Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and ß-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.

Optimal pain management for patients with cancer in the modern era.

Pain is a common symptom among patients with cancer. Adequate pain assessment and management are critical to improve the quality of life and health outcomes in this population. In this review, the authors provide a framework for safely and effectively managing cancer-related pain by summarizing the evidence for the importance of controlling pain, the barriers to adequate pain management, strategies to assess and manage cancer-related pain, how to manage pain in patients at risk of substance use disorder, and considerations when managing pain in a survivorship population. CA Cancer J Clin 2018;68:182-196. © 2018 American Cancer Society.

Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia.

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signalling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signalling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management.

Physicians prescribe fewer analgesics during night shifts than day shifts.

Adequate pain management is one of the biggest challenges of the modern healthcare system. Physician perception of patient subjective pain, which is crucial to pain management, is susceptible to a host of potential biases. Here we explore the timing of physicians' work as a previously unrecognized source of systematic bias in pain management. We hypothesized that during night shifts, sleep deprivation, fatigue, and stress would reduce physicians' empathy for others' pain, leading to underprescription of analgesics for patient pain relief. In study 1, 67 resident physicians, either following a night shift or not, performed empathy for pain assessment tasks and simulated patient scenarios in laboratory conditions. As predicted, following a night shift, physicians showed reduced empathy for pain. In study 2, we explored this phenomenon in medical decisions in the field. We analyzed three emergency department datasets from Israel and the United States that included discharge notes of patients arriving with pain complaints during 2013 to 2020 (n = 13,482). Across all datasets, physicians were less likely to prescribe an analgesic during night shifts (compared to daytime shifts) and prescribed fewer analgesics than generally recommended by the World Health Organization. This effect remained significant after adjusting for patient, physician, type of complaint, and emergency department characteristics. Underprescription for pain during night shifts was particularly prominent for opioids. We conclude that night shift work is an important and previously unrecognized source of bias in pain management, likely stemming from impaired perception of pain. We consider the implications for hospitals and other organizations employing night shifts.

"To prescribe or not to prescribe, that is the question": Perspectives on opioid prescribing for chronic, cancer-related pain from clinicians who treat pain in survivorship.

BACKGROUND: Opioid pain management in cancer survivorship is a complex and understudied topic. METHODS: The authors conducted in-depth, qualitative interviews to understand clinician approaches to opioid pain management in chronic cancer pain and to generate ideas for improvement. They used a rigorous, inductive, qualitative, descriptive approach to examine clinician (n = 20) perspectives about opioid pain management in survivorship, including oncologists (n = 5), palliative care clinicians (n = 8), primary care clinicians (n = 5), and pain management specialists (n = 2). RESULTS: The findings indicated that no consistent medical home exists for chronic pain management in cancer survivors and that there are fundamental differences in how each subspecialty approaches chronic pain management in survivorship (e.g., "Do we think of this as noncancer pain or cancer pain?… This is in this limbo zone-this gray zone-because it's cancer-related pain, right?"). Simultaneously, clinicians are influenced by their peers' perceptions of their opioid prescribing decisions, sparking intraprofessional tension when disagreement occurs. In these instances, clinicians described overthinking and doubting their clinical decision-making as well as a sense of judgment, pressure, and/or shame. Finally, clinicians acknowledged a fear of consequences for opioid prescribing decisions. Specifically, participants cited conflict with patients, sometimes escalating to aggression and threats of violence, as well as potential disciplinary actions and/or legal consequences. CONCLUSIONS: Participants suggested that opportunities to improve chronic cancer pain care include developing clear, systematic guidance for chronic cancer pain management, facilitating clinician communication and consultation, creating tailored survivorship care plans in partnership with patients, and developing accessible, evidence-based, complementary pain treatments.

Opioid and Non-Opioid Pharmacotherapy Use for Pain Management Among Privately Insured Pediatric Patients With Cancer in the United States.

