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Biomedicine & Pharmacotherapy =... Jul 2024The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently....
The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently. As the ABCB1 gene encodes for the transporter P-glycoprotein in the brain and intestine involved in the pharmacokinetics of opioids, we investigated the effects of ABCB1 genetic polymorphisms on doses of opioids for pain relief and determined which pharmacokinetic process was affected in cancer pain patients. Sixty-eight cancer pain patients admitted for intrathecal therapy (ITT) were included. The association between ABCB1 genetic polymorphisms (C3435T, C1236T, G2677T/A and A61G) and systemic doses of opioids before ITT were investigated. Concentrations of oxycodone in plasma and cerebrospinal fluid (CSF) were determined by HPLC-MS/MS in 17 patients treated with oral oxycodone before ITT, and the influences of ABCB1 genetic polymorphisms on plasma-concentration to oral-dose ratios and CSF-concentration to plasma-concentration ratios of oral oxycodone were further analyzed. ABCB1 C3435T and G2677T/A polymorphisms were significantly associated with systemic doses of opioids before ITT, which coincided with the influences of ABCB1 C3435T and G2677T/A polymorphisms on the ratios of plasma-concentration to oral-dose. However, no significant difference was found in ratios of CSF-concentration to plasma-concentration among ABCB1 SNP genotypes. The present study provided the first evidence that ABCB1 C3435T and G2677T/A polymorphisms affect opioid requirement in cancer pain patients via altering transportation function of P-glycoprotein in the intestine, which will further expand our knowledge about pharmacokinetics of opioids and could contribute to the individualization of opioids use.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B; Male; Female; Analgesics, Opioid; Middle Aged; Polymorphism, Single Nucleotide; Aged; Oxycodone; Cancer Pain; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Intestinal Mucosa; Genotype
PubMed: 38850645
DOI: 10.1016/j.biopha.2024.116897 -
Harm Reduction Journal Jun 2024As the opioid public health crisis evolves to include fentanyl and other potent synthetic opioids, more patients are admitted to the hospital with serious complications...
BACKGROUND
As the opioid public health crisis evolves to include fentanyl and other potent synthetic opioids, more patients are admitted to the hospital with serious complications of drug use and frequently require higher levels of care, including intensive care unit (ICU) admission, for acute and chronic conditions related to opioid use disorder (OUD). This patient population poses a unique challenge when managing sedation and ensuring adequate ventilation while intubated given their high opioid requirements. Starting a patient on medications such as buprenorphine may be difficult for inpatient providers unfamiliar with its use, which may lead to undertreatment of patients with OUD, prolonged mechanical ventilation and length of stay.
METHODS
We developed a 7-day buprenorphine low dose overlap initiation (LDOI) schedule for patients with OUD admitted to the ICU (Table 1). Buprenorphine tablets were split by pharmacists and placed into pre-made blister packs as a kit to be loaded into the automated medication dispensing machine for nursing to administer daily. An internal quality review validated the appropriate dosing of split-dose tablets. To simplify order entry and increase prescriber comfort with this new protocol, we generated an order set within our electronic health record software with prebuilt buprenorphine titration orders. This protocol was implemented alongside patient and healthcare team education and counseling on the LDOI process, with follow-up offered to all patients upon discharge.
RESULTS
Here we report a series of 6 ICU patients started on buprenorphine using the LDOI schedule with split buprenorphine tablets. None of the 6 patients experienced precipitated withdrawal upon buprenorphine initiation using the LDOI schedule, and 5/6 patients were successfully extubated during the buprenorphine initiation. Four of six patients had a decrease in daily morphine milligram equivalents, with 3 patients transitioning to buprenorphine alone.
CONCLUSION
Initiating buprenorphine via LDOI was found to be successful in the development of a protocol for critically ill patients with OUD. We examined LDOI of buprenorphine in intubated ICU patients and found no events of acute precipitated withdrawal. This protocol can be used as a guide for other institutions seeking to start critically ill patients on medication treatment for OUD during ICU admission.
