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PloS One 2015Morphinan alkaloids are the most powerful narcotic analgesics currently used to treat moderate to severe and chronic pain. The feasibility of morphinan synthesis in...
Morphinan alkaloids are the most powerful narcotic analgesics currently used to treat moderate to severe and chronic pain. The feasibility of morphinan synthesis in recombinant Saccharomyces cerevisiae starting from the precursor (R,S)-norlaudanosoline was investigated. Chiral analysis of the reticuline produced by the expression of opium poppy methyltransferases showed strict enantioselectivity for (S)-reticuline starting from (R,S)-norlaudanosoline. In addition, the P. somniferum enzymes salutaridine synthase (PsSAS), salutaridine reductase (PsSAR) and salutaridinol acetyltransferase (PsSAT) were functionally co-expressed in S. cerevisiae and optimization of the pH conditions allowed for productive spontaneous rearrangement of salutaridinol-7-O-acetate and synthesis of thebaine from (R)-reticuline. Finally, we reconstituted a 7-gene pathway for the production of codeine and morphine from (R)-reticuline. Yeast cell feeding assays using (R)-reticuline, salutaridine or codeine as substrates showed that all enzymes were functionally co-expressed in yeast and that activity of salutaridine reductase and codeine-O-demethylase likely limit flux to morphine synthesis. The results of this study describe a significant advance for the synthesis of morphinans in S. cerevisiae and pave the way for their complete synthesis in recombinant microbes.
Topics: Chromatography, High Pressure Liquid; Fourier Analysis; Mass Spectrometry; Morphinans; Saccharomyces cerevisiae; Stereoisomerism
PubMed: 25905794
DOI: 10.1371/journal.pone.0124459 -
Addiction (Abingdon, England) May 2017To test whether an incentive-based intervention that increased adherence to naltrexone also increased opiate abstinence.
AIM
To test whether an incentive-based intervention that increased adherence to naltrexone also increased opiate abstinence.
DESIGN
Post-hoc combined analysis of three earlier randomized controlled trials that showed individually that incentives for adherence to oral and to extended-release injection naltrexone dosing schedules increased naltrexone adherence, but not opiate abstinence.
SETTING
Out-patient therapeutic work-place in Baltimore, MD, USA.
PARTICIPANTS
One hundred and forty unemployed heroin-dependent adults participating from 2006 to 2010.
INTERVENTIONS
Participants were hired in a model work-place for 26 weeks and randomized to a contingency (n = 72) or prescription (n = 68) group. Both groups were offered naltrexone. Contingency participants were required to take scheduled doses of naltrexone in order to work and earn wages. Prescription participants could earn wages independent of naltrexone adherence.
MEASURES
Thrice-weekly and monthly urine samples tested for opiates and cocaine and measures of naltrexone adherence (percentage of monthly urine samples positive for naltrexone or percentage of scheduled injections received). All analyses included pre-randomization attendance, opiate use and cocaine use as covariates. Additional analyses controlled for cocaine use and naltrexone adherence during the intervention.
FINDINGS
Contingency participants had more opiate abstinence than prescription participants (68.1 versus 52.9% opiate-negative thrice-weekly urine samples, respectively; and 71.9 versus 61.7% opiate-negative monthly urine samples, respectively) based on initial analyses [thrice-weekly samples, odds ratio (OR) = 3.3, 95% confidence interval (CI) = 1.7-6.5, P < 0.01; monthly samples, OR = 2.6, 95% CI = 1.0-7.1, P = 0.06] and on analyses that controlled for cocaine use (thrice-weekly samples, OR = 3.9, 95% CI = 3.3-4.5, P < 0.01; monthly samples, OR = 3.4, 95% CI = 1.1-11.1, P = 0.04), which was high and associated with opiate use. The difference in opiate abstinence rates between contingency and prescription participants was reduced when controlling for naltrexone adherence (monthly samples, OR = 1.1, 95% CI = 0.7-1.7, P = 0.84).
CONCLUSIONS
Incentives for naltrexone adherence increase opiate abstinence in heroin-dependent adults, an effect that appears to be due to increased naltrexone adherence produced by the incentives.
