A genome-wide Association study of the Count of Codeine prescriptions.

Opioid prescription records in existing electronic health record (EHR) databases are a potentially useful, high-fidelity data source for opioid use-related risk phenotyping in genetic analyses. Prescriptions for codeine derived from EHR records were used as targeting traits by screening 16 million patient-level medication records. Genome-wide association analyses were then conducted to identify genomic loci and candidate genes associated with different count patterns of codeine prescriptions. Both low- and high-prescription counts were captured by developing 8 types of phenotypes with selected ranges of prescription numbers to reflect potentially different levels of opioid risk severity. We identified one significant locus associated with low-count codeine prescriptions (1, 2 or 3 prescriptions), while up to 7 loci were identified for higher counts (≥ 4, ≥ 5, ≥6, or ≥ 7 prescriptions), with a strong overlap across different thresholds. We identified 9 significant genomic loci with all-count phenotype. Further, using the polygenic risk approach, we identified a significant correlation (Tau = 0.67, p = 0.01) between an externally derived polygenic risk score for opioid use disorder and numbers of codeine prescriptions. As a proof-of-concept study, our research provides a novel and generalizable phenotyping pipeline for the genomic study of opioid-related risk traits.

Intrathecal pain treatment for severe pain in patients with terminal cancer: A retrospective analysis of treatment-related complications and side effects.

OBJECTIVES: Two-thirds of patients with advanced cancer experience pain. Some of these patients have severe pain refractory to oral and parenteral medication, for whom intrathecal pain treatment could be an option. While intrathecal therapy is presently used with good results in clinical practice, the current evidence is limited. Hence, increased knowledge of intrathecal pain treatment is needed. This retrospective study aimed to assess complications and side effects related to intrathecal pain treatment in patients with terminal cancer. METHODS: A retrospective study on all patients who received intrathecal treatment with morphine and bupivacaine through externalized catheters for cancer-related pain at a single university hospital during a 5-year period. RESULTS: Treatment-related complications were reported in 24 out of 53 patients. The most common complications were catheter dislocation (13%), catheter occlusion (9%), falls due to bupivacaine-related numbness or weakness (9%), and reversible respiratory depression (8%). There were five serious complications, i.e., meningitis or neurological impairment, of which four were reversible. Side effects related to intrathecal drugs, or the implantation procedure were observed in 35 patients. The most common were bupivacaine-related numbness or weakness (57%) and reversible post-dural puncture headache (19%). Systemic opioid doses decreased during the first 3 weeks of intrathecal treatment, from a median daily dose of 681 to 319 oral morphine milligram equivalents. The median treatment duration time was 62 days. CONCLUSIONS: Complications related to intrathecal treatment are common, but mostly minor and reversible. Side effects are predominantly related to unwanted pharmacological effects from intrathecal drugs. Intrathecal treatment enables the reduction of systemic opioid doses, which indicates a good treatment effect on pain. Hence, intrathecal therapy can be considered a safe pain-relieving treatment in patients with severe refractory cancer-related pain. Future research is warranted on patient acceptability and satisfaction of intrathecal pain treatment.

Inadequate management of opioid-induced constipation in European cancer pain patients: results of a real-world, multicentre, observational study ("E-StOIC").

PURPOSE: The objectives of the study were to determine the prevalence of (uncontrolled) OIC, relevant medications / interventions employed by healthcare professionals, and the additional strategies utilised by patients, amongst European patients with cancer pain. METHODS: This study was a prospective observational study conducted at 24 research sites in ten European countries. Cancer patients receiving opioid analgesics for at least a week were recruited, and asked to complete a questionnaire including background information, single question (Are you constipated?), Rome IV diagnostic criteria for OIC, Bowel Function Index (BFI), and Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL). Participants were characterised as having / not having OIC on the basis of the Rome IV diagnostic criteria. RESULTS: 1200 participants completed the study. 59.5% met the Rome IV diagnostic criteria for OIC: only 61.5% that met these criteria self-reported constipation. 72% participants were prescribed a regular conventional laxative / peripherally acting mu-opioid receptor antagonist (PAMORA). However, only 66% took their prescribed laxatives every day. Many participants had utilised other strategies / interventions to manage their OIC. Furthermore, 27% had needed to use suppositories, 26.5% had needed to use an enema, and 8% had had a manual evacuation. The use of PAMORAs, and other novel effective medications, was relatively uncommon. CONCLUSION: The results of this study suggest that management in Europe is often inadequate, and this undoubtedly relates to a combination of inadequate assessment, inappropriate treatment, and inadequate reassessment.

