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The Journal of Clinical Investigation Jan 2024Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting...
Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity and dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.
Topics: Humans; Opiate Alkaloids; Morphine; Mitochondrial Dynamics; Analgesics, Opioid; Dopaminergic Neurons; Dopamine; Substance Withdrawal Syndrome
PubMed: 38236644
DOI: 10.1172/JCI171995 -
The International Journal on Drug Policy Jun 2021The COVID-19 pandemic poses significant challenges to people with opioid use disorder (OUD). As localities enforce lockdowns and pass emergency OUD treatment...
BACKGROUND
The COVID-19 pandemic poses significant challenges to people with opioid use disorder (OUD). As localities enforce lockdowns and pass emergency OUD treatment regulations, questions arise about how these changes will affect access and retention in care. In this study, we explore the influence of COVID-19 on access to, experiences with, and motivations for OUD treatment through a qualitative analysis of public discussion forums on Reddit.
METHODS
We collected data from Reddit, a free and international online platform dedicated to public discussions and user-generated content. We extracted 1000 of the most recent posts uploaded between March 5th and May 13th, 2020 from each of the two most popular opioid subreddits "r/Opiates" and "r/OpiatesRecovery" (total 2000). We reviewed posts for relevance to COVID-19 and opioid use and coded content using a hybrid inductive-deductive approach. Thematic analysis identified common themes related to study questions of interest.
RESULTS
Of 2000 posts reviewed, 300 (15%) discussed topics related to the intersection of opioid use and COVID-19. Five major themes related to OUD treatment were identified: Concern about closure of OUD treatment services; transition to telehealth and virtual care; methadone treatment requirements and increased exposure to COVID-19; reactions to changing regulations on medications for OUD; and influences of the pandemic on treatment motivation and progress.
CONCLUSION
In the face of unprecedented challenges due to COVID-19, reactions of Reddit opioid forum users ranged from increased distress in accessing and sustaining treatment, to encouragement surrounding new modes of treatment and opportunities to engage in care. New and less restrictive avenues for treatment were welcomed by many, but questions remain about how new norms and policy changes will be sustained beyond this pandemic and impact OUD treatment access and outcomes long-term.
Topics: Analgesics, Opioid; Buprenorphine; COVID-19; Communicable Disease Control; Humans; Opiate Substitution Treatment; Opioid-Related Disorders; Pandemics; SARS-CoV-2
PubMed: 33558165
DOI: 10.1016/j.drugpo.2021.103140 -
Journal of Analytical Toxicology Aug 2022Every year, thousands of suspicious deaths are accounted for by an overdose of opioids. Occasionally all traditional matrices are unavailable due to decomposition....
Every year, thousands of suspicious deaths are accounted for by an overdose of opioids. Occasionally all traditional matrices are unavailable due to decomposition. Skeletal tissue may pose a valid alternative. However, reference data on postmortem concentrations in bone tissue and bone marrow (BM) is sparse. Therefore, a liquid chromatography--tandem mass spectrometry method was developed and fully validated for the analysis of four opioids and two metabolites (tramadol, O-desmethyltramadol, morphine, fentanyl, norfentanyl, codeine) in bone tissue and BM. Sample preparation was performed using solid phase extraction (BM), methanolic extraction (bone) and a protein precipitation (whole blood). All validation parameters were successfully fulfilled. This method was applied to analyze 22 forensic cases involving opioids. All six opioids were proven to be detectable and quantifiable in all specimens sampled. When tramadol blood concentrations were correlated with bone concentrations, a linear trend could be detected. The same was seen between tramadol blood and BM concentration. A similar linear trend was seen when correlating codeine blood concentration with bone and BM concentration. Although some variability was detected, the same linear trend was seen for morphine. For fentanyl and norfentanyl, the sample size was too small to draw conclusions, regarding correlation. As far as the authors know this is the first-time fentanyl and norfentanyl are quantified in skeletal tissue. In conclusion, due to the absence of reference data for drugs in skeletal tissue, these findings are a step forward toward a more thorough understanding of drug concentration found in postmortem skeletal tissue.