Topics: Adult; Ambulatory Care; Employment, Supported; Female; Heroin Dependence; Humans; Male; Medication Adherence; Middle Aged; Motivation; Naltrexone; Narcotic Antagonists; Randomized Controlled Trials as Topic
PubMed: 27936293
DOI: 10.1111/add.13724 -
The American Journal of Drug and... Sep 2011Clinical parameters for determining buprenorphine dose have not been adequately examined in treatment outcome research. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Clinical parameters for determining buprenorphine dose have not been adequately examined in treatment outcome research.
OBJECTIVES
This study is a secondary analysis of data collected in a recently completed comparison of buprenorphine taper schedules conducted as part of the National Institute on Drug Abuse's Clinical Trials Network to assess whether participant baseline characteristics are associated with buprenorphine dose.
METHODS
After 3 weeks of flexible dosing, 516 participants were categorized by dose provided in the final dosing week (9.3% received a final week dose of 8 mg buprenorphine, 27.3% received 16 mg, and 63.4% received 24 mg).
RESULTS
Findings show that final week dose groups differed in baseline demographic and drug use characteristics including education, heroin use, route of drug administration, withdrawal symptoms, and craving. These groups also differed in opioid use during the four dosing weeks, with the lowest use in the 8 mg group and highest use in the 24 mg group (p < .0001). Additional analyses address withdrawal symptoms and craving.
CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE
Final week dose groups differed in demographic and drug use characteristics, and the group receiving the largest final week dose had the highest rate of continued opioid use. These findings may contribute to the development of clinical guidelines regarding buprenorphine dose in the treatment of opioid dependence; however, further investigations that include random assignment to dose by baseline characteristics are needed.
Topics: Adult; Analgesics, Opioid; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heroin Dependence; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; National Institute on Drug Abuse (U.S.); Opiate Substitution Treatment; Opioid-Related Disorders; United States
PubMed: 21854290
DOI: 10.3109/00952990.2011.596974 -
The International Journal on Drug Policy Dec 2021The Ottawa Inner City Health's Managed Opioid Program is the first, to our knowledge, to pair injectable opioid agonist hydromorphone treatment with assisted housing for...
BACKGROUND
The Ottawa Inner City Health's Managed Opioid Program is the first, to our knowledge, to pair injectable opioid agonist hydromorphone treatment with assisted housing for people experiencing homelessness with severe opioid use disorder (OUD) and injection drug use. We aimed to describe this program and evaluate retention, health, and social wellbeing outcomes.
METHODS
We retrospectively assessed the first cohort of clients enrolled in the Managed Opioid Program between August 2017-2018. The primary outcome was retention at 12 months. Secondary outcomes included injectable and oral opioid dose titration, non-prescribed opioid use, overdoses, connection with behavioural health services, and social well-being. Descriptive statistics were used to summarize baseline demographics and secondary outcomes. Actuarial survival analysis was used to assess retention among participants.
RESULTS
The study sample included 26 participants: median age was 36 years, 14 were female, 22 were White, eight had alcohol use disorders, 25 had stimulant use disorders, and all had a history of concurrent psychiatric illness. Retention at 12 months was 77% (95% CI 62-95). Throughout the first-year participants' opioid treatment doses increased. The median daily dose of injectable hydromorphone was 36 mg [17-54 mg] and 156 mg [108-188 mg] at enrollment and one year respectively. The median daily dose of oral opioid treatment was 120-milligram morphine equivalents [83-180 mg morphine equivalents] and 330-milligram morphine equivalents [285-428 mg morphine equivalents] at enrollment and one year respectively. Over half had no overdoses and there were no deaths among participants who remained enrolled. At one year, 45% stopped non-prescribed opioid use, 96% connected to behavioral health services, 73% reconnected with estranged families, and 31% started work or vocational programs.
CONCLUSION
Individuals with severe OUD engaged in injectable hydromorphone treatment and housing showed high retention in care and substantive improvements in patient-centered health and social well-being outcomes.
Topics: Adult; Alcoholism; Analgesics, Opioid; Canada; Female; Heroin; Housing; Humans; Hydromorphone; Opioid-Related Disorders; Retrospective Studies
PubMed: 34469781
DOI: 10.1016/j.drugpo.2021.103400 -
BMJ Open Sep 2020Despite a recent meta-analysis including 31 randomised controlled trials comparing methadone and buprenorphine for the treatment of opioid use disorder, important...
Comparative effectiveness of buprenorphine-naloxone versus methadone for treatment of opioid use disorder: a population-based observational study protocol in British Columbia, Canada.
