Steady-state methadone pharmacokinetics in opioid agonist treatment: Influencing factors and clinical outcomes

Bakgrunn: Metadonsubstitusjon er anbefalt for behandling av opioidavhengighet. En betydelig inter-individuell variasjon i metadons daglige doser og oppnådde serumkonsentrasjoner er rapportert. Mulige underliggende årsaker er imidlertid ikke fullt ut forstått. Formålet med denne forskningen var å undersøke om genetiske, pato-fysiologiske og farmakologiske faktorer kan påvirke metadon serumkonsentrasjon-dose-ratio (CDR), og å utforske sammenhengen mellom serumkonsentrasjon og kliniske utfall i metadon substitusjonsbehandling. Metoder: Dette prosjektet har brukt observasjonsdata fra tre forskjellige kilder, inkludert to retrospektive laboratoriedatabaser av terapeutisk legemiddelovervåking (artiklene I og II), og en prospektiv kohortdatabase om pasienter under substitusjonsbehandling med metadon (artiklene III og IV). Lineær regresjon analysemetode ble brukt for å undersøke effekten av CYP genetiske polymorfismer (artikkel I), alder, kjønn og samtidig behandling med andre legemidler (artikkel II), samt leverfibrose og BMI (artikkel III) på metadon CDR. Sammenhengen mellom metadon serumkonsentrasjon og subjektive abstinenssymptomer og bivirkninger ble også undersøkt (artikkel IV). Resultater: Artikkel I: Homozygote bærere av CYP2B6*6 hadde signifikant høyere metadon CDR sammenlignet med ikke-bærere (P < 0.001). Artikkel II: Kvinner hadde sammenlignet med menn 9 % lavere CDR, mens denne ratioen ikke var påvirket av alder. Samtidig medisinering med CYP induserende legemidler reduserte metadon CDR med 36 %, mens CYP3A4 hemmende legemidler økte denne med 36 %. Artikkel III: Det var ingen signifikant sammenheng mellom CDR og leverfibrose (koeffisient: 0.70; 95% KI: -2.16, 3.57; P: 0.631) eller cirrhose (-0.50; -4.59, 3.59; 0.810) sammenlignet med ingen/begrenset fibrose. Deltakerne med en BMI på 25-30 kg/m² hadde høyere CDR (2.34; 0.22, 4.45; 0.031) sammenlignet med de som hadde lavere BMI. Artikkel IV: Total SOWS-score (P < 0,001), de spesifikke subjektive abstinenssymptomene angst (P = 0.004), ben- og muskelsmerter (P = 0.003), rastløshet (P = 0.017) og (i lavere grad) skjelving (P = 0.046), også bruk av heroin (P = 0.015) og alkohol (P = 0.011) var assosiert med lavere metadonkonsentrasjoner i serum. Cannabisbruk var (i lavere gard) relatert til høyere serumkonsentrasjoner av metadon (P = 0.049). Konklusjon: Våre forskningsfunn viser at genetiske polymorfismer i CYP2B6, kjønn, BMI og samtidig behandling med CYP induserende og/eller CYP3A4 hemmende legemidler kan forklare noen av variasjonene i dosejusterte serumkonsentrasjoner av metadon. Alder, grad av leverfibrose og andre CYP polymorfismer ser ikke ut til å være assosiert med metadon CDR. Vi har også funnet assosiasjoner mellom subjektive opioidabstinenssymptomer samt rusmiddelbruk, og metadonkonsentrasjoner i serum. Våre funn bekrefter dagens kliniske og forskningsmessige utfordringer knyttet til metadonbehandling med tanke på en stor intra-individuell variasjon i legemiddelets farmakokinetikk. Resultatene er også i tråd med tidligere forskning som viser at metabolismen av metadon kan bli påvirket av flere faktorer. Samlet sett støtter vår forskning viktigheten av en individuelt tilpasset dosering basert på mulige involverte faktorer og selvopplevde opioidabstinenssymptomer