Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

Natasha Hall; Long Le; Ishani Majmudar; Maree Teesson; Cathy Mihalopoulos

doi:10.1371/journal.pone.0258620

. 2021 Oct 15;16(10):e0258620. doi: 10.1371/journal.pone.0258620

Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

Natasha Hall ^1,^*, Long Le ¹, Ishani Majmudar ¹, Maree Teesson ², Cathy Mihalopoulos ¹

Editor: Adam Todd³

PMCID: PMC8519451 PMID: 34653220

Abstract

Objectives

To determine treatment seeking behaviour in those with opioid use disorder (OUD) in the high-income countries.

Methods

Five databases were searched in November 2019 for quantitative studies that reported OUD treatment seeking behaviour. Data analysis involved determining an overall pooled proportion estimate of treatment seeking behaviour for the two base groups, lifetime treatment and past 12-month or less treatment using the IVhet effect model. Subgroup analysis included heroin OUD, prescription OUD and general OUD. The sensitivity analysis included removal of outliers, separating adults and adolescents and the metaXL sensitivity analysis (studies are excluded if outside the pooled proportion confidence interval of the base case). Systematic review Prospero database registration number [CRD42020159531].

Results

There were 13 quantitative studies included in the systematic review, with all studies being from the United States of America (USA). IVhet models showed that 40% (95% CI: 23%, 58%) and 21% (95% CI: 16%, 26%) sought treatment in their lifetime and past 12 months respectively. Sub-group analysis found that lifetime treatment seeking for prescription OUD, 29% (95% CI: 27%, 31%), was less than for heroin plus combined OUD, 54% (95% CI: 26%, 82%). Most of the pooled results had high heterogeneity statistics except for results of lifetime treatment seeking for prescription OUD and past 12-month treatment seeking for prescription OUD.

Conclusion

All included studies in this meta-analysis were from the USA and indicate modest levels of treatment seeking for those with OUD. In particular, this review found that in the USA one in five people with OUD sought OUD treatment in the previous 12 months and two in five people with OUD sought OUD treatment in their lifetime. Further research is urgently required to explore the barriers and facilitators that can improve this low treatment seeking in those with OUD.

Introduction

Opioid use disorder (OUD) worldwide is increasing. From 1990 to 2016 the number of opioid harm related cases worldwide increased by almost 50% [1]. OUD has reached epidemic levels in high income regions such as the United States of America (USA) (1.17%), or Australasia (0.41%) [1]. Compared to the general population, OUDs have been associated with increased risk of premature death [2], increased risk of hepatitis C and human immunodeficiency virus (HIV) [3, 4], increased risk of mental health comorbidities and [3, 5] crime [6], and reduced quality of life [7–9].

Evidence supports opioid agonist treatment (OAT) in terms of reduced illicit opioid use as well as mortality and crime [10, 11]; however, the treatment-seeking behaviour of those with OUD is low. In the USA, less than one in three people with prescription or general OUD sought OUD treatment in the previous year [12–19]. However, it is noteworthy that 81% of those with heroin dependence and 69% of those with heroin abuse sought treatment in the lifetime [20]. An Australian treatment history study of heroin dependence, found that 88% had previously sought treatment in their lifetime [21].

To our knowledge, there is no systematic review and/or meta-analysis that evaluates the proportion of people who are seeking treatment for OUD. Furthermore, the treatment seeking behaviour in those with differing types of OUDs (prescription versus heroin) has not been evaluated. The World Health Organisation (WHO) appraised the current data and found that the treatment gap for alcohol use disorder (AUD) was 78.1%, however no unmet treatment need was provided for OUDs [22]. Therefore, the aim of this review is to determine the proportion of people in high income countries who seek treatment during their lifetime and the last 12-months.

Method

The systematic review follows Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [23]. The protocol for this review was registered on the Prospero database [CRD42020159531].

Data source

Databases were searched using keywords and Medical Subject Headings (MeSH) on the 28^th November 2019. (Appendix A for search terms in S1 File) There was no restriction placed on the publication year. Electronic database searches were conducted in EMBASE and through the EBSCOhost platform for MEDLINE, CINAHL, PsycINFO and SocINDEX databases. Terms relating to OUD treatments (including methadone and buprenorphine), opioid use disorder and treatment-seeking behaviour were included. There was no significant difference in the search strategies in all the databases. Strategies for specific databases only differed on the subject headings used for indexing. Subject headings were searched and uniquely utilised for each database. Grey literature was searched via google scholar using the search term “treatment-seeking behaviour in opioid use disorder” and the reference list of included articles. Grey literature searching led to the inclusion of 18 further studies for primary screening, of which three articles were included in the systematic review [13, 15, 16].

Study selection

Studies included in the systematic review were published in English, reported the proportion of treatment-seeking behaviour of those with OUD and described treatment-seeking as seeking any type of treatment for OUD. No limit on publication year was specified. Studies were included where participants had a clinical diagnosis of OUD (using Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria) and where OUD (prescription OUD for those using prescription opioids, heroin OUD for those using heroin and general OUD for unspecified or mixed opioid use) was the primary diagnosis. Qualitative studies, protocol papers, expert reviews or conference abstracts were excluded. Studies where OUD was self-reported by participants were excluded from the review. Studies from non-developed low-income countries as per the United Nations were excluded from the review [24]. Studies from non-developed countries were not included in this review because the treatment seeking for opioid agonist treatment (OAT) is much lower compared with developed countries. Non-developed low-income regions such as Eastern Europe, Latin America and Africa have OAT usage rates of 1%, whereas developed high-income regions such as Australia and North America have OAT usage levels of 23% and 13% respectively [25], and therefore to avoid skewed results only developed countries were included in this review. Further research is required in treatment seeking behaviour in developed countries.

