Pre-treatment preference, opioid use, and life satisfaction among heroin dependent users receiving treatment with buprenorphine-naloxone or extended-release naltrexone : A 12 week randomized trial and a 36 week follow-up study

Bakgrunn: Opioidavhengighet er en kompleks, alvorlig og langvarig sykdom. Legemiddelassistert rehabilitering med metadon eller buprenorfin-nalokson (BP- NLX), er en anerkjent metode for å redusere opioidbruk og risiko for overdose, samt forbedre psykososial helse. For pasienter som ønsker abstinens og foretrekker behandling uten opioider, er behandling med naltrekson (XR-NTX) antagonist mulig i noen få land. XR-NTX er en intramuskulær injeksjon gitt hver fjerde uke. Det er få studier om behandlingspreferanse blant opioidavhengige og ingen studier har sammenlignet dette hos pasienter medisinert med XR-NTX eller BP-NLX. I tillegg har betydningen av livstilfredshet som utfall hos denne pasientgruppen blitt oversett sammenlignet med studier av andre kliniske populasjoner. Formål: Målene med studien var (i) å vurdere risikoen for tilbakefall til illegale opioider; (ii) å sammenligne effekten av behandlingspreferanser på retensjon i behandling, ulovlig opioidbruk og risiko for tilbakefall; (iii) å evaluere endringer i livstilfredshet i RCT blant deltakerne randomisert til XR-NTX og BP-NLX, og i oppfølgingsstudien blant de som fortsatte XR-NTX og byttet fra BP-NLX til XR-NTX. Materiale og metoder: Dette er en åpen klinisk randomisert studie med flere opptaksområder. N=159 pasienter med opioidavhengighet ble randomisert til enten månedlig intramuskulær XR-NTX-injeksjoner eller daglig oral BP-NLX i 12 uker. Deltakerne (n=117) i den påfølgende 36-ukers XR-NTX oppfølgingsstudien fortsatte enten XR-NTX eller ble indusert på XR-NTX. Preferanse for behandling ble målt før studien. Data om illegal opioidbruk, annen rusmiddelbruk, og livstilfredshet målt med Temporal Satisfaction with Life-skalaen (TSWL) ble registrert hver fjerde uke. Resultater: Risikoen for tilbakefall til illegal opioidbruk var signifikant lavere i XR- NTX-gruppen sammenlignet med BP-NLX-gruppen. Den lave risikoen for tilbakefall var stabil blant XR-NTX-deltakere også i oppfølgingsstudien. Graden av foretrukket behandling var like på tvers av de randomiserte gruppene, uten signifikante assosiasjoner mellom preferanse og retensjon i av behandling, opioidbruk eller tilbakefall i RCT. I oppfølgingsperioden, blant alle deltakerne, var retensjon i behandling dobbelt så høy blant deltakere med høyest preferanse sammenlignet med deltakere med lavest preferanse. Opioidbruk var signifikant høyere blant deltakerne med lavest preferanse enn medium eller høyest preferanse i gruppen byttet til XR-NTX. Risikoen for tilbakefall var signifikant høyere blant deltakerne med lavest eller middels preferanse enn de med høyest preferanse i gruppen som fortsatte med XR-NTX. I RCT-delen var TSWL-skåre signifikant høyere i XR-NTX-gruppen ved uke 4 og uke 8, sammenlignet med BP-NLX-gruppen. I oppfølgingsperioden var gruppene signifikant forskjellige ved uke 16 og uke 48, med høyere TSWL-skåre i gruppen som fortsatte med XR-NTX. En økning i opioidbruk med én dag var assosiert med lavere TSWL-skåre. Både i gruppene med lav og høy livstilfredshet, viste TSWL-skåre en betydelig økning fra baseline og ved uke 12. I oppfølgingsperioden viste TSWL-skåre en betydelig økning fra uke 16 til uke 48 i høy livstilfredshet-gruppen, mens lav livstilfredshet-gruppen viste vedvarende lavere verdier gjennom denne perioden. Konklusjon: Under behandling med XR-NTX var risikoen for tilbakefall til illegal opioidbruk signifikant redusert sammenlignet med BP-NLX-behandlingen i RCT- perioden. Forbedringer var assosiert med matching til den foretrukne behandlingen, samt styrken i preferansen til pasientene. Livstilfredsheten økte betydelig mer i XR- NTX-gruppen enn i BP-NLX-gruppen og i den fortsettende XR-NTX gruppen sammenlignet med den post RCT induserte på XR-NTX gruppen. De deltakerne som i utgangspunktet hadde relativt lav livstilfredshet viste ingen endring med lengre behandling. Hyppig bruk av opioider var signifikant assosiert med lav eller redusert livstilfredshet. Behandling med langtidsvirkende naltrekson bør være et tilgjengelig tilbud for pasienter med opioidavhengighet som er motivert og interessert i