Brief Assessment of Patient Phenotype to Explain Variability in Postsurgical Pain and Opioid Consumption after Cesarean Delivery: Performance of a Novel Brief Questionnaire Compared to Long Questionnaires.

BACKGROUND: Understanding factors that explain why some women experience greater postoperative pain and consume more opioids after cesarean delivery is crucial to building an evidence base for personalized prevention. Comprehensive psychosocial assessment with validated questionnaires in the preoperative period can be time-consuming. A three-item questionnaire has shown promise as a simpler tool to be integrated into clinical practice, but its brevity may limit the ability to explain heterogeneity in psychosocial pain modulators among individuals. This study compared the explanatory ability of three models: (1) the 3-item questionnaire, (2) a 58-item questionnaire (long) including validated questionnaires (e.g., Brief Pain Inventory, Patient Reported Outcome Measurement Information System [PROMIS]) plus the 3-item questionnaire, and (3) a novel 19-item questionnaire (brief) assessing several psychosocial factors plus the 3-item questionnaire. Additionally, this study explored the utility of adding a pragmatic quantitative sensory test to models. METHODS: In this prospective, observational study, 545 women undergoing cesarean delivery completed questionnaires presurgery. Pain during local anesthetic skin wheal before spinal placement served as a pragmatic quantitative sensory test. Postoperatively, pain and opioid consumption were assessed. Linear regression analysis assessed model fit and the association of model items with pain and opioid consumption during the 48 h after surgery. RESULTS: A modest amount of variability was explained by each of the three models for postoperative pain and opioid consumption. Both the brief and long questionnaire models performed better than the three-item questionnaire but were themselves statistically indistinguishable. Items that were independently associated with pain and opioid consumption included anticipated postsurgical pain medication requirement, surgical anxiety, poor sleep, pre-existing pain, and catastrophic thinking about pain. The quantitative sensory test was itself independently associated with pain across models but only modestly improved models for postoperative pain. CONCLUSIONS: The brief questionnaire may be more clinically feasible than longer validated questionnaires, while still performing better and integrating a more comprehensive psychosocial assessment than the three-item questionnaire.

Pain Severity and Pain Interference in Late Pregnancy: An Analysis of Biopsychosocial Factors Among Women Scheduled for Cesarean Delivery.

OBJECTIVE: Pain is a variably experienced symptom during pregnancy, and women scheduled for cesarean delivery, an increasingly common procedure, are a relatively understudied group who might be at higher pain risk. Although biopsychosocial factors are known to modulate many types of chronic pain, their contribution to late pregnancy pain has not been comprehensively studied. We aimed to identify biopsychosocial factors associated with greater pain severity and interference during the last week of pregnancy. METHODS: In this prospective, observational study, 662 pregnant women scheduled for cesarean delivery provided demographic and clinical information and completed validated psychological and pain assessments. Multivariable hierarchical linear regressions assessed independent associations of demographic, clinical, and psychological characteristics with pain severity and pain interference during the last week of pregnancy. RESULTS: Women in the study had a mean age of 34 years, and 73% identified as White, 11% as African American, 10% as Hispanic/Latina, and 6% as Asian. Most women (66%) were scheduled for repeat cesarean delivery. Significant independent predictors of worse pain outcomes included identifying as African American or Hispanic/Latina and having greater depression, sleep disturbance, and pain catastrophizing. Exploratory analyses showed that women scheduled for primary (versus repeat) cesarean delivery reported higher levels of anxiety and pain catastrophizing. CONCLUSIONS: Independent of demographic or clinical factors, psychological factors, including depression, sleep disturbance, and pain catastrophizing, conferred a greater risk of late pregnancy pain. These findings suggest that women at higher risk of pain during late pregnancy could benefit from earlier nonpharmacological interventions that concurrently focus on psychological and pain symptoms.

A Systematic Scoping Review of Peridelivery Pain Management for Pregnant People With Opioid Use Disorder: From the Society for Obstetric Anesthesia and Perinatology and Society for Maternal Fetal Medicine.

