Flexibilidad en las pautas take home de metadona en los CAD de Madrid Salud durante la pandemia de Covid-19 / Flexibility in the methadone take home guidelines in the CAD of Madrid Salud during the Covid-19 pandemic

El objetivo del estudio fue examinar qué cambios se realizaron en los horarios de dispensación y las pautas take home de metadona solución oral y comprimidos, en los siete Centros de Atención a las Adicciones (CAD) de Madrid Salud, a raíz del estado de emergencia y a lo largo de un año posterior a su entrada. Se realizó un estudio descriptivo longitudinal, obteniendo los datos de la revisión de los informes elaborados por la unidad de farmacia, encargada del suministro y control de la metadona, en tres momentos: febrero de 2020 y marzo de 2021, para las pautas de metadona quincenal; y además en noviembre de 2020 para las de tratamiento con metasedín. Se realizó un análisis de estadística descriptiva, calculándose frecuencias absolutas y relativas, así como el porcentaje de variación entre el primer momento y el último momento de medición. En todos los centros se redujeron los días de dispensación. Las pautas quincenales take home de solución de metadona aumentaron más del 50% en todos los centros, manteniéndose un año después un incremento total del 97%. Las personas en tratamiento de mantenimiento con Metasedín se incrementaron en un 45,3%. Las restricciones de movilidad debido al confinamiento por Covid-19 obligaron a flexibilizar y ampliar el take home. La buena respuesta de las personas en tratamiento ha favorecido el mantenimiento de los cambios, lo que ayuda a la normalización de un tratamiento estigmatizado. (AU)

The objective of the study was to examine the changes made in the dispensing schedules and oral solution methadone take home doses and tablets, in the seven Addiction Care Centers (CAD) of Madrid Salud, because of the state of emergency, and which ones remain one year later. A longitudinal descriptive study was conducted, obtaining the data from the review of the reports prepared by the pharmacy unit, responsible for supply and control of methadone, at three times: February 2020 and March 2021, for the two weeks methadone doses; in addition, people treated with Metasedín were included in November 2020. A descriptive statistical analysis was performed, calculating absolute and relative frequencies, as well as the percentage of variation between the first moment and the last moment of measurement. Dispensing days were reduced in all centers. Two weeks methadone solution take home doses increased by more than 50% in all centers, maintaining a total increase of 97% one year later. People in Metasedín maintenance treatment increased by 45.3%. Mobility restrictions due to confinement by Covid-19 forced to make more flexible and expand the take home. The good response of people in treatment has favored maintaining the changes, which helps to normalize a stigmatized treatment. (AU)

Satisfacción y experiencia de pacientes en tratamiento con sustitutivos opioides en España. Estudio PREDEPO / Patients’satisfaction and experience in treatment with opioid substitution therapy in Spain. The PREDEPO study

El objetivo es comparar la satisfacción, experiencia, objetivos y opinión de los pacientes con trastorno por consumo de opioides (TCO) en base a su tratamiento sustitutivo de opioides (TSO) actual (metadona o buprenorfina/naloxona (B/N)). El estudio PREDEPO es un estudio observacional, transversal, multicéntrico desarrollado en España que incluyó pacientes adultos, diagnosticados de TCO y en TSO, quienes contestaron una encuesta sobre su tratamiento actual. Se incluyeron 98 pacientes (B/N:50%, metadona:50%): edad media de 47 ± 8 años y el 80% varones. A nivel de la satisfacción con su tratamiento, los resultados fueron similares entre grupos. El factor “muy/bastante satisfactorio” que se reportó con mayor frecuencia fue “poder repartir las dosis en varios momentos del día” (44% B/N vs. 63% metadona; p = ,122). Se encontraron diferencias significativas en “tener que recoger la medicación diariamente” donde una menor proporción en el grupo B/N contestaron “muy/bastante molesto” versus el grupo metadona (19% vs. 52%, p = ,032). Los objetivos reportados por la mayoría de los pacientes fueron similares entre grupos (“no sentir más síndrome de abstinencia”, “disminuir o dejar definitivamente mi consumo de drogas”, “mejorar mi estado de salud” y “dejar de pensar en consumir todos los días”) excepto en “no tener más problemas de dinero” (72% B/N vs. 92% metadona; p = ,012). Estos resultados evidencian que existen expectativas no cubiertas con los TSO actuales y la necesidad de nuevos tratamientos que disminuyan la carga de la enfermedad, eviten la necesidad de una dosificación diaria y reduzcan el estigma, mejorando así el manejo del paciente, su adherencia y calidad de vida. (AU)