BACKGROUND: This study examined the trends and patterns of opioid and non-opioid pharmacotherapy use among a large national sample of privately insured pediatric patients with cancer in the United States. MATERIALS AND METHODS: We identified pediatric (aged < 21) patients diagnosed with central nervous system (CNS), lymphoma, gonadal, leukemia, or bone cancer from MarketScan data 2005-2019. We examined the proportion of patients who filled a prescription for the following 5 types of pharmacotherapy: opioid, anticonvulsant, non-steroidal anti-inflammatory drug (NSAID), antidepressant, and muscle relaxant during active cancer treatment. We assessed the trends and patterns in pharmacotherapy using multivariable logistic regressions. RESULTS: Among 4174 patients included, 2979 (71%) had an opioid prescription; 746 (18%), 384 (9%), 202 (5%), and 169 (4%) had anticonvulsant, NSAID, antidepressant and muscle relaxant prescriptions, respectively. Multivariable logistic regression showed a nonlinear trend in the use of opioids among pediatric patients with cancer over time such that use slightly increased until 2012 (OR of 1.40 [95% CI, 1.12-1.73] for 2012 vs. 2006) but then decreased thereafter (OR of 0.51 [0.37-0.68] for 2018 vs. 2012). The use of anticonvulsants, NSAIDs, and muscle relaxants increased significantly linearly over time (all P < .005). CONCLUSION: There has been a downward trend in the use of opioids in recent years among pediatric patients with cancer and an upward trend in the use of non-opioid pharmacotherapy for pain management potentially as an alternative to opioids.

ECM-mimetic, NSAIDs loaded thermo-responsive, immunomodulatory hydrogel for rheumatoid arthritis treatment.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and it leads to irreversible inflammation in intra-articular joints. Current treatment approaches for RA include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, and biological agents. To overcome the drug-associated toxicity of conventional therapy and transdermal tissue barrier, an injectable NSAID-loaded hydrogel system was developed and explored its efficacy. RESULTS: The surface morphology and porosity of the hydrogels indicate that they mimic the natural ECM, which is greatly beneficial for tissue healing. Further, NSAIDs, i.e., diclofenac sodium, were loaded into the hydrogel, and the in vitro drug release pattern was found to be burst release for 24 h and subsequently sustainable release of 50% drug up to 10 days. The DPPH assay revealed that the hydrogels have good radical scavenging activity. The biocompatibility study carried out by MTT assay proved good biocompatibility and anti-inflammatory activity of the hydrogels was carried out by gene expression study in RAW 264.7 cells, which indicate the downregulation of several key inflammatory genes such as COX-2, TNF-α & 18s. CONCLUSION: In summary, the proposed ECM-mimetic, thermo-sensitive in situ hydrogels may be utilized for intra-articular inflammation modulation and can be beneficial by reducing the frequency of medication and providing optimum lubrication at intra-articular joints.

Neurotechnology for Pain.

Neurotechnologies for treating pain rely on electrical stimulation of the central or peripheral nervous system to disrupt or block pain signaling and have been commercialized to treat a variety of pain conditions. While their adoption is accelerating, neurotechnologies are still frequently viewed as a last resort, after many other treatment options have been explored. We review the pain conditions commonly treated with electrical stimulation, as well as the specific neurotechnologies used for treating those conditions. We identify barriers to adoption, including a limited understanding of mechanisms of action, inconsistent efficacy across patients, and challenges related to selectivity of stimulation and off-target side effects. We describe design improvements that have recently been implemented, as well as some cutting-edge technologies that may address the limitations of existing neurotechnologies. Addressing these challenges will accelerate adoption and change neurotechnologies from last-line to first-line treatments for people living with chronic pain.

Improved Postoperative Pain Management Outcomes After Implementation of Enhanced Recovery After Surgery (ERAS) Protocol for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC).

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for patients with peritoneal carcinomatosis is promising but has potential for significant morbidity and prolonged hospitalization. Enhanced Recovery After Surgery (ERAS) is a standardized protocol designed to optimize perioperative care. This study describes trends in epidural and opioid use after implementing ERAS for CRS-HIPEC at a tertiary academic center. METHODS: A retrospective analysis of patients undergoing CRS-HIPEC from January 2020 to September 2023 was conducted. ERAS was implemented in February 2022. Medication and outcomes data were compared before and after ERAS initiation. All opioids were converted to morphine milligram equivalents (MMEs). RESULTS: A total of 136 patients underwent CRS-HIPEC: 73 (54%) pre- and 63 (46%) post-ERAS. Epidural usage increased from 63% pre-ERAS to 87% post-ERAS (p = 0.001). Compared with those without epidurals, patients with epidurals had decreased total 7-day oral and intravenous (IV) opioid requirements (45 MME vs. 316 MME; p < 0.001). There was no difference in 7-day opioid totals between pre- and post-ERAS groups. After ERAS, more patients achieved early ambulation (83% vs. 53%; p < 0.001), early diet initiation (81% vs. 25%; p < 0.001), and early return of bowel function (86% vs. 67%; p = 0.012). CONCLUSIONS: ERAS implementation for CRS-HIPEC was associated with increased epidural use, decreased oral and IV opioid use, and earlier bowel function return. Our study demonstrates that epidural analgesia provides adequate pain control while significantly decreasing oral and IV opioid use, which may promote gastrointestinal recovery postoperatively. These findings support the implementation of an ERAS protocol for effective pain management in patients undergoing CRS-HIPEC.