opioidfri behandling.Background: Opioid dependence is a complex, severe and long-term chronic disease. Opioid maintenance treatment with methadone and buprenorphine-naloxone (BP- NLX) is a recognized method of reducing opioid use and the risk of overdose, as well as improving psychosocial health. For those who want to achieve abstinence and prefer treatment without opioids, naltrexone (XR-NTX) antagonist treatment is possible in a few countries. XR-NTX is an intramuscular injection given every fourth week. There are few studies on treatment preference among opioid-dependent people. No studies have previously compared XR-NTX with BP-NLX. In addition, the importance of life satisfaction as the outcome has been overlooked compared to studies in other clinical populations. Study aims: The aims were (i) to assess the risk of relapse to illicit opioids; (ii) to compare the effect of treatment preference on adherence, illicit opioid use and risk of relapse; and (iii) to evaluate changes in life satisfaction in the RCT among participants randomized to XR-NTX and BP-NLX, and in the follow-up study among those who continued XR-NTX and switched from BP-NLX to XR-NTX. Material and methods: In a Norwegian, multi-site, open-label clinical trial, n=159 participants with opioid use disorder were randomized to either monthly XR-NTX or daily BP-NLX for 12 weeks. Participants (n=117) in a subsequent 36-week XR-NTX follow-up study either continued XR-NTX or were switched to XR-NTX. Preference for treatment was measured prior to the study. Data on illicit opioid use, other substance use, life satisfaction measured with the Temporal Satisfaction with Life scale (TSWL), and covariates were collected every fourth week. Results: The risk of relapse to illicit opioid use was significantly lower in the XR-NTX group compared to the BP-NLX group. Subsequently, the low risk of relapse remained stable among XR-NTX participants in the follow-up study. Preference levels were similar across the randomized groups, with no significant associations between preference and adherence to treatment, opioid use or relapse in the RCT. In the follow-up period, among all participants, the rate of adherence was twice as high among participants with the highest preference compared to participants with the lowest preference. Opioid use was significantly higher among participants with the lowest preference than the medium or the highest preference in the switched to XR-NTX group. The risk of relapse was significantly higher among participants with the lowest or the medium preference than those with the highest preference in the continued on XR-NTX group. TSWL scores were significantly higher in the XR-NTX group at Week 4 and Week 8 compared to the BP-NLX group in the RCT. In the follow-up period, the groups were significantly different at Week 16 and Week 48, with the higher TSWL scores in the continued on XR-NTX group. An increase in opioid use by one day was associated with lower TSWL scores. In both the low and high life satisfaction groups, TSWL scores exhibited a significant increase from baseline and at Week 12. In the follow-up period, TSWL scores exhibited a significant increase from Week 16 to Week 48 in the high Life Satisfaction group, while the low Life Satisfaction group showed persistently lower values throughout that period. Conclusions: During treatment with XR-NTX, the risk of relapse to illicit opioid use was significantly reduced compared to the BP-NLX treatment in the RCT. Improvements were associated with the matching to the preferred treatment as well as the strength of the preference. Life satisfaction increased significantly more in the XR- NTX group than in the BP-NLX group and in the continued on XR-NTX group compared to the post RCT switched to XR-NTX group. Those participants who initially had relatively low life satisfaction showed no change with longer treatment. Frequent use of opioids was significantly associated with low or reduced life satisfaction. Our results support XR-NTX treatment as an alternative option for patients with opioid dependence who are motivated and interested in opioid-free treatment.Doktorgradsavhandlin

Risk of Relapse Among Opioid‐Dependent Patients Treated With Extended‐Release Naltrexone or Buprenorphine‐Naloxone: A Randomized Clinical Trial

