Decision Support and Behavioral Health for Reducing High-Dose Opioids in Comorbid Chronic Pain, Depression and Anxiety: Stepped-Wedge Cluster Randomized Trial.

BACKGROUND: High prevalence of depression or anxiety with opioid use for chronic pain complicates co-management and may influence prescribing behaviors. OBJECTIVE: Compare clinical effectiveness of electronic medical record clinical decision support (EMR-CDS) versus additional behavioral health (BH) care management for reducing rates of high-dose opioid prescriptions. DESIGN: Type 2 effectiveness-implementation hybrid stepped-wedge cluster randomized trial in 35 primary care clinics within a health system in LA, USA. PARTICIPANTS: Patients aged 18+ receiving chronic opioid therapy for non-cancer pain with depression or anxiety and matched controls. INTERVENTION: EMR-CDS included opioid risk mitigation procedures. BH care included cognitive behavioral therapy; depression or anxiety medication adjustments; and case management. MAIN MEASURES: Outcomes of interest included difference-in-difference (DID) estimate of changes in probability for prescribing high-dose morphine equivalent daily dose (MEDD ≥50 mg/day and MEDD ≥90), average MEDD, and rates of hospitalization, emergency department use, and opioid risk mitigation. KEY RESULTS: Most participants were female with 3+ pain syndromes. Data analysis included 632 patients. Absolute risk differences for MEDD≥50 and ≥90 decreased post-index compared to pre-index (DID of absolute risk difference [95%CI]: -0.036 [-0.089, 0.016] and -0.029 [-0.060, 0.002], respectively). However, these differences were not statistically significant. The average MEDD decreased at a higher rate for the BH group compared to EMR-CDS only (DID rate ratio [95%CI]: 0.85 [0.77, 0.93]). There were no changes in hospitalization and emergency department utilization. The BH group had higher probabilities of new specialty referrals and prescriptions for naloxone and antidepressants. CONCLUSIONS: Incorporation of a multidisciplinary behavioral health care team into primary care did not decrease high-dose prescribing; however, it improved adherence to clinical guideline recommendations for managing chronic opioid therapy for non-cancer pain. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03889418.

Comprehensive overview of analytical and bioanalytical methodologies for the opioid analgesics - Tramadol and combinations.

Synthetic opioids like Tramadol are used to treat mild to moderate pain. Its ability to relieve pain is about a tenth that of morphine. Furthermore, Tramadol shares similar effects on serotonin and norepinephrine to several antidepressants known as serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine. The present review paper discusses the recent developments in analytical methods for identifying drugs in pharmaceutical preparations and toxicological materials, such as blood, saliva, urine, and hair. In recent years, a wide variety of analytical instruments, including capillary electrophoresis, NMR, UV-visible spectroscopy, HPTLC, HPLC, LC-MS, GC, GC-MS, and electrochemical sensors, have been used for drug identification in pharmaceutical preparations and toxicological samples. The primary quantification techniques currently employed for its quantification in various matrices are highlighted in this research.

Microglial inflammation modulates opioid analgesic tolerance.

As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore, understanding the mechanisms underlying opioid tolerance and designing strategies for increasing the efficacy of opioids in chronic pain are important areas of research. Microglia are brain macrophages that remove debris and dead cells from the brain and participate in immune defense of the central nervous system during an insult or injury. However, recent studies indicate that microglial activation and generation of proinflammatory molecules (e.g., cytokines, nitric oxide, eicosanoids, etc.) in the brain may contribute to opioid tolerance and other side effects of opioid use. In this review, we will summarize the evidence and possible mechanisms by which proinflammatory molecules produced by activated microglia may antagonize the analgesic effect induced by opioids, and thus, lead to opioid tolerance. We will also delineate specific examples of studies that suggest therapeutic targets to counteract the development of tolerance clinically using suppressors of microglial inflammation.

Medicines stewardship.