Outcomes After a Statewide Policy to Improve Evidence-Based Treatment of Back Pain Among Medicaid Enrollees in Oregon.

BACKGROUND: A novel Oregon Medicaid policy guiding back pain management combined opioid restrictions with emphasis on non-opioid and non-pharmacologic therapies. OBJECTIVE: To examine the effect of the policy on prescribing, health outcomes, and health service utilization. DESIGN: Using Medicaid enrollment, medical and prescription claims, prescription drug monitoring program, and vital statistics files, we analyzed the policy's association with selected outcomes using interrupted time series models. SUBJECTS: Adult Medicaid patients with back pain enrolled between 2014 and 2018. INTERVENTION: The Oregon Medicaid back pain policy. MAIN MEASURES: Opioid and non-opioid medication prescribing, procedural care, substance use and mental health conditions, and outpatient and inpatient healthcare utilization. KEY RESULTS: The policy was associated with decreases in the percentage of Medicaid enrollees with back pain receiving any opioids (- 2.68 percentage points [95% CI - 3.14, - 2.23] level, - 1.01 pp [95% CI - 1.1, - 0.92] slope), days of short-acting opioid use (- 0.4 days [95% CI - 0.53, - 0.26] slope), receipt of more than 7 days of short-acting opioids (- 2.36 pp [95% CI - 2.76, - 1.95] level, - 0.91 pp [95% CI - 1, - 0.83] slope), chronic opioid use (- 1.27 pp [95% CI - 1.59, - 0.94] level, - 0.46 [95% CI - 0.53, - 0.39 slope), and spinal surgeries and procedures. Among secondary outcomes, we found no increase in opioid overdose and a small, statistically significant trend decrease in opioid use disorders. There were small increases in non-opioid substance use and mental health diagnoses and visits but no increase in self-harm. CONCLUSIONS: A state Medicaid policy emphasizing evidence-based back pain management was associated with decreases in opioid prescribing, spinal surgeries, and opioid use disorder trends, but also short-term increases in mental health encounters and an increase in non-opioid substance use disorder trends. Such policies may help reinforce evidence-based care, but must be designed with consideration of potential harms.

Racial and Ethnic Disparities in Opioid Prescribing on Hospital Discharge Among Older Adults: A National Retrospective Cohort Study.

BACKGROUND: Disparities in opioid prescribing among racial and ethnic groups have been observed in outpatient and emergency department settings, but it is unknown whether similar disparities exist at discharge among hospitalized older adults. OBJECTIVE: To determine filled opioid prescription rates on hospital discharge by race/ethnicity among Medicare beneficiaries. DESIGN: Retrospective cohort study. PARTICIPANTS: Medicare beneficiaries 65 years or older discharged from hospital in 2016, without opioid fills in the 90 days prior to hospitalization (opioid-naïve). MAIN MEASURES: Race/ethnicity was categorized by the Research Triangle Institute (RTI), grouped as Asian/Pacific Islander, Black, Hispanic, other (American Indian/Alaska Native/unknown/other), and White. The primary outcome was an opioid prescription claim within 2 days of hospital discharge. The secondary outcome was total morphine milligram equivalents (MMEs) among adults with a filled opioid prescription. KEY RESULTS: Among 316,039 previously opioid-naïve beneficiaries (mean age, 76.8 years; 56.2% female), 49,131 (15.5%) filled an opioid prescription within 2 days of hospital discharge. After adjustment, Black beneficiaries were 6% less likely (relative risk [RR] 0.94, 95% CI 0.91-0.97) and Asian/Pacific Islander beneficiaries were 9% more likely (RR 1.09, 95% CI 1.03-1.14) to have filled an opioid prescription when compared to White beneficiaries. Among beneficiaries with a filled opioid prescription, mean total MMEs were lower among Black (356.9; adjusted difference - 4%, 95% CI - 7 to - 1%), Hispanic (327.0; adjusted difference - 7%, 95% CI - 10 to - 4%), and Asian/Pacific Islander (328.2; adjusted difference - 8%, 95% CI - 12 to - 4%) beneficiaries when compared to White beneficiaries (409.7). CONCLUSIONS AND RELEVANCE: Black older adults were less likely to fill a new opioid prescription after hospital discharge when compared to White older adults and received lower total MMEs. The factors contributing to these differential prescribing patterns should be investigated further.