Association Between Opioid and Benzodiazepine Use and All-Cause Mortality in Individuals with Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study.

Background: Opioids and benzodiazepines are frequently prescribed for managing pain and anxiety in chronic obstructive pulmonary disease (COPD) patients. This study aimed to determine whether opioid use, with or without benzodiazepine use, is associated with increased all-cause mortality in COPD patients. Methods: This prospective cohort study included adults aged ≥20 years with COPD from the US National Health and Nutrition Examination Survey 2007-2012. The primary outcome was all-cause mortality, which were obtained through linkage to registries. Weighted Cox proportional hazards regression models were used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. Additionally, subgroup and sensitivity analyses were used to evaluate the robustness of our findings. Results: This study enrolled 811 participants, representing 10.84 million COPD individuals in the United States (mean [standard error] age, 58.7 [0.6] years). During a median follow-up of 9.6 years, mortality rates were 57.8 per 1000 person-years in patients using only opioids, 41.3 per 1000 person-years in patients using only benzodiazepines, 45.7 per 1000 person-years in patients using both opioids and benzodiazepines, and 27.0 per 1000 person-years in patients using neither. In the fully adjusted model, COPD patients prescribed both opioids and benzodiazepines (HR: 1.76; 95% CI: 1.11-2.78) and those prescribed opioids only (HR: 1.68; 95% CI: 1.13-2.49) had significantly higher all-cause mortality compared to non-users. After adjusting for propensity scores, the mortality risk for opioid-only users slightly increased (HR: 1.87; 95% CI: 1.25-2.81). Further, subgroup analysis revealed an elevated mortality risk in patients over 60 years receiving coprescriptions or opioids only, but not in younger participants. In contrast, benzodiazepine-only users aged 60 or younger showed increased mortality risk. Conclusion: Opioid use, with or without benzodiazepine use, was associated with higher mortality in COPD patients over 60, while benzodiazepine-only use was associated with higher mortality aged 60 or younger.

Fentanyl: New Wave, New Age, New Addiction?

This paper aims to take over the rampant phenomenon of the illicit use/abuse for volutary purposes of fentanyl. This synthetic drug is normally used as a potent anaesthetic and analgesic molecule. Unfortunately, in recent decades, this substance has conquered and seduced millions of people in the 'westernised' world, claiming numerous victims, especially young people. To this end, the most recent scientific literature will be examined and the pharmacological effects of both therapeutic and intentional abuse will be considered. Finally, the consequences and psychosocial damage produced will be described.

Opioids for the palliation of symptoms in people with serious respiratory illness: a systematic review and meta-analysis.

BACKGROUND: People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear. METHODS: We examined the efficacy and safety of opioids for symptom management in people with serious respiratory illness. Embase, MEDLINE and the Cochrane Central Register of Controlled Trials were searched up to 11 July 2022. Reports of randomised controlled trials administering opioids to treat symptoms in people with serious respiratory illness were included. Key exclusion criteria included <80% of participants having a nonmalignant lung disease. Data were extracted regarding study characteristics, outcomes of breathlessness, cough, health-related quality of life (HRQoL) and adverse events. Treatment effects were pooled using a generic inverse variance model with random effects. Risk of bias was assessed using the Cochrane Risk of Bias tool version 1. RESULTS: Out of 17 included trials, six were laboratory-based exercise trials (n=70), 10 were home studies measuring breathlessness in daily life (n=788) and one (n=18) was conducted in both settings. Overall certainty of evidence was "very low" to "low". Opioids reduced breathlessness intensity during laboratory exercise testing (standardised mean difference (SMD) -0.37, 95% CI -0.67- -0.07), but not breathlessness measured in daily life (SMD -0.10, 95% CI -0.64-0.44). No effects on HRQoL (SMD -0.42, 95% CI -0.98-0.13) or cough (SMD -1.42, 95% CI -3.99-1.16) were detected. In at-home studies, opioids led to increased frequency of nausea/vomiting (OR 3.32, 95% CI 1.70-6.51), constipation (OR 3.08, 95% CI 1.69-5.61) and drowsiness (OR 1.37, 95% CI 1.01-1.86), with serious adverse events including hospitalisation and death identified. CONCLUSIONS: Opioids improved exertional breathlessness in laboratory exercise studies, but did not improve breathlessness, cough or HRQoL measured in daily life at home. There were significant adverse events, which may outweigh any benefits.