The aim of this study was to compare patients’ satisfaction, experience, objectives, and opinion based on their current opioid substitution therapy (OST) (buprenorphine/naloxone (B/N) or methadone). The PREDEPO study is an observational, cross-sectional, multicentric study performed in Spain. Adult patients diagnosed with opioid use disorder (OUD) receiving OST were included. They were asked to fill in a questionnaire regarding their current OST. A total of 98 patients were enrolled (B/N: 50%, methadone: 50%). Mean age was 47 ± 8 years old and 80% were male. Treatment satisfaction was similar between groups. The most frequently reported factor for being “very/quite satisfied” was “being able to distribute the dose at different times throughout the day” (44% B/N vs. 63% methadone; p = .122). A significantly lower proportion of patients in the B/N group versus the methadone group reported that having to collect the medication daily was “very/quite annoying” (19% vs. 52%, p = .032). Treatment objectives reported by the majority of patients were similar between groups (“not feeling in withdrawal anymore”, “reduce/definitely stop drug use”, “improve my health”, and “stop thinking about using daily”) except for “not having money problems anymore” (73% B/N vs. 92% methadone; p = .012). These results suggest there are several unmet expectations regarding current OST. There is a need for new treatments that reduce the burden of OUD, avoid the need for daily dosing, and are less stigmatizing which in turn could improve patient management, adherence and, quality of life. (AU)

The Role of Pharmacogenomics in Opioid Prescribing.

OPINION STATEMENT: Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

Association Between Increased Dispensing of Opioid Agonist Therapy Take-Home Doses and Opioid Overdose and Treatment Interruption and Discontinuation.

Importance: During the COVID-19 pandemic, modified guidance for opioid agonist therapy (OAT) allowed prescribers to increase the number of take-home doses to promote treatment retention. Whether this was associated with an increased risk of overdose is unclear. Objective: To evaluate whether increased take-home doses of OAT early in the COVID-19 pandemic was associated with treatment retention and opioid-related harm. Design, Setting, and Participants: A retrospective propensity-weighted cohort study of 21 297 people actively receiving OAT on March 21, 2020, in Ontario, Canada. Changes in OAT take-home dose frequency were assessed between March 22, 2020, and April 21, 2020, and individuals were observed for up to 180 days to assess outcomes (last date of follow-up, October 18, 2020). Exposures: Exposure was defined as extended take-home doses in the first month of the pandemic within each of 4 cohorts based on OAT type and baseline take-home dose frequency (daily dispensed methadone, 5-6 take-home doses of methadone, daily dispensed buprenorphine/naloxone, and 5-6 take-home doses of buprenorphine/naloxone). Main Outcomes and Measures: Primary outcomes were opioid overdose, interruption in OAT, and OAT discontinuation. Results: Among 16 862 methadone and 4435 buprenorphine/naloxone recipients, the median age ranged between 38 and 42 years, and 29.1% to 38.2% were women. Among individuals receiving daily dispensed methadone (n = 5852), initiation of take-home doses was significantly associated with lower risks of opioid overdose (6.9% vs 9.5%/person-year; weighted hazard ratio [HR], 0.73 [95% CI, 0.56-0.96]), treatment discontinuation (51.0% vs 63.6%/person-year; weighted HR, 0.80 [95% CI, 0.72-0.90]), and treatment interruption (19.0% vs 23.9%/person-year; weighted HR, 0.80 [95% CI, 0.67-0.95]) compared with no change in take-home doses. Among individuals receiving daily dispensed buprenorphine/naloxone (n = 662), there was no significant difference in any outcomes between exposure groups. Among individuals receiving weekly dispensed OAT (n = 11 010 for methadone; n = 3773 for buprenorphine/naloxone), extended take-home methadone doses were significantly associated with lower risks of OAT discontinuation (14.1% vs 19.6%/person-year; weighted HR, 0.72 [95% CI, 0.62-0.84]) and interruption in therapy (5.1% vs 7.4%/person-year; weighted HR, 0.69 [95% CI, 0.53-0.90]), and extended take-home doses of buprenorphine/naloxone were significantly associated with lower risk of interruption in therapy (9.5% vs 12.9%/person-year; weighted HR, 0.74 [95% CI, 0.56-0.99]) compared with no change in take-home doses. Other primary outcomes were not significantly different between groups. Conclusions and Relevance: In Ontario, Canada, during the COVID-19 pandemic, dispensing of increased take-home doses of opioid agonist therapy was significantly associated with lower rates of treatment interruption and discontinuation among some subsets of patients receiving opioid agonist therapy, and there were no statistically significant increases in opioid-related overdoses over 6 months of follow-up. These findings may be susceptible to residual confounding and should be interpreted cautiously.