Medicines stewardship refers to coordinated strategies and interventions to optimise medicines use, usually within a specific therapeutic area. Medicines stewardship programs can reduce variations in practice and improve patient outcomes. Therapeutic domains for medicines stewardship are chosen to address frequently used drug classes associated with a high risk of adverse outcomes. Some examples include antimicrobial, opioid analgesic, anticoagulation and psychotropic stewardship. Common elements of successful stewardship programs include multidisciplinary leadership, stakeholder engagement, tailored communication strategies, behavioural changes, implementation science methodologies, and ongoing program monitoring, evaluation and reporting. Medicines stewardship is a continual quality improvement process that requires ongoing support and resources, as well as clinician and consumer engagement, to remain sustainable. It is critical for hospital-based medicines stewardship programs to consider impacts on care in the community when making and communicating changes to patient therapy. This ensures that stewardship efforts are sustained across transitions of care.

Rapid Discontinuation of Chronic, High-Dose Opioid Treatment for Pain: Prevalence and Associated Factors.

PURPOSE: To examine the prevalence of rapid discontinuation of chronic, high-dose opioid analgesic treatment, and identify associated patient, clinician, and community factors. METHODS: Using 2017-2018 retail pharmacy claims data from IQVIA, we identified chronic, high-dose opioid analgesic treatment episodes discontinued during these years and determined the percent of episodes meeting criteria for rapid discontinuation. We used multivariable logistic regression to estimate the probability of rapid discontinuation, conditional on having a discontinued chronic, high-dose opioid treatment episode, as a function of patient, provider, and county characteristics. RESULTS: We identified 810,120 new, chronic, high-dose opioid treatment episodes discontinued in 2017 or 2018, of which 72.0% (n=583,415) were rapidly discontinued. Rapid discontinuation was significantly more likely among Medicare (aOR 1.14, 95% CI 1.12 to 1.15) and Medicaid enrollees (aOR 1.03, 95% CI 1.02 to 1.05) compared to the commercially insured; in counties with higher fatal overdose rates (aOR 1.03, 95% CI 1.01 to 1.04) compared to counties with the lowest fatal overdose rates; and in counties with a higher percentage of non-white residents (aOR 1.21 for counties in the highest quartile relative to the lowest, 95% CI 1.19 to 1.24). Likelihood of rapid discontinuation also varied by prescriber specialty. CONCLUSIONS: Most chronic, high-dose opioid treatment episodes that ended in 2017 or 2018 were discontinued more rapidly than recommended by clinical guidelines, raising concerns about adverse patient outcomes. Our findings highlight the need to understand what drives discontinuation and to inform safer opioid tapering and discontinuation practices.

Evaluating opioid analgesic prescribing limits: A narrative review.

PURPOSE: In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research. METHODS: We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization). RESULTS: Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms. CONCLUSIONS: We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies.

Primary care provider perspectives on and utilization of a mandatory prescription drug monitoring program in New York City.

BACKGROUND: The ways in which prescription drug monitoring programs (PDMPs) have been integrated into primary care practice remain understudied, and research into physician utilization of PDMPs in states where PDMP use is mandated remains scant. OBJECTIVES: To characterize primary care physician perspectives on and utilization of a mandatory PDMP in New York City. METHODS: We conducted face-to-face, in-depth interviews with primary care physicians who reported that they currently prescribed opioid analgesic medication. We used a thematic analytic approach to characterize physician perspectives on the PDMP mandate and physician integration of mandatory PDMP use into primary care practice. RESULTS: Primary care providers demonstrated a continuum of PDMP utilization, ranging from consistent use to the specifications of the mandate to inconsistent use to no use. Providers reported a range of perspectives on the purpose and function of the PDMP mandate, as well as a lack of clarity about the mandate and its enforcement. CONCLUSION: Findings suggest a need for increased clinical and public health education about the use of PDMPs as clinical tools to identify and treat patients with potential substance use disorders in primary care.

A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor.

An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (Ki low micromolar) µ-opioid agonists, which led to the design of bilorphin, a potent and selective µ-opioid receptor (MOPr) agonist (Ki 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit ß-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting ß-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.

Patients with substance use disorders receiving continued care in skilled nursing facilities following hospitalization.

