Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 https://doi.org/10.1186/s12954-022-00592-x REVIEW Open Access Interim opioid agonist treatment for opioid addiction: a systematic review Laura Samsó Jofra1 , Teresa Puig1,2,3,4 , Ivan Solà1,2,5,6 and Joan Trujols2,7,8* Abstract Background: Opioid use disorder is a public health problem and treatment variability, coverage and accessibil- ity poses some challenges. The study’s objective is to review the impact of interim opioid agonist treatment (OAT), a short-term approach for patients awaiting standard OAT, in terms of treatment retention, access to standard OAT, quality of life and satisfaction with treatment. Method: We conducted a systematic review searching MEDLINE, EMBASE, PsycINFO, and CENTRAL up to May 2020. Due to variability between studies and outcome measurements, we did not pool effect estimates and reported a nar- rative synthesis of findings rating their certainty according to GRADE. Results: We identified 266 unique records and included five randomized trials with some limitations in risk of bias and one observational study limited by selection bias. The studies assessed similar approaches to interim OAT but were compared to three different control conditions. Four studies reported on treatment retention at 4 months or less with no significant differences between interim OAT and waiting list or standard OAT. Two studies reported treatment retention at 12 months with no differences between interim OAT and standard OAT. Two trials assessed access to standard OAT and showed significant differences between interim OAT and waiting list for standard OAT. We rated the quality of evidence for these outcomes as moderate due to the impact of risk of bias. Data on quality of life or satisfac- tion with treatment was suboptimal. Conclusions: Interim OAT is likely more effective than a waiting list for standard OAT in access to treatment, and it is probably as effective as standard OAT regarding treatment retention. PROSPERO registration CRD42018116269. Keywords: Opioid use disorder, Opioid agonist treatment, Interim treatment, Methadone, Buprenorphine, Systematic review Background used OAT medications (i.e., methadone and buprenor- Opioid agonist treatments (OATs) reduce injection- phine) have been widely researched and proved [9–12]. related mortality and morbidity [1–3], all-cause and over- Despite this evidence, there is great worldwide vari- dose mortality [4–6], and improve quality of life [7, 8] ability in OAT practices and coverage. A recently pub- among people with opioid use disorder. In fact, the safety, lished, global systematic review [13] found wide variation efficacy and effectiveness of the two most commonly between—and within—countries in the way OAT is deliv- ered (e.g., treatment eligibility criteria, mean opioid dose prescribed, access to unsupervised dosing, and urine drug screening practices) in routine clinical practice. *Correspondence: jtrujols@santpau.cat By 2020, many countries in Asia, Latin America 2 Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain and Africa had very low levels of OAT coverage [14]. Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 2 of 18 In Europe it is estimated that treatment coverage is Method around 50% but there is also great variability and some We conducted a systematic review according to a countries have low or insufficient levels (< 30%) [15]. protocol (International Prospective Register of Sys- In USA, demand for OAT far exceeds available capa- tematic Reviews (PROSPERO) registration number bility, with an alarming number of OAT clinics hav- CRD42018116269), which is available at Open Science ing extensive waitlists (even of years) [16] and, despite Framework (https://​osf.​io/​fsvte/), following the meth- the current opioid crisis, treatment coverage does not odological standards from Cochrane Collaboration [23] improve proportionally [17]. These waitlists have a and reported the results following the Preferred Report- direct detrimental effect on people awaiting treatment, ing Items for Systematic Review and Meta-Analysis placing them at high risk for criminal activity, infec- (PRISMA) statement [24] (Additional file 1). tious disease, overdose, and mortality [16, 18]. In fact, the costs of untreated opioid use disorder of patients Study selection placed on a methadone treatment waiting list also We included studies that: (1) assessed interim metha- entail a significant financial burden to society [19]. done or buprenorphine treatment for individuals with In this context of insufficient coverage and increas- opioid use disorder awaiting entry into standard OAT; ing waiting lists, low-threshold treatments such as (2) included any control condition such as placebo, no interim OAT have been proposed and introduced. This intervention (waiting list), or standard OAT; (3) were treatment option provides limited services to people published in a peer-reviewed journal. In addition to ran- with opioid use disorder who would otherwise be on a domized control trials we included comparative observa- waiting list for comprehensive, standard OAT. Interim tional studies, follow-up studies assessing the long-term clinics usually provide intake physical examination, effects of interim OAT, and economic evaluation studies. education about acquired immune deficiency syn- Eligible studies included patients with an opioid use drome (AIDS) and opioid agonist medication but do disorder diagnosed according to standardized criteria not provide psychosocial interventions as such. They (e.g., Diagnostic and Statistical Manual of Mental Dis- are expected to bridge waitlist for at risk populations orders (DSM), International Classification of Diseases and reduce harm to them; therefore, these clinics’ (ICD)) who were candidates to be admitted into a stand- main aim is harm reduction. Interim OAT is dispensed ard OAT. We included studies assessing an interim OAT daily by a nurse and usually taken with direct obser- (methadone or buprenorphine) defined by the provision vation, and the treatment should last no longer than of opioid agonist medication without other interventions 120 days [20]. Interim OAT was first mentioned in the to people who were suffering opioid use disorder and 1970’s [21] and has been introduced in some countries whose only other option would have been a waiting list since then. In USA, it was approved by the Food and for the standard OAT [22]. Drug Administration (FDA) in 1993 [22]. Given (i) the anticipated heterogeneity of outcome var- Given the current opioid crisis, the ongoing global iables in eligible studies, (ii) the lack of a core outcome variability in OAT’s accessibility and coverage keeps set for OAT research [25–27], and (iii) the fact that some putting patients at risk and has negative consequences of the commonly used outcome variables in OAT evalu- for both patients and society. Interim OAT has been ations may not adequately reflect patient perspectives proposed as an option to mitigate these problems but [28–30], we decided to not restrict our review to a few has not yet been evaluated globally. particular outcome variables. We considered the follow- The objective of the study is to conduct a systematic ing primary outcomes: retention in treatment, access review in order to synthetize the current knowledge on to standard OAT, quality of life or well-being and users’ the following clinical question (according to the PICO satisfaction with treatment. Secondary outcomes were framework): among people with opioid use disorder the use of illicit opioid and/or non-prescribed psychoac- (population), is interim OAT (intervention), compared