Self-harm and suicide during and after opioid agonist treatment among primary care patients in England: a cohort study.

BACKGROUND: The first 4 weeks after initiation and cessation of opioid agonist treatment for opioid dependence are associated with an increased risk of all-cause mortality and overdose. We aimed to investigate whether the rate of self-harm and suicide among people who were prescribed opioid agonist treatment differs during initiation, cessation, and the remainder of time on and off treatment. METHODS: We did a retrospective cohort study and used health-care records from UK Clinical Practice Research Datalink, linked to mortality and hospital admission data, for adults (age 18-75 years at cohort entry) who were prescribed opioid agonist treatment at least once in primary care in England between Jan 2, 1998, and Nov 30, 2018. We estimated rates and adjusted risk ratios (aRRs) of hospital admissions for self-harm and death by suicide, comparing time during and after treatment, as well as comparing stable periods of time on treatment with treatment initiation, cessation, and the remaining time off treatment. FINDINGS: Between Jan 2, 1998, and Nov 30, 2018, 8070 patients (5594 [69·3%] men and 2476 [30·7%] women) received 17 004 episodes of opioid agonist treatment over 40 599 person-years. Patients were mostly of White ethnicity (7006 [86·8%] patients). 807 episodes of self-harm (1·99 per 100 person-years) and 46 suicides (0·11 per 100 person-years) occurred during the study period. The overall age-standardised and sex-standardised mortality ratio for suicide was 7·5 times (95% CI 5·5-10·0) higher in the study cohort than in the general population. Opioid agonist treatment was associated with a reduced risk of self-harm (aRR in periods off treatment 1·50 [95% CI 1·21-1·88]), but was not significantly associated with suicide risk (aRR in periods off treatment 1·21 [0·64-2·28]). Risk of self-harm (aRR 2·60 [95% CI 1·83-3·70]) and suicide (4·68 [1·63-13·42]) were both elevated in the first 4 weeks after stopping opioid agonist treatment compared with stable periods on treatment. INTERPRETATION: Stable periods of opioid agonist treatment are associated with reduced risk of self-harm, emphasising the importance of improving retention of patients in treatment. The first month following cessation of opioid agonist treatment is a period of increased risk of suicide and self-harm, during which additional psychosocial support is required. FUNDING: Medical Research Council.

Implementing a Methadone Delivery System in New York City in Response to COVID-19.

Opioid agonist medication, including methadone, is considered the first-line treatment for opioid use disorder. Methadone, when taken daily, reduces the risk of fatal overdose; however, overdose risk increases following medication cessation. Amid an overdose epidemic accelerated by the proliferation of fentanyl, ensuring continuity of methadone treatment during the COVID-19 pandemic is a vital public health priority. (Am J Public Health. 2021;111(12):2115-2117. https://doi.org/10.2105/AJPH.2021.306523).

Tapentadol in Cancer Patients with Neuropathic Pain: A Comparison of Methadone, Oxycodone, Fentanyl, and Hydromorphone.

Tapentadol has µ-opioid receptor stimulating and noradrenaline reuptake inhibiting properties, and should be effective for neuropathic pain (NP). However, the efficacy of tapentadol for NP in cancer patients is unclear. Ashiya Municipal Hospital (Hyogo, Japan) enrolled five groups of Japanese cancer patients between January 1, 2013, and December 31, 2019. Patients with NP were administered tapentadol (n = 29), methadone (n = 32), oxycodone (n = 20), fentanyl (n = 26), or hydromorphone (n = 20). The primary endpoint was the difference in the verbal rating scale (VRS) scores between days 0 and 7. The secondary endpoint was the tolerability of each opioid. Before administering opioids among the five groups, there was no significant difference in the VRS score (p = 0.99). The mean reduction in the VRS score on day 7 was significantly greater in the tapentadol group than in the oxycodone group (p = 0.0024) and was larger than that of the methadone, fentanyl, and hydromorphone groups. Regarding safety, the discontinuation rate in the tapentadol group was the lowest of all groups (tapentadol vs. methadone vs. oxycodone vs. fentanyl vs. hydromorphone, 0.0% vs. 6.3% vs. 5.0% vs. 3.8% vs. 10.0%, respectively). This study suggests that tapentadol could be efficacious for cancer patients with NP, and a preferred option in cases that require immediate dose adjustment or for those at high risk for adverse effects. However, the pain intensity was evaluated without pain assessment scales specific to NP. Thus, we think that it is desirable to validate our findings using assessment scales, such as the painDETECT questionnaire in future.