Data extraction

After removing all duplicates—titles, abstracts and full text were screened by two independent reviewers (NH & IM) and discrepancies were resolved by a third reviewer (LL). Data was extracted from the final included studies and entered into a standardized table. The data extraction sheet included the following categories to describe and compare the studies: author, year, country, sample description, study design, sample size, opioid type, OUD diagnosis tool, participant mean age and gender, type of treatment sought, treatment time frame and percentage or proportion that sought treatment. Independence of all studies was required and therefore one study was not included in the meta-analysis due to the same sample being used in another study [13, 15]. Where the studies reported help-seeking behaviour for both opioid dependence and opioid abuse, opioid dependence was reported. Where studies reported help-seeking behaviour for OUD in differing mental health status groups, no mental health status was chosen. Where studies reported both heroin OUD and prescription OUD, both results were reported in the main analyses and subgroup analyses if appropriate.

Data analysis

Data analysis involved determining an overall pooled proportion estimate of treatment seeking behaviour. In the primary analysis, the lifetime treatment and past 12 months treatment was conducted. Sub-group analysis and sensitivity analysis were reported. Sub-group analysis involved separating prescription OUD and general OUD (heroin OUD and combined OUD). These distinct groups were decided because treatment outcomes with prescription OUD were found to differ from heroin OUD and combined OUD in terms of more negative urine samples and longer periods of opioid abstinence for prescription OUD compared with heroin and combined OUD [26]. Furthermore, the treatment seeking behaviour and perceived need for treatment was higher for those with heroin OUD (including combined OUD) than for those with prescription OUD [17, 18]. Examination of pooled effect sizes allowed for identification of outliers. Outliers were defined as studies where the individual effect size and associated 95% CI were outside the 95% CI of the pooled studies (on both CI sides) [27]. The random effects (RE) model and Inverse variance heterogeneity (IVhet) model were chosen and where differences arose, results from both models were presented. If the two models were the same, the IVhet model only was presented while results from the RE model were presented in the Appendices. The IVhet model was chosen because it is an improvement over the RE model and is better able to handle heterogeneity [28]. The RE model provides an underestimation of statistical error and produces overconfident results, which the IVhet model (an estimator model using the fixed effects model assumption that has a quasi-likelihood based variance structure) has been shown to resolve [28].

All data analysis was conducted on Excel using the metaXL as an add-on software package [29]. Statistical heterogeneity between the studies was evaluated using the I² statistic and Cochran’s Q test. As per the Cochrane Collaboration recommendation, heterogeneity was considered important if the I² statistic was greater than 40% and/or the Q statistic was significant at a P value of 0.01 [30]. Publication bias was assessed using the Doi plot asymmetry index (LFK index). An LFK index of ±1 means no asymmetry, between ±1 and ±2 means minor asymmetry and > ±2 means major asymmetry [29].

Quality assessment or risk of bias assessment

The studies were assessed for methodological rigour using the Joanna Briggs Institute (JBI) quality assessment tool for cross-sectional studies [31]. The JBI quality assessment tools were used to assess the internal validity and the risk of bias in the studies. The research team determined that good quality studies needed to score 70% or more (score of six or higher out of eight), moderate studies needed to score 50% to 70% (score of four or five out of eight) and poor quality studies scored less than 50% (score of three or less out of eight). Quality assessment was performed on all included studies independently by two reviewers (NH and LL). Any conflicts that arose between the reviewers was resolved by discussion among team members.

Results

Study characteristics

There were 13 studies published from 2008 onwards that met the inclusion criteria. See Fig 1 for the PRISMA flow diagram.

Two studies reported results from the same sample population leaving 12 studies included in the meta-analysis. Saha et al. [15] reviewed help seeking in total population whereas Kerridge et al. [13] determined help seeking proportion in men versus woman. Saha et al. [15] was the study included in the overall pooled proportion estimate. All 12 studies were conducted in the USA. Most studies [10/12] used nationally representative cross-sectional surveys in the US including the National Survey on Drug Use and Health (NSDUH) and the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Participant recruitment of the remaining two studies [32, 33] occurred via multi-site and single site health care facilities. Eleven of the studies reviewed OUD in adults and two of the studies included only adolescents in the sample [12, 33]. The key characteristics of the included studies can be found in Appendix B in S1 File.

Quality assessment of the included studies

Most of the included studies [11/12], were of good quality according to the JBI checklist. The remaining study was of moderate quality [33]. The quality assessment score for each included study can be seen in Appendix B in S1 File.

Meta-analysis base case results

The included studies investigated OUD help-seeking behaviour from lifetime treatment and 12-month or less treatment. These time frame differences contribute to increased heterogeneity between the studies and therefore the base cases examined for this meta-analysis will be lifetime treatment seeking and 12-month or less treatment seeking.

Lifetime OUD treatment seeking

The RE model (Appendix C in S1 File) and IVhet models produced similar results and therefore the IVhet model will be used. Fig 2 shows that 40% (95% CI: 23%, 58%) of people with OUD sought help for OUD treatment in their lifetime. The I² statistic for heterogeneity is 98%, which suggests a considerable amount of difference between the studies. The five studies included in the lifetime treatment seeking base group were cross-sectional studies from online recruitment samples [33] or nationally representative surveys [15, 18, 20, 34]. Two of the studies determined help-seeking behaviour for prescription OUD [15, 34], one study reviewed OUD help-seeking behaviour for all opioids [18] and the final study reviewed treatment seeking from both heroin and prescription opioids [20]. One of the included studies was undertaken in adolescents only [33] and in the remainder of the studies the population was adults. The LFK index, which reports publication bias, reported no asymmetry with LFK = -0.14. (see Appendix D in S1 File).

12-month or less OUD treatment seeking

The RE model (Appendix E in S1 File) and IVhet models were comparable and therefore only the IVhet model was used. Fig 3 shows that of those with OUD, 21% (95% CI: 16%, 26%) sought treatment in the past 12 months. The 95% CI interval is small, there are several outliers and the I² statistic is high [97%]. Eight of the nine studies included used a nationally representative survey and examined help-seeking over the past 12 months, the remaining study was a multi-site study and reviewed help-seeking behaviour in the past 6 months [32]. The type of OUD that was present in the included studies were prescription OUD [12, 14, 15], combined OUD [16–19, 35] and one study reported both prescription OUD and heroin OUD [32]. One of the included studies was undertaken in adolescents only [12] and the remaining eight studies were all done in adults. The LFK index for model 2 reported major asymmetry with LFK = -2.01. (see Appendix F in S1 File).