tive substances, criminal activity and/or illegal income, to other approaches (comparison), more effective mental and/or physical health status, the rate of adverse and cost-effective in terms of retention in treatment, effects and the costs of this intervention. access to standard OAT, quality of life or well-being, satisfaction with treatment, use of non-prescribed psy- Search methods for identification of studies choactive substances, criminal activities, mental and We searched MEDLINE, EMBASE, PsycINFO, and physical health status and adverse effects (outcomes)? Cochrane Central Register of Controlled Trials from their inception until May 2020, without limitations in language or publication status. We designed a search Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 3 of 18 strategy (Additional file 2) using text words related to Due to the heterogeneity in outcome measurements, the intervention and population of interest combined we were not able to pool data with meta-analytical tech- with controlled vocabulary, adapted to the requirements niques; therefore, we performed a narrative synthesis of of each database. We searched the International Clini- the results. We describe the intended analytical plan in cal Trials Register for ongoing studies. Additionally, we the protocol of this review (available at Open Science screened the reference lists of relevant studies. Framework: https://​osf.​io/​fsvte/). We rated the quality of evidence for the primary out- comes according GRADE guidance [32] as an expression Data extraction and management of the extent to which one can be confident in the effect We constructed a database in a reference management estimates. We assessed the following domains: risk of software (EndNote X2; Clarivate Analytics, Boston, bias, directness of evidence, heterogeneity, precision, and MA, USA) to store the results from searches and elimi- publication bias. Each outcome was classified as high, nate duplicates between bibliographic databases. Two moderate, low or very low depending on the presence researchers screened titles and abstracts independently of limitations in the mentioned domains. Evidence from and discarded studies that were not eligible. We obtained randomized trials was considered as high and down- a full text copy of the references considered relevant at graded on the basis of these limitations. Finally, outcomes this stage to determine their final inclusion. We handled with findings from estimates from observational studies disagreements by discussion between the two researchers were rated as low due to the impact of risk of bias. and sought arbitration from a third researcher. Two independent researchers extracted data using a predesigned data extraction form. We collected data to Results describe the main characteristics of each of the included Search results studies in terms of design, risk of bias, participants, inter- We identified 471 citations and, after removing dupli- ventions and outcomes assessed. Where more than one cates, 266 records were left for screening title and publication of one study existed, we grouped the reports abstract. Once the screening process was completed, we together and used the publication(s) with the most com- obtained full text copies of 42 articles to decide their final plete data according our outcomes of interest. The two eligibility (Fig. 1). researchers reviewed and discussed any disagreements We excluded 29 studies for the following reasons: 3 arisen in the data extraction process and, when needed, publications were excluded due to a non-eligible study we sought arbitration from a third researcher. design, 8 were excluded because their intervention was not eligible according to the definition of interim OAT, 2 were excluded because they reported irrelevant data for Assessment of risk bias the purposes of this review, 4 were excluded because they Two researchers assessed the risk of bias of each included are ongoing studies and 12 were excluded because they study. For clinical trials we used the Cochrane Risk of were conference communications or comments on other Bias Assessment Tool and made explicit judgments on articles (Additional file 3). selection, performance, detection, attrition and reporting Finally we included 6 studies that reported their results biases [23]. in 13 publications [21, 33–44] (Additional file 4). For the rest of study designs we used a modified Risk Of Bias In Non-randomized Studies—of Interven- Characteristics of included studies tions (ROBINS-I) tool, which is specifically designed to We included 5 randomized trials [21, 35, 37, 41, 44] and 1 assess non-randomized studies that measure the impact observational retrospective study [33]. In addition, one of of interventions [31]. We focused the assessment in the trials included a publication with an economic evalu- confounding, selection bias, bias in measurement of ation [36]. Table 1 outlines the main characteristics of the interventions, bias due to deviations from intended included studies that are described in detail at the Addi- interventions, bias due to missing data, bias in outcome tional file 4. All the studies included in this review were assessment, and bias in the selection of the reported carried out in the United States of America, except one results. that was carried out in Norway [35]. Sample sizes ranged from 50 [41] to 977 participants [33]. Data analysis and synthesis All participants in the included trials were adults with We obtained effects estimates for our outcomes of inter- an opioid use disorder diagnosed according to DSM (IV est to ascertain the impact of interim OAT and the mag- or DSM V) and/or were on a waiting list for standard nitude of effect and compare them between studies and OAT. The observational study [33] included all consecu- the comparisons set at the included studies. tive admissions to an interim clinic during 2 years. Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 4 of 18 Records identified through Idenficaon database searching (n = 471) (197 MEDLINE, 118 EMBASE, 49 PsycINFO, 107 CENTRAL) Records after duplicates removed (n = 266) Screening Records excluded by title Records screened and abstract (n = 266) (n = 224) Full-text articles assessed Full-text articles excluded Eligibility for eligibility · Non eligible study design (n = 3) (n = 42) · Non eligible intervention according to the definition set at the review protocol (n = 8) · Reported irrelevant data for the purposes of the review (n = 2) 6 studies included in narrative synthesis of 13 · Ongoing study (n = 4) Included publications · Congress presentation / Comment (n = 12) Fig. 1 PRISMA 2009 flow diagram of the search and selection process The interventions assessed in the included studies of interim treatment, one with buprenorphine and the met the pre-defined definition of interim OAT set in the other with placebo. review protocol (Table 1). Interventions had slight differ- Primary outcomes among the studies mainly included ences among studies, such as the medication used. While retention in treatment, access to standard OAT, use of most of the studies used methadone, two used buprenor- illicit drugs and criminal activities or illegal income. Of phine [35, 41]. these, only two outcomes (retention in treatment and Most of the studies did not allow take-home medica- access to standard OAT) were a priori considered as tion [21, 35, 37] or allowed just one take-home dose per main outcomes for the purpose of this review. Outcome week [33, 44]; nevertheless, one study used a portable measurements across studies were very heterogeneous, dispenser device holding multiple-day doses in