Background: As hospitals in the US face pressures to reduce lengths of stay, healthcare systems are increasingly utilizing skilled nursing facilities (SNFs) to continue treating patients stable enough to leave the hospital, but not to return home. Substance use disorder (SUD) can complicate care of patients transferred to SNFs. The objective of this paper is to understand SNF experiences for this population of patients with comorbid SUD transferred to SNFs and examine care experiences in these facilities. Methods: This secondary mixed-methods analysis focuses on SNF experiences from a clinical trial of patient navigation services for medically-hospitalized adults with comorbid opioid, cocaine, and/or alcohol use disorder. This study compared baseline assessments and medical record review for participants (N = 400) with vs. without SNF transfer, and analyzed semi-structured qualitative interviews with a subsample of 15 participants purposively selected based on their transfer to a SNF. Results: Over 1 in 4 participants had a planned discharged to a SNF (26.8% sub-acute, 3.3% acute). Compared to participants with other types of discharge, participants discharged to a SNF had longer initial hospitalizations (4.9 vs. 11.8 days, p < 0.001), and were more likely to be White (38.6 vs. 50.8%; p = 0.02), female (38.9 vs. 52.5%; p = 0.01), have opioid use disorder (75.7 vs. 85.0%, p = 0.03), and be hospitalized for infection (43.6 vs. 58.3%; p = 0.007), and less likely to have worked prior to hospitalization (24.3 vs. 12.5%; p = 0.006). Qualitative narratives identified several themes from the SNF experience, including opioid analgesic dosing issues, challenges to the use of opioid agonist treatment of OUD, illicit opioid dealing/use, and limited access to addiction recovery support services during and following the SNF stay. Conclusions: SNFs are a common disposition for patients in need of subacute services following hospitalization but may be ill-equipped to properly manage patients in need of new or continuing SUD treatment.

A population-based study of concurrent prescriptions of opioid analgesic and selective serotonin reuptake inhibitor medications during pregnancy and risk for adverse birth outcomes.

BACKGROUND: Pregnant women with painful conditions often have mental health problems, including depression and anxiety. Co-morbid conditions may cause pregnant women to use multiple medications, although safety of such practice is poorly understood. OBJECTIVES: We investigated the influence of combined prescriptions of opioid analgesics and selective serotonin reuptake inhibitors (SSRIs) during pregnancy on two adverse birth outcomes. METHODS: We analysed Swedish population-based births (n = 688 914) between 2007 and 2013. Using national registers, we obtained data on filled medication prescriptions, birth outcomes, and a wide range of parental characteristics. We estimated preterm birth and small-for-gestational-age risk following independent or combined prescriptions of the two medications compared with no filled prescriptions for either medication. We adjusted for confounders using inverse probability of treatment weights. RESULTS: After adjusting for confounders, preterm birth risk was higher among women with opioid analgesic prescriptions only (5.9%; risk ratio [RR] 1.27, 95% confidence interval [CI] 1.22, 1.33), SSRIs only (6.2%; RR 1.34, 95% CI 1.27, 1.42), and both medications (7.8%; RR 1.70, 95% CI 1.47, 1.96) compared with unexposed women (4.6%). The interaction between the medications on preterm birth was small (risk difference [RD] 0.4%, 95% CI -0.8%, 1.6%); relative excess risk due to interaction [RERI] 0.09, 95% CI -0.17, 0.34; RR 1.00, 95% CI 0.85, 1.17). For small for gestational age, risk was approximately 2% across all groups, and there was no interaction between the medications (RD 0.3%, 95% CI -0.4%, 1.1%); RERI 0.15, 95% CI -0.16, 0.47; RR 1.15, 95% CI 0.87, 1.52). CONCLUSIONS: Compared with unexposed pregnancies, those with either medication alone had a small increased risk for preterm birth but no increased risk for small for gestational age. The magnitude of associations with combined exposure to both medications were not greater than the sum of the associations with each medication considered individually.

Efficacy of Pregabalin and Antioxidants Combination in Reducing Pain in Chronic Pancreatitis: A Double Blind Randomized Trial.