Meta-analysis subgroup results

Subgroup analysis, where the different types of OUD were grouped together, was undertaken. These subgroups included prescription OUD and heroin plus combined OUD. These two subgroup analyses were done within the two base groups.

Lifetime treatment seeking

Lifetime treatment-seeking proportion of those with OUD with primary heroin use plus combined OUD included 3 studies [18, 20, 33] (Appendix G in S1 File). The treatment-seeking proportion was 54% [95% CI: 26%, 82%], with a high I² statistic (90%). Two of the studies used national surveys and included adults [18, 20] and the third was a single treatment site including only adolescents [33]. The treatment-seeking proportion of those with lifetime treatment history for prescription OUD was 29% (95% CI: 27%, 31%) (see Appendix H in S1 File), with no heterogeneity (I² = 0%).

12-month or less treatment seeking

Six studies [16–19, 32, 35] examined 12-month treatment seeking with heroin plus combined OUD. The treatment seeking for those with heroin plus combined OUD over the past 12 months was 22% (95% CI: 17%, 28%, I² = 98%). (Appendix I in S1 File) One study examined heroin OUD only [32] and five studies examined combined OUD [16–19, 35]. Five studies used the NSDUH survey and the remaining study used a multi-site sample [32]. All six studies included adults only.

The treatment seeking percentage for those with prescription OUD over the past 12-months was 16% (95% CI: 15%, 17%) (see Appendix J in S1 File), with no heterogeneity (I² = 0%) of 0%. The past 12-month treatment seeking proportion for general OUD was 22% (95% CI: 16%, 18%) (see Appendix K in S1 File). The heterogeneity was high between the five studies, with the I² statistic being 98%. The studies were all undertaken in adults and used nationally representative surveys, however because all opioids were included the varying types of OUD may be contributing to heterogeneity.

Meta-analysis sensitivity analysis results

Due to high heterogeneity, three sensitivity analyses were undertaken. These were to remove the outliers, separate adults from adolescents and lastly the metaXL sensitivity analysis. The outliers were removed in both the base case models; lifetime treatment seeking for OUD and 12-month treatment seeking for OUD.

One outlier was outside the 95% CI range and was removed from the lifetime treatment base case (see Appendix L in S1 File) [20]. The help-seeking percentage, 39%, (95% CI: 23%, 56%) did not change with removal of the outlier, due to the small weight (2%) the outlier had on the overall pooled proportion. I² statistic was 98%, indicating significant heterogeneity. The outlier study included individuals with heroin OUD, used a nationally representative sample and had a small sample size (n = 150). The included studies were related to prescription OUD [15, 33, 34], and general OUD [18]. Three of the included studies were nationally representative samples [15, 18, 34] and the remaining study was a single site sample [33].

Four outlier studies were removed from the 12-month treatment seeking base case [14, 18, 19, 35] and in one study the prescription OUD treatment seeking was an outlier, but not the heroin OUD treatment seeking proportion [32]. (Appendix M in S1 File) Removal of the outliers reduced the treatment seeking percentage from 21% to 20% and narrowed the confidence interval. The I² statistic reduced from 97% to 69% with removal of the outliers [14, 18, 19, 32, 35]. The outlier studies were related to prescription OUD [14, 32] and general OUD [14, 19, 35] and all used nationally representative samples. The included studies were reviewing treatment seeking in those with prescription OUD [12, 15], combined OUD [16, 17] and heroin OUD [32].

The second sensitivity analysis was to separate adults and adolescents within the two base case models; lifetime treatment seeking for OUD and 12-month treatment seeking for OUD.

Lifetime OUD treatment seeking

Four studies were included when the sensitivity analysis was adults only lifetime treatment seeking (see Appendix N in S1 File). The pooled percentage of treatment seeking was 40% (95% CI: 22%, 59%), with significant heterogeneity (I² = 98%). The included studies were identifying treatment seeking in prescription OUD [15, 34], heroin OUD [20] and general OUD [18]. Four of the five included studies used nationally representative samples and the remaining study used an online opportunistic sample [16]. One study examined lifetime OUD treatment seeking in adolescents [33] with treatment seeking proportions for both heroin OUD and prescription OUD. The treatment seeking was 35% (95% CI: 17%, 54%, I² = 72%). (Appendix O in S1 File) The study used a single-site sample.

12-month OUD treatment seeking

Eight studies were included in this sensitivity analysis for adults only (see Appendix P in S1 File). One study [12] was not included in this model when compared with the 12-month treatment seeking base case. Hence the pooled proportion is the same as the base case, 21% (95% CI: 16%, 27%, I² = 97%). The included studies were identifying treatment seeking in prescription OUD [14, 15, 32], combined OUD [16–19, 35] and one study reported for both heroin OUD and prescription OUD [32]. Seven of the studies used nationally representative surveys and one study used a multi-site survey [32].

Only one study reviewed 12-month treatment seeking in adolescents [12], which means a sensitivity analysis could not be completed.

Lastly, the final sensitivity analysis was using the metaXL sensitivity analysis for the two base cases; lifetime treatment seeking for OUD and 12-month treatment seeking for OUD. Results will only be reported if the pooled proportion value for the excluded study is outside the pooled proportion confidence interval of the base case.

Table 1 show the metaXL sensitivity analysis where the pooled proportion is given when the specified study is removed in turn. This sensitivity analysis found no outlier cases. The pooled proportion lifetime treatment seeking was 31% to 45%.

Table 1. Lifetime OUD treatment seeking IVhet base model metaXL sensitivity.

Removed each study in turn	Pooled prevalence	LCI 95%	HCI 95%	Cochran Q	I²	I² LCI 95%	I² HCI 95%
Blanco 2013	0.438	0.201	0.683	140.864	97.160	95.348	98.267
Choi 2019	0.312	0.163	0.472	62.104	93.559	87.877	96.578
Mowbray 2010	0.391	0.231	0.557	145.355	97.248	95.513	98.312
Saha 2016	0.445	0.208	0.689	131.828	96.966	94.977	98.167
Subramaniam 20091	0.399	0.218	0.587	183.388	97.819	96.565	98.615
Subramaniam 20092	0.402	0.225	0.587	179.294	97.769	96.475	98.588

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Table 2 show the metaXL sensitivity analysis where the pooled proportion is given when the specified study is removed in turn. This sensitivity analysis reported no outlier cases. The pooled proportion 12-month treatment seeking was 20% to 22%.

