-milk. Lower odds were associated with increasing birth year, skin-to-skin (STS) care, and rooming-in. CONCLUSION: Male, out-born infants exposed to MOUD with additional non-prescribed opioids, nicotine, benzodiazepines and SSSRIs with mothers ineligible to provide breast-milk were more likely to require PT, while modifiable care practices including STS care, and rooming-in decreased the likelihood of PT.

Racial and Ethnic Disparities in Maternal and Infant Outcomes Among Opioid-Exposed Mother-Infant Dyads in Massachusetts (2017-2019).

Objectives. To examine the extent to which differences in medication for opioid use disorder (MOUD) in pregnancy and infant neonatal opioid withdrawal syndrome (NOWS) outcomes are associated with maternal race/ethnicity.Methods. We performed a secondary analysis of a statewide quality improvement database of opioid-exposed deliveries from January 2017 to April 2019 from 24 hospitals in Massachusetts. We used multivariable mixed-effects logistic regression to model the association between maternal race/ethnicity (non-Hispanic White, non-Hispanic Black, or Hispanic) and prenatal receipt of MOUD, NOWS severity, early intervention referral, and biological parental custody at discharge.Results. Among 1710 deliveries to women with opioid use disorder, 89.3% (n = 1527) were non-Hispanic White. In adjusted models, non-Hispanic Black women (AOR = 0.34; 95% confidence interval [CI] = 0.18, 0.66) and Hispanic women (AOR = 0.43; 95% CI = 0.27, 0.68) were less likely to receive MOUD during pregnancy compared with non-Hispanic White women. We found no statistically significant associations between maternal race/ethnicity and infant outcomes.Conclusions. We identified significant racial/ethnic differences in MOUD prenatal receipt that persisted in adjusted models. Research should focus on the perspectives and treatment experiences of non-Hispanic Black and Hispanic women to ensure equitable care for all mother-infant dyads.

A quality improvement initiative to implement the eat, sleep, console neonatal opioid withdrawal syndrome care tool in Massachusetts' PNQIN collaborative.

OBJECTIVE: To support hospitals in the Massachusetts PNQIN collaborative with adoption of the ESC Neonatal Opioid Withdrawal Syndrome (NOWS) Care Tool© and assess NOWS hospitalization outcomes. STUDY DESIGN: Statewide QI study where 11 hospitals adopted the ESC NOWS Care Tool©. Outcomes of pharmacotherapy and length of hospital stay (LOS) and were compared in Pre- and Post-ESC implementation cohorts. Statistical Process Control (SPC) charts were used to examine changes over time. RESULTS: The Post-ESC group had lower rates of pharmacotherapy (OR 0.35, 95% CI 0.26, 0.46) with shorter LOS (RR 0.79, 95% CI 0.76, 0.82). The 30-day NOWS readmission rate was 1.2% in the Pre- and 0.4% in the Post-ESC cohort. SPC charts indicate a shift in pharmacotherapy from 54.8 to 35.0% and LOS from 14.2 to 10.9 days Post-ESC. CONCLUSIONS: The ESC NOWS Care Tool was successfully implemented across a state collaborative with improvement in NOWS outcomes without short-term adverse effects.

Thermal QST Phenotypes Associated with Response to Lumbar Epidural Steroid Injections: A Pilot Study.

OBJECTIVE: Response to lumbar epidural steroid injection in lumbar radicular pain varies. The purpose of this study is to characterize the changes in quantitative sensory testing (QST) phenotypes of subjects and compare the QST characteristics in patients who do respond to treatment of radicular pain with a lumbar epidural steroid injection (ESI). DESIGN: Prospective, observational pilot study. SETTING: Outpatient pain center. METHODS: Twenty subjects with a lower extremity (LE) radicular pain who were scheduled to have an ESI were recruited. At the visit prior to and four weeks following an ESI, subjects underwent QST measurements of both the affected LE and the contralateral unaffected UE. RESULTS: Following an ESI, nine subjects reported a greater than 30% reduction in radicular pain and 11 reported a less than 30% reduction in radicular pain. Subjects who had less than 30% pain reduction response (nonresponders) to an ESI had increased pre-injection warm sensation threshold (37.30 °C, SD = 2.51 vs 40.39, SD = 3.36, P = 0.03) and heat pain threshold (47.22 °C, SD = 1.38, vs 48.83 °C, SD = 2.10, P = 0.04). Further, the nonresponders also showed increased pre-injection warm sensation threshold as measured in the difference of warm sensation detection threshold difference in the affected limb and the unaffected arm (2.68 °C, SD = 2.92 vs 5.67 °C, SD = 3.22, P = 0.045). Other QST parameters were not affected. CONCLUSIONS: The results show that the nonresponders to ESIs have increased detection threshold to heat pain and warm sensation, suggesting that a preexisting dysfunction in the C fibers in this group of subjects who can be detected by QST. Such altered QST characteristics may prognosticate the response to ESIs.

Effects of Spinal Cord Stimulation on Pain Thresholds and Sensory Perceptions in Chronic Pain Patients.