Topics: Humans; Buprenorphine; Opioid-Related Disorders; Intensive Care Units; Male; Analgesics, Opioid; Female; Opiate Substitution Treatment; Adult; Middle Aged; Narcotic Antagonists; Intubation, Intratracheal
PubMed: 38849912
DOI: 10.1186/s12954-024-01028-4 -
Trials Jun 2024Obese patients undergoing laparoscopic sleeve gastrectomy (LSG) are particularly at risk of opioid-related side effects. To reduce patient exposure to opioids,...
The effect of pre-emptive oral pregabalin on opioid consumption in patients undergoing laparoscopic sleeve gastrectomy with an analysis of intraoperative hemodynamic stability and quality of recovery: study protocol for a randomized, prospective, double-blind study.
BACKGROUND
Obese patients undergoing laparoscopic sleeve gastrectomy (LSG) are particularly at risk of opioid-related side effects. To reduce patient exposure to opioids, multimodal analgesia, which involves the use of drugs of different classes, may be utilized. One of the drugs under consideration is pregabalin. Despite an opioid-sparing potential, few studies assess the role of pregabalin as an element of multimodal analgesia in LSG. Considering the limited number and inconsistent results of available studies, we decided to conduct a randomized, prospective study on the effect of preemptive pregabalin administration in obese patients on opioid consumption, pain scores, the incidence of opioid side effects, and hemodynamical stability.
METHODS
The study is designed as a prospective randomized controlled trial with double-blinding. Randomization will be performed in a block with a parallel 1:1 allocation. The intervention will involve receiving a pregabalin 150 mg capsule 1-2 h before the surgery, whereas the control group will receive an identically looking placebo. The primary outcome measure will be total oxycodone consumption in the first 24 h following surgery. Secondary outcome measures will be pain severity assessed using the Numerical Rating Scale (NRS) 1, 6, 12, and 24 h after surgery, postoperative sedation on the Ramsay scale, PONV impact scale, the incidence of desaturation episodes < 94%, and episodes of blurred vision at 1, 6, 12, and 24 h after surgery, intraoperative hemodynamic parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), total fluid volume, and total ephedrine dose. Patient comfort will be additionally assessed using the QoR-40 questionnaire at discharge.
DISCUSSION
The study will explore the efficacy and safety of preemptive pregabalin in a dose of 150 mg as a co-analgesic used in multimodal analgesia for LSG. As studies on opioid-sparing regimes concern the safety of obese patients, we aim to contribute objective data with a relatively large study sample size. The result of the present clinical trial may support the reassessment of recommendations to use pregabalin in the studied population.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05804591. Registered on 07.04.2023.
Topics: Humans; Pregabalin; Double-Blind Method; Prospective Studies; Analgesics, Opioid; Gastrectomy; Pain, Postoperative; Laparoscopy; Hemodynamics; Randomized Controlled Trials as Topic; Adult; Treatment Outcome; Pain Measurement; Administration, Oral; Analgesics; Middle Aged; Male; Time Factors; Female; Young Adult; Recovery of Function; Oxycodone
PubMed: 38849875
DOI: 10.1186/s13063-024-08225-3 -
JMIR Research Protocols Jun 2024Chronic pain affects tens of millions of US adults and continues to rise in prevalence. Nonpharmacologic behavioral pain treatments are greatly needed and yet are often...
BACKGROUND
Chronic pain affects tens of millions of US adults and continues to rise in prevalence. Nonpharmacologic behavioral pain treatments are greatly needed and yet are often inaccessible, particularly in settings where medication prescribing is prioritized.
OBJECTIVE
This study aims to test the feasibility of a live-instructor, web-based 1-session pain relief skills class in an underserved and potentially at-risk population: people with chronic pain prescribed methadone or buprenorphine either solely for pain or for comorbid opioid use disorder (OUD).