INTRODUCTION
Despite a recent meta-analysis including 31 randomised controlled trials comparing methadone and buprenorphine for the treatment of opioid use disorder, important knowledge gaps remain regarding the long-term effectiveness of different treatment modalities across individuals, including rigorously collected data on retention rates and other treatment outcomes. Evidence from real-world data represents a valuable opportunity to improve personalised treatment and patient-centred guidelines for vulnerable populations and inform strategies to reduce opioid-related mortality. Our objective is to determine the comparative effectiveness of methadone versus buprenorphine/naloxone, both overall and within key populations, in a setting where both medications are simultaneously available in office-based practices and specialised clinics.
METHODS AND ANALYSIS
We propose a retrospective cohort study of all adults living in British Columbia receiving opioid agonist treatment (OAT) with methadone or buprenorphine/naloxone between 1 January 2008 and 30 September 2018. The study will draw on seven linked population-level administrative databases. The primary outcomes include retention in OAT and all-cause mortality. We will determine the effectiveness of buprenorphine/naloxone vs methadone using intention-to-treat and per-protocol analyses-the former emulating flexible-dose trials and the latter focusing on the comparison of the two medication regimens offered at the optimal dose. Sensitivity analyses will be used to assess the robustness of results to heterogeneity in the patient population and threats to internal validity.
ETHICS AND DISSEMINATION
The protocol, cohort creation and analysis plan have been approved and classified as a quality improvement initiative exempt from ethical review (Providence Health Care Research Institute and the Simon Fraser University Office of Research Ethics). Dissemination is planned via conferences and publications, and through direct engagement and collaboration with entities that issue clinical guidelines, such as professional medical societies and public health organisations.
Topics: Adult; Analgesics, Opioid; British Columbia; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Humans; Methadone; Observational Studies as Topic; Opiate Substitution Treatment; Opioid-Related Disorders; Retrospective Studies
PubMed: 32912944
DOI: 10.1136/bmjopen-2019-036102 -
Journal of Pharmaceutical and... Sep 2022Sedative use can result in adverse drug reactions. Intensive care unit patients are especially at risk and pharmacokinetic modeling of drug concentrations is an approach...
Sedative use can result in adverse drug reactions. Intensive care unit patients are especially at risk and pharmacokinetic modeling of drug concentrations is an approach to develop precision dosing strategies. However, limited blood sampling availability in critically ill children and need for multiple assays to quantify a variety of commonly used sedatives creates logistical challenges. The goal of this project was to develop a sensitive and selective assay for the simultaneous quantification of a panel of sedatives comprised of midazolam (MDZ), alpha hydroxymidazolam (1- OH MDZ), dexmedetomidine (DEX), morphine (MOR), morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), fentanyl (FEN), norfentanyl (NF), and hydromorphone (HM) in small volume pediatric plasma samples. A sensitive and efficient ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed following FDA guidance for bioanalytical validation. Minimal sample preparation consisting of simple protein precipitation extraction using acetonitrile with internal standards was utilized. Analyte separation was achieved using a gradient mixture of (A: 0.15% formic acid in water and B: Acetonitrile) and a Waters Acquity C18, 1.7 µm (2.1 × 100 mm) column. Assays were linear over the clinical concentration ranges: MDZ, MOR, HM: 0.5-125 ng/mL; 1-OH MDZ, M3G, M6G: 5-500 ng/mL; and DEX, FEN, NF: 0.05-7.5 ng/mL (R > 0.99 for all). Assay run time was 10 min and required only 100 μL of plasma. Initial testing of samples from pediatric patients demonstrates adequacy of assay to measure sedatives and metabolites at clinical concentrations confidently in low volumes of plasma. This novel highly-sensitive and specific method to measure a total of nine different analytes (five sedatives, four metabolites) simultaneously enables comprehensive analysis of a panel of sedatives in small volumes such as in pediatric ICU patients.
Topics: Acetonitriles; Child; Chromatography, High Pressure Liquid; Chromatography, Liquid; Critical Illness; Humans; Hypnotics and Sedatives; Morphine; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 35659658
DOI: 10.1016/j.jpba.2022.114853 -
JAMA Network Open May 2022Despite prevalent polysubstance use, treatment patterns and outcomes for individuals with opioid use disorder (OUD) and cooccurring substance use disorders (SUD) are... (Observational Study)
Observational Study
IMPORTANCE
Despite prevalent polysubstance use, treatment patterns and outcomes for individuals with opioid use disorder (OUD) and cooccurring substance use disorders (SUD) are understudied.