Enhanced Recovery After Surgery (ERAS) consensus recommendations for opioid-minimising pharmacological neonatal pain management.

OBJECTIVE: Enhanced recovery after surgery (ERAS) guidelines have been successfully applied to children and neonates. There is a need to provide evidence-based consensus recommendations to manage neonatal pain perioperatively to ensure adequate analgesia while minimising harmful side effects. METHODS: Following a stakeholder needs assessment, an international guideline development committee (GDC) was established. A modified Delphi consensus iteratively defined the scope of patient and procedure inclusion, topic selection and recommendation content regarding the pharmacologic management of neonatal pain. Critical appraisal tools assessed the relevance and quality of full-text studies. Each recommendation underwent a formal Grades of Recommendation, Assessment, Development and Evaluation (GRADE) assessment of the quality of evidence and expert consensus was used to determine the strength of recommendations. RESULTS: The GDC included paediatric anaesthesiologists, surgeons, and ERAS methodology experts. The population was defined as neonates at >32 weeks gestational age within 30 days of life undergoing surgery or painful procedures associated with surgery. Topic selection targeted pharmacologic opioid-minimising strategies. A total of 4249 abstracts were screened for non-opioid analgesia and 738 abstracts for the use of locoregional analgesia. Full-text review of 18 and 9 articles, respectively, resulted in two final recommendations with a moderate quality of evidence to use regular acetaminophen and to consider the use of locoregional analgesia. There was inadequate evidence to guide the use of other non-opioid adjuncts in this population. CONCLUSIONS: Evidence-based, ERAS-driven consensus recommendations were developed to minimise opioid usage in neonates. Further research is required in this population to optimize multimodal strategies for pain control.

Tramadol use and incident dementia in older adults with musculoskeletal pain: a population-based retrospective cohort study.

We aimed to assess the association of tramadol use with the risk of dementia. This population-based retrospective cohort study using the Korean National Health Insurance Service database included a total of 1,865,827 older adult patients aged 60 years or older with common musculoskeletal pain between January 1, 2003, and December 31, 2007. Individuals who were newly dispensed tramadol (N = 41,963) were identified and propensity score-matched with those who were not (N = 41,963). Over a maximum of 14-year follow-up, the incidence rates (events per 1000 person-years) of all-cause dementia were 6.1 for nonusers, 6.2 for those with cumulative tramadol use of 1-14 days, 7.7 for those with 15-90 days of use, and 8.0 for those with > 90 days of use. Longer cumulative duration of tramadol use was associated with an increased risk of all-cause dementia compared with nonuse (1 to 14 days: aHR 1.06, 95% CI 0.96-1.17; 15 to 90 days: aHR 1.14, 95% CI 1.10-1.35; and more than 90 days: aHR 1.18, 95% CI 1.00-1.39; test for trend: P < 0.001). The results showed a similar pattern for Alzheimer's disease and were robust across subgroup and sensitivity analyses, but not for vascular dementia. This study found that exposure to tramadol was associated with an increased risk of dementia. Taking this potential risk into consideration, clinicians should carefully weigh potential benefits and risks when prescribing tramadol to older adults with musculoskeletal pain.

Prescription opioid use in Israel - the tide has risen, but it's not a tidal wave.

The devastating human and financial costs of the ongoing global opioid crisis underscore the need for comprehensive public health strategies, effective treatment programs, and robust policy interventions to mitigate its impact. Regarding Israel, numerous reports highlight a steady increase since 2000 in prescription opioid use and the shift to more potent opioids particularly fentanyl, particularly among more marginalized population groups. In response to growing concern in the country about the rise in prescription opioid use and the consequential risk of opioid use disorder, the Israeli government, together with the country's health service providers, implemented a series of measures to monitor and regulate opioid prescriptions and balance the need for effective pain management with the prevention of opioid abuse and its associated harms. A national opioid data monitoring system is being established, alongside the provision of addiction training for health professionals, the integration of treatment services for opioid use disorder into the nationalized primary healthcare system, and the expansion of harm reduction strategies to mitigate the health risks associated with opioid use. Additional funding for opioid-related research, and for the broader fields of addictions and mental health, is vital. In conclusion, the sum of the evidence suggests that Israel is not facing an "opioid crisis" Continued commitment, resources, and innovative approaches will be crucial to ensure that the rising tide of opioid use in Israel, particularly during and in the aftermath of the ongoing war, will not become a tidal wave.