individu- and did not allow us to obtain pooled estimates for them. ally locked compartments and allowed access to the med- ication during a 3-h window every day [41]. Risk of bias What made the studies differentiate the most were the Although most of the included trials had a low risk in control conditions since some included a waiting list for selection bias (only one trial [41] did not provide details standard OAT as a control condition [21, 41, 44] and oth- on the efforts to conceal the participants assignment to ers used standard OAT as a control condition [33, 37]. study groups), we had some concerns regarding the rest Finally, one of the studies [35] compared two modalities of domains (Table 1). As we had already anticipated in Table 1 Summary of characteristics of included studies and Risk of Bias (RoB) Study ID (Design, Country) Participants Intervention Study’s primary outcomes Risk of Bias (RoB) Yancovitz et al. 1991 301 participants: Interim Clinic: Methadone administered by a Change in heroin use Random sequence generation: Unclear (Randomized Controlled 149 Treatment group nurse 5 days a week. Saturday medication and Allocation concealment: Low Trial (RCT), USA) [44] 152 Frequent contact group one take-home were provided at another site Blinding of participants and personnel: High in the same building + AIDS education + free Blinding of outcome assessment (objective out- condoms. Minimal counseling on an ad hoc basis. comes): Unclear Biweekly urine samples. Maintenance dose of Blinding of outcome assessment (subjective out- 80 mg/d approximately comes): Unclear Control: Waiting list, biweekly follow-up and Incomplete data outcome: High urine samples, and free condoms. Time spent Selective reporting bias: Unclear Samsó Jofra et al. Harm Reduction Journal limited to one month and then switched into experimental group Schwartz et al. 2006 319 participants: Interim Treatment: Methadone provided under Entry into comprehensive Random sequence generation: Low (RCT, USA) [21] 199 Treatment group direct observation, participants attended 7 days methadone treatment Allocation concealment: Low 120 Waiting list a week (as the federal regulation required). 3 Self-reported days of heroin use Blinding of participants and personnel: High consecutive unexcused missed doses resulted in Self-reported days of cocaine Blinding of outcome assessment (objective out- (2022) 19:7 discharge from treatment. Mean dose of metha- use comes): Low done was 78.4 mg/d Self-reported criminal behavior Blinding of outcome assessment (subjective Control: Waiting list; no further contact with Number of urine drug test outcomes): High clinical staff unless their name came up on the results positive for heroin and Incomplete data outcome: High waiting list cocaine Selective reporting bias: Unclear Retention in treatment NCT02360007 50 participants: Interim Treatment: Interim buprenorphine Negative results for illicit opioids Random sequence generation: Low (RCT, USA) [41] 25 Treatment group treatment (IBT) participants will complete Allocation concealment: Unclear 25 Waiting list buprenorphine (BUP) induction in Week 1 (or Blinding of participants and personnel: High longer if required), during which they will attend Blinding of outcome assessment (objective out- the clinic daily. Thereafter, during Weeks 2–12 IBT comes): Unclear participants will visit the clinic every two weeks Blinding of outcome assessment (subjective out- to take their BUP dose, provide a urine specimen comes): Unclear and receive their remaining doses in a secure Incomplete data outcome: High dispenser that makes each day’s dose available Selective reporting bias: High during a 3-h window Control: Waitlist control (WLC) participants will remain on the waitlist for their treatment of choice. They will visit the clinic to complete follow-up assessments and provide staff- observed urines according to the same schedule as IBT participants Participants in both conditions will complete follow-up assessments and provide a urine speci- men at 4, 8, 12, 18 and 24 weeks after trial entry. WLC participants who have not entered treat- ment by Week 12 will be offered IBT at that time, providing an additional within-subject evaluation of IBT effects. Thus the overall possible study duration may vary between 12—28 weeks Page 5 of 18 Table 1 (continued) Study ID (Design, Country) Participants Intervention Study’s primary outcomes Risk of Bias (RoB) NCT00712036 230 participants: Interim Treatment (IM): Methadone treatment Opiate positive drug test Random sequence generation: Low (RCT, USA) [37] 99 Treatment group (IM) for up to 4 months with emergency counseling Allocation concealment: Low 104 Control condition 1 (SM) only. Treatment was provided following federal Blinding of participants and personnel: High 27 Control condition 2 (RM) regulations. Mean methadone dose of 91.8 mg/d Blinding of outcome assessment (objective out- (SD 21.3) comes): Low Control: Blinding of outcome assessment (subjective 1. Scheduled counseling/Standard Metha- outcomes): High done Treatment (SM): Methadone treatment Incomplete data outcome: Low with counseling as usual. Methadone treatment Selective reporting bias: Low Samsó Jofra et al. Harm Reduction Journal programs (MTPs) usual practices, which permitted take-home doses contingent upon tenure and progress in treatment (e.g., negative drug tests), required regularly scheduled counseling, treat- ment planning, other psychosocial treatment as needed, and more frequent drug testing than in (2022) 19:7 IM. Mean methadone dose of 79.4 mg/d (SD 22.3) 2. Restored Methadone Treatment (RM): Methadone treatment with counseling provided by a clinician with a lower caseload than coun- seling as usual. That counselor carried a reduced case load not to exceed 25 patients and was instructed to see the participants as frequently as the participants wanted and the counselor deemed appropriate. Mean methadone dose of 64.7 mg/d (SD 15.6) Krook et al. 2002 106 participants: Buprenorphine: Buprenorphine without addi- Retention (is the patient still in Random sequence generation: Low (RCT, Norway) [35] 55 Treatment group tional rehabilitation or support. 4 mg Subutex® the project?) Allocation concealment: Low 51 Control condition on the first day, increased to 16 mg/d on the Compliance (how many of the Blinding of participants and personnel: Low following 8 days. At the ­12th week, dosage was total number of doses had been Blinding of outcome assessment (objective out- scaled down to 4 mg/d taken?) comes): Low Control: Placebo without additional rehabilitation Blinding of outcome assessment (subjective or support. 