for å oppnå en tilstrekkelig og ønsket serumkonsentrasjon som kan redusere tilbakefall til rusmiddelbruk med tilhørende risiko og for å optimalisere behandlingen.Background: Methadone maintenance treatment (MMT) is recommended for the treatment of opioid addiction. A considerable inter-individual variability in methadone daily doses and serum concentrations has been reported; however, the underlying causes are not fully understood. The aim of this thesis was to investigate the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration-to-dose ratio (CDR), and to explore the relationship between serum methadone concentration and clinical outcomes in MMT. Methods: The thesis has used observational data from three different sources including two retrospective laboratory databases on therapeutic drug monitoring (TDM) (papers I and II), and a prospective cohort data on patients undergoing MMT (papers III and IV). Linear mixed model analyses were used to investigate the impact of CYP genetic polymorphisms (paper I), age, gender and co-medication (paper II), as well as liver fibrosis and BMI (paper III) on methadone CDR. Association between serum methadone concentrations and subjective symptoms of withdrawal and adverse effects were also investigated (paper IV). Results: Paper I: The homozygous carriers of CYP2B6*6 had significantly higher methadone CDR compared with non-carriers (P < 0.001). Paper II: Women as compared to men had 9% lower CDR, whereas the ratio was not influenced by age. Concomitant medication with CYP inducers reduced methadone CDR by 36%, whereas CYP3A4 inhibitors increased it by 36%. Paper III: There was no significant relationship between CDR and liver fibrosis (coefficient: 0.70; 95% CI: -2.16, 3.57; P: 0.631) or cirrhosis (-0.50; -4.59, 3.59; 0.810) compared to no/limited fibrosis. Participants with a BMI of 25-30 kg/m² had higher CDR (2.34; 0.22, 4.45; 0.031) compared with those who had lower BMI. Paper IV: The total SOWS score (P < 0.001); the specific subjective withdrawal symptoms of anxiety (P = 0.004), bone and muscle aches (P = 0.003), restlessness (P = 0.017), and (slightly) shaking (P = 0.046), also use of heroin (P = 0.015) and alcohol (P = 0.011) were associated with lower methadone concentrations. Cannabis use was slightly related to higher methadone concentrations (P = 0.049). Conclusion: This thesis demonstrates that genetic polymorphisms in CYP2B6, gender, BMI and concurrent medication with CYP inducers and CYP3A4 inhibitors may explain some of the variations in dose-adjusted serum methadone concentrations. Age, degree of liver fibrosis and the other CYP polymorphisms do not seem to be associated with methadone CDR. Additionally; we have shown associations between the subjective opioid withdrawal symptoms as well as substance use, and serum methadone concentrations. Our findings confirm the current clinical and research challenges in MMT regarding a large intra-individual variability in methadone pharmacokinetics and influence of several factors. The thesis supports the importance of an individually tailored dosage based on the possible factors involved and self-perceived opioid withdrawal symptoms to achieve the desired serum methadone concentration. This is crucial to reduce relapse to substance use with associated risks and to optimize the treatment outcomes.Doktorgradsavhandlin