METHODS
This is a national, prospective, single-arm, uncontrolled feasibility trial. The trial is untethered from medical care; to enhance participants' willingness to join the study, no medical records or drug-monitoring records are accessed. At least 45 participants will be recruited from outpatient pain clinics and from an existing research database of individuals who have chronic pain and are taking methadone or buprenorphine. Patient-reported measures will be collected at 6 time points (baseline, immediately post treatment, 2 weeks, and months 1-3) via a web-based platform, paper, or phone formats to include individuals with limited internet or computer access and low literacy skills. At baseline, participants complete demographic questions and 13 study measures (Treatment Expectations, Body Pain Map, Medication Use, Pain Catastrophizing Scale [PCS], Patient-Reported Outcomes Measurement Information System [PROMIS] Measures, and Opioid Craving Scale). Immediately post treatment, a treatment satisfaction and acceptability measure is administered on a 0 (very dissatisfied) to 10 (completely satisfied) scale, with 3 of these items being the primary outcome (perceived usefulness, participant satisfaction, and likelihood of using the skills). At each remaining time point, the participants complete all study measures minus treatment expectations and satisfaction. Participants who do not have current OUD will be assessed for historical OUD, with presence of OUD (yes or no), and history of OUD (yes or no) reported separately. Feasibility threshold is set as an overall group treatment satisfaction rating of 8 of 10. In-depth qualitative interviews will be conducted with about 10 participants to obtain additional data on patient perceptions, satisfactions, needs, and wants. To assess preliminary efficacy, we will examine changes in pain catastrophizing, pain intensity, pain bothersomeness, sleep disturbance, pain interference, depression, anxiety, physical function, global impression of change, and opioid craving at 1 month post treatment.
RESULTS
This project opened to enrollment in September 2021 and completed the recruitment in October 2023. The data collection was completed in February 2024. Results are expected to be published in late 2024.
CONCLUSIONS
Results from this trial will inform the feasibility and preliminary efficacy of Empowered Relief in this population and will inform the design of a future randomized controlled trial testing web-based Empowered Relief in chronic pain and comorbid OUD.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05057988; https://clinicaltrials.gov/study/NCT05057988.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/53784.
Topics: Humans; Buprenorphine; Chronic Pain; Methadone; Feasibility Studies; Prospective Studies; Male; Female; Analgesics, Opioid; Adult; Pain Management; Opiate Substitution Treatment; Internet-Based Intervention; Internet; Opioid-Related Disorders; Middle Aged
PubMed: 38843513
DOI: 10.2196/53784 -
Aging Jun 2024Morphine tolerance refers to gradual reduction in response to drug with continuous or repeated use of morphine, requiring higher doses to achieve same effect.
BACKGROUND
Morphine tolerance refers to gradual reduction in response to drug with continuous or repeated use of morphine, requiring higher doses to achieve same effect.
METHODS
The morphine tolerance dataset GSE7762 profiles, obtained from gene expression omnibus (GEO) database, were used to identify differentially expressed genes (DEGs). Weighted Gene Co-expression Network Analysis (WGCNA) was applied to explore core modules of DEGs related to morphine tolerance. Core genes were input into Comparative Toxicogenomics Database (CTD). Animal experiments were performed to validate role of Tsc22d3 in morphine tolerance and its relationship with ferroptosis-related pathway.
RESULTS
500 DEGs were identified. DEGs were primarily enriched in negative regulation of brain development, neuronal apoptosis processes, and neurosystem development. Core gene was identified as Tsc22d3. Tsc22d3 gene-associated miRNAs were mmu-miR-196b-5p and mmu-miR-196a-5p. Compared to Non-morphine tolerant group, Tsc22d3 expression was significantly upregulated in Morphine tolerant group. Tsc22d3 expression was upregulated in Morphine tolerant+Tsc22d3_OE, expression of HIF-1alpha, GSH, GPX4 in GPX4 ferroptosis-related pathway showed a more pronounced decrease. As Tsc22d3 expression was downregulated in Morphine tolerant+Tsc22d3_KO, expression of HIF-1alpha, GSH, GPX4 in GPX4 ferroptosis-related pathway exhibited a more pronounced increase. Upregulation of Tsc22d3 in Morphine tolerant+Tsc22d3_OE led to a more pronounced increase in expression of apoptosis proteins (P53, Caspase-3, Bax, SMAC, FAS). The expression of inflammatory factors (IL6, TNF-alpha, CXCL1, CXCL2) showed a more pronounced increase with upregulated Tsc22d3 expression in Morphine tolerant+Tsc22d3_OE.
