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Stem Cell Research Dec 2020Prenatal opioids exposure can lead to both neonatal abstinence syndrome in newborns and neurological deficits later in life. Although opioids have been well studied in...
Prenatal opioids exposure can lead to both neonatal abstinence syndrome in newborns and neurological deficits later in life. Although opioids have been well studied in general, the cellular and molecular mechanisms by which opioids affect human fetal brain development has not been well understood. In this work, we have taken advantage of a human 3D-brain cortical organoid (hCO) that facilitated enormously the investigation of early human brain development. Using imaging, immunofluorescence, multi-electrode array (MEA) and patch clamp recording techniques, we have investigated the effect of methadone, a frequently used opioid during pregnancy, on early neural development, including neuronal growth, neural network activity and synaptic transmission in hCOs. Our results demonstrated that methadone dose-dependently halted the growth of hCOs and induced organoid disintegration after a prolonged exposure. In addition, methadone dose-dependently suppressed the firing of spontaneous action potentials in hCOs and this suppression could be reversed upon methadone withdrawal in hCOs treated with lower dosages. Further investigation using patch clamp whole cell configuration revealed that, at clinically relevant concentrations, methadone decreased the frequency and amplitude of excitatory postsynaptic currents in neurons, indicating a critical role of methadone in weakening synaptic transmission in neural networks in hCOs. In addition, methadone significantly attenuated the voltage-dependent Na current in hCOs. We conclude that methadone interrupts neural growth and function in early brain development.
Topics: Action Potentials; Female; Humans; Infant, Newborn; Methadone; Organoids; Patch-Clamp Techniques; Pregnancy; Synaptic Transmission
PubMed: 33137567
DOI: 10.1016/j.scr.2020.102065 -
American Journal of Veterinary Research Jun 2022To assess the pharmacokinetics, clinical efficacy, and adverse effects of injectable methadone with the pharmacokinetic enhancer fluconazole (methadone-fluconazole),...
Long-acting injectable methadone (methadone-fluconazole) provides safe and effective postoperative analgesia in a randomized clinical trial for dogs undergoing soft tissue surgery.
OBJECTIVE
To assess the pharmacokinetics, clinical efficacy, and adverse effects of injectable methadone with the pharmacokinetic enhancer fluconazole (methadone-fluconazole), compared with the standard formulation of injectable methadone, in dogs after ovariohysterectomy. We hypothesized that 2 doses of methadone-fluconazole would provide 24 hours of postoperative analgesia.
ANIMALS
3 purpose-bred dogs (pharmacokinetic preliminary study) and 42 female dogs from local shelters (clinical trial) were included.
PROCEDURES
Pharmacokinetics were preliminarily determined. Clinical trial client-owned dogs were blocked by body weight into treatment groups: standard methadone group (methadone standard formulation, 0.5 mg/kg, SC, q 4 h; n = 20) or methadone-fluconazole group (0.5 mg/kg methadone with 2.5 mg/kg fluconazole, SC, repeated once at 6 h; n = 22). All dogs also received acepromazine, propofol, and isoflurane. Surgeries were performed by experienced surgeons, and dogs were monitored perioperatively using the Glasgow Composite Measure Pain Scale-Short Form (CMPS-SF) and sedation scales. Evaluators were masked to treatment.
RESULTS
Findings from pharmacokinetic preliminary studies supported that 2 doses of methadone-fluconazole provide 24 hours of drug exposure. The clinical trial had no significant differences in treatment failures or postoperative CMPS-SF scores between treatments. One dog (methadone-fluconazole group) had CMPS-SF > 6 and received rescue analgesia. All dogs had moderate sedation or less by 1 hour (methadone-fluconazole group) or 4 hours (standard methadone group) postoperatively. Sedation was completely resolved in all dogs the day after surgery.
CLINICAL RELEVANCE
Methadone-fluconazole with twice-daily administration was well tolerated and provided effective postoperative analgesia for dogs undergoing ovariohysterectomy. Clinical compliance and postoperative pain control may improve with an effective twice-daily formulation.