Effectiveness and Safety of Low-Threshold Opioid-Agonist Treatment in Hard-To-Reach Populations with Opioid Dependence

Objectives: Opioid-use disorder is related to premature death worldwide. Opioid-agonist treatment (OAT) is an effective treatment for opioid dependence. OAT delivery platforms may influence treatment access and outcomes, especially for the most vulnerable groups. The aim of this study was to determine the effectiveness and safety of low-threshold OAT compared to the standard treatment. Methods: Patients with diagnosed opioid dependence undergoing low-threshold OAT at the Bergen delivery platform in Norway were enrolled in a cohort study in 2014–2019. A national OAT cohort was the reference group. The main outcomes were treatment retention, the use of illicit opioids, non-fatal overdose, overdose death, and all-cause mortality during the first year following treatment initiation and the full treatment period. Additionally, healthcare utilization in the periods before and during OAT was investigated. Results: Compared to the reference cohort, the low-threshold cohort (n = 128, mean age: 38 years, women: 28%) showed treatment retention rates of 95% versus 92%, illicit opioid use of 7% versus 10%, non-fatal overdose of 7% versus 6%, and death at 1.0% versus 1.3%, respectively. The incident rate ratios (IRRs) for healthcare utilization increased substantially during the OAT period compared to the period before; the IRR increased by 3.3 (95% confidence interval (CI): 2.8, 3.9) and 3.4 (95% CI: 3.1, 3.9) for all in- and outpatient healthcare, respectively. Conclusions: Low-threshold OAT was at least as effective and safe as the standard OAT in terms of treatment retention, the use of illicit opioids, non-fatal overdose, and death. Healthcare utilization increased during the OAT compared to the period before. Lowering the threshold for OAT entrance within proper delivery platforms should be broadly considered to reduce harm and improve healthcare access among patients with opioid dependence.publishedVersio

Changes in substance use during outpatient treatment for substance use disorders: a prospective Norwegian cohort study from 2016 to 2020

Background Continuous use of amphetamines, alcohol, benzodiazepines, cannabis, cocaine, or opioids contributes to health impairments, increased morbidity, and overdose deaths among patients with substance use disorders (SUDs). This study evaluates the impact of inpatient detoxification, injecting substance use, age, and gender on substance use over time among patients undergoing outpatient SUD treatment. Methods We used data from a cohort of SUD patients in Norway obtained from health assessments of self-reported substance use and sociodemographic and clinical factors. A total of 881 substance use measurements, including substances and frequency of use, were assessed for 708 SUD patients in 2016–2020. Of those, 171 patients provided two or more substance use measurements. The total substance use was calculated, creating a substance use severity index (SUSI), ranging from zero (no use) to one (daily use of all substances). We defined baseline as the first substance use measurement when the measurements were listed chronologically. Time was defined as years from baseline. We used a linear mixed model to analyze the SUSI at baseline and over time, and its associations with inpatient detoxification, injecting substance use, gender, and age, presented with coefficients and 95% confidence intervals (CI). Results No longitudinal changes in the SUSI were found compared with baseline (change in SUSI (cSUSI): 0.04, 95% CI: − 0.05;0.13, p = 0.397). Likewise, “inpatient detoxification” was not associated with changes in the SUSI compared with “no inpatient detoxification” (cSUSI: 0.00, 95% CI: − 0.04;0.04, p = 0.952). However, injecting substances were associated with a higher SUSI than not injecting substances at baseline (difference in SUSI: 0.19, 95% CI: 0.16;0.21, p = < 0.001), and starting to inject substances was associated with increasing SUSI over time compared with not starting to inject substances (cSUSI: 0.11, 95% CI: 0.07;0.15, p = < 0.001). Gender was not significantly associated with changes in the SUSI (cSUSI: − 0.04, 95% CI: − 0.07;0.00, p = 0.052), while patients over 60 years of age had a lower SUSI than those under the age of 30 at baseline (difference in SUSI: − 0.08, 95% CI: − 0.14;− 0.01, p = 0.018), with no change over time (cSUSI: − 0.05, 95% CI: − 0.16;0.05, p = 0.297). Conclusion The present study demonstrates that inpatient detoxification was not associated with substance use changes over time for patients undergoing outpatient SUD treatment. Otherwise, injecting substance use was a particular risk factor for a high level of substance use. Future research needs to evaluate the impact of other treatment approaches on substance use, ideally in randomized controlled trials.publishedVersio

Dispensations of benzodiazepines, zhypnotics, and gabapentinoids to patients receiving opioid agonist therapy; a prospective cohort study in Norway from 2013 to 2017