The Perfect Storm: Abnormal Baseline QT With Chronic Methadone Use and Serious Hypokalemia.

Methadone, a well-known drug used for pain control and as a treatment for opioid addiction, can cause arrhythmias, including torsades de pointes (TdP), which may progress to ventricular fibrillation and sudden death. We present a case of a middle-aged woman with a long history of methadone use who presented to the emergency department after experiencing cardiac arrest at home. During her hospitalization, she experienced multiple episodes of TdP that improved with isoproterenol and potassium correction. The initial diagnosis was methadone-induced prolonged QT. However, even with discontinuation of methadone, her QTc remained prolonged. Congenital long QT syndrome was suspected, and genetic testing was instructed to test in the outpatient setting. She was discharged on nadolol and a LifeVest.

Does IV fentanyl, frequently used in emergency departments, change QTC value? A prospective observational study.

BACKGROUND: Fentanyl is an opioid analgesic frequently used in the emergency department (ED) and is usually administered without knowing the QTC values of the patients or being monitored. However, the effect of fentanyl on QTC, prolongation or shortening, has not been elucidated. This study aimed to determine the effect of fentanyl on QTC. METHODS: This is a prospective observational study in the ED of a tertiary hospital on patients who received intravenous fentanyl for procedures other than intubation. ECG was performed before and at 1, 5, 15, 30, and 60 min after the initiation of fentanyl administration, and QTC value was calculated. Primary outcomes were QTC prolongation, defined as an increase in the QTC to ≥ 500 ms or any increase in QTC by ≥ 60 ms. RESULTS: The study included 109 patients. Of these, 60 patients were male, and the median age was 40. Compared with the baseline QTC value, statistically significant prolongation was detected at the 5th, 15th, 30th, and 60th minutes, with the maximum prolongation at 30 min, and the median was 13.08 ms. Most patients with QTC prolongation were female and over 40 years of age. Clinically, none of these patients developed malignant arrhythmias during the 60-minute monitored observation period. CONCLUSION: Fentanyl prolonged the QTC value statistically significantly. Although no patient developed malignant arrhythmia clinically, our results suggest that this QTC-prolonging effect should be considered when using fentanyl in patients at risk of torsades.

Evaluating fentanyl test strips as a harm reduction strategy in rural and urban counties: study protocol for a randomized controlled trial.

BACKGROUND: Opioid-related fatalities are a leading cause of death in Ohio and nationally, with an increasing number of overdoses attributable to fentanyl. Rapid fentanyl test strips can identify fentanyl and some fentanyl analogs in urine samples and are increasingly being used to check illicit drugs for fentanyl before they are used. Fentanyl test strips are a promising harm reduction strategy; however, little is known about the real-world acceptability and impact of fentanyl test strip use. This study investigates fentanyl test strip distribution and education as a harm reduction strategy to prevent overdoses among people who use drugs. METHODS: The research team will recruit 2400 individuals ≥ 18 years with self-reported use of illicit drugs or drugs purchased on the street within the past 6 months. Recruitment will occur at opioid overdose education and naloxone distribution programs in 16 urban and 12 rural Ohio counties. Participating sites will be randomized at the county level to the intervention or non-intervention study arm. A brief fentanyl test strip educational intervention and fentanyl test strips will be provided to participants recruited from sites in the intervention arm. These participants will be eligible to receive additional fentanyl test strips for 2 years post-enrollment. Participants recruited from sites in the non-intervention arm will not receive fentanyl test strip education or fentanyl test strips. All participants will be followed for 2 years post-enrollment using biweekly, quarterly, and 6-month surveys. Primary outcomes include (1) identification of perceived barriers and facilitating factors associated with incorporating fentanyl test strip education and distribution into opioid overdose education and naloxone distribution programs; (2) differences in knowledge and self-efficacy regarding how to test drugs for fentanyl and strategies for reducing overdose risk between the intervention and non-intervention groups; and (3) differences in non-fatal and fatal overdose rates between the intervention and non-intervention groups. DISCUSSION: Findings from this cluster randomized controlled trial will contribute valuable information about the feasibility, acceptability, and impact of integrating fentanyl test strip drug checking in rural and urban communities in Ohio and help guide future overdose prevention interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05463341. Registered on July 19, 2022. https://clinicaltrials.gov/study/NCT05463341.