The Associations Between Opioid Use Disorder and Healthcare-Related Outcomes in Vaso-occlusive Crisis.

BACKGROUND: In patients who experience frequent vaso-occlusive crises (VOC), opioid dependence may be due to a need for pain control as opposed to addiction; the implications of opioid use disorder (OUD) in this population are unclear. OBJECTIVE: To compare outcomes in hospitalizations for VOC in those with a history of OUD to those without a history of OUD. DESIGN: A retrospective assessment of hospitalizations for adults in the USA with a primary discharge diagnosis of VOC using the National Inpatient Sample database from 2016 to 2019. We also compared VOC hospitalizations to hospitalizations for all other reasons to assess differences in OUD-associated clinical factors. PARTICIPANTS: In total, 273,460 hospitalizations for VOC; 23,120 (8.5%) of these hospital stays involved a secondary diagnosis of OUD. MAIN MEASURES: Primary outcomes were length of hospital stay and cost. Mortality was a secondary outcome. KEY RESULTS: Hospital length of stay was increased (mean 6.2 vs 4.9 days) in patients with OUD (adjusted rate ratio = 1.24, 95% CI 1.20-1.29, p < 0.001). Mean cost was also higher in those with OUD ($9076) than those without OUD ($8020, p < 0.001). Mortality was decreased in VOC hospitalizations in those with OUD, but the difference was not statistically significant (adjusted OR = 0.64, 95% CI 0.028-1.48, p = 0.30). CONCLUSIONS: OUD is associated with increased length of stay and costs in patients with VOC. While there are many possible explanations, providers should consider undertreatment of pain due to addiction concerns as a potential factor; individualized pain plans to mitigate this challenge could be explored.

A Pharmacogenomics-Based In Silico Investigation of Opioid Prescribing in Post-operative Spine Pain Management and Personalized Therapy.

Considering the variability in individual responses to opioids and the growing concerns about opioid addiction, prescribing opioids for postoperative pain management after spine surgery presents significant challenges. Therefore, this study undertook a novel pharmacogenomics-based in silico investigation of FDA-approved opioid medications. The DrugBank database was employed to identify all FDA-approved opioids. Subsequently, the PharmGKB database was utilized to filter through all variant annotations associated with the relevant genes. In addition, the dpSNP ( https://www.ncbi.nlm.nih.gov/snp/ ), a publicly accessible repository, was used. Additional analyses were conducted using STRING-MODEL (version 12), Cytoscape (version 3.10.1), miRTargetLink.2, and NetworkAnalyst (version 3). The study identified 125 target genes of FDA-approved opioids, encompassing 7019 variant annotations. Of these, 3088 annotations were significant and pertained to 78 genes. During variant annotation assessments (VAA), 672 variants remained after filtration. Further in-depth filtration based on variant functions yielded 302 final filtered variants across 56 genes. The Monoamine GPCRs pathway emerged as the most significant signaling pathway. Protein-protein interaction (PPI) analysis revealed a fully connected network comprising 55 genes. Gene-miRNA Interaction (GMI) analysis of these 55 candidate genes identified miR-16-5p as a pivotal miRNA in this network. Protein-Drug Interaction (PDI) assessment showed that multiple drugs, including Ibuprofen, Nicotine, Tramadol, Haloperidol, Ketamine, L-Glutamic Acid, Caffeine, Citalopram, and Naloxone, had more than one interaction. Furthermore, Protein-Chemical Interaction (PCI) analysis highlighted that ABCB1, BCL2, CYP1A2, KCNH2, PTGS2, and DRD2 were key targets of the proposed chemicals. Notably, 10 chemicals, including carbamylhydrazine, tetrahydropalmatine, Terazosin, beta-methylcholine, rubimaillin, and quinelorane, demonstrated dual interactions with the aforementioned target genes. This comprehensive review offers multiple strong, evidence-based in silico findings regarding opioid prescribing in spine pain management, introducing 55 potential genes. The insights from this report can be applied in exome analysis as a pharmacogenomics (PGx) panel for pain susceptibility, facilitating individualized opioid prescribing through genotyping of related variants. The article also points out that African Americans represent an important group that displays a high catabolism of opioids and suggest the need for a personalized therapeutic approach based on genetic information.