BACKGROUND: In patients with chronic pancreatitis (CP), pain relief is a dilemma. Antioxidants with pregabalin therapy have been reported to be useful. Hence, this study was carried out to determine the efficacy of the combination of antioxidant and pregabalin therapy in reducing pain in patients with CP. METHODS: This was a prospective, double blind, superiority, and randomized trial in patients with CP. The treatment group received pregabalin with antioxidants therapy for 8 weeks, and a similar placebo was administered to the controls. Primary outcome was to determine the change in maximum pain intensity assessed by visual analog scale (VAS) and Izbicki pain score. Secondary outcomes were the number of painful days, opioid and non-opioid requirements, improvement in quality of life, number of hospital admission, and overall patient satisfaction. RESULTS: A total of 90 patients were randomized to 45 in each arm. Demographic profile and baseline pain score were comparable. Patients in treatment group when compared to placebo group had a significant reduction in pain intensity (VAS score 2 ± 0.8 vs. 1.3 ± 0.9; p = 0.007), non-opioid analgesic requirement in days (54.4±2.9 vs. 55.7±1.5; p = 0.014), and number of hospital admissions (0.2 ± 0.5 vs. 0.6 ± 0.7; p = 0.002), respectively. Significant proportion of patients was satisfied in the treatment group compared to placebo group (18% vs. 11%; p = 0.03). CONCLUSION: The combination of pregabalin and antioxidant significantly reduces the pain, requirement of non-opioid analgesics, and the number of hospital admissions in patients with CP. It also significantly improves the overall patient satisfaction. CLINICAL TRIALS REGISTER NUMBER: CTRI/2017/05/008492.

Analysis of Predictive Factors for Diarrhea after the Administration of Naldemedine.

Naldemedine (NAL), a peripherally acting µ-opioid receptor antagonist, is effective for opioid-induced constipation (OIC). However, diarrhea is the most common adverse event. We investigated the incidence of NAL-induced diarrhea in patients who started NAL at Nagasaki University Hospital between June 2017 and March 2019. Predictors of NAL-induced diarrhea were analyzed using a multivariate logistic regression model. Two hundred and forty-two patients were included in the present study, and NAL-induced diarrhea was observed in 17.8% (43 patients). The results of multiple logistic regression analyses identified the administration of opioid analgesics for 8 d or longer before the initiation of NAL (odds ratio (OR): 2.20, 95% confidence interval (95% CI): 1.04-4.64, p = 0.039), the combination of a laxative (OR: 2.22, 95%CI: 1.03-4.81, p = 0.042), and the combination of CYP3A4 inhibitors (strong/moderate) (OR: 2.80, 95%CI: 1.02-7.67, p = 0.045) as risk factors. Therefore, the development of diarrhea needs to be considered in patients with these risk factors. Furthermore, diarrhea may be controlled by the initiation of NAL within 7 d of opioid analgesics and, where possible, the discontinuation of or change in the combination of moderate or strong CYP3A4 inhibitors.

Simultaneous trace-level monitoring of seven opioid analgesic drugs in biological samples by pipette-tip micro solid phase extraction based on PVA-PAA/CNT-CNC composite nanofibers followed by HPLC-UV analysis.

Electrospun poly(vinyl alcohol)-(PVA)-poly(acrylic acid) (PAA)/carbon nanotubes(CNTs)-cellulose nanocrystal (CNC) (PVA-PAA/CNT-CNC) composite nanofibers were prepared and characterized using Fourier transform-infrared spectroscopy and field emission scanning electron microscopy. The resultant composite was used as an effective and novel sorbent for pipette-tip micro-solid phase extraction (PT-µSPE) of seven opioid analgesics (OAs) in biological samples followed by HPLC-UV analysis. Addition of CNT-CNC with the high specific surface area and plenty of OH-functional groups endows the nanofibers with considerable extraction efficiency. Under the optimum conditions, the linearity was obtained in the range 1.5 to 700.0 ng mL-1 for morphine, codeine, oxycodone, and tramadol, and 0.5 to 1000.0 ng mL-1 for nalbuphine, thebaine, and noscapine with coefficient of determination (r2) ≥ 0.9990. Detection limits (LODs) based on S/N = 3 were in the range of 0.15-0.50 ng mL-1. The relative standard deviations (RSDs) of 4.1-5.4% (intra-day, n = 5) and 5.2-6.4% (inter-day, n = 3) for three consecutive days were achieved. Finally, the efficiency of the PT-µSPE-HPLC-UV method was evaluated for the determination of OAs in human plasma and urine samples with good recoveries (87.3 to 97.8%). A: Schematic illustration for the preparation of PVA-PAA/CNT-CNC composite nanofibers. B: Schematic presentation of applying PVA-PAA/CNT-CNC composite nanofibers as the sorbent in pipette-tip micro solid-phase extraction (PT-µSPE) for the preconcentration of seven opioid analgesic drugs in biological samples before HPLC-UV analysis.