CONCLUSIONS
Tsc22d3 is highly expressed in brain tissue of morphine-tolerant mice, activating ferroptosis pathway, enhancing apoptosis, promoting inflammatory responses in brain cells.
Topics: Animals; Ferroptosis; Morphine; Mice; Phospholipid Hydroperoxide Glutathione Peroxidase; Drug Tolerance; Male; MicroRNAs; Signal Transduction; Mice, Inbred C57BL
PubMed: 38843390
DOI: 10.18632/aging.205903 -
Scandinavian Journal of Pain Jan 2024Addressing the challenges of ambulatory surgery involves balancing effective pain relief with minimizing the side effects of pain medication. Due to the heightened risk...
OBJECTIVES
Addressing the challenges of ambulatory surgery involves balancing effective pain relief with minimizing the side effects of pain medication. Due to the heightened risk of opioid abuse, Helsinki University Hospital (Finland) has had a stringent oxycodone prescription policy. This policy prompts an exploration into whether ambulatory surgery patients experience severe post-surgical pain and whether an increase in prescribed opioids would cause elevation in adverse effects.
METHODS
This prospective cohort study, with a 1-week follow-up, included 111 adult ambulatory surgery patients (orthopaedics, urology). The patients documented their pain levels within the first postoperative week (using a numerical rating scale [NRS] of 0-10) and pain medication intake up to two days postoperatively. Furthermore, they completed a questionnaire assessing their satisfaction with pain relief, medication-related adverse effects, and adherence to instructions. Medication intake was cross-referenced with the provided instructions and prescriptions.
RESULTS
A notable 56% of patients reported experiencing intense pain (NRS ≥5) within a week following surgery. Of these, 52% received a single dose of slow-release oxycodone (5-20 mg) at discharge for use on the night of surgery. Predominantly prescribed pain medications included a combination of paracetamol and codeine (64%) or ibuprofen (62%). Satisfaction rates were high, with 87% expressing satisfaction with pain medication given at hospital discharge and 90% expressing contentment with the prescribed medication. The most common adverse effects were tiredness/grogginess (45%), sleep disturbances (38%), nausea (37%), and constipation (27%). Also, 24% of patients self-reported deviations from medication instructions. A comparison of self-reported and instructed medications revealed that 14% exceeded prescribed dosages, and 28% opted for preparations different from those prescribed. Notably, patients who self-reported deviations from instructions differed from those objectively deviating from instructions.
CONCLUSIONS
Although 56% of patients had intense pain, the majority expressed satisfaction with the provided pain relief. Instances of non-adherence to medication instructions were prevalent, often going unnoticed by the patients themselves.
Topics: Humans; Male; Female; Patient Satisfaction; Middle Aged; Pain, Postoperative; Prospective Studies; Ambulatory Surgical Procedures; Adult; Oxycodone; Analgesics, Opioid; Aged; Finland; Medication Adherence; Pain Measurement
PubMed: 38843006
DOI: 10.1515/sjpain-2023-0133 -
Plastic and Reconstructive Surgery.... Jun 2024Although the transversus abdominal plane (TAP) block is commonly used in abdominal surgery as part of enhanced recovery after surgery pathways, the quadratus lumborum...
BACKGROUND
Although the transversus abdominal plane (TAP) block is commonly used in abdominal surgery as part of enhanced recovery after surgery pathways, the quadratus lumborum (QL) block has been hypothesized as an effective alternative to the TAP block in some areas. This review evaluates the current literature, as it relates to the QL block in plastic and reconstructive surgery.
METHODS
A systematic review using PubMed searched for all original, peer-reviewed articles, including the term "quadratus lumborum block." In total, 509 articles were identified for review by two independent reviewers. Original articles evaluating the use of a QL block in any plastic surgery operation were included. Articles evaluating pediatric patients, animal trials, and the use of a QL block in any nonplastic surgery operation were excluded.
RESULTS
Three articles met inclusion criteria. One trial demonstrated decreased subjective pain scores and total opioid use, whereas the second found no statistically significant difference. A case study described the use of a QL block for unilateral breast reconstruction with minimal opiate use and reduced pain scores postoperatively. Limitations include the limited number of studies and the heterogeneity in study type and design, making analysis difficult.