Add-On Selective Estrogen Receptor Modulators for Methadone Maintenance Treatment.

Methadone maintenance treatment (MMT) remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism (SNP) associated with estrogen receptor (ER) regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Moreover, this article provides a pharmacological perspective on the targeting of estrogen signals through the use of selective ER modulators (SERMs) during MMT. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism.

Risk of motor vehicle collisions after methadone use.

Methadone maintenance treatment (MMT) can alleviate opioid dependence. However, MMT possibly increases the risk of motor vehicle collisions. The current study investigated preliminary estimation of motor vehicle collision incidence rates. Furthermore, in this population-based retrospective cohort study with frequency-matched controls, opiate adults receiving MMT (cases) and those not receiving MMT (controls) were identified at a 1:2 ratio by linking data from several nationwide administrative registry databases. From 2009 to 2016, the crude incidence rate of motor vehicle collisions was the lowest in the general adult population, followed by that in opiate adults, and it was the highest in adults receiving MMT. The incidence rates of motor vehicle collisions were significantly higher in opiate users receiving MMT than in those not receiving MMT. Kaplan-Meier curves of the incidence of motor vehicle collisions differed significantly between groups, with a significant increased risk during the first 90 days of follow-up. In conclusion, drivers receiving MMT have higher motor vehicle collision risk than those not receiving MMT in opiate users, and it is worthy of noticing road safety in such drivers, particularly during the first 90 days of MMT.

In 2019, 58 million people were estimated to use opioids ­ a group of substances that include drugs like heroin and morphine. Dependence on opioids can be managed using a prescribed dose of an opioid called methadone, which is administered through a controlled treatment plan. This so-called methadone maintenance treatment manages withdrawal symptoms in opioid-dependent individuals and can reduce the occurrences of overdose, criminal activity and transmission of diseases such as HIV. However, methadone acts on the same brain receptors as other opioids, and individuals receiving methadone may experience impaired motoric and cognitive functioning, including reduced driving ability. It is therefore important to know whether methadone maintenance treatment may increase an individual's risk to cause road accidents. To assess motor vehicle collision risk associated with individuals receiving methadone maintenance treatment, Yang et al. analysed data from the Taiwan National Health Insurance Research Database and six Taiwanese administrative registries, including the ministries of health and welfare, interior and justice, and registries in substitution maintenance therapy, road accidents and the National Police Agency. Initial analyses found that individuals receiving treatment had a higher risk to be involved in car accidents than the general adult population or those without methadone maintenance treatment. Further tests showed that individuals receiving treatment were at three times higher risk of collisions than individuals not receiving treatment, particularly in the first 90 days. These findings may help individuals undergoing methadone maintenance treatment manage their risk of motor vehicle collisions. Further investigation is needed to reveal the underlying mechanisms of methadone-related impairment of driving ability.

Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy.

BACKGROUND AND OBJECTIVE: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. METHODS: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal ß-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) and Cmax/MIC. RESULTS: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 µg/mL (CV: 0.32) and 8.7 µg/mL (CV: 0.59), respectively; the mean calculated AUC0-24 was 742.7 µg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers. CONCLUSIONS: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.

Hydromorphone and codeine concentrations in oral fluid specimens from patients receiving substitution therapy with Substitol™ (morphine sulfate).