The Legal Landscape for Opioid Treatment Agreements.

Policy Points Opioid treatment agreements (OTAs) are controversial because of the lack of evidence that their use reduces opioid-related harms and the potential risks they pose of stigmatizing patients and undermining the clinician-patient relationship. Even so, their use is now required in most jurisdictions, and their use is influencing the outcomes of civil and criminal lawsuits. More research is needed to evaluate how OTAs are implemented given existing requirements. If additional research does not resolve the current level of uncertainty regarding OTA benefits, then policymakers in jurisdictions where they are required should consider eliminating OTA mandates or providing flexibility in the legal requirements to make room for clinicians and health care institutions to implement best practices. CONTEXT: Opioid treatment agreements (OTAs) are documents that clinicians present to patients when prescribing opioids that describe the risks of opioids and specify requirements that patients must meet to receive their medication. Notwithstanding a lack of evidence that OTAs effectively mitigate opioids' risks, professional organizations recommend that they be implemented, and jurisdictions increasingly require them. We sought to identify the jurisdictions that require OTAs, how OTAs might affect the outcomes of lawsuits that arise when things go wrong, and instances in which the law permits flexibility for clinicians and health care institutions to adopt best practices. METHODS: We surveyed the laws and regulations of all 50 states and the District of Columbia to identify which jurisdictions require the use of OTAs, the circumstances in which OTA use is mandatory, and the terms OTAs must include (if any). We also surveyed criminal and civil judicial decisions in which OTAs were discussed as evidence on which a court relied to make its decision to determine how OTA use influences litigation outcomes. FINDINGS: Results show that a slight majority (27) of jurisdictions now require OTAs. With one exception, the jurisdictions' requirements for OTA use are triggered at least in part by long-term prescribing. There is otherwise substantial variation and flexibility within OTA requirements. Results also show that even in jurisdictions where OTA use is not required by statute or regulation, OTA use can inform courts' reasoning in lawsuits involving patients or clinicians. Sometimes, but not always, OTA use legally protects clinicians from liability. CONCLUSIONS: Our results show that OTA use is entwined with legal obligations in various ways. Clinicians and health care institutions should identify ways for OTAs to enhance clinician-patient relationships and patient care within the bounds of relevant legal requirements and risks.

Promoting pain coping skills in haemophilia: A remote intervention integrating exercise and pain education.

BACKGROUND: Chronic joint pain is a significant and widespread symptom in people with haemophilia (PWH). Despite medical advancements, effective pain management remains challenging. AIM: This study presents an innovative approach that integrates remote physical exercises, pain neuroscience education, and coping strategies to address chronic pain in PWH. METHODS: The remote intervention consisted of sixteen 5-min videos encompassing physical exercises for chronic pain management and pain education strategies. These videos formed an 8-week remote intervention program. Clinical and physical assessments were conducted before and after the intervention. RESULTS: A total of thirty-one PWHs, with a median age of 34 years (ranging from 16 to 59 years), completed the remote intervention. The study revealed significant improvements in pain intensity, disability, and physical performance among PWH with chronic pain. Enhanced functional capacity was evident in the Timed Up and Go and Single Leg Stance tests, accompanied by improved scores on the Functional Independence Score in Haemophilia (FISH). Although lacking a control group, our findings are consistent with other successful exercise and pain education programs. CONCLUSIONS: This innovative intervention holds promise for managing chronic pain in PWH, underscoring patient empowerment, education, and collaboration. Notably, our study stands out by uniquely combining pain education and coping strategies, bolstering evidence for effective pain management.

The good, the bad and the ugly of pain in haemophilia: Recent evidence on the epidemiology, molecular mechanisms and knowledge gaps preventing optimal treatment.