The prevalence of pregnant people with opioid use disorder (OUD), including those receiving medications for opioid use disorder (MOUD), is increasing. Challenges associated with pain management in people with OUD include tolerance, opioid-induced hyperalgesia, and risk for return to use. Yet, there are few evidence-based recommendations for pain management in the setting of pregnancy and the postpartum period, and many peripartum pain management studies exclude people with OUD. This scoping review summarized the available literature on peridelivery pain management in people with OUD, methodologies used, and identified specific areas of knowledge gaps. PubMed and Embase were comprehensively searched for publications in all languages on peripartum pain management among people with OUD, both treated with MOUD and untreated. Potential articles were screened by title, abstract, and full text. Data abstracted were descriptively analyzed to map available evidence and identify areas of limited or no evidence. A total of 994 publications were imported for screening on title, abstracts, and full text, yielding 84 publications identified for full review: 32 (38.1%) review articles, 14 (16.7%) retrospective studies, and 8 (9.5%) case reports. There were 5 randomized controlled trials. Most studies (64%) were published in perinatology (32; 38.1%) journals or anesthesiology (22; 26.2%) journals. Specific areas lacking trial or systematic review evidence include: (1) methods to optimize psychological and psychosocial comorbidities relevant to acute pain management around delivery; (2) alternative nonopioid and nonpharmacologic analgesia methods; (3) whether or not to use opioids for severe breakthrough pain and how best to prescribe and monitor its use after discharge; (4) monitoring for respiratory depression and sedation with coadministration of other analgesics; (5) optimal neuraxial analgesia dosing and adjuncts; and (6) benefits of abdominal wall blocks after cesarean delivery. No publications discussed naloxone coprescribing in the labor and delivery setting. We observed an increasing number of publications on peripartum pain management in pregnant people with OUD. However, existing published works are low on the pyramid of evidence (reviews, opinions, and retrospective studies), with a paucity of original research articles (<6%). Opinions are conflicting on the utility and disutility of various analgesic interventions. Studies generating high-quality evidence on this topic are needed to inform care for pregnant people with OUD. Specific research areas are identified, including utility and disutility of short-term opioid use for postpartum pain management, role of continuous wound infiltration and truncal nerve blocks, nonpharmacologic analgesia options, and the best methods to support psychosocial aspects of pain management.

Less stress, better success: a scoping review on the effects of anxiety on anesthetic and analgesic consumption.

Preoperative anxiety has an incidence of 11-80% in patients undergoing surgical or interventional procedures. Understanding the role of preoperative anxiety on intraoperative anesthetic requirements and postoperative analgesic consumption would allow personalized anesthesia care. Over- or under-anesthetizing patients can lead to complications such as postoperative cognitive dysfunction in elderly patients, or procedural discomfort, respectively. Our scoping review focuses on the current evidence regarding the association between preoperative anxiety and intraoperative anesthetic and/or postoperative analgesic consumption in patients undergoing elective surgical or interventional procedures. Based on 44 studies that met the inclusion criteria, we found that preoperative anxiety has a significant positive correlation effect on intraoperative propofol and postoperative opioid consumption. The analysis of the literature is limited by the heterogeneity of preoperative anxiety tools used, study designs, data analyses, and outcomes. The use of shorter, validated preoperative anxiety assessment tools may help optimize the intraoperative anesthetic and postoperative analgesic regimen. Further research to determine the most feasible and clinically relevant preoperative anxiety tool and subsequent implementation has the potential to optimize perioperative care and improve patient outcomes.

Prediction of Persistent Pain Severity and Impact 12 Months After Breast Surgery Using Comprehensive Preoperative Assessment of Biopsychosocial Pain Modulators.