OBJECTIVE: Spinal cord stimulation (SCS) has been in clinical use for nearly four decades. In earliest observations, researchers found a significant increase in pain threshold during SCS therapy without changes associated with touch, position, and vibration sensation. Subsequent studies yielded diverse results regarding how SCS impacts pain and other sensory thresholds. This pilot study uses quantitative sensory testing (QST) to objectively quantify the impact of SCS on warm sensation, heat pain threshold, and heat pain tolerance. MATERIALS AND METHODS: Nineteen subjects with an indwelling SCS device for chronic pain were subjected to QST with heat stimuli. QST was performed on an area of pain covered with SCS-induced paresthesia and an area without pain and without paresthesia, while the SCS was turned off and on. The temperature at which the patient detected warm sensation, heat pain, and maximal tolerable heat pain was used to define the thresholds. RESULTS: We found that all three parameters, the detection of warm sensation, heat pain threshold, and heat pain tolerance, were increased during the period when SCS was on compared with when it was off. This increase was observed in both painful and non-painful sites. CONCLUSION: The observed pain relief during SCS therapy seems to be related to its impact on increased sensory threshold as detected in this study. The increased sensory threshold on areas without pain and without the presence of SCS coverage may indicate a central (spinal and/or supra-spinal) influence from SCS.

Effect of 1.5% Topical Diclofenac on Clinical Neuropathic Pain.

BACKGROUND: Neuropathic pain is a condition resulting from injury to the peripheral and/or central nervous system. Despite extensive research over the last several decades, neuropathic pain remains difficult to manage. METHODS: The authors conducted a randomized, placebo-controlled, double-blinded, and crossover clinical trial to examine the effect of 1.5% topical diclofenac (TD) on neuropathic pain. The authors hypothesized that 1.5% TD would reduce the visual pain score and improve both quantitative sensory testing and functional status in subjects with neuropathic pain. The authors recruited subjects with postherpetic neuralgia and complex regional pain syndrome. The primary outcome was subject's visual pain score. RESULTS: Twenty-eight subjects completed the study (12 male and 16 female) with the mean age of 48.8 yr. After 2 weeks of topical application, subjects in 1.5% TD group showed lower overall visual pain score compared with placebo group (4.9 [1.9] vs. 5.6 [2.1], difference: 0.8; 95% CI, 0.1 to 1.3; P = 0.04) as well as decreased burning pain (2.9 [2.6] vs. 4.3 [2.8], difference, 1.4; 95% CI, 0.2 to 2.6; P = 0.01). There were no statistical differences in constant pain, shooting pain, or hypersensitivity over the painful area between the groups. This self-reported improvement of pain was corroborated by the decreased pain summation detected by quantitative sensory testing. There were no statistically significant changes in functional status in these subjects. There were no complications in both groups. CONCLUSION: The findings indicate that 1.5% TD may serve as an effective treatment option for patients with neuropathic pain from postherpetic neuralgia and complex regional pain syndrome.

Increased pain sensitivity in chronic pain subjects on opioid therapy: a cross-sectional study using quantitative sensory testing.

OBJECTIVE: The aim of this study was to compare the sensitivity to experimental pain of chronic pain patients on opioid therapy vs chronic pain patients on non-opioid therapy and healthy subjects by quantitative sensory testing (QST). SETTING: There is a growing body of evidence demonstrating that chronic use of opioid drugs may alter pain sensitivity. Identifying the characteristic changes in thermal pain sensitivity in chronic opioid users will be helpful in diagnosing pain sensitivity alterations associated with chronic opioid use. METHODS: Utilizing an office-based QST technique, we examined thermal pain threshold, tolerance, and temporal summation in 172 chronic pain subjects receiving opioid therapy, 121 chronic pain subjects receiving non-opioid therapy, and 129 healthy subjects. RESULTS: In chronic pain subjects receiving opioid therapy, there were detectable differences in QST characteristics compared with both chronic pain subjects receiving non-opioid therapy and healthy subjects. Specifically, in chronic pain subjects receiving opioid therapy, 1) sensitivity to heat pain was increased; threshold to heat pain was significantly lower; 2) tolerance to supra-threshold heat pain was significantly decreased; and 3) temporal pain summation was exacerbated, as compared with chronic pain subjects receiving non-opioid therapy. In a subgroup of chronic pain subjects receiving opioid therapy with increased heat pain sensitivity, their average opioid medication dosage was significantly higher than those who had an above-average heat pain threshold. Moreover, a subset of chronic pain subjects on opioid therapy exhibited a significant decrease in diffuse noxious inhibitory control (DNIC) compared with chronic pain subjects on non-opioid therapy. CONCLUSION: These findings suggest that a subset of QST parameters can reflect opioid-associated thermal pain sensitivity alteration, including decreased heat pain threshold, decreased cold and heat pain tolerance, diminished DNIC, and/or exacerbated temporal summation.

Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

Lack of correlation between opioid dose adjustment and pain score change in a group of chronic pain patients.