4 mg of Subutex® on the first day and outcomes): Low then the dose was decreased to 0 in 9 days and Incomplete data outcome: Unclear thereafter replaced by placebo Selective reporting bias: Low Page 6 of 18 Samsó Jofra et al. Harm Reduction Journal Table 1 (continued) Study ID (Design, Country) Participants Intervention Study’s primary outcomes Risk of Bias (RoB) (2022) 19:7 Friedmann et al. 1994 977 participants: Interim Methadone Treatment: A physical Retention rate in treatment Confounding: Serious (Cohort study, USA) [33] 314 Treatment group examination on admission was performed by Selection of participants: Serious 663 Control condition a physician, methadone was administered by Classification of intervention: Low a registered nurse six days per week with one Deviation from intended intervention: Serious take-home dose for Sunday, and education about Missing outcome data: Low AIDS-risk reduction was provided. Only crisis Measurement of the outcome: Low counseling services were provided, and the focus Selection of the reported result: Low of the interim clinic counselors was otherwise limited to AIDS-risk reduction. The clinic had a capacity of 150 patients, thus providing a ratio of 1 counselor to 75 patients Control: The comparison group includes all con- secutive 1990 and 1991 admissions to Beth Israel’s traditional methadone clinics located in the same immediate area as the interim clinic Page 7 of 18 Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 8 of 18 our protocol due to the nature of the intervention, per- Finally, one study [35] comparing interim OAT with formance bias was at higher risk for all the included tri- buprenorphine to interim treatment with placebo found als with the exception of one of them [35]. Regarding significant differences in the proportion of patients detection bias, we distinguished between the assessment remaining in treatment at 12 weeks (16 vs. 1 patients, of objective and of subjective outcomes since we consid- p < 0.001) and in the mean number of days of participa- ered that objective outcomes were less likely to be biased tion in treatment (42 vs. 14 days), with the intervention despite the outcome assessors were not blinded. Hence group showing higher retention rates in both cases. We this domain was mainly rated as low risk of bias for objec- rated the quality of evidence as low for this comparison tive outcomes and as unclear or high risk for subjective due to indirectness (the trial compared two interim treat- outcomes. We rated attrition bias as high for most of the ment modalities) and the imprecision of effect estimates. studies mainly because either some trial did not provide a sample size estimate or they did not reach it, or the rea- Access to standard OAT son for the losses was not clear enough. Finally, we rated Two trials comparing interim OAT with a waiting list reporting bias as unknown for most trials due to lack of for standard OAT [21, 44] evaluated the access to stand- information. For the observational study, we considered ard OAT. One of these studies [21] found a significant that the risk of bias was serious due to its selection and difference when assessing this outcome at both 4 and performance biases. 10 months after starting the treatment. At 4 months, 75.9% of the patients in the intervention group accessed a standard OAT while only 20.8% from the control group Effect of intervention did (p < 0.001). At 10 months this difference remained Due to the huge variability between study characteristics significant (64.8% vs. 27.5%; p < 0.001). In total, at the (mostly because their planned interventions and con- end of the study, the authors reported that 78.4% of the trols and the outcomes measures) we did not perform participants in interim OAT group had entered standard a pooled analysis from the study results. We provide a OAT compared to 32.5% in the comparison group. narrative summary of the review findings according to The other study [44] also found significant differences its outcomes of interest and the comparisons assessed in (p < 0.005) in this outcome measured 16 months after the the included trials. We present the detailed review find- beginning of the study, with 72% of patients in the inter- ings in Table 2. We also report the quality of evidence for vention group and 56% in the control group accessing each primary outcome and each comparison of interest standard OAT. We rated the quality of evidence as mod- in Table 2. erate for this outcome due to the impact of risk of bias. Retention in interim OAT Retention in standard OAT Three trials [35, 38, 41] and one observational study [33] Two studies comparing interim OAT with standard OAT, reported on retention at or before 4 months of treatment. one trial [37] and one observational study [33], evalu- This can be interpreted as a measure of retention in the ated the retention in standard OAT at 12 months after interim OAT itself since this treatment approach lasts a the beginning of the study. The trial [37] found no signifi- maximum of 120 days. cant differences between groups for this outcome (60.6% One trial did not find significant differences in reten- for IM, 54.8% for SM, and 37.0% for RM). Similarly, the tion rates between interim OAT and a group of patients observational study [33] did not show any significant dif- in a waiting list for standard OAT (92% vs. 80%) [41]. ferences in retention rates at 12 months when comparing Two studies [33, 38] compared interim OAT with stand- interim OAT with standard OAT (55% vs. 61%, p = 0.17). ard OAT. One trial [38] found no significant differences We rated the quality of evidence as moderate for this out- in treatment retention rates at 4 months between the 3 come due to the impact of risk of bias. comparison groups (91.9%, 80.8%, and 88.9% respectively for interim methadone treatment (IM), standard metha- Quality of life or well‑being done treatment (SM) and restored methadone treatment None of the studies comparing the impact of an (RM); see Table 1 and Additional file 4 for a detailed interim OAT with a waiting list or standard OAT description). Similarly, the observational study [33] did reported on quality of life. Only the trial that compared not find significant differences with regards to retention interim OAT with buprenorphine to interim treatment rate at 3 months (78% vs. 84%). For the comparisons of with placebo [35] assessed this outcome at 3 months of interim OAT versus waiting lists or standard OAT we follow-up with a visual analogic scale and a validated rated the quality of evidence as moderate for the impact instrument. Both scales showed a greater and sig- of risk of bias. nificant increase in well-being for the buprenorphine Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 9 of 18 Table 2 Findings by outcome OUTCOME FINDINGS PRIMARY OUTCOMES Retention in (Interim/Standard) Treatment (4 studies) Interim versus Waiting List for Standard OAT (1 study) Moderate quality of evidence due to risk of bias (the trial did not describe the efforts to conceal the allocation sequence, and had a high performance and attri- tion risk of bias) Retention at 3 months 23/25 versus 20/25 (no significant difference) (NCT02360007) [41] Interim versus Standard OAT (2 studies) Moderate quality of evidence due to risk of bias (effects estimates at least from one observational study) Retention at 3 months 245/314 versus 557/663 (no significant difference) (Friedmann et al. 1994) [33] Retention at 4 months 91/99 versus 84/104 with SM (Standard Methadone Treatment) versus 24/27 with RM (Restored Methadone Treatment) (p = 0.06) (NCT00712036) [37] Retention at 6 months 217/314 versus 504/663 (no significant difference) (Friedmann et al. 1994) [33] Retention at 12 months 60/99 versus 57/104 with SM versus 10/27 with RM (p = 0.09) (NCT00712036) [37] 173/314 versus 404/663 (no significant difference) (Friedmann et al. 1994) [33] Interim with Buprenorphine versus Interim with Placebo (1 study) Low quality of evidence due to indirectness (comparison of two interim treatment modalities) and imprecision in effect estimates Retention at 3 months 16/55 versus 1/51 (p < 0.001) (Krook et al. 2002) [35] Access to Standard OAT (2 studies) Interim versus Waiting List for Standard OAT (2 studies) Moderate quality of evidence due to risk of bias (although trials were at low risk of selection bias, were limited in terms of performance, detection and attrition bias) Access at 4 months 151/199 versus 25/120 (p < 0.001) (Schwartz et al. 2006) [21] Access at 10 months 129/199 versus 33/120 (p < 0.001) (Schwartz et al. 2006) [21] Access at 16 months 107/149 versus 85/152 (p < 0.005) (Yancovitz et al. 1991) [44] There