BACKGROUND: Persistent post-mastectomy pain (PPMP) is a significant negative outcome occurring after breast surgery, and understanding which individual women are most at risk is essential to targeting of preventive efforts. The biopsychosocial model of pain suggests that factors from many domains may importantly modulate pain processing and predict the progression to pain persistence. METHODS: This prospective longitudinal observational cohort study used detailed and comprehensive psychosocial and psychophysical assessment to characterize individual pain-processing phenotypes in 259 women preoperatively. Pain severity and functional impact then were longitudinally assessed using both validated surgery-specific and general pain questionnaires to survey patients who underwent lumpectomy, mastectomy, or mastectomy with reconstruction in the first postsurgical year. An agnostic, multivariable modeling strategy identified consistent predictors of several pain outcomes at 12 months. RESULTS: The preoperative characteristics most consistently associated with PPMP outcomes were preexisting surgical area pain, less education, increased somatization, and baseline sleep disturbance, with axillary dissection emerging as the only consistent surgical variable to predict worse pain. Greater pain catastrophizing, negative affect, younger age, higher body mass index (BMI), and chemotherapy also were independently predictive of pain impact, but not severity. Sensory disturbance in the surgical area was predicted by a slightly different subset of factors, including higher preoperative temporal summation of pain. CONCLUSIONS: This comprehensive approach assessing consistent predictors of pain severity, functional impact, and sensory disturbance may inform personalized prevention of PPMP and also may allow stratification and enrichment in future preventive studies of women at higher risk of this outcome, including pharmacologic and behavioral interventions and regional anesthesia.

Biosynthetic metabolomes of cysteinyl-containing immunoresolvents.

Resolution of inflammation is an active process regulated by specialized proresolving mediators where we identified 3 new pathways producing allylic epoxide-derived mediators that stimulate regeneration [i.e., peptido-conjugates in tissue regeneration (CTRs)]. Here, using self-limited Escherichia coli peritonitis in mice, we identified endogenous maresin (MaR) CTR (MCTR), protectin (PD) CTR (PCTR), and resolvin CTR in infectious peritoneal exudates and distal spleens, as well as investigated enzymes involved in their biosynthesis. PCTRs were identified to be temporally regulated in peritoneal exudates and spleens. PCTR1 and MCTR1 were each produced by human recombinant leukotriene (LT) C4 synthase (LTC4S) and glutathione S-transferases (GSTs) [microsomal GST (mGST)2, mGST3, and GST-µ (GSTM)4] from their epoxide precursors [16S,17S-epoxy-PD (ePD) and 13S,14S-epoxy-MaR (eMaR)], with preference for GSTM4. Both eMaR and ePD inhibited LTB4 production by LTA4 hydrolase. LTC4S, mGST2, mGST3, and GSTM4 were each expressed in human M1- and M2-like macrophages where LTC4S inhibition increased CTRs. Finally, PCTR1 showed potent analgesic action. These results demonstrate CTR biosynthesis in mouse peritonitis, human spleens, and human macrophages, as well as identification of key enzymes in these pathways. Moreover, targeting LTC4S increases CTR metabolomes, giving a new strategy to stimulate resolution and tissue regeneration.-Jouvene, C. C., Shay, A. E., Soens, M. A., Norris, P. C., Haeggström, J. Z., Serhan, C. N. Biosynthetic metabolomes of cysteinyl-containing immunoresolvents.

Association of Interindividual Variation in Plasma Oxytocin With Postcesarean Incisional Pain.

Oxytocin has known antinociceptive effects and is upregulated perinatally. This pilot study investigated the association of plasma oxytocin and postcesarean incisional pain. Plasma samples from 18 patients undergoing elective cesarean delivery were drawn at 1 hour preoperatively and 1 and 24 hours postoperatively and analyzed by using enzyme-linked immunosorbent assay. Pain was assessed at 1 day, 8 weeks, 3 months, and 6 months postoperatively. Incisional pain at 24 hours was inversely correlated with 1- and 24-hour oxytocin levels, with higher plasma oxytocin associated with lower pain (ρ, -0.52 and -0.66; P < .05).