INTRODUCTION: Haemophilia is an inherited, X-linked blood clotting disorder caused by the deficiency of coagulation factors VIII (FVIII, haemophilia A) or IX (FIX, haemophilia B). Spontaneous bleeds are common in severe forms of haemophilia and can also occur in moderate and mild haemophilia. Severe or repeated bleeding at a joint can evolve into chronic haemophilic arthropathy, with functional damage of the joint, disability, and intense chronic articular pain. Nonetheless, acute and chronic pain may emerge due to secondary conditions related to bleedings. AIM: This narrative review aims to critically discuss the most recent evidence about pain in haemophilia to give healthcare professionals a clear picture of current knowledge hence favouring the optimisation of clinical management of pain. METHODS: Extensive literature search with the terms 'hemophilia' AND 'pain', focusing on the time window 2021-2023. RESULTS: Acute and chronic pain is a critical aspect of haemophilia at all ages. It should be considered a multifaceted phenomenon, with a positive role as an early emergency signal of a clinical event (haemarthrosis), and numerous detrimental aspects linked to its burden that heavily affects the health-related quality of life, with psychological and social consequences. CONCLUSION: Despite its prevalence and frequency in people with haemophilia, pain is often underestimated by healthcare professionals, leading to insufficient and inadequate treatment, also due to uncertainty linked to the presence of the coagulation disorder or arthritic flares.

A bundle of opioid-sparing strategies to eliminate routine opioid prescribing in a urogynecology practice.

BACKGROUND: Current evidence supports that many patients do not use prescribed opioids following reconstructive pelvic surgery, yet it remains unclear if it is feasible to eliminate routine opioid prescriptions without a negative impact on patients or providers. OBJECTIVE: To determine if there is a difference in the proportion of patients discharged without opioids after implementing a bundle of opioid-sparing strategies and tiered prescribing protocol compared to usual care after minimally invasive pelvic reconstructive surgery (transvaginal, laparoscopic, or robotic). Secondary objectives include measures of patient-perceived pain control and provider workload. STUDY DESIGN: The bundle of opioid-sparing strategies and tiered prescribing protocol intervention was implemented as a division-wide evidence-based practice change on August 1, 2022. This retrospective cohort compares a 6-month postintervention (bundle of opioid-sparing strategies and tiered prescribing protocol) cohort to 6-month preintervention (usual care) of patients undergoing minimally invasive pelvic reconstructive surgery. A 3-month washout period was observed after bundle of opioid-sparing strategies and tiered prescribing protocol initiation. We excluded patients <18 years, failure to consent to research, combined surgery with other specialties, urge urinary incontinence or urinary retention procedures alone, and minor procedures not typically requiring opioids. Primary outcome was measured by proportion discharged without opioids and total oral morphine equivalents prescribed. Pain control was measured by pain scores, postdischarge prescriptions and refills, phone calls and visits related to pain, and satisfaction with pain control. Provider workload was demonstrated by phone calls and postdischarge prescription refills. Data were obtained through chart review on all patients who met inclusion criteria. Primary analysis only included patients prescribed opioids according to the bundle of opioid-sparing strategies and tiered prescribing protocol protocol. Two sample t tests compared continuous variables and chi-square tests compared categorical variables. RESULTS: Four hundred sixteen patients were included in the primary analysis (207 bundle of opioid-sparing strategies and tiered prescribing protocol, 209 usual care). Baseline demographics were similar between groups, except a lower proportion of irritable bowel syndrome (13% vs 23%; P<.01) and pelvic pain (15% vs 24.9%; P=.01), and higher history of prior gynecologic surgery (69.1% vs 58.4%; P=.02) in the bundle of opioid-sparing strategies and tiered prescribing protocol cohort. The bundle of opioid-sparing strategies and tiered prescribing protocol cohort was more likely to be discharged without opioids (68.1% vs 10.0%; P<.01). In those prescribed opioids, total oral morphine equivalents on discharge was significantly lower in the bundle of opioid-sparing strategies and tiered prescribing protocol cohort (48.1 vs 81.8; P<.01). The bundle of opioid-sparing strategies and tiered prescribing protocol cohort had a 20.6 greater odds (confidence interval 11.4, 37.1) of being discharged without opioids after adjusting for surgery type, arthritis/joint pain, IBS, pelvic pain, and contraindication to nonsteroidal anti-inflammatory drugs. The bundle of opioid-sparing strategies and tiered prescribing protocol cohort was also less likely to receive a rescue opioid prescription after discharge (1.4% vs 9.5%; P=.03). There were no differences in opioid prescription refills (19.7% vs 18.1%; P=.77), emergency room visits for pain (3.4% vs 2.9%; P=.76), postoperative pain scores (mean 4.7 vs 4.0; P=.07), or patient satisfaction with pain control (81.5% vs 85.6%; P=.21). After bundle of opioid-sparing strategies and tiered prescribing protocol implementation, the proportion of postoperative phone calls for pain also decreased (12.6% vs 21.5%; P=.02). Similar results were identified when nonadherent prescribing was included in the analysis. CONCLUSION: A bundle of evidence-based opioid sparing strategies and tiered prescribing based on inpatient use increases the proportion of patients discharged without opioids after minimally invasive pelvic reconstructive surgery without evidence of uncontrolled pain or increased provider workload.