were no studies that assessed this outcome for the following comparisons: Interim versus standard OAT Interim with buprenorphine versus interim with placebo Quality of Life or Well-Being (1 study) Interim with Buprenorphine versus Interim with Placebo (1 study) Low quality of evidence due to indirectness (comparison of two interim treatment modalities) and imprecision in effect estimates Subjective well-being at 3 months [Visual analogue Scale (VAS); 10 = very bad, 0 = very well] 4.82 (SD not reported) versus 5.92 (SD not reported) (p < 0.001) (Krook et al. 2002) [35] Change in well-being at 3 months − 2.00 (Confidence Interval (CI) − 2.95; − 1.04) versus − 0.43 (CI − 1.32;0.45) (p < 0.001) (Krook et al. 2002) [35] Temporal satisfaction with life scale (TSLS) at 3 months [TSLS; 15 items, 7 point Likert response, 0 = “very well” and 7 = “very bad”] 4.81 (SD not reported) versus 5.11(SD not reported) (p < 0.05) (Krook et al. 2002) [35] Change in temporal satisfaction with life scale at 3 months − 0.65 (CI − 1.00; − 0.31) versus − 0.24 (CI − 0.57;0.09) (p < 0.05) (Krook et al. 2002) [35] There were no studies that assessed this outcome for the following comparisons: Interim versus waiting list to standard OAT Interim versus standard OAT Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 10 of 18 Table 2 (continued) OUTCOME FINDINGS Satisfaction with Treatment (1 study) Interim versus Waiting List for Standard OAT (1 study) Very low quality of evidence due to risk of bias (some concerns about selection bias, and high risk for performance and attrition bias), indirectness (effect estimate obtained only from the intervention arm from one trial) and imprecision in effect estimates User satisfaction for patients at the interim intervention group at 3 months [according to a 5-point Likert score, with a higher score corresponding to greater satisfaction] 4.6 (SD 0.7) (NCT02360007) [41] There were no studies that assessed this outcome for the following comparisons: Interim versus standard OAT Interim with buprenorphine versus interim with placebo SECONDARY OUTCOMES Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances Interim versus Waiting List for Standard OAT (3 studies) (Heroin Positive Urine Tests) (4 studies) At 1 month 22/75 versus 56/94 (Odds Ratio (OR) 3.55; CI 95% 1.862–6.771) (p < 0.001) (Yanco- vitz et al. 1991) [44] At 3 months 17/25 versus 0/25 (number of negative tests) (p < 0.001) (NCT02360007) [41] At 4 months 99/175 versus 80/113 (p < 0.001) (Schwartz et al. 2006) [21] At10 months 75/156 versus 73/101 (p = 0.001) (Schwartz et al. 2006) [21] Interim versus Standard OAT (1 study) At 4 months 44/96 versus 47/92 with SM versus 10/25 with RM (p = 0.98) (NCT00712036) [37] At 12 months 0.46 (Standard error (SE) 0.05) versus 0.48 (SE 0.05) with SM versus 0.51 (SE 0.11) with RM (p = 0.91) (NCT00712036) [37] There were no studies that assessed this outcome for the following comparison: Interim with buprenorphine versus interim with placebo Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances Interim versus Waiting List for Standard OAT (2 studies) (Heroin Self-Reported) (4 studies) At 1 month 21/75 versus 83/94 (p < 0.001) (Yancovitz et al. 1991) [44] At 4 months Days of heroin use in the past 30 days: 4.2 (SD 8.6) versus 26.4 (SD 8.8) (p < 0.001) (Schwartz et al. 2006) [21] At 10 months Days of heroin use in the past 30 days: 5.7 (SE 0.90) versus 17.7 (SE 1.2) (p < 0.001) (Schwartz et al. 2006) [21] Interim versus Standard OAT (1 study) At 4 months Days of heroin use in the past 30 days: 2.6 (SE 0.5) versus 3.6 (SE 0.8) with SM versus 2.8 (SE 1.0) with RM (p = 0.21) (NCT00712036) [37] At 12 months Days of heroin use in the past 30 days: 4.4 (SE 0.98) versus 6.2 (SE 1.2) with SM versus 6.9 (SE 2.4) with RM (p = 0.57) (NCT00712036) [37] Interim with Buprenorphine versus Interim with Placebo (1 study) At 3 months 3.99 (SD not reported) versus 6.63 (SD not reported) (using a VAS from 0 = “drug free” to 10 = “daily heavy drug abuse”) (p < 0.001) (Krook et al. 2002) [35] Change in self-reported heroin use − 3.21 (CI − 4.29; − 2.13) versus 0.52 (− 0.64; 1.68) (p < 0.001) (Krook et al. 2002) [35] Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 11 of 18 Table 2 (continued) OUTCOME FINDINGS Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances Interim versus Waiting List for Standard OAT (2 studies) (Cocaine Positive Urine Tests) At 1 month (3 studies) 51/75 versus 66/94 (OR 1.109; CI 95% 0.575–2.138) (p = 0.76) (Yancovitz et al. 1991) [44] At 4 months 107/174 versus 62/99 At 10 months (p = 0.85) (Schwartz et al. 2006) [21] At 10 months 79/153 versus 60/101 (no significant differences) (Schwartz et al. 2006) [21] Interim versus Standard OAT (1 study) At 4 months 32/96 versus 41/92 with SM versus 6/25 with RM (p = 0.75) (NCT00712036) [37] At 12 months 0.39 (SE 0.05) versus 0.36 (SE 0.05) with SM versus 0.32 (SE 0.10) with RM (p = 0.23) (NCT00712036) [37] There were no studies that assessed this outcome for the following comparison: Interim with buprenorphine versus interim with placebo Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances Interim versus Waiting List for Standard OAT (2 studies) (Cocaine Self-Reported) At 1 month (3 studies) 29/75 versus 79/94 (p < 0.001) (Yancovitz et al. 1991) [44] At 4 months Days of cocaine use in the last 30 days: 2.4 (SD 5.5) versus 5.8 (SD 8.8) (p < 0.001) (Schwartz et al. 2006) [21] At 10 months Days of cocaine use in the last 30 days: 3.5 (SE 0.63) versus 5.8 (SE 0.83) (p = 0.001) (Schwartz et al. 2006) [21] Interim versus standard OAT (1 study) At 4 months Days of cocaine use in the last 30 days: 1.6 (SE 3.8) versus 3.0 (SE 7.3) with SM versus 1.4 (SE 0.8) with RM (p = 0.082) (NCT00712036) [37] At 12 months Days of cocaine use in the last 30 days: 1.8 (SE 0.62) versus 2.9 (SE 0.74) with SM versus 1.0 (SE 0.82) with RM (p = 0.42) (NCT00712036) [37] There were no studies that assessed this outcome for the following comparison: Interim with buprenorphine versus interim with placebo Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances Interim versus Waiting List for Standard OAT (1 study) (Non-Prescribed Methadone Self-Reported) At 1 month (1 study) 1/75 versus 37/94 (p < 0.001) (Yancovitz et al. 1991) [44] There were no studies that assessed this outcome for the following comparisons: Interim versus standard OAT Interim with buprenorphine versus interim with placebo Use of Illicit Drugs and/or Non-Prescribed Psychoactive Substances Interim with Buprenorphine versus Interim with Placebo (1 study) (Other Drugs Self-Reported) At 3 months (1 study) 3.56 (SD not reported) versus 4.4 (SD not reported) (using a VAS from 0 = “drug free” to 10 = “daily heavy drug abuse”) (p < 0.01) (Krook et al. 2002) [35] Change in self-reported use of other drugs 0.66 (CI − 1.77; 0.44) versus 1.11 (CI 0.18; 2.05) (p < 0.01)(Krook et al. 2002) [35] There were no studies that assessed this outcome for the following comparisons: Interim versus waiting list to standard OAT Interim versus standard OAT Criminal Activities/Illegal Income Interim versus Waiting List for Standard OAT (1 study) (Illegal Income) At 4 months (2 studies) 36$ (SD 160) versus 412$ (SD 1391) (p < 0.02) (Schwartz et al. 2006) [21] At 10 months 40$ (SE 18.21) versus 135$ (SE 23.69) (p = 0.018) (Schwartz et al. 2006) [21] Interim versus Standard OAT (1 study) At 4 months 8$ (SE 3) versus 336$ (SE 287) with SM versus 113$ (SE 113) with RM (p < 0.001) (NCT00712036) [37] At 12 months 27$ (SE 12) versus 55$ (SE 19) with SM versus 14$ (SE 14) with RM (p < 0.001) (NCT00712036) [37] There were no studies that assessed this outcome for the following comparison: Interim