Topics: Analgesics, Opioid; Chromatography, Liquid; Codeine; Fentanyl; Morphine; Tramadol
PubMed: 34480794
DOI: 10.1093/jat/bkab095 -
The Journal of Pharmacology and... Aug 2022Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and...
Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified , a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. SIGNIFICANCE STATEMENT: Our findings show that genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite after oxycodone administration, reinforcing the need for sex as a biological factor in pharmacogenomic studies. The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.
Topics: Analgesics, Opioid; Animals; Brain; Female; Homeodomain Proteins; Male; Mice; Mice, Inbred BALB C; Oxycodone; Oxymorphone; Reward
PubMed: 35688478
DOI: 10.1124/jpet.122.001217 -
Psychopharmacology Jul 2022Tianeptine is a mu-opioid receptor (MOR) agonist with increasing reports of abuse in human populations. Preclinical data regarding the abuse potential and other...
RATIONALE
Tianeptine is a mu-opioid receptor (MOR) agonist with increasing reports of abuse in human populations. Preclinical data regarding the abuse potential and other opioid-like adverse effects of tianeptine at supratherapeutic doses are sparse.
OBJECTIVES
The present study evaluated tianeptine in a rat model of abuse potential assessment and in mouse models of motor, gastrointestinal, and respiratory adverse effects.
METHODS
Abuse potential was assessed in adult male Sprague-Dawley rats using an intracranial self-stimulation (ICSS) procedure to determine effects of acute and repeated tianeptine on responding for electrical brain stimulation. Male ICR mice were used to determine the effects of tianeptine in assays of locomotor behavior and gastrointestinal motility. Male Swiss-Webster mice were monitored for respiratory changes using whole-body plethysmography.
RESULTS
In rats, acute tianeptine produced weak and delayed evidence for abuse-related ICSS facilitation at an intermediate dose (10 mg/kg, IP) and pronounced, naltrexone-preventable ICSS depression at a higher dose (32 mg/kg, IP). Repeated 7-day tianeptine (10 and 32 mg/kg/day, IP) produced no increase in abuse-related ICSS facilitation, only modest tolerance to ICSS depression, and no evidence of physical dependence. In mice, tianeptine produced dose-dependent, naltrexone-preventable locomotor activation. Tianeptine (100 mg/kg, SC) also significantly inhibited gastrointestinal motility and produced naloxone-reversible respiratory depression.
CONCLUSIONS
Tianeptine presents as a MOR agonist with resistance to tolerance and dependence in our ICSS assay in rats, and it has lower abuse potential by this metric than many commonly abused opioids. Nonetheless, tianeptine produces MOR agonist-like acute adverse effects that include motor impairment, constipation, and respiratory depression.
Topics: Analgesics, Opioid; Animals; Male; Mice; Mice, Inbred ICR; Naltrexone; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Self Stimulation; Thiazepines
PubMed: 35211768
DOI: 10.1007/s00213-022-06093-w -
Mathematical Biosciences and... Jun 2023We study a switching heroin epidemic model in this paper, in which the switching of supply of heroin occurs due to the flowering period and fruiting period of opium...
We study a switching heroin epidemic model in this paper, in which the switching of supply of heroin occurs due to the flowering period and fruiting period of opium poppy plants. Precisely, we give three equations to represent the dynamics of the susceptible, the dynamics of the untreated drug addicts and the dynamics of the drug addicts under treatment, respectively, within a local population, and the coefficients of each equation are functions of Markov chains taking values in a finite state space. The first concern is to prove the existence and uniqueness of a global positive solution to the switching model. Then, the survival dynamics including the extinction and persistence of the untreated drug addicts under some moderate conditions are derived. The corresponding numerical simulations reveal that the densities of sample paths depend on regime switching, and larger intensities of the white noises yield earlier times for extinction of the untreated drug addicts. Especially, when the switching model degenerates to the constant model, we show the existence of the positive equilibrium point under moderate conditions, and we give the expression of the probability density function around the positive equilibrium point.