Topics: Analgesia; Analgesics, Opioid; Animals; Dog Diseases; Dogs; Female; Fluconazole; Hysterectomy; Methadone; Ovariectomy; Pain, Postoperative
PubMed: 35895789
DOI: 10.2460/ajvr.22.01.0014 -
Postgraduate Medical Journal Nov 2004This article reviews the unique pharmacological properties of methadone and outlines its appropriate clinical application, with focus upon its use in the treatment of... (Review)
Review
This article reviews the unique pharmacological properties of methadone and outlines its appropriate clinical application, with focus upon its use in the treatment of chronic pain. Although methadone is most widely known for its use in the treatment of opioid dependence, methadone also provides effective analgesia. Patients who experience inadequate pain relief or intolerable side effects with other opioids or who suffer from neuropathic pain may benefit from a transition to methadone as their analgesic agent. Adverse effects, particularly respiratory depression and death, make a fundamental knowledge of methadone's pharmacological properties essential to the provider considering methadone as analgesic therapy for a patient with chronic pain.
Topics: Analgesics, Opioid; Chronic Disease; Humans; Methadone; Opioid-Related Disorders; Pain
PubMed: 15537850
DOI: 10.1136/pgmj.2004.022988 -
The Canadian Veterinary Journal = La... Nov 2023Opioid analgesics are routinely used during the perioperative period, to provide analgesia and reduce anesthetics doses required to maintain a surgical plane of... (Review)
Review
Opioid analgesics are routinely used during the perioperative period, to provide analgesia and reduce anesthetics doses required to maintain a surgical plane of anesthesia in companion animals. Acting on receptors in the brain, spinal cord, and peripheral nervous system, opioids provide reliable and consistent analgesia; however, they are not without adverse effects. Methadone, a mu agonist opioid analgesic, was recently licensed for veterinary use in Canada. In addition to its action on opioid receptors, methadone contributes to analgesia through other pathways, including inhibition of N-methyl-D-aspartate (NMDA) receptors. It has physiologic effects similar to other mu opioid agents, but fewer adverse gastrointestinal effects. This review discusses methadone's mechanism of action, pharmacologic characteristics, and clinical effects in dogs and cats. Current recommendations for using methadone in companion animals are also provided.
Topics: Animals; Cats; Dogs; Methadone; Pets; Cat Diseases; Dog Diseases; Analgesics, Opioid; Anesthesia; Pain
PubMed: 37915778
DOI: No ID Found -
Molecules (Basel, Switzerland) Nov 2022(1) Background: Methadone, along with buprenorphine, is the most commonly used drug for the treatment of opioid dependence. This study aimed to analyze methadone and its...
(1) Background: Methadone, along with buprenorphine, is the most commonly used drug for the treatment of opioid dependence. This study aimed to analyze methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenyl pyrrolidine (EDDP), in the urine and plasma of opiate addicts. The study group consisted of drug users voluntarily admitted to the detoxification center C.E.T.T.T. "St. Stelian" of Bucharest. Secondly, the study aimed to identify whether urine or plasma provides better results for the proposed method. (2) Methods: A GC-MS method, using an internal standard (diphenylamine) in the FULL-SCAN and SIM modes of operation and using the m/z = 72 ion for methadone and the m/z = 277 ion for EDDP, combined with a liquid-liquid extraction procedure was performed. (3) Results: The applied procedure allows the detection and quantification of methadone in both urine and plasma samples. EDDP was identified in patients with higher levels of methadone. Higher levels of methadone were detected in urine than in plasma samples. (4) Conclusions: This procedure can be used in clinical laboratories for the rapid determination of methadone levels in urine rather than in plasma. The procedure can be applied for the monitoring of methadone substitution treatment.
Topics: Humans; Methadone; Gas Chromatography-Mass Spectrometry; Buprenorphine; Opioid-Related Disorders; Pyrrolidines
PubMed: 36500452
DOI: 10.3390/molecules27238360 -
The American Journal of Psychiatry Sep 2021The authors conducted a scoping review to survey the evidence landscape for studies that assessed outcomes of treating patients with opioid use disorder with methadone...