A Randomized, Double-blinded Trial of a "Rule of Threes" Algorithm versus Continuous Infusion of Oxytocin during Elective Cesarean Delivery.

BACKGROUND: The administration of uterotonic agents during cesarean delivery is highly variable. The authors hypothesized a "rule of threes" algorithm, featuring oxytocin 3 IU, timed uterine tone evaluations, and a systematic approach to alternative uterotonic agents, would reduce the oxytocin dose required to obtain adequate uterine tone. METHODS: Sixty women undergoing elective cesarean delivery were randomized to receive a low-dose bolus or continuous infusion of oxytocin. To blind participants, the rule group simultaneously received intravenous oxytocin (3 IU/3 ml) and a "wide-open" infusion of 0.9% normal saline (500 ml); the standard care group received intravenous 0.9% normal saline (3 ml) and a "wide-open" infusion of oxytocin (30 IU in 0.9% normal saline/500 ml). Uterine tone was assessed at 3, 6, 9, and 12 min, and if inadequate, additional uterotonic agents were administered. Uterine tone, total dose and timing of uterotonic agent use, maternal hemodynamics, side effects, and blood loss were recorded. RESULTS: Adequate uterine tone was achieved with lower oxytocin doses in the rule versus standard care group (mean, 4.0 vs. 8.4 IU; point estimate of the difference, 4.4 ± 1.0 IU; 95% CI, 2.60 to 6.15; P < 0.0001). No additional oxytocin or alternative uterotonic agents were needed in either group after 6 min. No differences in the uterine tone, maternal hemodynamics, side effects, or blood loss were observed. CONCLUSION: A "rule of threes" algorithm using oxytocin 3 IU results in lower oxytocin doses when compared with continuous-infusion oxytocin in women undergoing elective cesarean delivery.

Systemic Progesterone Administration in Early Life Alters the Hyperalgesic Responses to Surgery in the Adult: A Study on Female Rats.

BACKGROUND: There has recently been a substantial increase in the survival of prematurely born neonates and an increase of in utero surgeries. Noxious stimulation in the newborn alters the pain response to injury in adult life. Progesterone, an effective antihyperalgesic agent in the adult, is at high concentration in the pregnant mother. Therefore, we investigated the effects of early-life progesterone on postsurgical outcomes in adult rats. METHODS: Female rat pups were administered progesterone or vehicle during the first 7 days postpartum (P1-P7). A second control group had no injections. Half of each of these groups received an incision of the hindpaw at P3 and the other half did not. At P60, all groups of these now adult rats received a second paw incision. Tactile sensitivity and thermal sensitivity were measured weekly at P14-P42 (period I), at P60 (just before the second incision), and every 2 days of P61-P70 (period II). At P67, rats were fixed by systemic paraformaldehyde perfusion and their spinal cords taken for staining and immunocytochemical analysis of activated p-p38 mitogen-activated protein kinase. RESULTS: Rats with surgery at P3 had greater tactile and thermal hyperalgesia in period I than the nonoperated rats, a difference abolished by progesterone treatment. P3 incision also resulted in long-lasting tactile and thermal hyperalgesia after the P60 incision (period II), both of which were markedly smaller in degree and faster to resolve in rats receiving early progesterone. Even in rats that were not operated on in period I, neonatal progesterone lessened the tactile hyperalgesia in period II. More spinal cells showed p-p38 staining in vehicle-treated rats as a result of the early-life incision but not in those treated with progesterone. CONCLUSIONS: These findings suggest that endogenously high progesterone in utero may have a similarly protective action and that the development of nociceptive circuitry can be strongly influenced by neonatal progesterone.

The effect of vitamin D and omega-3 fatty acid supplementation on pain prevalence and severity in older adults: a large-scale ancillary study of the VITamin D and OmegA-3 triaL (VITAL).