Background Dispensations of benzodiazepines, z-hypnotics, and gabapentinoids to patients on opioid agonist therapy (OAT) are common and have pros and cons. The objectives of the current study are to define the dispensation rates of these potentially addictive drugs, and whether the number and the mean daily doses of dispensed OAT opioids and discontinuing OAT, are associated with being dispensed benzodiazepines, z-hypnotics and gabapentinoids among patients on OAT in Norway in the period 2013 to 2017. Methods Information about all dispensed opioids, benzodiazepines, z-hypnotics and gabapentinoids were recorded from the Norwegian Prescription Database (NorPD). A total of 10,371 OAT patients were included in the study period. The dispensation rates were defined as the number of patients who were dispensed at least one of the potentially addictive drugs divided among the number of patients who have dispensed an OAT opioid per calendar year. Mean daily doses were calculated, and for benzodiazepines and z-hypnotics, stated in diazepam equivalents. The association between dispensed potentially addictive drugs, and the number and the type of dispensed OAT opioids were calculated by using logistic regression models. Results Half of the OAT patients received at least one dispensation of a benzodiazepine or z-hypnotic, and 11% were dispensed at least a gabapentinoid in 2017. For dispensed benzodiazepines or z-hypnotics, the mean daily dose was reduced from 21 mg (95% confidence interval (CI): 20–23) diazepam equivalents in 2013 to 17 mg (95% CI: 16–17) in 2017. The mean daily dose of pregabalin increased from 365 mg (95% CI: 309–421) in 2013 to 386 mg (95% CI: 349–423) in 2017. Being dispensed a gabapentinoid (adjusted odds ratio (aOR) = 2.5, 95% CI: 2.1–3.0) or a non-OAT opioid (aOR = 3.0, 95% CI: 2.6–3.5) was associated with being dispensed a benzodiazepine or z-hypnotic. Discontinuing OAT did not affect the number of dispensations and the doses of potentially addictive drugs. Conclusion The dispensation rates of potentially addictive drugs are high in the OAT population. Treatment indications, as well as requirements for prescription authority, need to be debated and made explicit. Randomized controlled trials evaluating the benefits and risks of such co-prescription are required.publishedVersio

On the path towards universal coverage of hepatitis C treatment among people receiving opioid agonist therapy (OAT) in Norway: A prospective cohort study from 2013 to 2017

Objectives We aimed to calculate cumulative hepatitis C virus (HCV) treatment coverage among individuals enrolled in opioid agonist therapy (OAT) in Norway between 2013 and 2017 and to document the treatment transition to direct-acting antiviral (DAA) agents. Moreover, we aimed to describe adherence to DAAs in the same cohort. Design Prospective cohort, registry data. Setting Specialist healthcare service (secondary) Participants and outcomes This observational study was based on data from The Norwegian Prescription Database. We studied dispensed OAT and HCV treatment annually to calculate the cumulative frequency, and employed secondary sources to calculate prevalence, incidence and HCV treatment coverage from 2013 to 2017, among the OAT population. Factors associated with adherence to DAAs were identified a priori and subject to logistic regression. Results 10 371 individuals were identified with dispensed OAT, 1475 individuals of these were identified with dispensed HCV treatment. Annual HCV treatment coverage increased from 3.5% (95% CI: 3.2 to 4.4) in 2013 to 17% (95% CI: 17 to 20) in 2017, giving a cumulative HCV coverage among OAT patients in Norway of 38.5%. A complete shift to interferon-free treatment regimens occurred, where DAAs accounting for 32% of HCV treatments in 2013 and 99% in 2017. About two-thirds of OAT patients were considered adherent to their DAA regimens across all genotypes. High level of OAT continuity was associated with improved adherence to DAAs (adjusted OR 1.4, 95% CI: 1 to 2, p=0.035). Conclusions A large increase in HCV treatment coverage attributed by a complete shift to interferon-free regimens among the Norwegian OAT population has been demonstrated. However, treatment coverage is inadmissibly too low and a further substantial scale-up in HCV treatment is required to reach the universal targets of controlling and eliminating the HCV endemic.publishedVersio