Pharmacokinetic properties of tramadol and M1 metabolite in Northeast Brazilian donkeys (Equus asinus).

There is currently little information available on the pharmacokinetics and pharmacodynamics of the analgesic opioid tramadol when used in the veterinary medicine of domestic species. In this study, we aimed to determine the pharmacokinetics of tramadol and its active metabolite M1 following intravenous administration of 2 (T2) and 4 (T4) mg/kg to Northeast Brazilian donkeys. Tramadol and M1 plasma levels were quantified using a validated liquid chromatography-tandem mass spectrometry method. We found that plasma levels of tramadol and M1 were higher than those reported as clinically meaningful in humans for at least 3 hr. However, the pharmacokinetic parameter calculation corrected by dose analysis identified no proportional increase with dose for the AUC of tramadol (T2: 2,663 ± 1,827 vs. T4: 2,964 ± 1,038 ng*h/ml) and M1 (T2: 378 ± 237 vs. T4: 345 ± 142 ng*h/ml). This finding appears to be attributable to a significant increase in clearance and a reduction in the terminal half-life of tramadol. The frequency of adverse effects observed at the higher dose indicates that 2 mg/kg administered intravenously would be suitable for donkeys. Clinical studies are required to determine the implications of these observations regarding the pharmacodynamic response to tramadol in Northeast Brazilian donkeys.

Pharmacokinetic properties of metamizole active metabolites in Northeastern Brazilian donkeys (Equus asinus).

Metamizole (MT), also known as dipyrone, is an analgesic and antipyretic drug labeled for use in humans and domestic animals in some countries. As with other drugs, the administration of MT in donkeys is based on studies carried out with horses. In the present report, we aimed to determine the pharmacokinetics of the two main metamizole active metabolites (N-methyl-4-aminoantipyrine [MAA] and 4-aminoantipyrine [AA]) following 10 (M10 ) and 25 mg/kg (M25 ) IV metamizole doses in Northeast Brazilian donkeys (n = 10). Blood was collected at predetermined times within over 48 h; MAA and AA plasma concentrations were determined by a validated LC-MS/MS method. The metabolites were quantifiable in the M10 until 12 h and M25 until 24 h after drug administration. As expected, AUC0→t , AUC0→∞, and Cmax demonstrated significant differences increases in metamizole metabolites profiles when groups were compared. No adverse effects were observed. This study indicates the need for an extremely sensitive analytical method to adequately characterize the pharmacokinetics of active metabolites of MT, MAA, and AA. In conclusion, the method developed in this research was able to measure the active metabolites of metamizole and with that it was possible to establish their pharmacokinetic profile. Furthermore, after projection of the minimum MAA concentrations, it is possible to infer that the dose of 10 mg/kg will be used on donkeys at 6 h intervals, while the M25 group at 12 h intervals. However, clinical studies are needed to assess this hypothesis.

What proportion of patients with chronic noncancer pain are prescribed an opioid medicine? Systematic review and meta-regression of observational studies.