with buprenorphine versus interim with placebo Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 12 of 18 Table 2 (continued) OUTCOME FINDINGS Criminal Activities/Illegal Income Interim versus Waiting List for Standard OAT (1 study) (Illegal Activities) At 4 months (2 studies) 1.7 days (SE 0.60) versus 6.9 (SE 0.79) (p < 0.001) (Schwartz et al. 2006) [21] At 10 months 2.1 days (SE 0.67) versus 7.3 (SE 0.88) (p < 0.001) (Schwartz et al. 2006) [21] Interim versus Standard OAT (1 study) At 4 months 0.48 days (SE 0.29) versus 1.11 (SE 0.47) with SM versus 1.13 (SE 1.13) with RM (p = 0.003) (NCT00712036) [37] At 12 months 0.96 days (SE 0.47) versus 2.00 (SE 0.66) with SM versus 1.30 (SE 1.20) with RM (p = 0.46) (NCT00712036) [37] There were no studies that assessed this outcome for the following comparison: Interim with buprenorphine versus interim with placebo Criminal Activities/Illegal Income Interim versus Waiting List for Standard OAT (1 study) (Arrests) At 6 months (1 study) Number of participants arrested: 31/198 versus 24/119 (p = 0.18) (Schwartz et al. 2006) [21] Mean number of arrests: 0.2 arrests (SE 0.06) versus 0.34 arrests (SE 0.09) (p = 0.02) (Schwartz et al. 2006) [21] At 12 months Number of participants arrested: 53/198 versus 31/119 (p = 0.96) (Schwartz et al. 2006) [21] Mean number of arrests: 0.33 (SE 0.09) versus 0.39 (SE 0.11) (p = 0.16) (Schwartz et al. 2006) [21] At 24 months Number of participants arrested: 77/198 versus 54/119 (p = 0.75) (Schwartz et al. 2006) [21] Mean number of arrests: 0.61 (SE 0.14) versus 0.76 (SE 0.18) (p = 0.16) (Schwartz et al. 2006) [21] There were no studies that assessed this outcome for the following comparisons: Interim versus standard OAT Interim with buprenorphine versus interim with placebo Criminal Activities/Illegal Income Interim versus Waiting List for Standard OAT (1 study) (Severe Crimes) At 6 months (1 study) 6/198 versus 1/119 (p = 0.23) (Schwartz et al. 2006) [21] At 12 months 7/198 versus 3/119 (p = 0.62) (Schwartz et al. 2006) [21] At 24 months 10/198 versus 6/119 (p = 1.0) (Schwartz et al. 2006) [21] There were no studies that assessed this outcome for the following comparisons: Interim versus standard OAT Interim with buprenorphine versus interim with placebo Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 13 of 18 Table 2 (continued) OUTCOME FINDINGS Mental/Physical Health Interim versus Waiting List for Standard OAT (1 study) (Mental Health) Global Severity Index (GSI) above cut-off at 3 months [a widely used indicator (3 studies) for distress, using a cut-off > or = 63] 7/23 versus 13/25 (significance not reported) (NCT02360007) [41]; this trial also reports more data on mental health (Beck Anxiety Inventory, Beck Depression Inventory, Brief Symptom Inventory and Addiction Severity Index (ASI) Psychiatric composite score) but further data could not be extracted because the authors reported the significances of the change in mean measures, but not the actual measures Interim versus Standard OAT (1 study) Psychiatric ASI composite score at 4 months [score ranging from 0 = “no prob- lem” to 1 = “extreme problem”] 0.05 (SE 0.01) versus 0.02 (SE 0.01) with SM versus 0.01 (SE 0.02) with RM (p = 0.75) (NCT00712036) [37] Psychiatric ASI composite score at 12 months 0.06 (SE 0.02) versus 0.06 (SE 0.02) with SM versus 0.02 (SE 0.03) with RM (p = 0.61) (NCT00712036) [37] Interim with Buprenophine versus Interim with Placebo (1 study) Anxiety and depression at 3 months [measured with Symptom Checklist-5 on a four-point scale ranging from 1 = ‘not at all’ to 4 = ‘extremely’] 2.51 (SD not reported) versus 2.63 (SD not reported) (no significant difference) (Krook et al. 2002) [35] Change in anxiety and depression (at 3 months) − 0.3 (CI − 0.52; − 0.08) versus − 0.17 (CI − 0.40; 0.07) (no significant difference) (Krook et al. 2002) [35] Mental/PhysicalHealth Interim versus Waiting List for Standard OAT (1 study) (Physical Health) One study (Schwartz et al. 2006) [21] reports on Human Immunodeficiency Virus (2 studies) (HIV) risk behaviors, but data could not be extracted as the authors only report p-values and statistic test results Interim versus Standard OAT (1 study) Medical ASI Composite score at 4 months [score ranging from 0 = “no problem” to 1 = “extreme problem”] 0.13 (SE 0.03) versus 0.10 (SE 0.03) with SM versus 0.19 (SE 0.06) with RM (p = 0.70) (NCT00712036) [37] HIV risk in injector subsample at 4 months 0.08 (SE 0.06) times injected with unsterilized needles versus 0.00 (SE 0.05) with SM versus 0.04 (SE 0.04) with RM (p > 0.05) (NCT00712036) [37] Medical ASI Composite score at 12 months 0.19 (SE 0.03) versus 0.12 (SE 0.03) with SM versus 0.12 (SE 0.06) with RM (p = 0.56) (NCT00712036) [37] HIV risk in injector subsample at 12 months 0.00 (SE 0.00) times injected with unsterilized needles versus 0.00 (SE 0.0) with SM versus 0.00 (SE 0.0) with RM (p > 0.05) (NCT00712036) [37] There were no studies that assessed this outcome for the following comparison: Interim with buprenorphine versus interim with placebo Adverse Effects (2 studies) Interim versus Standard OAT (1 study) Number of participants with at least one serious adverse effect at 12 months 19/99 versus 9/104 with SM versus 4/27 with RM (NCT00712036) [37] Interim with Buprenophine versus Interim with Placebo (1 study) One trial narratively reported that no deaths or other serious side effects were observed during the 3 months of follow-up but provided no data (Krook et al. 2002) [35] There were no studies that assessed this outcome for the following comparison: Interim versus waiting list to standard maintenance treatment group compared to the placebo group. As we did not Satisfaction with treatment obtain results from trials comparing interim OAT ver- Only one study comparing interim OAT to a waiting list sus waiting lists or standard OAT we rated the qual- for standard OAT [41] assessed patient satisfaction with ity of the evidence as low for this outcome due to the treatment at 3 months of follow-up. The authors used a 5 impact of indirectness. point scale with a higher score corresponding to greater satisfaction and reported a mean score for participants at interim OAT of 4.6 (SD 0.7) at 3 months. However, this Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 14 of 18 was only measured on the intervention group, as for this 4 and 10 months of follow-up, favoring the intervention reason we rated the quality of evidence for this outcome group. Similarly, another trial comparing interim OAT as very low due to the impact of risk of bias, indirectness with standard OAT [37] that measured these two out- and the imprecision of results. comes at 4 and 12 months found a significant difference in their change over time in favor of the intervention Use of illicit drugs and/or non‑prescribed psychoactive group for most measures except for illegal activities at substances 12 months where no significant differences were found. All the trials reported this outcome but it was the most The number of arrests and severe crimes at 6, 12 and heterogeneously measured outcome from those of inter- 24 months was also assessed in one trial comparing est. The trials provided information about self-reported interim OAT with a waiting list for standard OAT [39] use of drugs or urine drug test results for heroin, cocaine, and found no significant differences between groups for non-prescribed methadone and other drugs. most of these measures. For heroin use determined by urine drug test, three trials comparing interim OAT with a waiting list for Mental and/or physical health standard OAT found significant group differences either Three trials reported