OBJECTIVE
To evaluate the distribution of buprenorphine and naltrexone initiation among individuals with OUD with vs without cooccurring SUD and to assess the comparative effectiveness associated with buprenorphine and naltrexone against drug-related poisonings.
DESIGN, SETTING, AND PARTICIPANTS
This observational comparative effectiveness study used insurance claims from 2011 to 2016 from the US IBM MarketScan databases to study initiation of medications for OUD (MOUD) among treatment-seeking individuals aged 12 to 64 years with a primary diagnosis of OUD. Cooccurring SUD was defined as SUD diagnosed concurrent with or in the 6 months prior to OUD treatment initiation. Treatment was codified as psychosocial treatment without MOUD or initiation or buprenorphine or naltrexone (including extended-release or oral). Methadone recipients were excluded from analysis. Data were analyzed from February 3, 2021, through February 26, 2022.
EXPOSURES
MOUD.
MAIN OUTCOMES AND MEASURES
Associations between cooccurring SUD diagnoses with treatment type were assessed with multivariable regression. The association of drug-related poisoning admissions with days covered with buprenorphine or naltrexone prescriptions vs days without prescriptions was assessed among MOUD initiators. Odds ratios from within-person fixed effects models were estimated as a function of MOUD and stratified by cooccurring SUDs.
RESULTS
Among 179 280 individuals with OUD (mean [SD] age, 33.2 [11.0] years; 90 196 [50.5%] men), 102 930 (57.4%) received psychosocial treatment without MOUD. Across 47 488 individuals with cooccurring SUDs, 33 449 (70.4%) did not receive MOUD, whereas across 131 792 individuals without cooccurring SUDs, 69 481 (52.7%) did not receive MOUD. Cooccurring SUD was associated with decreased odds of initiating buprenorphine (risk ratio [RR], 0.55 [95% CI, 0.54-0.56]) but increased odds of initiating naltrexone (extended release: RR, 1.12 [95% CI, 1.05-1.20]; oral: RR, 1.95 [95% CI, 1.86-2.03]). Among 12 485 individuals initiating MOUD who experienced at least 1 drug-related poisoning during insurance enrollment, buprenorphine treatment days were associated with decreased poisonings compared with days without MOUD for individuals with cooccurring SUD (odds ratio [OR], 0.56 [95% CI, 0.48-0.65]) and individuals without cooccurring SUD (OR, 0.57 [95% CI, 0.53-0.63]), with comparable associations observed for extended-release naltrexone. No protective association was observed for oral naltrexone.
CONCLUSIONS AND RELEVANCE
These findings suggest that individuals with OUD and polysubstance use were less likely to initiate buprenorphine and naltrexone than individuals without polysubstance use. Among individuals initiating MOUD, polysubstance use was associated with decreased buprenorphine and increased naltrexone initiation, despite buprenorphine's protective associations against drug-related poisoning.
Topics: Adult; Analgesics, Opioid; Buprenorphine; Female; Humans; Male; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders
PubMed: 35536575
DOI: 10.1001/jamanetworkopen.2022.11363 -
Journal of Pharmaceutical and... Feb 2013Degradation of heroin to 6-monoacetylmorphine (6-MAM) and then morphine happens rapidly in vivo and in vitro. The rates of heroin and 6-MAM degradation depend on the...
Degradation of heroin to 6-monoacetylmorphine (6-MAM) and then morphine happens rapidly in vivo and in vitro. The rates of heroin and 6-MAM degradation depend on the type of biological samples, and the duration and conditions of storage. In order to optimize conditions for measuring heroin and its metabolites in samples collected for pharmacokinetic studies in rats, we investigated the time course of degradation of heroin, 6-MAM, and morphine in four biological matrices: rat blood, rat brain homogenate, bovine serum, and human plasma under various conditions. Analyte concentrations were measured by LC-MS. The goal was to identify conditions that allow maximum flexibility in scheduling sample collection and analysis, as well as gain more information on the stability of heroin in blood and tissue samples. A solid-phase extraction method with ice-cold solvents, sodium fluoride (NaF) and a low pH (3.0) maintained sample stability. Quality controls were within 94.0-105% of the target value. Variability was 4.0-8.9% for all analytes within the range of 5-200 ng/mL for heroin, 5-1000 ng/mL for 6-MAM, and 10-200 ng/mL for morphine. Heroin degradation to 6-MAM was faster in rat whole blood than in plasma, and faster in rat plasma than in rat brain homogenate. Maintaining NaF at 4 mg/mL throughout processing enhanced stability; higher NaF concentrations added to whole blood caused hemolysis. Samples processed through solid phase extraction and stored as dried pellets at 80°C constituted the most stable environment for heroin, and was superior to the storing of samples in solution prior to or after extraction. Nevertheless, post-extraction heroin and 6-MAM levels declined by 6.7-8.3% over one week in rat plasma under these conditions, and by <1-4.7% in bovine serum or human plasma.