This study aimed to determine whether hydromorphone and codeine can be detected in oral fluid specimens following administration of Substitol™, a slow-release formulation of morphine. This is of interest for those monitoring treatment compliance using drug testing. Oral fluid specimens collected for compliance assessment in routine clinical practice or as part of a clinical trial were subjected to quantitative analysis of hydromorphone, morphine, codeine, and 6-acetylmorphine using highly sensitive mass spectrometric methods. Oral fluid was collected using a Greiner Bio-One saliva collection system. Patients undergoing substitution treatment with Substitol™, methadone, or buprenorphine were included, together with patients undergoing pain treatment with hydromorphone. Hydromorphone was detected in 642 of the 663 (97%) samples from substitol-treated patients. Concentrations were not higher in methadone- and buprenorphine-treated patients who relapsed into heroin use, or in patients on hydromorphone therapy. Codeine was detected in 29% of the samples. These concentrations were lower than those in patients who had relapsed to heroin use. Clinical administration of morphine can lead to detectable concentrations of both hydromorphone and codeine in oral fluids. This should be taken into consideration when using drug testing in oral fluid samples for compliance assessment in this patient group.

Use of an electronic pillbox to increase number of methadone take-home doses during the COVID-19 pandemic.

This study describes use of the commercially available Medminder electronic pillbox at a community substance use disorder treatment program to safely increase the number of methadone take-home doses administered during the COVID-19 pandemic. The pillbox contains 28 cells that lock independently and can be opened only during preprogrammed time windows. This study provided patients (n = 42) deemed vulnerable to take-home mismanagement or more severe symptoms from COVID-19 infection the pillbox and observed them for 11 weeks. A telephone support line was staffed daily to manage technical issues. Overall, patients received about 14 more take-home doses per month after receiving the pillbox. Most medication was dispensed within scheduled windows. The study observed few incidents of suspected tampering, though five patients had their pillbox rescinded to allow more intensive on-site clinical monitoring. The study supports use of an electronic pillbox with a telephone support line to help vulnerable patients to better observe stay-at-home guidelines during the COVID-19 pandemic. The pillbox may offer public health and clinical benefits that extend beyond the pandemic by increasing program treatment capacity and patient satisfaction.

Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children.

Aim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion: We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV.

The Abuse Characteristics of Amphetamine-Type Stimulants in Patients Receiving Methadone Maintenance Treatment and Buprenorphine Maintenance Treatment.

OBJECTIVE: The purpose of this study was to retrospectively investigate the abuse characteristics of amphetamine-type stimulants (ATS) in patients receiving methadone maintenance treatment (MMT) and buprenorphine maintenance treatment (BMT). METHODS: A total of 58 MMT and 51 BMT patients abusing ATS were recruited from the drug maintenance treatment clinic of Ningbo Addiction Research and Treatment Center from January 2018 to December 2019. They were assessed using the amphetamine abuse questionnaire (AAQ), addiction severity index (ASI) and Barratt impulsiveness scale (BIS). Moreover, 40 MMT control patients, 40 BMT control patients and 20 healthy controls were also assessed using the BIS. All information was collected using the amphetamine abuse questionnaire (AAQ), Chinese version of addiction severity index (ASI-C) and Chinese version of Barratt impulsiveness scale (BIS-C) conducted by qualified psychologists. RESULTS: The interval of amphetamine use in the MMT group was shorter than the BMT group (P < 0.05). The drug use subscale score of ASI was higher in the MMT group than the BMT group (P < 0.05). The respective and total scores of attentional impulsiveness, motor impulsiveness and non-planning impulsiveness in BIS in the MMT group were all higher than the MMT control group (P < 0.05). The scores of motor impulsiveness and non-planning impulsiveness in the BMT group were higher than the BMT control group (P < 0.05). The respective and total scores in BIS in the MMT control group and the BMT control group were all higher than those in the healthy controls. CONCLUSION: The patients showing amphetamine abuse in maintenance therapy had a greater impulsiveness than those having other simple maintenance treatments, and patients under MMT may be more addicted to amphetamines in comparison with those having BMT.

Antinociceptive synergism upon the joint use of methadone and Phα1ß in a model of cancer-related pain in C57BL/6J mice.

Opioids are the first-line treatment for cancer pain. Incomplete pain relief and the high rate of adverse effects of these compounds bring a need to combine them with other drugs acting on different targets. AIMS: We here evaluate the antinociceptive interaction and adverse events of methadone combined with recombinant Phα1ß, an analgesic toxin from Phoneutria nigriventer. MAIN METHODS: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw. von Frey filaments measured the paw-withdrawal threshold after administration of methadone, Phα1ß, and their combination. The degree of interaction was evaluated using isobolographic analysis. Spontaneous performance and forced motor performance were assessed with the open-field and rotarod tests, respectively. Intestinal function was evaluated by the distance traveled by charcoal and opioid tolerance was induced by daily morphine injections. KEY FINDINGS: Co-administration of Phα1ß with methadone synergistically reverses the melanoma-induced mechanical hypersensitivity. No motor alterations were observed but mild alterations on intestinal function after treatment with the combination that was also capable of restoring morphine analgesia in the tail-flick test after an opioid-induced tolerance. SIGNIFICANCE: Combinatorial treatment with Phα1ß and methadone produces synergistic analgesic potentiation with potential implications to pain treatment even under opioid tolerance conditions.