Table 2. 12-month OUD treatment seeking IVhet base model metaXL sensitivity.

Removed each study in turn	Pooled prevalence	LCI 95%	HCI 95%	Cochran Q	I²	I² LCI 95%	I² HCI 95%
Becker 2008	0.218	0.166	0.272	247.045	96.762	95.329	97.755
Choi 2019	0.208	0.161	0.257	234.927	96.595	95.060	97.653
Feder 2018	0.198	0.156	0.242	147.481	94.576	91.666	96.469
Novak 2019	0.218	0.169	0.270	233.948	96.580	95.037	97.644
Ober 20181	0.213	0.164	0.264	289.910	97.241	96.091	98.052
Ober 20182	0.213	0.163	0.264	290.328	97.244	96.097	98.054
Saha 2016	0.213	0.163	0.265	288.621	97.228	96.072	98.044
Saloner 2015	0.211	0.146	0.280	290.997	97.251	96.107	98.058
Wu 2011	0.213	0.163	0.266	287.549	97.218	96.055	98.038
Wu 2016	0.22	0.155	0.289	274.016	97.080	95.838	97.952

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Discussion

Our systematic review and meta-analysis found that one in five people (20%) or one in two people (50%) with OUD sought help during the previous 12-months and during their lifetime in the USA, respectively. It is noteworthy that it is the first review including a meta-analysis to quantify the proportion of people with OUD seeking treatment. A study conducted by the World Health Organisation (WHO) found that the 12-month treatment seeking proportion for mood disorders and substance use disorders in the USA was 35% and 10% respectively [36]. The treatment seeking proportion for OUD in our study is therefore slightly less than the treatment seeking for mood disorders and slightly higher than the treatment seeking for substance use disorders [36]. The lower treatment seeking levels in those with substance use disorders could be due to lack of established effective and available treatments for other substance use disorders such as cocaine and methamphetamine compared to available and effective opioid replacement treatments for OUDs [37]. It is expected that treatment seeking occurs at a higher proportion within a longer timeframe (12 months versus lifetime) and other studies have also found that increased disease duration and severity increase the likelihood of treatment seeking for OUD [15, 21, 32]. Treatment seeking for prescription OUD was the lowest (16% for 12-month treatment and 29% for lifetime treatment) and for heroin plus combined OUD was the highest (54% for lifetime treatment). Reduced treatment seeking in those with prescription OUD when compared with heroin OUD could be explained by the difficulty in diagnosing prescription OUD due to co-existing complex pain management needs and long term opioid use [38]. Secondly, lower levels of treatment seeking in those with prescription OUD may be related to treatment appropriateness. Although treatment seeking for opioid agonist treatment (OAT) has been demonstrated to be effective for prescription OUD [39], the differing characteristics between prescription OUD and heroin OUD [40, 41] (together with OUD treatment being developed primarily for illicit drug users) suggests that treatment options, and therefore treatment-seeking may be less acceptable or accessible to those with prescription OUD. For example, those with prescription OUD often have associated pain [41, 42]. Opioids are used to treat chronic pain and therefore those with prescription OUD experience fear that seeking OUD treatment will lead to uncontrolled pain [43]. The fear of uncontrolled pain requires attention so that those with dual pain and OUD can be better engaged in OUD treatment. Those with prescription OUD were also more likely to access health services, be prescribed antidepressants, use benzodiazepines, were older and had higher anxiety scores than those with heroin OUD [40–42, 44]. This emphasises that treatment compliance is not the problem and that reduced treatment seeking for prescription OUD is related to another factor. Furthermore, depression as a comorbidity can exacerbate the experience of pain, leading to increased need for pain relief [45, 46]. Stigma may also play a role in reduced treatment seeking for those with prescription OUD. A recent systematic review found that stigma was the third most common reported barrier to OAT [47]. Those with prescription OUD experience addiction and treatment stigma in different ways than those with heroin OUD [43]. An Australian study found that those with prescription OUD thought OAT was for heroin users or for illicit drug users, which creates a separation between themselves (prescription opioid users) and heroin users [48]. Prescription and heroin OUD related stigma may be reduced by improving community understanding of addiction and reducing societal impacts of drug use such as crime (via harm reduction services such as safe injecting rooms) [49].

All studies in this systematic review were from the USA. It is noteworthy that other high-income countries report proportion of seeking treatment in substance use disorders in general, but not specific to opioid use disorders. Australian studies using the National Survey of Mental Health and Wellbeing found that one third of those with a SUD sought professional help in the past 12 months in 1997 [50] and 11% (16–24 year-olds), 32% (25–44 year-olds) and 29% (45–85 year-olds) sought professional help in the past 12 months in 2007 [51]. Therefore this review, with studies only from the USA, found that less people with an OUD sought treatment (one in five people with OUD sought treatment in the past 12 months) than those with SUD in Australia (one in three people with SUD sought treatment in the past 12 months). Treatment seeking within 50 years of SUD onset was examined by Western Europe, New Zealand and Japan. In Western Europe lifetime treatment seeking ranged from two in five (Spain) to four in five (Germany) [36]. In New Zealand and Japan, the lifetime treatment seeking proportion was four in five and three in ten, respectively [36]. The 50-year treatment seeking results for SUD reported in these regions are mostly higher (except for Spain and Japan) than found in our review, which reported that one in two people sought treatment for OUD over their lifetime. Treatment programs, differing health systems, stigma in differing culture as well as stigma surrounding specific drug used all play a role in treatment seeking behaviour. In contrast to the USA, European countries, such as Germany and Portugal, have decriminalised drugs for personal use, have medically supervised injecting rooms and have many OUD treatments (including heroin assisted treatment) covered by public health insurance [52–54]. These steps have been shown to increase treatment uptake for OUD [52, 53]. The treatment of OUD as a health condition by these countries has the potential to further reduce stigma by improving community understanding of addiction [49]. Furthermore, stigma is experienced differently with different drugs. Internalised stigma is heightened in heroin users compared with marijuana [55], alcohol and methamphetamine users [56]. Perceived stigma is heightened towards those who use opioids non-medically compared to alcohol, marijuana, ecstasy, and other stimulant users [56, 57]. More research on OUD specific treatment seeking in countries other than the USA is urgently required to better understand treatment seeking within differing countries with differing health systems.