UNLABELLED: Despite the increasing use of opioid analgesics for chronic pain management, it is unclear whether opioid dose escalation leads to better pain relief during chronic opioid therapy. In this study, we retrospectively analyzed clinical data collected from the Massachusetts General Hospital Center for Pain Medicine over a 7-year period. We examined 1) the impact of opioid dose adjustment (increase or decrease) on clinical pain score; 2) gender and age differences in response to opioid therapy; and 3) the influence of clinical pain conditions on the opioid analgesic efficacy. A total of 109 subjects met the criteria for data collection. We found that neither opioid dose increase, nor decrease, correlated with point changes in clinical pain score in a subset of chronic pain patients over a prolonged course of opioid therapy (an average of 704 days). This lack of correlation was consistent regardless of the type of chronic pain including neuropathic, nociceptive, or mixed pain conditions. Neither gender nor age differences showed a significant influence on the clinical response to opioid therapy in these subjects. These results suggest that dose adjustment during opioid therapy may not necessarily alter long-term clinical pain score in a group of chronic pain patients and that individualized opioid therapy based on the clinical effectiveness should be considered to optimize the treatment outcome. PERSPECTIVE: The study reports a relationship, or lack thereof, between opioid dose change and clinical pain score in a group of chronic pain patients. The study also calls for further investigation into the effectiveness of opioid therapy in the management of chronic nonmalignant pain conditions.

Opioid therapy for chronic pain: physicians' attitude and current practice patterns.

Although opioid therapy is widely used for the treatment of chronic pain conditions, there is a lack of consensus on a number of practical issues related to the use of prescription opioids. The authors conducted a comprehensive practice-oriented survey to examine physicians' attitudes, knowledge, experience, and practice patterns regarding opioid therapy for chronic pain management. The survey was conducted during 2007 and 2008 through nationwide direct mails and e-mails to physicians who are currently practicing in the United States. The survey contained 23 questions divided into six categories: (1) physicians' overall view on opioid therapy for chronic pain management; (2) clinical indications for opioid therapy; (3) patient-related factors influencing the decision to begin opioid therapy; (4) effectiveness of opioid therapy; (5) choice of opioid regimen; and (6) opioid agreement and opioid abuse behavior. The survey results suggest that opioid therapy remains as an important treatment option for chronic malignant and nonmalignant pain. However, the survey results should be viewed in the context of a low response rate (18.2 percent). These results also suggest that by improving the clinical knowledge of physicians participating in opioid therapy through education and collaboration, including a team approach with consultation from pain specialists, psychologists, and others, a better outcome for opioid therapy in patients with chronic pain conditions could be achieved.

A survey of selected physician views on acupuncture in pain management.

OBJECTIVES: To collect information on the role of acupuncture in pain management from pain physicians and referral physicians who manage clinical pain conditions. METHODS: The survey was conducted between 2007 and 2008 through nationwide direct mail or e-mail to 1083 physicians who are currently practicing in the United States. We divided our 16 survey questions into five categories: 1) physician's attitude toward acupuncture as a modality of pain management; 2) physician's preference or belief with regard to the type of pain condition suitable for acupuncture referrals; 3) timing for making acupuncture referrals (e.g., acupuncture as a first line pain treatment option or a last approach after failed conventional pain management); 4) clinical assessment criteria for the effectiveness of acupuncture therapy; and 5) barriers to making acupuncture referrals (e.g., physician's personal view, insurance issues, patient refusal, etc.). The survey results were calculated and interpreted as the percentage rate of response. RESULT: The results indicate that an overwhelming majority of survey responders have a positive attitude and favorable experience with using acupuncture as an alternative modality for chronic pain management. However, our survey responders are mostly from teaching hospitals, suggesting a possible gap between teaching hospitals and other medical facilities (private practice and community hospitals) in utilizing acupuncture for pain management. The lack of insurance coverage and facility for acupuncture treatment are two primary barriers to making acupuncture referrals. CONCLUSIONS: The survey results indicate that acupuncture is considered by many physicians to be a useful alternative modality for chronic pain management.

Altered quantitative sensory testing outcome in subjects with opioid therapy.

Preclinical studies have suggested that opioid exposure may induce a paradoxical decrease in the nociceptive threshold, commonly referred as opioid-induced hyperalgesia (OIH). While OIH may have implications in acute and chronic pain management, its clinical features remain unclear. Using an office-based quantitative sensory testing (QST) method, we compared pain threshold, pain tolerance, and the degree of temporal summation of the second pain in response to thermal stimulation among three groups of subjects: those with neither pain nor opioid therapy (group 1), with chronic pain but without opioid therapy (group 2), and with both chronic pain and opioid therapy (group 3). We also examined the possible correlation between QST responses to thermal stimulation and opioid dose, opioid treatment duration, opioid analgesic type, pain duration, or gender in group 3 subjects. As compared with both group 1 (n=41) and group 2 (n=41) subjects, group 3 subjects (n=58) displayed a decreased heat pain threshold and exacerbated temporal summation of the second pain to thermal stimulation. In contrast, there were no differences in cold or warm sensation among three groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of the second pain in group 3 subjects. These results indicate that decreased heat pain threshold and exacerbated temporal summation of the second pain may be characteristic QST changes in subjects with opioid therapy. The data suggest that QST may be a useful tool in the clinical assessment of OIH.