ABSTRACT: A diet supplemented with vitamin D and marine omega-3 fatty acids may prevent and treat painful disorders by promoting the resolution of inflammation. However, large, randomized placebo-controlled trials evaluating the effects of supplementation with omega-3 fatty acids and vitamin D on the presence and severity of pain are lacking. VITamin D and OmegA-3 triaL-Pain (VITAL-Pain) is an ancillary study to the VITAL trial, a large randomized, double-blind, placebo-controlled trial of vitamin D (2000 IU/day) and omega-3 supplementation (1 g/day) over 5.3 years of median follow-up, among 25,871 older men and women. We assessed pain among those reaching the end of the VITAL intervention phase using questions from the 2012 National Health Interview Survey. We used ordinal logistic regression to test the effect of vitamin D and omega-3 fatty acids on the odds ratio (OR) and 95% confidence interval [CI] of reporting higher pain prevalence or severity. Overall, 19,611 participants provided complete pain information at the end of the VITAL trial. The ORs for higher pain prevalence or severity for vitamin D and omega-3 supplementation vs placebo were 0.99 ([CI] 0.94-1.05) and 0.99 ([CI] 0.94-1.04), respectively. There was no interaction between the 2 active treatments. Dietary supplementation with commonly used moderate doses of vitamin D or omega-3 fatty acids over a median of 5.3 years did not result in a lower prevalence or severity of pain in middle-aged and older U.S. adults.

Perioperative Sleep Disturbance Following Mastectomy: A Longitudinal Investigation of the Relationship to Pain, Opioid Use, Treatment, and Psychosocial Symptoms.

OBJECTIVES: Sleep disturbance negatively impacts the quality of life and recovery. Our objective was to evaluate the relationship between the individual patient and surgical factors with greater sleep disturbance following breast surgery. METHODS: In this prospective longitudinal study, patients completed validated measures regarding sleep disturbance, pain, opioid use, and psychological symptoms preoperatively and then 2 weeks, 6 and 12 months postoperatively. Univariable and multivariable generalized estimating equations evaluated demographic, surgical, pain, and psychological predictors of sleep disturbance during the first year after breast surgery. RESULTS: Female patients (n=259) reported varying degrees of sleep disturbance, which were longitudinally associated with pain and psychosocial factors (eg, anxiety, depression, and affect). Independent preoperative predictors of worse sleep disturbance included younger age (B=-0.09, P =0.006), opioid use (B=3.09, P =0.02), and higher pain (B=0.19, P =<0.001) and anxiety (B=0.45, P =<0.001) at baseline. In addition, higher baseline positive affect (B=-0.14, P =<0.012) and the surgical category total mastectomy without reconstruction (B=-2.81, P =<0.006) were independently associated with lower sleep disturbance. Those with worse baseline sleep required more opioid analgesics during surgical recovery, and continued use of opioids at 2 weeks postsurgery was associated with disturbed sleep. DISCUSSION: Certain patient characteristics, including younger age and baseline anxiety, positive affect, pain, and opioid use, were associated with greater sleep disturbance in the first year after breast surgery. Sleep disturbance was also associated with the greater perioperative and postoperative opioid requirements. Preoperative interventions (eg, anxiety management, cultivating positive affect, and multimodal pain management) in high-risk individuals may enhance sleep and recovery postoperatively, and allow more moderate and less prolonged opioid use.

Anesthesia considerations and post-operative pain management in pregnant women with chronic opioid use.

The prevalence of opioid use disorder in pregnancy has escalated markedly in recent years. Chronic opioid use during pregnancy poses several challenges for providing adequate analgesia and anesthesia in the peripartum period. These challenges include the potential for withdrawal, opioid tolerance and opioid-induced hyperalgesia. Here we discuss alterations in analgesic pharmacokinetics and pharmacodynamics that are associated with chronic opioid use. In addition, when treating pain in patients with opioid use disorder it is important to distinguish between different subgroups. In this review, we will discuss practical management strategies for parturients with (1) untreated opioid use disorder, (2) parturients on medication-assisted treatment (methadone, buprenorphine) and (3) patients recovering from opioid use disorder that are currently abstinent. Finally, we offer an overview of non-opioid strategies that may be utilized as part of a multimodal approach to providing optimal analgesia in this patient population.