Society for Maternal-Fetal Medicine Consult Series #68: Sickle cell disease in pregnancy.

Pregnant individuals with sickle cell disease have an increased risk of maternal and perinatal morbidity and mortality. However, prepregnancy counseling and multidisciplinary care can lead to favorable maternal and neonatal outcomes. In this consult series, we summarize what is known about sickle cell disease and provide guidance for sickle cell disease management during pregnancy. The following are Society for Maternal-Fetal Medicine recommendations.

Endovascular revascularization of critical limb ischemia: the role of ultrasound-guided popliteal sciatic nerve block for the procedural pain management.

OBJECTIVES: To evaluate the impact of the ultrasound-guided popliteal sciatic nerve block (PSNB) for pain management during endovascular treatment of chronic limb-threatening ischemia (CLTI). MATERIAL AND METHODS: From November 2020 to January 2022, 111 CLTI patients that underwent endovascular procedures were prospectively enrolled in this prospective single-arm interventional study. Ultrasound-guided PSNB was used for procedural pain control. Pain intensity was evaluated throughout the procedure (baseline, 10 min after the block, pain peak, and at the end of the procedure) with the visual analog scale (VAS). RESULTS: Forty-six patients underwent above-the-knee revascularization (ATK), 20/111 below-the-knee (BTK) revascularization, 20/111 to both ATK and BTK revascularization. In 25 cases, no endovascular option was feasible at diagnostic angiography. The PSNB was effective in 96% of patients, with no need for further pain management with a statistically significant reduction (p < 0.0001) in the mean value of the VAS from 7.86 ± 1.81 (pre-procedural) to 2.04 ± 2.20 after 10 min from the block and up to 0.74 ± 1.43 at the end of the procedure (mean time 43 min). Only 1 complication related to the popliteal sciatic nerve block was registered (a temporary foot drop, completely resolved within 48 h). The time necessary to perform the block ranged between 4 and 10 min. CONCLUSION: Ultrasound-guided PSNB is a feasible and effective method to manage patients with rest pain and increase comfort and compliance during endovascular procedures. CLINICAL RELEVANCE STATEMENT: An ultrasound-guided popliteal sciatic nerve block is a safe, feasible, and effective technique to manage pain during endovascular treatment of chronic limb-threatening ischemia, especially in frail patients with multiple comorbidities who are poor candidates for deep sedoanalgesia or general anesthesia. KEY POINTS: Endovascular treatment of CTLI may require long revascularization sessions in patients with high levels of pain at rest, which could be exacerbated during the revascularization procedure. The PSNB is routinely used for anesthesia and analgesia during foot and ankle surgery, but the experience with lower limb revascularization procedures is very limited and not included in any international guideline. Ultrasound-guided PSNB is a feasible and effective regional anesthesia technique to relieve procedural and resting pain. Because of its safety and availability, every interventional radiologist should know how to perform this type of loco-regional anesthesia.

A Bayesian phase II proof-of-concept design for clinical trials with longitudinal endpoints.

Existing phase II clinical trial designs focus on a single scalar endpoint, such as a binary, continuous, or survival endpoint. In some clinical trials, such as pain management studies, the efficacy endpoint of interest is measured longitudinally. We propose a Bayesian phase II design for such clinical trials. We model the longitudinal measurement process using Bayesian hierarchical model, where subject-specific trajectory shrinks toward the population trajectory to borrow information across subjects. The Bayesian penalized spline is used to model subject-specific and population trajectories without making strong parametric assumption on their shapes. We use the area under the curve of the trajectory as the summary of the treatment effect over time. The design takes a group sequential approach and takes into account both statistical significance and clinical relevance. Bayesian criteria is proposed to make interim and final decisions based on the evidence of statistical significance and clinical relevance. The proposed design is highly flexible and can accommodate trials with one or multiple longitudinal endpoints, as well as a longitudinal primary endpoint with a secondary endpoint. Simulation study shows that the proposed design is robust with desirable operating characteristics.