Guidelines now discourage opioid analgesics for chronic noncancer pain because the benefits frequently do not outweigh the harms. We aimed to determine the proportion of patients with chronic noncancer pain who are prescribed an opioid, the types prescribed and factors associated with prescribing. Database searches were conducted from inception to 29 October 2018 without language restrictions. We included observational studies of adults with chronic noncancer pain measuring opioid prescribing. Opioids were categorized as weak (e.g. codeine) or strong (e.g. oxycodone). Study quality was assessed using a risk of bias tool designed for observational studies measuring prevalence. Individual study results were pooled using a random-effects model. Meta-regression investigated study-level factors associated with prescribing (e.g. sampling year, geographic region as per World Health Organization). The overall evidence quality was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Of the 42 studies (5,059,098 participants) identified, the majority (n = 28) were from the United States of America. Eleven studies were at low risk of bias. The pooled estimate of the proportion of patients with chronic noncancer pain prescribed opioids was 30.7% (95% CI 28.7% to 32.7%, n = 42 studies, moderate-quality evidence). Strong opioids were more frequently prescribed than weak (18.4% (95% CI 16.0-21.0%, n = 15 studies, low-quality evidence), versus 8.5% (95% CI 7.2-9.9%, n = 15 studies, low-quality evidence)). Meta-regression determined that opioid prescribing was associated with year of sampling (more prescribing in recent years) (P = 0.014) and not geographic region (P = 0.056). Opioid prescribing for patients with chronic noncancer pain is common and has increased over time.

Clinical Effectiveness of Decision Support for Prescribing Opioids for Chronic Noncancer Pain: A Prospective Cohort Study.

OBJECTIVES: This prospective cohort study examines the clinical effectiveness of electronic medical record clinical decision support (EMR CDS) for opioid prescribing. METHODS: Data analysis included primary care patients with chronic opioid therapy for noncancer pain seen within an integrated health delivery system in Louisiana between January 2017 and October 2018. EMR CDS incorporated an opioid health maintenance tool to display the status of risk mitigation, and the medication order embedded the morphine equivalent daily dose (MEDD) calculator and a hyperlink to the Louisiana pharmacy drug monitoring program. Outcome measures included change in the average MEDD and rates of opioid risk mitigation, hospitalization, and emergency department use. RESULTS: Among 14 221 patients, 9% had prescriptions with an average MEDD ≥90 mg. There were no significant changes in MEDD after EMR CDS implementation. Increasing age, Charlson Comorbidity Index score, female sex, black non-Hispanic race, non-opioid pain medication co-prescriptions, and specialty referrals were associated with a lower odds of MEDD ≥90 (high-dose threshold). Medicare or self-pay, substance abuse history, and pain agreements were associated with increased odds of prescribing above this high-dose threshold. After incorporation of EMR CDS, patients had higher rates of urine drug screens (17% vs 7%) and naloxone prescriptions (3% vs 1%, all P < .001). In addition, specialty referrals to physical or occupational therapy, orthopedics, neurology, and psychiatry or psychology increased in the postintervention period. Although emergency department use decreased (rate ratio 0.92; 95% confidence interval 0.89-0.95), hospitalization rates did not change. CONCLUSIONS: EMR CDS improved adherence to opioid risk mitigation strategies. Further research examining which practice redesign interventions effectively reduce high-dose opioid prescribing is needed.

The effect of intraoperative lidocaine infusion on opioid consumption and pain after totally extraperitoneal laparoscopic inguinal hernioplasty: a randomized controlled trial.

BACKGROUND: As a component of multimodal analgesia, the administration of systemic lidocaine is a well-known technique. We aimed to evaluate the efficacy of lidocaine infusion on postoperative pain-related outcomes in patients undergoing totally extraperitoneal (TEP) laparoscopies inguinal hernioplasty. METHODS: In this randomized controlled double-blind study, we recruited 64 patients to receive either lidocaine 2% (intravenous bolus 1.5 mg. kg - 1 followed by an infusion of 2 mg. kg- 1. h- 1), or an equal volume of normal saline. The infusion was initiated just before the induction of anesthesia and discontinued after tracheal extubation. The primary outcome of the study was postoperative morphine equivalent consumption up to 24 h after surgery. Secondary outcomes included postoperative pain scores, nausea/vomiting (PONV), sedation, quality of recovery (scores based on QoR-40 questionnaire), patient satisfaction, and the incidence of chronic pain. RESULTS: The median (IQR) cumulative postoperative morphine equivalent consumption in the first 24 h was 0 (0-1) mg in the lidocaine group and 4 [1-8] mg in the saline group (p < 0.001). Postoperative pain intensity at rest and during movement at various time points in the first 24 h were significantly lower in the lidocaine group compared with the saline group (p < 0.05). Fewer patients reported PONV in the lidocaine group than in the saline group (p < 0.05). Median QoR scores at 24 h after surgery were significantly better in the lidocaine group (194 (194-196) than saline group 184 (183-186) (p < 0.001). Patients receiving lidocaine were more satisfied with postoperative analgesia than those receiving saline (p = 0.02). No difference was detected in terms of postoperative sedation and chronic pain after surgery. CONCLUSIONS: Intraoperative lidocaine infusion for laparoscopic TEP inguinal hernioplasty reduces opioid consumption, pain intensity, PONV and improves the quality of recovery and patient satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov- NCT02601651. Date of registration: November 10, 2015.