Topics: Heroin; Markov Chains; Likelihood Functions; Time; Survival Analysis
PubMed: 37501486
DOI: 10.3934/mbe.2023590 -
Drug and Alcohol Review Jul 2022In early 2020, many services modified their delivery of opioid treatment in response to the COVID-19 pandemic, to limit viral spread and maintain treatment continuity....
INTRODUCTION
In early 2020, many services modified their delivery of opioid treatment in response to the COVID-19 pandemic, to limit viral spread and maintain treatment continuity. We describe the changes to treatment and preliminary analysis of the association with patients' substance use and well-being.
METHODS
A pre-post comparison of treatment conditions and patient self-reported outcomes using data extracted from electronic medical records in the 5 months before (December 2019-April 2020) and after (May 2020-September 2020) changes were implemented in three public treatment services in South Eastern Sydney Local Health District.
RESULTS
Data are available for 429/460 (93%) patients. Few (21, 5%) dropped out of treatment. In the 'post' period there was significantly more use of depot buprenorphine (12-24%), access to any take-away doses (TAD; 24-69%), access to ≥6 TAD per week (7-31%), pharmacy dosing (24-52%) and telehealth services. There were significant reductions in average opioid and benzodiazepine use, increases in cannabis use, with limited group changes in social conditions, or quality of life, psychological and physical health. At an individual level, 22% of patients reported increases in their use of either alcohol, opioids, benzodiazepines or stimulants of ≥4 days in the past 4 weeks. Regression analysis indicates increases in substance use were associated with higher levels of supervised dosing.
DISCUSSION AND CONCLUSIONS
These preliminary findings suggest that the modified model of care continued to provide safe and effective treatment, during the pandemic. Notably, there was no association between more TAD and significant increases in substance use. Limitations are discussed and further evaluation is needed.
Topics: Analgesics, Opioid; Australia; Benzodiazepines; Buprenorphine; COVID-19; Humans; Opiate Substitution Treatment; Opioid-Related Disorders; Pandemics; Quality of Life
PubMed: 34520592
DOI: 10.1111/dar.13382 -
The American Journal of Drug and... Jan 2023Accurate drug use identification through subjective self-report and toxicological biosample (hair) analysis are necessary to determine substance use sequelae in youth....
Accurate drug use identification through subjective self-report and toxicological biosample (hair) analysis are necessary to determine substance use sequelae in youth. Yet consistency between self-reported substance use and robust, toxicological analysis in a large sample of youth is understudied. We aim to assess concordance between self-reported substance use and hair toxicological analysis in community-based adolescents. Hair results by LC-MS/MS and GC-MS/MS and self-reported past-year substance use from an Adolescent Brain Cognitive Development (ABCD) Study subsample ( = 1,390; ages 9-13; 48% female) were compared. The participants were selected for hair selection through two methods: high scores on a substance risk algorithm selected 93%; 7% were low-risk, randomly selected participants. Kappa coefficients the examined concordance between self-report and hair results. 10% of youth self-reported any past-year substance use (e.g. alcohol, cannabis, nicotine, and opiates), while a mostly non-overlapping 10% had hair results indicating recent substance use (cannabis, alcohol, non-prescription amphetamines, cocaine, nicotine, opiates, and fentanyl). In randomly selected low-risk cases, 7% were confirmed positive in hair. Combining methods, 19% of the sample self-reported substance use and/or had a positive hair sample. Kappa coefficient of concordance between self-report and hair results was low (kappa = 0.07; = .007). Hair toxicology identified substance use in high-risk and low-risk ABCD cohort subsamples. Given low concordance between hair results and self-report, reliance on either method alone would incorrectly categorize 9% as non-users. Multiple methods for characterizing substance use history in youth improves accuracy. Larger representative samples are needed to assess the prevalence of substance use in youth.
Topics: Humans; Adolescent; Female; Child; Male; Self Report; Hair Analysis; Nicotine; Tandem Mass Spectrometry; Chromatography, Liquid; Substance Abuse Detection; Substance-Related Disorders; Opiate Alkaloids
PubMed: 36812240
DOI: 10.1080/00952990.2023.2164931 -
Pain Physician Oct 2022Pelvic floor dysfunction and its associated symptoms are a common clinical challenge in the cancer population. Despite the noninvasive nature of pelvic floor...