Perioperative Regional Anesthesia on Persistent Opioid Use and Chronic Pain after Noncardiac Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Whether regional anesthesia impacts the development of chronic postsurgical pain is currently debateable, and few studies have evaluated an effect on prolonged opioid use. We sought to systematically review the effect of regional anesthesia for adults undergoing noncardiac elective surgery on these outcomes. METHODS: A systematic search was conducted in MEDLINE, EMBASE, CENTRAL, and CINHAL for randomized controlled trials (from inception to April 2022) of adult patients undergoing elective noncardiac surgeries that evaluated any regional technique and included one of our primary outcomes: (1) prolonged opioid use after surgery (continued opioid use ≥2 months postsurgery) and (2) chronic postsurgical pain (pain ≥3 months postsurgery). We conducted a random-effects meta-analysis on the specified outcomes and used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to rate the quality of evidence. RESULTS: Thirty-seven studies were included in the review. Pooled estimates indicated that regional anesthesia had a significant effect on reducing prolonged opioid use (relative risk [RR] 0.48, 95% CI, 0.24-0.96, P = .04, I 2 0%, 5 trials, n = 348 patients, GRADE low quality). Pooled estimates for chronic pain also indicated a significant effect favoring regional anesthesia at 3 (RR, 0.74, 95% CI, 0.59-0.93, P = .01, I 2 77%, 15 trials, n = 1489 patients, GRADE moderate quality) and 6 months (RR, 0.72, 95% CI, 0.61-0.85, P < .001, I 2 54%, 19 trials, n = 3457 patients, GRADE moderate quality) after surgery. No effect was found in the pooled analysis at 12 months postsurgery (RR, 0.44, 95% CI, 0.16-1.17, P = .10). CONCLUSIONS: The results of this study suggest that regional anesthesia potentially reduces chronic postsurgical pain up to 6 months after surgery. Our findings also suggest a potential decrease in the development of persistent opioid use.

A state-level history of opioid overdose deaths in the United States: 1999-2021.

We examined a natural history of opioid overdose deaths from 1999-2021 in the United States to describe state-level spatio-temporal heterogeneity in the waves of the epidemic. We obtained overdose death counts by state from 1999-2021, categorized as involving prescription opioids, heroin, synthetic opioids, or unspecified drugs. We developed a Bayesian multivariate multiple change point model to flexibly estimate the timing and magnitude of state-specific changes in death rates involving each drug type. We found substantial variability around the timing and severity of each wave across states. The first wave of prescription-involved deaths started between 1999 and 2005, the second wave of heroin-involved deaths started between 2010 and 2014, and the third wave of synthetic opioid-involved deaths started between 2014 and 2021. The severity of the second and third waves was greater in states in the eastern half of the country. Our study highlights state-level variation in the timing and severity of the waves of the opioid epidemic by presenting a 23-year natural history of opioid overdose mortality in the United States. While reinforcing the general notion of three waves, we find that states did not uniformly experience the impacts of each wave.

A protocol for enhancing the diagnostic accuracy and predictive validity of neonatal opioid withdrawal syndrome: The utility of non-invasive clinical markers.

Every 15 minutes in the US, an infant exposed to opioids is born. Approximately 50% of these newborns will develop Neonatal Opioid Withdrawal Syndrome (NOWS) within 5 days of birth. It is not known which infants will develop NOWS, therefore, the current hospital standard-of-care dictates a 96-hour observational hold. Understanding which infants will develop NOWS soon after birth could reduce hospital stays for infants who do not develop NOWS and decrease burdens on hospitals and clinicians. We propose noninvasive clinical indicators of NOWS, including newborn neurobehavior, autonomic biomarkers, prenatal substance exposures, and socioeconomic environments. The goals of this protocol are to use these indicators shortly after birth to differentiate newborns who will be diagnosed with NOWS from those who will have mild/no withdrawal, to determine if the indicators predict development at 6 and 18 months of age, and to increase NOWS diagnostic sensitivity for earlier, more accurate diagnoses.