Background and Objectives Compare the risk of relapse to heroin and other illicit opioids among opioid-dependent patients receiving treatment with extended-release naltrexone (XR-NTX) or buprenorphine-naloxone (BP-NLX). Methods Re-analyzed data from a 12-week multicenter, open-label, randomized treatment study with a subsequent 36-week open-label follow-up study. All patients, N = 143, had completed detoxification and received at least one dose of study medication. Results Of 143 patients (72% men), mean age 36 years, 71 received XR-NTX and 72 BP-NLX. The risk of first relapse and the risk of any relapse to heroin and other illicit opioids were both significantly lower in the XR-NTX group compared with the BP-NLX group (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.28-0.76; P = .002, and HR, 0.11; 95% CI, 0.04-0.29; P < .001, respectively) and (HR, 0.15; 95% CI, 0.09-0.27; P < .001 and HR, 0.05; 95% CI, 0.03-0.09; P < .001, respectively). There was a stable low risk of relapse among participants receiving XR-NTX in the follow-up. Discussion and Conclusions Compared to BP-NLX, patients on XR-NTX had a substantially reduced risk of relapse to illicit opioids and showed a stable low risk of relapse over time in longer-term treatment. Scientific Significance Our data support XR-NTX as a first-line treatment option for patients with opioid addiction both in short and longer-term treatment. This is the first European study showing that XR-NTX significantly reduces the risk of first and any relapse to heroin use in opioid-dependent patients compared to BP-NLX. Our data contradict previous data from the X:BOT study, showing no significant difference in relapse risk between the groups in a 6-month randomised controlled trial. (© 2021 Authors. The American Journal on Addictions published by Wiley Periodicals LLC on behalf of The American Academy of Addiction Psychiatry). (Am J Addict 2021;30:451–458)publishedVersio

Life satisfaction among individuals with opioid use disorder receiving extended-release naltrexone: A 12-week randomized controlled trial and a 36-week follow-up

Introduction Life satisfaction (LS) in opioid-dependent individuals is lower than in the general population. This study aimed to explore changes in LS during short- and long-term treatment with extended-release naltrexone (XR-NTX). Methods This open-label 12-week clinical trial randomized 159 participants to either monthly XR-NTX or daily buprenorphine-naloxone (BP-NLX). In a subsequent 36-week follow-up study on XR-NTX, participants either continued or switched to XR-NTX. The study collected data on the Temporary Satisfaction with Life (TSWL) and illicit opioid use every fourth week. The research team assessed changes in TSWL by a linear mixed model and growth mixture model. The study assessed relationship between opioid use and TSWL by a linear mixed model. Results Change in LS differed significantly between the groups in both study periods. TSWL scores were significantly higher in the XR-NTX group at week 4 (p = 0.013) and week 8 (p = 0.002). In the follow-up period, the groups were significantly different only at week 16 (p = 0.031) and week 48 (p = 0.025), with the higher TSWL scores in the XR-NTX continued group. Increase in opioid use by one day was associated with a 0.12 point lower mean TSWL score. Both study periods identified groups with low and high LS levels. In the trial period, the TSWL scores exhibited a significant increase from baseline to week 12 in both groups, p < 0.001 and p = 0.011 in the low and high LS group, respectively. In the follow-up period, the TSWL scores exhibited a significant increase from week 16 to week 48 (p = 0.003) in the high LS group, while the low LS group showed persistently lower values throughout that period. Conclusions XR-NTX treatment given once monthly is associated with higher LS, as measured by TSWL, compared to daily use of BP-NLX. The majority of the participants had relatively low TSWL scores and did not report any change in TSWL during longer-term treatment. The study found a significant association between more frequent illicit opioid use and a low or decreased LS during follow-up

Design of a randomized controlled trial of extended-release naltrexone versus daily buprenorphine-naloxone for opioid dependence in Norway (NTX-SBX)