BACKGROUND
Pelvic floor dysfunction and its associated symptoms are a common clinical challenge in the cancer population. Despite the noninvasive nature of pelvic floor rehabilitation (PFR) for this condition and the promising clinical results observed with its use, PFR appears to be an underused therapy.
OBJECTIVES
The purpose of this study was to quantify the association between physical therapy of the pelvic floor and its effect on pain relief and the associated symptoms in cancer patients with pelvic floor dysfunction.
STUDY DESIGN
Retrospective cohort study.
METHODS
With the use of an electronic database in our pain medicine department, we retrospectively quantified the pain relief and symptom improvement in patients diagnosed as having chronic pelvic floor dysfunction who had undergone PFR.
RESULTS
Of the 68 patients available for analysis, 49 met the inclusion criteria. Baseline characteristics of included patients were generally similar. The duration of pelvic pain before PFR was 53.7 months (mean) (SD, 182.5 months; median, 12 months). Of the 49 study patients, 23 (47%) had bladder dysfunction, 24 (49%) had dyspareunia, 2 (4%) had erectile dysfunction, and one (2%) had rectal dysfunction. Most symptoms associated with pelvic floor dysfunction resolved after PFR.
LIMITATIONS
Single-center, small data, retrospective study.
CONCLUSIONS
PFR is an effective tool for treating the pain associated with pelvic floor dysfunction and its related symptoms. This conservative approach can contribute to lowering the use of opiate analgesics.
Topics: Male; Female; Humans; Pelvic Floor; Retrospective Studies; Pelvic Pain; Cohort Studies; Neoplasms; Opiate Alkaloids
PubMed: 36288598
DOI: No ID Found -
Drug Delivery and Translational Research Feb 2022Naloxone and nalmefene were administered to seven research beagle dogs (mean weight approximately 12 kg) at doses of 0.04 mg/kg and 0.014 mg/kg for naloxone and... (Clinical Trial)
Clinical Trial
Naloxone and nalmefene were administered to seven research beagle dogs (mean weight approximately 12 kg) at doses of 0.04 mg/kg and 0.014 mg/kg for naloxone and nalmefene, respectively. Each dose was administered intramuscularly (IM) with a standard IM injection and with a hollow microneedle device array using needles of 1 mm in length. The IM injection was delivered in the epaxial muscles, and the microneedle injection was delivered in the skin over the shoulder of each dog. Each dog received the same injections in a crossover design. Following the injection, blood samples were collected for plasma analysis of naloxone and nalmefene by high-pressure liquid chromatography with mass spectrometry detection (LCMS). The plasma sample concentrations were plotted for observed patterns of absorption and analyzed with non-compartmental pharmacokinetic methods (NCA). The results showed that the injection of naloxone from the microneedle device produced a higher peak concentration (C) by 2.15 × compared the IM injection of the same dose, and time to peak concentration (T) was similar. For the nalmefene injection, the peak was not as high (lower C) by 0.94 × for the microneedle injection compared to the IM injection of the same dose. The microneedle produced an exposure, measured by area under the curve (AUC), that was 0.85 × and 0.58 × as high for naloxone and nalmefene, respectively, than the injection by the IM route. We also observed that although the dose for naloxone was approximately 3 × higher for naloxone compared to nalmefene, the mean peak concentration achieved from the naloxone injection was more than 12 × higher than that from the nalmefene injection. These studies were designed to test the feasibility of using the hollow microneedle array as an effective method of naloxone and nalmefene delivery for emergency treatment of opioid-induced respiratory depression (OIRD). The results of these studies will form the basis of future studies, using the dog as a model, for development of hollow microneedle microarray devices to deliver opioid antagonists for treatment of OIRD in people.
Topics: Analgesics, Opioid; Animals; Cross-Over Studies; Dogs; Humans; Injections, Intramuscular; Naloxone; Naltrexone; Narcotic Antagonists
PubMed: 34817831
DOI: 10.1007/s13346-021-01096-0