Impact of liver fibrosis and clinical characteristics on dose-adjusted serum methadone concentrations

Background There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements. Objectives We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations. Methods We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016–2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis. Results When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5, the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: −2.16, 3.57; P: 0.631), even among those with advanced cirrhosis (−0.50; −4.59, 3.59; 0.810). Conclusions Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.publishedVersio

Methadone pharmacokinetics in opioid agonist treatment: Influencing factors and clinical implications

Background: A considerable inter-individual variability has been reported in the relationship between methadone doses applied and serum concentrations achieved in methadone maintenance treatment. However, the underlying causes for this variability are not fully understood. Objectives: We investigated the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration-to-dose ratio (CDR) and discussed the clinical implications of the findings. Methods: We used data from two retrospective laboratory databases and a prospective cohort study to investigate the impact on methadone CDR of hepatic cytochrome P450 enzyme system (CYP) genetic polymorphisms, age, sex, concomitant medication, liver fibrosis and body mass index through linear mixed model analyses. Findings: A positive association was found between CDR and the homozygous CYP2B6*6 genotype, concurrent treatment with CYP3A4 inhibitors and body mass index. CDR was lower among women and during concomitant use of CYP inducers. CDR was not associated with age or the degree of liver fibrosis in our investigations. Conclusions: This research work supports the need for individually tailored dosage considering the various factors that influence methadone CDR. The gained knowledge can contribute to reducing the risks associated with the treatment and optimizing the desired outcomes

Effectiveness and Safety of Low-Threshold Opioid-Agonist Treatment in Hard-To-Reach Populations with Opioid Dependence

Objectives: Opioid-use disorder is related to premature death worldwide. Opioid-agonist treatment (OAT) is an effective treatment for opioid dependence. OAT delivery platforms may influence treatment access and outcomes, especially for the most vulnerable groups. The aim of this study was to determine the effectiveness and safety of low-threshold OAT compared to the standard treatment. Methods: Patients with diagnosed opioid dependence undergoing low-threshold OAT at the Bergen delivery platform in Norway were enrolled in a cohort study in 2014–2019. A national OAT cohort was the reference group. The main outcomes were treatment retention, the use of illicit opioids, non-fatal overdose, overdose death, and all-cause mortality during the first year following treatment initiation and the full treatment period. Additionally, healthcare utilization in the periods before and during OAT was investigated. Results: Compared to the reference cohort, the low-threshold cohort (n = 128, mean age: 38 years, women: 28%) showed treatment retention rates of 95% versus 92%, illicit opioid use of 7% versus 10%, non-fatal overdose of 7% versus 6%, and death at 1.0% versus 1.3%, respectively. The incident rate ratios (IRRs) for healthcare utilization increased substantially during the OAT period compared to the period before; the IRR increased by 3.3 (95% confidence interval (CI): 2.8, 3.9) and 3.4 (95% CI: 3.1, 3.9) for all in- and outpatient healthcare, respectively. Conclusions: Low-threshold OAT was at least as effective and safe as the standard OAT in terms of treatment retention, the use of illicit opioids, non-fatal overdose, and death. Healthcare utilization increased during the OAT compared to the period before. Lowering the threshold for OAT entrance within proper delivery platforms should be broadly considered to reduce harm and improve healthcare access among patients with opioid dependence

Changes in substance use during outpatient treatment for substance use disorders: a prospective Norwegian cohort study from 2016 to 2020