Estimate cost of providing methadone maintenance treatment at a methadone clinic in Nairobi Kenya: direct costs.

Methadone maintenance treatment is reported as cost-effective in treatment of opioid use disorder. Estimated cost of providing methadone varies widely in different regions but there is no data regarding cost of methadone treatment in Kenya. The aim of this study was to estimate the cost of methadone maintenance treatment at a methadone maintenance treatment clinic in Nairobi, Kenya from the perspective of the government, implementing partner and the clients. Data was collected for the period of February 2017 to September 2018 for 700 enrolled clients. The cost of providing methadone treatment was estimated as the sum of salaries, laboratory test, methadone and other commodities costs. The outcome was daily cost of methadone per client. The costs are given in Kenya Shillings (Ksh). The cost of treating one client is approximately Ksh. 149 (US$1.49) per day which amounts to Ksh 4500 (US$ 45) per month. This is from the estimated direct costs such as salaries which accounted for 86.4%, methadone 9.6%, tests and other consumables at 4%. The estimated average dose per patient per day is 60mg.This excludes indirect costs such as capital and set up cost, maintenance cost, training, drug import and distribution and other bills. The findings of this study show that the estimate cost of providing methadone at Nairobi, Kenya is comparable to that in other centers. This can help to inform policy makers on continued provision of methadone treatment in the country.

Efficacy of methadone for the management of postoperative pain in laparoscopic cholecystectomy: A randomized clinical trial. / Eficacia de la metadona para el tratamiento del dolor postoperatorio en colecistectomía laparoscópica: ensayo clínico aleatorizado.

BACKGROUND: Postoperative pain management contributes to reducing postoperative morbidity and unscheduled readmission. Compared to other opioids that manage postoperative pain like morphine, few randomized trials have tested the efficacy of intraoperatively administered methadone to provide evidence for its regular use or be included in clinical guidelines. METHODS: We conducted a randomized clinical trial comparing the use of intraoperative methadone to assess its impact on postoperative pain. Eighty-six patients undergoing elective laparoscopic cholecystectomy were allocated to receive either methadone (0.08 mg/kg) or morphine (0.08 mg/kg). RESULTS: Individuals who received methadone required less rescue morphine in the Post Anesthesia Care Unit for postoperative pain than those who received morphine (p = 0.0078). The patients from the methadone group reported less pain at 5 and 15 minutes and 12 and 24 hours following Post Anesthesia Care Unit discharge, exhibiting fewer episodes of nausea. Time to eye-opening was equivalent between the two groups. CONCLUSION: Intraoperative use of methadone resulted in better management of postoperative pain, supporting its use as part of a multimodal pain management strategy for laparoscopic cholecystectomy under remifentanil-based anesthesia.

INTRODUCCIÓN: El manejo del dolor postoperatorio contribuye a reducir la morbilidad postoperatoria y los reingresos no programados. Pocos ensayos clínicos aleatorizados han evaluado la eficacia de la administración intraoperatoria de metadona en comparación con otros opioides como morfina, para el tratamiento del dolor postoperatorio, como para proporcionar evidencia de su uso regular o incluirse en guías clínicas. MÉTODOS: Realizamos un ensayo clínico aleatorizado comparando el uso de metadona intraoperatoria para evaluar su impacto sobre el dolor postoperatorio. Ochenta y seis pacientes sometidos a colecistectomía laparoscópica electiva fueron asignados para recibir metadona (0,08 mg/kg) o morfina (0,08 mg/kg). RESULTADOS: El grupo de pacientes que recibió metadona requirió menos morfina de rescate en la unidad de cuidados post-anestésicos para el manejo del dolor posoperatorio, en comparación con el grupo morfina (p = 0,0078). Los pacientes del grupo metadona reportaron menos dolor a los 5 y 15 minutos, y a las 12 y 24 horas postoperatorias, además de presentar menos episodios de náuseas. El tiempo de despertar entre ambos grupos fue equivalente. CONCLUSIÓN: El uso intraoperatorio de metadona es superior a morfina en el manejo del dolor postoperatorio, apoyando su uso como parte de la estrategia de manejo multimodal del dolor para colecistectomía laparoscópica bajo anestesia total endovenosa con remifentanilo.