The heterogeneity in most of the models was high and contributing factors are variability in OUD type, age of participants and methodological differences. Heterogeneity was low (I² = 0%) in two models, which evaluated prescription OUD during the past 12-months and lifetime. Lifetime treatment-seeking in those with OUD with primary heroin use plus combined OUD was the highest, but also had high heterogeneity (I² = 90%), a wide confidence interval and included only two studies in the meta-analysis, with one study reporting both prescription OUD and heroin OUD. These results imply that treatment seeking is more uniform in those with prescription OUD compared to heroin OUD. In the USA prescription OUD often predates heroin OUD [58, 59], which may allow health practitioners to notice and target prescription OUD in a more uniform way compared to if the client progresses to heroin OUD. Furthermore, one American study found that the prescription OUD group reported higher rates of other prescription drug abuse than the heroin OUD group [12]. The more regular and continuous contact with health professionals to access prescription medications could further explain the more uniform treatment seeking patterns in those with prescription OUD. More research is required to determine the true treatment seeking proportion for those with heroin OUD.

There is more research of treatment-seeking behaviour for OUD in adults. Only one study each examined 12-month and lifetime treatment-seeking behaviour for prescription OUD in adolescents and hence a meta-analysis model was not undertaken. This study indicated that 12-month and lifetime treatment seeking in adolescents for prescription OUD was 18% [12] and 24% [33] respectively, which is less than what is found in adults. These results imply that adolescents are less likely to seek treatment than older adults, which has been previously demonstrated in the literature [17, 60–62]. One reason may be because adolescents may have early disease progression and/or are less severe in the addiction trajectory compared to adults. Furthermore, reduced help seeking may be due to increased stigma and fear experienced in younger cohorts, low health literacy, less disease exposure, or even not knowing that there might be effective treatments available. Regardless, more research in needed in OUD treatment seeking behaviour of adolescents.

Several barriers to treatment seeking for OUD have been identified in the literature. These barriers are likely to contribute to the low treatment seeking rates we have found in the current study. Barriers to treatment seeking include: social stigma [63–73]; treatment cost [70, 74, 75]; perceived lack of flexibility around treatment [67, 74, 76, 77]; a lack of prescribers [64, 75, 78–80]; long waiting lists [61, 64, 67, 73, 75, 81–85]; geographical barriers [86, 87]; psychosocial barriers (feelings of worthlessness and low self-esteem) [64, 84, 88]; chaotic lifestyle [60, 61, 64, 86, 88–90]; cultural barriers [60, 66, 71, 84, 87, 89]; and finally, a lack of support services (psychologists) [70, 72, 80, 84]. Treatment programs need to be developed, which help to reduce these barriers and therefore encourage all those with OUD to seek treatment. The low levels of treatment seeking found in the USA in this systematic review are likely a combination of inadequate access to treatment programs and psychosocial challenges, which differ between countries with different health systems. For example, in the USA, only 13.8 percent of OUD treatment programs accepted Medicare and covered any Food and Drug Administration approved opioid use disorder medication [91]. This is compared with the UK, where the National Health System (NHS) fully covers any medications for OUD approved and recommended by the National Institute for Health and Care Excellence (NICE) [92]. More research is required to determine the most important barriers to OUD treatment from the perspective of both prescription OUD and heroin OUD in other countries.

Literature gap

The exclusion criteria for this review includes several exclusion categories that may show where the literature gaps are when studying treatment seeking behaviour in other countries (USA and non-developed countries are excluded). There was one study from the Netherlands where opioid use was not the main substance studied and rather SUD more generally was studied [93]. Similarly, there were two studies from the United Kingdom [94, 95] where OUD was not the main diagnosis and SUD more generally was studied. This emphasises the need for more specific OUD related treatment seeking behaviour. Furthermore, there are no reviews looking at treatment seeking in substance use disorders more generally indicating this is an area for further research. OUD diagnosis was not measured using a reliable diagnostic tool, for example the ICD-10 or the DSM-V, in studies from United Kingdom [96, 97], Canada [98] and Australia [99] meaning that a diagnosis is based on self-report or other unvalidated measures (e.g. self-report of illicit drug use in the past month or the presence of injecting marks).

Literature limitations

All included studies were from the USA, which means the results cannot be generalised to other countries due to the notable differences in health care systems, which may lead to differences in treatment seeking behaviours for those with OUD. In the USA healthcare is a market driven business opportunity whereas in other countries, for example the UK, healthcare is a public good [100]. It would be ideal to include other countries with varying health systems in the review, however presently these studies are not available in the literature. Secondly, all the included studies used cross-sectional surveys (see Appendix A in S1 File) and all but one study [32] assessed treatment seeking through self-reporting, which has the potential to introduce recall bias regarding treatment. Furthermore, although only studies with DSM and ICD OUD diagnoses were included in this review, self-reporting is used to input the data for these diagnostic tools, which may introduce recall bias. Lastly, ten of the 13 studies used the NSDUH and NESARC differing year surveys to provide nationally representative samples, however these surveys do not include homeless individuals. Those with OUD are often homeless and therefore this may underestimate the prevalence of treatment seeking for OUD in this vulnerable population.