Background Continuous use of amphetamines, alcohol, benzodiazepines, cannabis, cocaine, or opioids contributes to health impairments, increased morbidity, and overdose deaths among patients with substance use disorders (SUDs). This study evaluates the impact of inpatient detoxification, injecting substance use, age, and gender on substance use over time among patients undergoing outpatient SUD treatment. Methods We used data from a cohort of SUD patients in Norway obtained from health assessments of self-reported substance use and sociodemographic and clinical factors. A total of 881 substance use measurements, including substances and frequency of use, were assessed for 708 SUD patients in 2016–2020. Of those, 171 patients provided two or more substance use measurements. The total substance use was calculated, creating a substance use severity index (SUSI), ranging from zero (no use) to one (daily use of all substances). We defined baseline as the first substance use measurement when the measurements were listed chronologically. Time was defined as years from baseline. We used a linear mixed model to analyze the SUSI at baseline and over time, and its associations with inpatient detoxification, injecting substance use, gender, and age, presented with coefficients and 95% confidence intervals (CI). Results No longitudinal changes in the SUSI were found compared with baseline (change in SUSI (cSUSI): 0.04, 95% CI: − 0.05;0.13, p = 0.397). Likewise, “inpatient detoxification” was not associated with changes in the SUSI compared with “no inpatient detoxification” (cSUSI: 0.00, 95% CI: − 0.04;0.04, p = 0.952). However, injecting substances were associated with a higher SUSI than not injecting substances at baseline (difference in SUSI: 0.19, 95% CI: 0.16;0.21, p = < 0.001), and starting to inject substances was associated with increasing SUSI over time compared with not starting to inject substances (cSUSI: 0.11, 95% CI: 0.07;0.15, p = < 0.001). Gender was not significantly associated with changes in the SUSI (cSUSI: − 0.04, 95% CI: − 0.07;0.00, p = 0.052), while patients over 60 years of age had a lower SUSI than those under the age of 30 at baseline (difference in SUSI: − 0.08, 95% CI: − 0.14;− 0.01, p = 0.018), with no change over time (cSUSI: − 0.05, 95% CI: − 0.16;0.05, p = 0.297). Conclusion The present study demonstrates that inpatient detoxification was not associated with substance use changes over time for patients undergoing outpatient SUD treatment. Otherwise, injecting substance use was a particular risk factor for a high level of substance use. Future research needs to evaluate the impact of other treatment approaches on substance use, ideally in randomized controlled trials

Dispensation of attention deficit hyperactivity disorder (ADHD) medications in patients receiving opioid agonist therapy; a national prospective cohort study in Norway from 2015 to 2017

Background It is estimated that up to a third of patients on opioid agonist therapy (OAT) have attention deficit hyperactivity disorder (ADHD). Treatment by ADHD medication, including a centrally acting stimulant (CAS) or atomoxetine is one of the essential approaches. This study evaluates the use of dispensed ADHD medications in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of ADHD medications, co-dispensations of other potentially addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are investigated. Methods Information about all dispensed ADHD medication, OAT opioids, and the defined potentially addictive drugs were recorded from the Norwegian Prescription Database. Dispensation rates, the types, and the doses of dispensed ADHD medications were estimated by summarizing the number of dispensations, and the dispensed doses. Logistic regression analyses were employed to assess the associations between ADHD medication, and OAT opioid use, and dispensations of other potentially addictive drugs and DAAs against hepatitis C infection. Results A total of 9235 OAT patients were included. The proportion of patients who were dispensed ADHD medication increased from 3.5 to 4.6% throughout the study period. The three most dispensed CAS were short- and intermediate-acting methylphenidate (55%), lisdexamphetamine (24%), and dexamphetamine (17%) in 2017. Buprenorphine, rather than methadone, as OAT opioid (adjusted odds ratio: 1.6, CI: 1.2–2.1) was associated with being dispensed ADHD medication. Among patients who received CAS and OAT opioids each calendar year, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). Sixty percent of patients receiving ADHD medications were also dispensed other addictive drugs concomitantly in 2017. Similar results were found in 2015 and 2016. Conclusion Co-prescription of ADHD medications was low among patients on OAT in Norway, considering a high prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs were common in this population. Understanding the underlying reasons for such prescribing is essential, and research on how to optimize ADHD medication of patients with ADHD receiving OAT is needed