Topics: Animals; Cattle; Chromatography, Liquid; Drug Stability; Heroin; Humans; Male; Mass Spectrometry; Morphine; Morphine Derivatives; Rats; Rats, Sprague-Dawley; Time Factors
PubMed: 23245263
DOI: 10.1016/j.jpba.2012.10.033 -
Updates in Surgery Jan 2024There is an increase in outpatient procedures and this trend will continue in the future. For hemorrhoidectomy, it is the standard of treatment in many health care...
There is an increase in outpatient procedures and this trend will continue in the future. For hemorrhoidectomy, it is the standard of treatment in many health care systems. Perioperative management including adequate pain control is of paramount importance to ensure successful ambulatory surgery. This study investigates the role and effect of morphine compared to short-acting opiates applied before, during, or after proctological interventions and with focus on hemorrhoidectomy. A retrospective analysis of a prospective database was conducted comparing two populations. The control cohort received morphine (Yes-Mô) intra- and postoperatively, while the intervention group did not receive morphine (No-Mô) between January 2018 and January 2020. Both cohorts were balanced by propensity score matching. The outcomes were postoperative pain measured by numeric ratings scale (NRS) one hour postoperatively, pain 24 h postoperatively, success rate of outpatient management, and complication rate including postoperative nausea and vomiting as well as urinary retention. The intervention population comprised 54 patients and the control group contained 79 patients. One hour after surgery, patients in No-Mô reported lower NRS (1.44 ± 1.41) compared to Yes-Mô (2.48 ± 2.30) (p = 0.029). However, there was no difference in NRS 24 h postoperatively (No-Mô: 1.61 ± 1.41 vs Yes-Mô: 1.63 ± 1.72; p = 0.738). 100% of No-Mô was managed as outpatients while only 50% of Yes-Mô was dismissed on the day of the operation (p = < 0.001). There was no difference in postoperative complications (including postoperative nausea and vomiting (PONV) and urinary retention) between the two groups (PONV No-Mô 7.4% vs Yes-Mô 5.6%, p = 1.0 and urinary retention No-Mô 3.7% vs Yes-Mô 7.4%, p = 0.679). No-Mô received an oral morphine equivalent of 227.25 ± 140.35 mg intraoperatively and 11.02 ± 18.02 mg postoperatively. Yes-Mô received 263.17 ± 153.60 mg intraoperatively and 15.97 ± 14.17 mg postoperatively. The difference in received morphine equivalent between the groups was not significant after matching for the intraoperative (p = 0.212) and postoperative (p = 0.119) received equivalent. Omission of perioperative morphine is a viable but yet not understood method for reducing postoperative pain. Omission of morphine leads to a lower use of total morphine equivalent to attain satisfactory analgesia. The reduction of the overall opiate load and using opiates with a very short half-life potentially leads to a reduction of side effects like sedation. This in turn promotes discharge of the patient on the day of surgery. Omission of morphine is safe and does not increase postoperative complications.
Topics: Humans; Morphine; Postoperative Nausea and Vomiting; Retrospective Studies; Urinary Retention; Pain, Postoperative
PubMed: 37668891
DOI: 10.1007/s13304-023-01640-2 -
Pain Sep 2014The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side...
The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (eg, tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication-related side effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ(9)-THC, produced dose-related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.
Topics: Analgesics, Opioid; Animals; Conditioning, Operant; Hot Temperature; Male; Morphine; Naltrexone; Nociception; Pain; Pain Measurement; Pain Threshold; Saimiri
PubMed: 24968803
DOI: 10.1016/j.pain.2014.06.010