Study limitations

Although this review included studies that were conducted in developed countries, all studies were from the USA. Therefore, results are not transferable to countries other than the USA. More research is required on the treatment seeking levels in other countries. Secondly, the review only included studies published in English and therefore important treatment seeking studies published in other languages have been missed. Thirdly, the treatment seeking timeframe reported varied between studies and included past 6 months, 12-month and lifetime treatment seeking. This bias was able to be reduced by undertaking subgroup analysis of the results. Fourthly, treatment seeking in this review was treatment or counselling related to OUD. However, one study involved only pharmacological treatment for OUD [32] and the second included both OUD treatment and psychiatric treatment, which could not be separated [33]. Mostly, treatment was similar, however these minor differences in treatment items between studies could have introduced some bias. Lastly, although broad terms relating to OUD treatment and pharmacotherapy were used in the search strategy, the only specific treatment types included were methadone and buprenorphine. This means that studies with other specific treatment types, for example behavioural interventions or naltrexone, may have been missed. However, this review is determining the prevalence of treatment seeking to any treatment rather than individual treatment types and therefore the results may not be heavily impacted.

Conclusion

The overall pooled proportion of those with a lifetime OUD treatment history was about 40% and those with a 12-month OUD treatment history was around 20%. These results indicate low levels of treatment seeking for those with OUD in the USA. The reasons for these modest levels of treatment-seeking behaviour and barriers to treatment in this USA population require immediate attention and future work should be undertaken in this area. Treatment-seeking behaviour in the USA was found to be lowest in adolescents and adults with prescription OUD and highest in adults with heroin OUD.

Supporting information

S1 Checklist. PRISMA 2009 checklist.

(DOC)

Click here for additional data file.^{(65.5KB, doc)}

S1 File. Contains all the supporting tables and figures.

(DOCX)

Click here for additional data file.^{(1MB, docx)}

Data Availability

The paper contains the minimal data set, meaning the findings from this study can be replicated in their entirety.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0258620.r001

Decision Letter 0

Kyoung-Sae Na

15 Feb 2021

PONE-D-20-31370

Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Hall,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

However, this decision does not guarantee final acceptance. There seem to be several important issues that need to be clearly resolved by revision. Particularly, read through the comments of the reviewer #2 and #3 and then respond to them carefully.

Please submit your revised manuscript by Apr 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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We look forward to receiving your revised manuscript.

Kind regards,

Kyoung-Sae Na, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The current manuscript entitled “Treatment seeking behaviour among people with opioid use disorder in high income countries: A systematic review and meta-analysis” evaluates treatment seeking behavior in individuals with OUD. The protocol for the systematic review and meta-analysis appear sound and maintain rigor (although see point 1 below). The findings are interesting and add to the body of evidence that healthcare providers and programs need to do more to reduce barriers to OUD care and medication for OUD. There are a number of weakness that diminish enthusiasm and need to be addressed should the authors be invited to submit a revision. Most importantly, there is one article that was included but does not appear to meet inclusion criteria (see point 3 below). This may change the results and limits the scope to US populations. There are also some stigmatizing elements of the discussion that are unsupported or based on extremely outdated evidence. Major and minor issues detailed below.

Major

1) The manuscript stated that the search was performed on 11/28/2019 but the PROSPERO protocol was created on 04/20/20. This alone is not necessarily a problem, but registering after starting literature search is not consistent with PRISMA guidelines. The authors should state that the protocol was pre-registered after search was completed and clearly state what aspects of the protocol were completed prior to registration on PROSPERO. It is possible that registration was in response to a prior review at another journal, but the authors should be transparent.

2) Please consider using “medications for Opioid Use Disorder” instead of OST or, to better describe buprenorphine and methadone, use opioid agonist treatment.

3) The authors state that only studies that included DSM-5 or ICD diagnosed opioid use disorder were included and studies that relied on self-reported OUD were excluded. However at least one study (Kimergard et al., 2017) appears to have used online surveys from social media and treatment websites. It is easily assumed that the participants in these surveys self-reported OUD because the surveys were online links. In fact, the authors state that Kimergard used the Severity of Dependence Scale which is 5 items and, while potentially correlated with DSM and ICD OUD diagnosis, does not equate to an OUD diagnosis. Without this study, all the other studies are in the US which would change the scope of the article (i.e., not high income countries but rather just U.S.). This manuscript would appear to call into the full-text exclusion category of “OUD not appropriately/consistently measured”.”

4) “Heroin use disorder” is not a diagnosis; OUD with primary heroin use is more appropriate. The authors also separate findings into prescription OUD, heroin OUD, and general OUD. This may be unnecessarily confusing. It appears the difference between prescription OUD and non-prescription OUD (i.e. heroin and/or general OUD) is most informative with respect to treatment engagement. Also, the heterogeneity in the prescription OUD is substantially less than the other OUD categories. This is potentially useful and should be discussed more that it is in the findings. Why are the rates of treatment higher and more uniform in prescription OUD versus other OUD categories?

5) The study column in Table 1 and 2 states “Excluded Study.” These studies were not excluded though. Please clarify.

6) Discussions about treatment gap for the Europe are inappropriate because there is only one study (only UK and Ireland) and it appears this study should be excluded (see point 2 above). Even if the authors can justify including Kimergard, this single study is in no way representative of Europe.

7) The authors postulate that individuals with higher rates of OUD and primary heroin use are higher than prescription OUD because of the “heavy disruption of heroin use” on daily life. This is not always the case and potentially not related at all to treatment engagement. The authors also state that “heroin users often seek treatment after hitting ‘rock bottom’ and treatment is often initiated after court orders.” This language is incredibly stigmatizing and potentially inaccurate. In fact, the authors cite a paper from 1971 to justify this statement. Higher rates of treatment seeking for individuals with OUD and primary heroin use may be more likely due to stigma of heroin use and challenges diagnosing prescription OUD particularly in the context of long term opioid treatment for chronic pain (see Manhapra et al. (2020). Complex Persistent Opioid Dependence with Long-term Opioids: A Gray Area That Needs Definition, Better Understanding, Treatment Guidance, and Policy Changes. Journal of General Internal Medicine, 1-8.).

8) The authors state that individuals with prescription OUD are more likely to have comorbidities compared to those with OUD and primary heroin use. The type of comorbidities should be discussed. Medical comorbidities in individuals with prescription OUD may be driven by co-occurrence of chronic pain, which is associated with considerable multimorbidity.