Trends in Urine Drug Monitoring Among Persons Receiving Long-Term Opioids and Persons with Opioid Use Disorder in the United States.

BACKGROUND: Practice guidelines recommend urine drug monitoring (UDM) at least annually in the setting of chronic opioid therapy as an objective assessment of substance use. However, empirical evidence on who gets tested and how often testing occurs is lacking. OBJECTIVES: This study investigates 10-year UDM trends in the United States based on 2 factors: (1) the duration of prescription opioid treatment, and (2) having an opioid use disorder (OUD) diagnosis and medications for opioid use disorder (MOUD) prescriptions. STUDY DESIGN: Observational cross-sectional study. SETTING: Research was conducted using administrative claims data from Optum's deidentified Clinformatics Data Mart Database for the period 2007 to 2016. The dataset contained information on the plan enrollment and health care claims from 50 states and the District of Columbia. METHODS: To examine trends in UDM based on the duration of prescription opioid treatment, persons receiving prescription opioid analgesics were categorized into 4 groups based on the number of days covered: (a) less than 90 days, (b) 90 to 179 days, (c) 180 to 269 days, and (d) at least 270 days. To examine trends based on an OUD diagnosis and MOUD prescriptions, persons diagnosed with OUD were identified and categorized based on the presence of MOUD prescriptions as follows: (a) OUD with buprenorphine (BPN) and naltrexone (NTX) in the same year; (b) OUD with BPN only; (c) OUD with NTX only; (d) OUD with chronic prescription opioid analgesics (>= 90 days); (e) OUD without prescription opioid analgesics, BPN, or NTX; and (f) chronic prescription opioid analgesics (>= 90 days) without an OUD diagnosis. For analysis, the percent receiving UDM was estimated per group per year. Then the data were restricted to those receiving at least one UDM to estimate the average number of UDM per person. RESULTS: Data included an average of 364,485 persons per year receiving prescription opioid analgesics for chronic use, and 10,277 per year receiving an OUD diagnosis. Among those receiving prescription opioid analgesics, less than 50% received UDM. For those receiving at least one UDM, one additional UDM was performed per person as the duration of opioids increased by 90 days. Among persons with OUD, the percent receiving UDM was the highest for those receiving both BPN and NTX (87%), followed by those receiving BPN only (80%), chronic opioids (79%), NTX only (72%), and those not receiving any MOUD/opioids (54%). LIMITATIONS: Methadone dispensing for OUD treatments was not captured in administrative claims data. CONCLUSIONS: Although recommended for patients with chronic pain, UDM is provided less than half of the time for these patients. However, once patients received at least one UDM, they would continue to receive it on a fairly regular basis. Compared with those with chronic pain, persons diagnosed with OUD are more likely to receive UDM at a more frequent interval.

OPRM1 and CYP3A4 association with methadone dose in Iranian patients undergoing methadone maintenance therapy.

BACKGROUND: Investigations proposed that genetic polymorphisms within proteins in methadone pharmacokinetic and pharmacodynamics are critical factors in determination of methadone dose in methadone maintenance therapy (MMT). OBJECTIVE: This study aimed to assess the associations between two polymorphisms, CYP3A4 (rs2740574) and OPRM1 (rs1799971), with dose of methadone in Iranian patients undergoing MMT. METHODS: A total of 124 Iranian male subjects aged 18-65 years old who were confirmed to be addicted by the addiction diagnostic tests and underwent MMT were assessed. Patients were divided into three groups of low (less than 40 mg/day), moderate (more than 40 mg/day and less than 110 mg/day) and high (more than 110 mg/day) methadone dose consumption. DNAs of included patients were extracted from their blood samples and were assessed for CYP3A4 and OPRM1 polymorphisms. RESULTS: Results showed that there was no significant association between the studied polymorphisms and methadone dose in Iranian addicted patients underwent MMT (P > 0.05). CONCLUSIONS: CYP3A4 and OPRM1 single variations cannot explain variability in methadone dosage in MMT. Studying the interactions of more genetic factors in larger samples may elucidate factors influencing the required dose of methadone and better individualized therapy.