results on mental health, all of them at 1 month [44], at 3 months [41], at 4 months [21] or measuring the outcome with different instruments. One at 10 months [40] of follow-up. Two of those trials also trial comparing interim OAT with a waiting list for stand- found significant differences in the self-reported use of ard OAT [42] reported changes in psychiatric symptoms. heroin at 1 month [44], 4 months and 10 months [21] of All measures showed that the mean changes were sig- follow-up. For both outcomes, the intervention group nificantly different between the intervention and control showed better results. One trial comparing interim OAT group at 3 months of follow-up, with the intervention with standard OAT [37] assessed both outcomes and group showing an improvement in psychiatric symptoms. found no significant differences in their change over time Nevertheless, the magnitude of this effect could not be between groups at either 4 and 12 months of follow-up. assessed as the trial only reported p-values and statistical Finally, the trial comparing interim OAT with buprenor- test results. On the other hand, for the other two com- phine with interim treatment with placebo [35] only parisons, the trials that assessed this outcome [35, 37] did assessed self-reported heroin use at 3 months and found not find any statistical differences between groups. a significant difference in the change of this outcome in Two trials, one comparing interim OAT with a waiting favor of the intervention group. list for standard OAT [43] and the other one comparing Regarding cocaine use measured with urine drug tests, interim OAT with standard OAT [34] reported results two trials comparing interim OAT with a waiting list for on physical health. The first trial reported on Human standard OAT found no significant group differences at Immunodeficiency Virus (HIV) risk behaviors but data 1 month [44], 4 months [21] or 10 months [40] of fol- could not be extracted and the authors reported ambigu- low-up. Nevertheless the same trials found a significant ous conclusions about the effect of this intervention. The group difference when cocaine use was self-reported. For latter trial also measured HIV risk behaviors and found those two outcomes, one trial comparing interim OAT no significant differences between groups in frequency with standard OAT [37] also found no significant group of injection with unsterilized needles in the injector sub- differences in their change over time either at 4 or at sample at either 4 or 12 months. This trial also reported 12 months. on this outcome through the Addiction Severity Index Only one study comparing interim OAT with a waiting (ASI) medical composite score and found no significant list for standard OAT [44] reported on the use of non- differences between groups. prescribed methadone at one month. The authors found a trend toward increased non-prescribed methadone use Adverse effects in the control group. The full results for this outcome are No studies comparing interim OAT with a waiting list described in Table 2. for standard OAT reported this outcome. One trial com- paring interim OAT with standard OAT [37] reported Criminal activities and/or illegal income the number of serious adverse events and the number This outcome was reported in two trials but was also of participants with at least one serious adverse event quite heterogeneously measured. One trial comparing at 12 months but the authors considered that none of interim OAT with a waiting list for standard OAT [21] them were study related and they did not report differ- measured the amount of money the participants obtained ences between groups. One trial comparing interim OAT from illegal sources and the days spent in illegal activities with buprenorphine with interim treatment with placebo and reported a significant difference for both outcomes at Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 15 of 18 narratively reported that no deaths or other serious side evidence for this outcome is moderate due to some con- effects were observed during the 3 months of follow-up. cerns regarding the risk of bias from included trials. Two trials assessed access to standard OAT and Costs showed significant differences when comparing interim One trial comparing interim OAT with standard OAT OAT with a waiting list for a standard OAT with mod- [36] reported the results of a benefit cost analysis with a erate quality of evidence thus suggesting that patients in societal perspective calculated in 2010 US dollars (USD), interim OAT would be more likely to access a standard estimating health service utilization, criminal related OAT than those who are on a waiting list. costs, and other factors linked to employment in their It is worth mentioning that the other two outcomes trial sample. The authors estimated a cost of providing that we defined as primary outcomes—quality of life and interim OAT of around 3.5 USD per week or a weighted satisfaction with treatment—have not really been investi- mean total cost of 2,052 USD. The net benefit resulting gated. Only one trial assessed quality of life and another from a reduction in days in residential treatment, incar- one assessed satisfaction with treatment. We chose those ceration, arrests was equivalent to 5,939 USD and the outcomes because from a patient-centered perspective benefit–cost ratio was 3.9. The weighted mean cost for it is important to include a more comprehensive view of the standard OAT options combined was 3,411 USD, treatment outcomes [45]. Nevertheless the measurement with a net benefit of − 2246 USD and a benefit–cost ratio and standardization of these outcomes has proven to be of 0.3. However, there were no significant differences challenging as there is no consensus on which outcome between treatment conditions in total costs benefits dur- measures of functioning or quality of life really relate to ing the 12 months of follow up (mean difference between drug use and is a topic that still generates great debate treatment arms of 2155 USD, 95% CI − 582 to 5015 [46]. Moreover, there is still no consensus in what per- USD; p > 0.05). The major contributors to the net ben- spective should be prioritized to better reflect the ben- efit showed for the total study sample after the follow- efits of treatment (e.g., social negative outcomes to be up were related to the reduction of days of incarceration avoided, symptom reduction, or patient perspective). In and increases in legal income, but the researchers also fact, there is still an active, ongoing debate in the addic- observed an increase in days of hospitalization. tion treatment research field surrounding both the most appropriate consumption outcome measure [47, 48] and Discussion whether (and which, if any) non-consumption outcome Our systematic review identified 6 studies that evaluated measures should be incorporated [49, 50]. the intervention of interest against three different com- Our secondary outcomes are mainly related to drug use parisons in terms of a set of outcomes which have also and social impact although we also assessed other rele- been measured in very different ways and at different vant domains beyond drug use, including psychiatric and follow-up times. Therefore the available body of evidence medical status, safety and costs. Three trials assessed her- to inform on the impact of interim OAT is very hetero- oin use with urine drug tests at different follow-up times geneous and did not allow us to obtain a common effect and found that interim OAT reduced its use significantly estimate for the outcomes of interest. when compared with a waiting list for standard OAT [21, We defined four primary outcomes, which are mainly 41, 44]. On the other hand, another trial did not find dif- clinical and patient-centered. Most included studies ferences in this outcome between interim and standard [33, 35, 37, 41] reported on retention in treatment at OAT, thus suggesting that initiating OAT with interim 4 months or less (which we treated as retention in interim OAT may be as effective as initiating it directly with OAT), but few [33, 37] reported retention in treatment standard OAT in regards of heroin use reduction dur- at 12 months (which we treated as retention in standard ing the first year of follow-up and better than remaining OAT). Our findings suggest that interim OAT does not on a waiting list. There is not as much evidence and the differ from standard OAT in terms of retention in treat- results are not so clear when it comes to social impact. ment. The intervention did not result in higher retention Interim OAT seems to be more effective than a waiting rates at short term (i.e., in interim OAT) compared to a list for standard OAT in reducing the amount of money waiting list [41] or the participation in a standard OAT obtained from illegal sources and the days spent in ille- [33, 37]. Only one study offering buprenorphine showed gal activities, but showed no differences in the number better retention in the interim treatment compared to of arrests and severe crimes. In addition, interim OAT placebo [35]. The only trial that measured retention in seems to have similar results compared to standard OAT standard OAT did not show differences between the at reducing the amount of money obtained from illegal interim and standard OAT [37]. The overall quality of sources and the days spent in illegal activities, but seems to achieve these results faster. The impact of interim OAT Samsó Jofra et al. Harm Reduction Journal (2022) 19:7 Page 16 of 18 on mental and physical health is not as widely evaluated the broader area of substance abuse treatment [52], is not and results are more ambiguous. Interim OAT might be only not detrimental for patients but can also be benefi- more effective to improve mental health outcomes than cial when the only other options are a waiting list or no a waiting list for standard OAT (although these results treatment at all. Amidst the current global opioid crisis, were not assessed for a long term follow-up), but showed this is of particular relevance for contexts with a mark- no differences compared to interim treatment with pla- edly high prevalence of opioid use and/or low availabil- cebo. Interim OAT did not cause more adverse events ity of standard OAT due to a diversity of reasons such as when compared to standard OAT nor with interim treat- insufficient service providers, strict regulations or insuf- ment with placebo, which reinforces its safety profile. ficient funds. In a situation of shortage of standard OAT, And, finally, there were no statistical significant differ- where treatment demand exceeds availability, interim ences in terms of benefit cost analysis. OAT may be an essential asset to avoid unnecessary Our results align with those from a previous literature delays once the request for OAT is made and the indica- review [51] that summarized some articles evaluating tion is established. Other mechanisms and processes— interim OAT and found that interim OAT is better than a within and outside current regulatory systems—which waiting list for a standard OAT and no worse than stand- could expand and facilitate access and entry of people ard OAT in terms of retention, heroin use and criminal with opioid use disorder into OAT are also worth consid- activities among others. Nevertheless, our review also ering and studying [53, 54]. reports on other relevant outcomes, was conducted sys- In any case, further research is needed to establish a tematically, assessed the risk of bias for each included minimum, common set of outcomes to be assessed in study, and goes beyond a description of the included interim OAT research, and to identify the subgroup of studies by synthesizing the results together. A couple of people with opioid use disorder most likely to benefit Cochrane reviews on OAT [10, 11] also included some of from such treatment. the trials in this review and found similar results in terms of treatment retention, heroin use or criminal activities Conclusions [21, 35, 44]. Notwithstanding, these reviews included dif- Interim OAT likely results more effective than a wait- ferent approaches of OAT together and we have specifi- ing list for standard OAT in regards of access to stand- cally focused on assessing the impact of interim OAT. ard OAT, reduction in heroin use and criminal activities, and improvement in mental health. Nevertheless the Strengths and limitations evidence is uncertain about the effect of interim OAT on We conducted a review according pre-specified criteria physical health. Moreover, interim OAT probably is as and standardized methods that were publicly registered effective as standard OAT in regards to retention in treat- and identified studies through a comprehensive search to ment (both short and long term), reduction in heroin and assess the impact of the intervention of interest in terms cocaine use, reduction in criminal activities and improve- of patient centered outcomes. In results of that, our find- ment of mental and physical health without increasing ings provide reliable data to inform policy makers and adverse events. Interim OAT with buprenorphine is also other stakeholders in their decisions. likely more effective than interim treatment with placebo Nevertheless we acknowledge some limitations. Due to in regards of short term treatment retention and reduc- the heterogeneity in comparisons and outcome measure- tion in heroin use and has no differences in regards to ments of the primary studies we have not been able to adverse events. The effect of interim OAT on quality of perform a quantitative analysis and therefore our conclu- life and satisfaction with treatment is very uncertain as it sions do not provide definitive estimates of effect. has not been much investigated. Implications for practice and research Abbreviations The results of our review are probably more directed to AIDS: Acquired immune deficiency syndrome; ASI: Addiction Severity Index; policy-makers working in public health than practition- CENTRAL: Cochrane Central Register of Controlled Trials; DSM: Diagnostic and Statistical Manual of mental disorders; EMBASE: Excerpta Medica dataBASE; ers. With the current evidence, policy-makers operating FDA: Food and Drug Administration; GRADE: Grading of Recommendations in contexts where there is insufficient coverage and long Assessment, Development, and Evaluation; HIV: Human immunodeficiency waiting lists for standard OAT and/or high rates of opioid virus; ICD: International Classification of Diseases; IM: Interim methadone treat- ment; MEDLINE: MEDical LIterature analysis and retrieval system onliNE; OAT: use disorder should include interim OAT in their health Opioid agonist treatment; PRISMA: Preferred Reporting Items for Systematic policies. reviews and Meta-Analyses; PROSPERO: International PROSPEctive Register Furthermore, with this evidence, it seems reasonable Of systematic reviews; PsycINFO: Psychological INFOrmation database; RM: Restored methadone treatment; ROBINS-I: Risk Of Bias In Non-randomised to say that lowering treatment thresholds for a period of Studies—of Interventions; SM: Standard methadone treatment; USD: US time, as some other authors have previously suggested in dollars. 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