Obstetric anesthesia for the obese and morbidly obese patient: an ounce of prevention is worth more than a pound of treatment.

BACKGROUND: The incidence of obesity has been dramatically increasing across the globe. Anesthesiologists, are increasingly faced with the care for these patients. Obesity in the pregnant woman is associated with a broad spectrum of problems, including dramatically increased risk for cesarean delivery, diabetes, hypertension and pre-eclampsia. A thorough understanding of the physiology, associated conditions and morbidity, available options for anesthesia and possible complications is therefore important for today's anesthesiologist. METHODS: This is a personal review in which different aspects of obesity in the pregnant woman, that are relevant to the anesthesiologist, are discussed. An overview of maternal and fetal morbidity and physiologic changes associated with pregnancy and obesity is provided and different options for labor analgesia, the anesthetic management for cesarean delivery and potential post-partum complications are discussed in detail. RESULTS AND CONCLUSION: The anesthetic management of the morbidly obese parturient is associated with special hazards. The risk for difficult or failed intubation is exceedingly high. The early placement of an epidural or intrathecal catheter may overcome the need for general anesthesia, however, the high initial failure rate necessitates critical block assessment and catheter replacement when indicated.

Prolonged cutaneous analgesia with transdermal application of amitriptyline and capsaicin.

BACKGROUND AND OBJECTIVES: Capsaicin selectively binds to TRPV1, the vanilloid subtype 1 of the superfamily of transient receptor potential ion channels, which is highly expressed in pain-transmitting C fibers. Recent reports have demonstrated that the coadministration of capsaicin with a local anesthetic (LA) at the rat sciatic nerve elicits a prolonged nociceptive-selective nerve block, suggesting that activation of the TRPV1 receptor may allow LAs to enter the nerve through the TRPV1 pore. In previous studies, we demonstrated that transdermal amitriptyline achieves clinical analgesic effects and is more potent than lidocaine. Here we examine whether the combined application of amitriptyline and capsaicin as a transdermal patch will produce prolonged cutaneous analgesia compared with amitriptyline alone. METHODS: Male Sprague-Dawley rats (weights 250-300 g) were assigned to five treatment groups (n = 6-8 per group). Transdermal patches containing amitriptyline with different concentrations of capsaicin were applied for 3 hrs to rats' shaved backs: 2.5% amitriptyline alone (control group) and in combination with 0.05%, 0.15%, 1%, and 8% capsaicin. Behavioral testing for cutaneous nociception was conducted before drug application and after patch removal using the cutaneous trunci muscle reflex. In addition, skin appearance was assessed to determine irritation by these formulations. RESULTS: The cutaneous analgesic effect is significantly prolonged when amitriptyline is applied in combination with 8% capsaicin. Amitriptyline alone provided a complete block to pinprick for 4.5 hrs, and the time to full recovery was 96 hrs. Amitriptyline with 8% capsaicin produced a complete block to pinprick for 6 to 9 hrs, and the time to full recovery was 216 hrs (P = 0.002). Amitriptyline alone causes toxic effects in skin, whereas the higher the concentration of capsaicin, the less skin irritation was noted, and the combination of amitriptyline 2.5% with capsaicin 8% caused no adverse skin reactions. CONCLUSIONS: This study demonstrates that the combined application of amitriptyline and capsaicin results in prolonged cutaneous analgesia compared with amitriptyline alone, suggesting that the activation of the TRPV1 channel by capsaicin facilitates the passage of amitriptyline into nociceptors. This transdermal patch achieves far longer cutaneous analgesia than currently available patch applications such as EMLA cream. The mechanism that underlies the lesser skin irritation noted when amitriptyline is combined with higher doses of capsaicin compared with amitriptyline alone is unclear and may be related to a counteraction of amitriptyline-induced vasoconstriction.