A Scoping Review of Intravenous Opioid Pain Protocols and Their Dose-Time Intervals in the Management of Acute Postoperative Pain in the Postanesthesia Care Unit.

PURPOSE: This review aims to explore intravenous opioid pain protocols and their dose-time intervals in managing acute postoperative pain in adults in the postanesthesia care unit (PACU). DESIGN: A scoping review using a systematic search strategy. METHODS: Sixteen articles were identified from MEDLINE, CINAHL, PubMed, Embase, and Cochrane specific to the aims. FINDINGS: The literature demonstrated several variations on dose-time intervals used for opioid pain protocol administration globally. Furthermore, opioid analgesic pain protocols in the PACU appear to be effective in postoperative pain management. However, the literature did not identify optimal time intervals related to dose administration within these protocols. CONCLUSIONS: Literature gaps were identified regarding the significance of dose-time intervals when using opioid analgesic pain protocols in the PACU.

µ-Opioid receptors in primary sensory neurons are essential for opioid analgesic effect on acute and inflammatory pain and opioid-induced hyperalgesia.

KEY POINTS: µ-Opioid receptors (MORs) are expressed peripherally and centrally, but the loci of MORs responsible for clinically relevant opioid analgesia are uncertain. Crossing Oprm1flox/flox and AdvillinCre/+ mice completely ablates MORs in dorsal root ganglion neurons and reduces the MOR expression level in the spinal cord. Presynaptic MORs expressed at primary afferent central terminals are essential for synaptic inhibition and potentiation of sensory input by opioids. MOR ablation in primary sensory neurons diminishes analgesic effects produced by systemic and intrathecal opioid agonists and abolishes chronic opioid treatment-induced hyperalgesia. These findings demonstrate a critical role of MORs expressed in primary sensory neurons in opioid analgesia and suggest new strategies to increase the efficacy and reduce adverse effects of opioids. ABSTRACT: The pain and analgesic systems are complex, and the actions of systemically administered opioids may be mediated by simultaneous activation of µ-opioid receptors (MORs, encoded by the Oprm1 gene) at multiple, interacting sites. The loci of MORs and circuits responsible for systemic opioid-induced analgesia and hyperalgesia remain unclear. Previous studies using mice in which MORs are removed from Nav1.8- or TRPV1-expressing neurons provided only an incomplete and erroneous view about the role of peripheral MORs in opioid actions in vivo. In the present study, we determined the specific role of MORs expressed in primary sensory neurons in the analgesic and hyperalgesic effects produced by systemic opioid administration. We generated Oprm1 conditional knockout (Oprm1-cKO) mice in which MOR expression is completely deleted from dorsal root ganglion neurons and substantially reduced in the spinal cord, which was confirmed by immunoblotting and immunocytochemical labelling. Both opioid-induced inhibition and potentiation of primary sensory input were abrogated in Oprm1-cKO mice. Remarkably, systemically administered morphine potently inhibited acute thermal and mechanical nociception and persistent inflammatory pain in control mice but had little effect in Oprm1-cKO mice. The analgesic effect of intrathecally administered morphine was also profoundly reduced in Oprm1-cKO mice. Additionally, chronic morphine treatment-induced hyperalgesia was absent in Oprm1-cKO mice. Our findings directly challenge the notion that clinically relevant opioid analgesia is mediated mostly by centrally expressed MORs. MORs in primary sensory neurons, particularly those expressed presynaptically at the first sensory synapse in the spinal cord, are crucial for both opioid analgesia and opioid-induced hyperalgesia.