OBJECTIVE
The authors conducted a scoping review to survey the evidence landscape for studies that assessed outcomes of treating patients with opioid use disorder with methadone in office-based settings.
METHODS
Ovid MEDLINE and the Cochrane Database of Systematic Reviews were searched, and reference lists were reviewed to identify additional studies. Studies were eligible if they focused on methadone treatment in office-based settings conducted in the United States or other highly developed countries and reported outcomes (e.g., retention in care). Randomized trials and controlled observational studies were prioritized; uncontrolled and descriptive studies were included when stronger evidence was unavailable. One investigator abstracted key information, and a second verified data. A scoping review approach broadly surveyed the evidence, and therefore study quality was not rated formally.
RESULTS
Eighteen studies of patients treated with office-based methadone were identified, including six trials, eight observational studies, and four additional articles discussing use of pharmacies to dispense methadone. Studies on office-based methadone treatment, including primary care-based dispensing, were limited but consistently found that stable methadone patients valued office-based care and remained in care with low rates of drug use; outcomes were similar compared with stable patients in regular care. Office-based methadone treatment was associated with higher treatment satisfaction and quality of life. Limitations included underpowered comparisons and small samples.
CONCLUSIONS
Limited research suggests that office-based methadone treatment and pharmacy dispensing could enhance access to methadone treatment for patients with opioid use disorder without adversely affecting patient outcomes and, potentially, inform modifications to federal regulations. Research should assess the feasibility of office-based care for less stable patients.
Topics: Drug Prescriptions; Humans; Methadone; Narcotics; Opioid-Related Disorders; Pharmacies
PubMed: 34315284
DOI: 10.1176/appi.ajp.2021.20101548 -
Substance Abuse Treatment, Prevention,... Sep 2023The US federal regulations allow pharmacy administration and dispensing of methadone for opioid use disorder (PADMOUD) to increase the capability of opioid treatment...
BACKGROUND
The US federal regulations allow pharmacy administration and dispensing of methadone for opioid use disorder (PADMOUD) to increase the capability of opioid treatment programs (OTPs) in providing methadone maintenance treatment (MMT) for opioid use disorder (OUD) as part of a medication unit. However, there is a lack of research data from both pharmacy and OTP staff to inform the implementation of PADMOUD.
METHODS
Staff of a pharmacy (n = 8) and an OTP (n = 9) that participated in the first completed US trial on PADMOUD through electronic prescribing for methadone (parent study) were recruited to participate in this qualitative interview study to explore implementation-related factors for PADMOUD. Each interview was recorded and transcribed verbatim. NVivo was used to help identify themes of qualitative interview data. The Promoting Action on Research Implementation in Health Services (PARIHS) framework was used to guide the coding and interpretation of data.
RESULTS
Six pharmacy staff and eight OTP staff (n = 14) completed the interview. Results based on PARIHS domains were summarized, including evidence, context, and facilitation domains. Participants perceived benefits of PADMOUD for patients, pharmacies, OTPs, and payers. PADMOUD was considered to increase access for stable patients, provide additional patient service opportunities and revenues for pharmacies/pharmacists, enhance the capability of OTPs to treat more new patients, and reduce patients' cost when receiving medication at a pharmacy relative to an OTP. Both pharmacy and OTP staff were perceived to be supportive of the implementation of PADMOUD. Pharmacy staff/pharmacists were perceived to need proper training on addiction and methadone as well as a protocol of PADMOUD to conduct PADMOUD. Facilitators include having thought leaders to guide the operation, a certification program to ensure proper training of pharmacy staff/pharmacist, having updated pharmacy service software or technology to streamline the workflow of delivering PADMOUD and inventory management, and reimbursement for pharmacists.
CONCLUSION
This study presents the first findings on perspectives of PADMOUD from both staff of a community pharmacy and an OTP in the US. Finding on barriers and facilitators are useful data to guide the development of strategies to implement PADMOUD to help address the US opioid crisis.