9) The authors discuss lower treatment engagement in the current findings compared to general SUD in other developed nations. The authors fail to discuss possible reasons beyond different access to care across countries. This appears to be a great opportunity to talk about potential sigma as a barrier to treatment that may be specific to OUD and review ways to reduce barrier.

Minor

10) There are numerous awkward phrasing and grammatical issues in the text, most notably in the results. For example, in the results “Lifetime treatment-seeking proportion of those with heroin use disorder included 2 studies only and the treatment seeking proportion was 65% with a wide confidence interval as well as high I2 statistic, both indicating heterogeneity between studies.” This sentence contains a lot of information and is very difficult to follow. Suggest the authors structure reporting the findings in the same way and stick to a consistent presentation of findings. It is sometimes confusing which studies are connected to a reported I2 statistic.

11) Unclear why there are numbered commented in the meta-analysis sensitivity results.

12) Meta-analysis result figures in the supplemental materials are cut off on the right side. Please revise to include complete figure.

Reviewer #2: I found this to be a very interesting and well written article. My comments are relatively minor:

- Abstract. Please review the Objective sentence. There appears to be a word missing. Maybe "behaviour"?

Reviewer #3: This manuscript sought to understand the “gap” in treatment-seeking behavior among individuals with opioid use disorder in high-income countries. While a noble effort and important topic, there are significant concerns in the presentation of the information, as well concerns about biases in the data collection that warrant further understanding.

The title is a little misleading in that the review doesn’t cover “high-income countries” as a whole. Despite that being the intent, the data are nearly entirely focused on the United States, and so there is a potential for readers or others to generalize these results to other high-income countries where there are significant differences in healthcare compared to the United States. Given that the end result in the data, the authors may consider removing the single UK study and focusing the paper on the United States alone, which would still be of interest. The original methodology and research question could still be included, but with the decision given the search results, that the instead the data were limited to the United States.

The authors need to provide better context surrounding the complexity of the gap in treatment-seeking for opioid use disorder. The authors note previous research identifying gaps in treatment-seeking for alcohol use disorder, but opioid use disorder involves more complex substance use patterns that make it more difficult to account for treatment-seeking patterns, particularly when comparing 2008, the year of the first study reported in the analysis, to that of recent years.

Most notably, this span of years in the United States is complicated by two issues:

1. In 2008, opioid use predominantly involved prescription opioids, but over the past decade, heroin use drastically increased in the wake of prescription opioid use reductions resulting from prescription-focused interventions.

2. In addition, the provision of buprenorphine was extremely low early on, but has drastically increased, making treatment with buprenorphine not equally accessible across the study time period.

Even today, many treatment centers/programs in the United States, due to our disparate provision of healthcare, do not provide buprenorphine or methadone. According to the 2018 National Survey of Substance Abuse Treatment Facilities, 39.6% provide no pharmacotherapy treatment. Although the authors appear to use broad terms for opioid treatment, the lack of searching for other specific types of treatment like the inclusion of buprenorphine or methadone may have limited the results.

In addition, using only articles in English would also have been a significant factor in limiting the results. Not all high-income countries publish all of their articles in English, and suggesting there is not data from high income countries is different than saying there is not data published in English from high income countries.

It may be helpful to understand the exclusion criteria in the flow chart at a country level. This could help inform readers as to what the current limitations are, or what types of studies are being conducted in other countries, in order to spur more research on this issue in those countries.

The authors note that self-reported studies were excluded from the interview. However, they include data collected from NSDUH, which is self-reported. I believe NSDUH was included because DSM criteria are included in the questions, thus offering a way to “meet” diagnostic criteria, but this is still self-report.

“Where studies reported both heroin OUD and prescription OUD, prescription OUD was reported in the main analyses while heroin OUD was included in the subgroup analyses?” What was the rationale for this decision? This seems like it could have time-related bias.

11 of the 14 studies stem from two surveys NESARC and NSDUH, which suggests the results may be more indicative of these two national survey in the United States rather than “treatment-seeking behavior of high-income countries” and so these results would be limited in the same the way the data from these surveys are limited. The authors may consider limiting their paper to just the United States, where a synthesis of this data would be more meaningful.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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PLoS One. 2021 Oct 15;16(10):e0258620. doi: 10.1371/journal.pone.0258620.r002

Author response to Decision Letter 0

3 Mar 2021

Please see word document attached earlier titled " PLos one response to reviewers"

Attachment

Submitted filename: PLoS ONE response to reviewers.docx

Click here for additional data file.^{(54.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0258620.r003

Decision Letter 1

Kyoung-Sae Na

18 Mar 2021

PONE-D-20-31370R1

Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Hall,

==============================

Reviewer #1 and #2 generally agree with the publication of the paper. However, the reviewer #3 still raises critical issues that needed to be further addressed. It is up to the authors whether or not to revise the paper again. I think that the Reviewer #3 has a point.

==============================

Please submit your revised manuscript by May 02 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Kyoung-Sae Na, M.D.

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: No

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #1: The revised manuscript entitled “Treatment seeking behaviour among people with opioid use disorder in high income countries: A systematic review and meta-analysis” is significantly improved from the original submission. The authors have been comprehensive in their response to prior reviews. I have no additional major critiques. One suggestion would be to state in the abstract that while the search was intended to capture all high income countries only manuscripts from the US met inclusion criteria.

Reviewer #2: Upon re-reviewing this article I realized that the authors seem to use "treatment seeking" and "access to treatment" interchangeably. For instance, the Objective in the Abstract is to "To determine treatment seeking behaviour in those with opioid use disorder (OUD) in the high-income countries" but the authors present access to treatment. I do not think these 2 terms can be used interchangeably. It would be important for the authors to define/how they conceptualize "treatment seeking" and justify why they then move on to using the term "access". Alternatively, please remove the "access to treatment language".

Please also specify whether any relevant articles published before 2008 appeared in your search. If so, why were they excluded given that there were no year restrictions for your search.