CONCLUSIONS
Despite its demonstrated efficacy in other surgical subspecialties, there are limited data evaluating the use of the QL block in plastic and reconstructive surgery. Additional research is needed to evaluate the role of the QL block in plastic surgery and how it compares to the more widely utilized TAP block.
PubMed: 38841521
DOI: 10.1097/GOX.0000000000005863 -
Nature Jun 2024All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders. Another recently appreciated...
All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
Topics: Ventral Tegmental Area; Animals; Reward; Dopaminergic Neurons; Mice; Myelin Sheath; Morphine; Male; Nucleus Accumbens; Neuronal Plasticity; Oligodendroglia; GABAergic Neurons; Optogenetics; Analgesics, Opioid; Dopamine; Female; Mice, Inbred C57BL
PubMed: 38839962
DOI: 10.1038/s41586-024-07525-7 -
Journal of UOEH 2024A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of...
A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of unconsciousness and respiratory arrest at home. She was pronounced dead 12 hours after she was discovered. Her autopsy revealed symmetrical hemorrhagic necrosis in the putamen on both sides of her cerebrum. Although many drugs were detected in her blood, all of those other than dextromethorphan (DXM) were within or below the therapeutic range. Her blood DXM was 1.73 μg/ml at admission and 1.61 μg/ml at autopsy, which were within the toxic range or coma-to-death range. The cause of death was diagnosed as DXM poisoning. DXM can cause hallucinations and euphoria if taken in excess, but since it is available as an over-the-counter drug at general pharmacies, an increasing number of young people are overdosing on it, mistakenly believing it to be a safe drug with few side effects. We believe that further social measures against DXM are necessary in Japan, such as disseminating correct knowledge in society and regulating over-the-counter sales.
Topics: Humans; Dextromethorphan; Female; Autopsy; Adult; Fatal Outcome
PubMed: 38839290
DOI: 10.7888/juoeh.46.221 -
Scientific Reports Jun 2024Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by inflammatory cell infiltration and joint damage. The Chinese government has approved the...
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by inflammatory cell infiltration and joint damage. The Chinese government has approved the prescription medication sinomenine (SIN), an effective anti-inflammation drug, for treating RA. This study evaluated the possible anti-inflammatory actions of SIN in RA based on bioinformatics analysis and experiments. Six microarray datasets were acquired from the gene expression omnibus (GEO) database. We used R software to identify differentially expressed genes (DEGs) and perform function evaluations. The CIBERSORT was used to calculate the abundance of 22 infiltrating immune cells. The weighted gene co-expression network analysis (WGCNA) was used to discover genes associated with M1 macrophages. Four public datasets were used to predict the genes of SIN. Following that, function enrichment analysis for hub genes was performed. The cytoHubba and least absolute shrinkage and selection operator (LASSO) were employed to select hub genes, and their diagnostic effectiveness was predicted using the receiver operator characteristic (ROC) curve. Molecular docking was undertaken to confirm the affinity between the SIN and hub gene. Furthermore, the therapeutic efficacy of SIN was validated in LPS-induced RAW264.7 cells line using Western blot and Enzyme-linked immunosorbent assay (ELISA). The matrix metalloproteinase 9 (MMP9) was identified as the hub M1 macrophages-related biomarker in RA using bioinformatic analysis and molecular docking. Our study indicated that MMP9 took part in IL-17 and TNF signaling pathways. Furthermore, we found that SIN suppresses the MMP9 protein overexpression and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the LPS-induced RAW264.7 cell line. In conclusion, our work sheds new light on the pathophysiology of RA and identifies MMP9 as a possible RA key gene. In conclusion, the above findings demonstrate that SIN, from an emerging research perspective, might be a potential cost-effective anti-inflammatory medication for treating RA.
Topics: Morphinans; Arthritis, Rheumatoid; Matrix Metalloproteinase 9; Mice; Animals; RAW 264.7 Cells; Computational Biology; Cytokines; Humans; Molecular Docking Simulation; Gene Expression Regulation; Macrophages; Anti-Inflammatory Agents
PubMed: 38834626
DOI: 10.1038/s41598-024-61769-x