Topics: Humans; Pharmacies; Analgesics, Opioid; Pharmacists; Methadone; Pharmacy; Pharmaceutical Services; Pharmacy Administration; Opioid-Related Disorders
PubMed: 37697326
DOI: 10.1186/s13011-023-00563-w -
Drug and Alcohol Dependence Nov 2021The loosening of U.S. methadone regulations during the COVID-19 pandemic expanded calls for methadone reform. This study examines professional perceptions of methadone...
BACKGROUND
The loosening of U.S. methadone regulations during the COVID-19 pandemic expanded calls for methadone reform. This study examines professional perceptions of methadone take-home dose regulation before and during the COVID-19 pandemic to understand responses to varied methadone distribution policies.
METHODS
Fifty-nine substance use disorder treatment professionals were interviewed between 2017 and 2020 in-person or over video call. An inductive iterative coding process was used to analyze the data. Constructivist grounded theory guided the collection and analysis of in-depth interviews.
RESULTS
Treatment professionals expressed mixed views toward methadone take-home regulations. Participants justified regulation using several arguments: 1) patient care benefitting from supervision, 2) attributing improved patient safety to take-home regulation, 3) fearing liability for methadone-related harms, and 4) relying on buprenorphine as an "escape hatch" for patients who cannot manage MMT policies. Other professionals suggested partial deregulation, while others strongly opposed pre-pandemic take-home regulation, explaining such regulations impede medication access and hinder patient-centered care. Some professionals supported the COVID-19 policy changes and saw these as a test run for broader deregulation, while others framed the changes as temporary and cautiously applied deregulation to their services, at times revoking looser rules for patients they perceived as nonadherent.
CONCLUSION
Treatment professionals working in a range of modalities, including opioid treatment programs, expressed hesitation toward expanded take-home methadone access. While some participants also supported forms of deregulation, post-pandemic efforts to extend looser methadone distribution policies will have to address apprehensive professionals if such policy changes are to be meaningfully adopted in community services.
Topics: COVID-19; Humans; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Pandemics; Perception; SARS-CoV-2
PubMed: 34600251
DOI: 10.1016/j.drugalcdep.2021.109100 -
American Family Physician Jun 2001
Topics: Drug Administration Schedule; Humans; Methadone; Narcotics; Opioid-Related Disorders
PubMed: 11430450
DOI: No ID Found -
Annals of Palliative Medicine Sep 2021Methadone maintenance treatment (MMT) is widely used for heroin use disorder. Although its curative effect is remarkable, there are problems associated with its use....
BACKGROUND
Methadone maintenance treatment (MMT) is widely used for heroin use disorder. Although its curative effect is remarkable, there are problems associated with its use. While previous studies have found that methadone use may have certain effects on cerebral white matter, its effect on gray matter (GM) and its related neural networks is unclear. This study aimed to observe the effects of long-term methadone use on cerebral GM and the changes in related neural networks.
METHODS
Patients receiving MMT treatment for heroin use disorder (N=50) were recruited. Longitudinal self-control was adopted, and the voxel-based morphometry (VBM) was used to compare the difference in cerebral GM volume before and after 1 year of methadone use, then we select the brain region where the GM volume changed as the region of interest (ROI), and use the DPARSF software for the whole brain function connection, and the differences in brain function connections before and after 1year MMT treatment were compared.
RESULTS
Our results demonstrated that, after 1 year of MMT, patients showed smaller GM volume in the bilateral insula, occipital lingual gyrus, right cingulate gyrus, middle temporal gyrus, left inferior parietal lobule, caudate nucleus, temporal, and occipital regions, and the resting neural network of the brain also changed.
CONCLUSIONS
We speculate that long-term methadone use can lead to damage to GM structure and adaptive changes in the neural network of patients with heroin use disorder, mainly involving emotional perception, spatial localization, working memory, and other related functions.
Topics: Brain; Gray Matter; Humans; Magnetic Resonance Imaging; Methadone; Opiate Substitution Treatment
PubMed: 34628875
DOI: 10.21037/apm-21-2012