Background Current guidelines for opioid dependence recommend daily maintenance of physical dependence with methadone or buprenorphine, and discourage abstinence due to the high risk of relapse and overdose. Extended-release formulations of the opioid antagonist naltrexone (XR-NTX) block heroin and other opioid agonists competitively for around 4 weeks per administration. XR-NTX thus enables opioid users to experience abstinence from opioid agonists with greatly reduced risk of overdose compared to medication-free abstinence. While XR-NTX has shown promise compared to placebo and daily naltrexone tablets, there is limited information on long-term safety and its performance compared to daily maintenance treatment. Methods/Design In this five-hospital RCT with long-term follow-up, we aim to recruit n = 180 patients in treatment for opioid dependence and allocate them in an open, randomized manner (1:1) to receive either 4-week XR-NTX or daily buprenorphine-naloxone (BP-NLX) for the duration of 12 weeks. Allocation is open-label due to the risk of overdose during attempts to self-unmask allocation using heroin. Urine drug tests are scheduled every week with follow-up visits & assessment every 4 weeks. Primary outcomes are abstinence from illicit opioids in urine drug tests and self-report, as well as retention in treatment. Secondary outcomes include other substance use, injecting behavior, drug craving, mental health, quality of life, treatment satisfaction, abstinence motivation, opioid agonist effect rating, insomnia, and pain. Observation is continued for another 36 weeks in order to assess longer-term safety, adherence and effectiveness. The study is an investigator-initiated trial, funded by public grants and approved by an Independent Ethical Committee (the Regional Ethical Committee for Research South-East B # 2011/1320) and the Norwegian Medicines Agency. Discussion Despite minor implementation problems, the protocol appears sufficiently robust to generate results of high interest to patients, clinicians and policy makers. Trial registration Clinicaltrials.gov # NCT01717963 , first registered: Oct 28, 2012. Protocol version # 3C, June 12th 2012

Availability of extended-release naltrexone may increase the number of opioid-dependent individuals in treatment: Extension of a randomized clinical trial

Background and objective: Opioid maintenance treatment (OMT) is highly available in Norway, but only 50% of opioid-dependent individuals are enrolled in such programs. This study was aimed at examining if availability of extended-release naltrexone (XR-NTX) could attract individuals who for different reasons were not enrolled in an OMT program. Methods: In a Norwegian clinical study, n = 117 opioid-dependent adults volunteered to receive XR-NTX in a 9-month period, as an extension of a previous randomized clinical trial. Results: Before study inclusion, 40.2% (n = 47) of the study participants were not enrolled in OMT while the remainder were recruited from OMT. Participants not enrolled in OMT displayed more ongoing severe addiction-related problems such as heroin use (p = 0.002), but displayed a higher retention in treatment in the 9-month extension study (p = 0.048 for log-rank test) than participants enrolled in OMT. Conclusion: Availability of XR-NTX attracted opioid-dependent individuals not previously enrolled in OMT. While OMT may be perceived as a burden with regard to daily intake and control measures, one-monthly injections with XR-NTX may be perceived favourable, offering more freedom to the patients, not having addictive properties, and potentially reducing heroin craving. We suggest that an introduction of XR-NTX in Europe may increase the number of opioid-dependent individuals in treatment

Availability of extended-release naltrexone may increase the number of opioid-dependent individuals in treatment: Extension of a randomized clinical trial

Background and objective: Opioid maintenance treatment (OMT) is highly available in Norway, but only 50% of opioid-dependent individuals are enrolled in such programs. This study was aimed at examining if availability of extended-release naltrexone (XR-NTX) could attract individuals who for different reasons were not enrolled in an OMT program. Methods: In a Norwegian clinical study, n = 117 opioid-dependent adults volunteered to receive XR-NTX in a 9-month period, as an extension of a previous randomized clinical trial. Results: Before study inclusion, 40.2% (n = 47) of the study participants were not enrolled in OMT while the remainder were recruited from OMT. Participants not enrolled in OMT displayed more ongoing severe addiction-related problems such as heroin use (p = 0.002), but displayed a higher retention in treatment in the 9-month extension study (p = 0.048 for log-rank test) than participants enrolled in OMT. Conclusion: Availability of XR-NTX attracted opioid-dependent individuals not previously enrolled in OMT. While OMT may be perceived as a burden with regard to daily intake and control measures, one-monthly injections with XR-NTX may be perceived favourable, offering more freedom to the patients, not having addictive properties, and potentially reducing heroin craving. We suggest that an introduction of XR-NTX in Europe may increase the number of opioid-dependent individuals in treatment