Reviewer #3: The authors were very thoughtful in their responses to the reviewers. However, I still have significant concerns about the methodology that were not alleviated with inclusion of several items as limitations, but rather, call into question the appropriateness of the methodology. Some further detail and considerations may be warranted:

The authors note in their response that “only studies from the USA were available in the literature.” I believe there are still a number of issues that arise from this methodology and the objectiveness of this statement. Despite noting it in the limitations, the fact that only English language publications were used discounts a substantial amount of literature in high-income countries, and so continuing to use the title “High-income countries” is misleading to readers. In addition, there are nuances to other high income countries that may not be accounted for. For instance, were detoxification programs included? These are often referred to as simply ‘substance use detoxification’ programs. Would this be accounted for in the search criteria? Were studies on the prescribing of buprenorphine included? The Canadian Institute for Health publishes treatment-seeking statistics (i.e., proportion of Canadians starting opioid therapy) through assessments of prescriptions due to their ability to follow individuals through national health systems. It’s possible that the studies in the United States dominated the results because without nationalized healthcare, we rely on studies, as opposed to utilization of nationalized health systems for this information, which may see publication elsewhere than a study-based journal article. These are not just limitations, but raise questions about the appropriateness of this methodology. This could be why 11 of the 13 articles includes are from just two national studies in the US, which also raise questions about the generalizability of the information provided.

As noted in the previous review, NSDUH and NESARC are both interviews where an individual is asked to self-report behaviors, although the authors have updated the manuscript to note that they are asked specific criteria, here off the DSM. This leads to question of what the authors deemed to be “self-report” vs. “diagnosed” OUD that may have led to studies from other countries being excluded. Many other countries likely do not use the DSM, so there may be variations in how opioid use disorder is clinically diagnosed. In France, OUD is primarily treated by general practitioners who prescribe buprenorphine, and like Canada, this is tracked through the French National Health Insurance database. Did the authors only take articles where a diagnostic process was specifically outlined, or was a physician prescribing buprenorphine for OUD enough, on the assumption that the physician would not prescribe buprenorphine if there was not a clinical diagnosis? More information on needs to be provided on what constituted a “clinical diagnosis.”

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

PLoS One. 2021 Oct 15;16(10):e0258620. doi: 10.1371/journal.pone.0258620.r004

Author response to Decision Letter 1

29 Apr 2021

Please see word document with response to reviewers comments

Attachment

Submitted filename: Response to PLOS one reviewers 30042021.docx

Click here for additional data file.^{(29.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0258620.r005

Decision Letter 2

Kyoung-Sae Na

13 May 2021

PONE-D-20-31370R2

Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Hall,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Yours sincerely,

Kyoung-Sae Na, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

According to the reviewers, the revised version of the manuscript seems to be inappropriate for publication. Particularly, most of the methodological issues, which have been raised by the Reviewer 3, were not resolved.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Partly

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: No

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #2: I appreciate the authors taking the time to address my concerns. After this round of revision I must say these concerns have only been partially addressed. Namely, there continues to be confusion when discussing treatment seeking and unmet treatment needs. For instance, in the Conclusion of the Abstract the authors state that: "This review found that one in five people with OUD sought OUD treatment in the previous 12 months and two in five people with OUD sought OUD treatment in their lifetime. These results indicate a significant unmet treatment need for those with OUD, the reason for this low treatment seeking requires immediate attention and future work." To me, there is a logical gap about drawing conclusions on treatment gaps when the results presented pertain to treatment seeking. This argument would make sense if data presented pertained to people seeking treatment but not receiving it. We could then talk about an unmet need. I think it might be wise to revise the conclusion and focus on how we can move individuals toward treatment seeking. This misalignment is present throughout the manuscript.

Could you also please specify what is meant by treatment gap in the Discussion (line 305). Please also specify what other factors might be in line 330.

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No

- - - - -

For journal use only: PONEDEC3

PLoS One. 2021 Oct 15;16(10):e0258620. doi: 10.1371/journal.pone.0258620.r006

Author response to Decision Letter 2

5 Jul 2021

Please see rebuttal letter in the downloads section.

This has the responses to all issues raised by the reviewers.

Attachment

Submitted filename: Rebuttal letter and all manuscript changes_NH+LL+CM.docx

Click here for additional data file.^{(64.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0258620.r007

Decision Letter 3

Adam Todd

4 Oct 2021

Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

PONE-D-20-31370R3

Dear Dr. Hall,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Adam Todd, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I have reviewed this manuscript and I am satisfied that the authors responded to the comments in a robust and satisfactory way; the limitations are clearly described and the review has been reported according to the appropriate checklist. In addition, the paper has been reviewed by in expert in statistical methods who is happy by the approach taken by the authors. Overall, I am therefore satisfied that this paper meets the threshold for publication in PLOS ONE.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #4: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #4: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #4: (No Response)

**********

6. Review Comments to the Author

Reviewer #4: (No Response)

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PLoS One. doi: 10.1371/journal.pone.0258620.r008

Acceptance letter

Adam Todd

7 Oct 2021

PONE-D-20-31370R3

Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

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Data Availability Statement

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PERMALINK

Treatment-seeking behaviour among people with opioid use disorder in the high-income countries: A systematic review and meta-analysis

Natasha Hall

Long Le

Ishani Majmudar

Maree Teesson

Cathy Mihalopoulos

Roles

Abstract

Objectives

Methods

Results

Conclusion

Introduction

Method

Data source

Study selection

Data extraction

Data analysis

Quality assessment or risk of bias assessment

Results

Study characteristics

Fig 1. PRISMA flow diagram.

Quality assessment of the included studies

Meta-analysis base case results

Lifetime OUD treatment seeking

Fig 2. Lifetime treatment seeking for OUD IVhet model.

12-month or less OUD treatment seeking

Fig 3. 12-month or less treatment seeking for OUD IVhet model.

Meta-analysis subgroup results

Lifetime treatment seeking

12-month or less treatment seeking

Meta-analysis sensitivity analysis results

Lifetime OUD treatment seeking

12-month OUD treatment seeking

Table 1. Lifetime OUD treatment seeking IVhet base model metaXL sensitivity.

Table 2. 12-month OUD treatment seeking IVhet base model metaXL sensitivity.

Discussion

Literature gap

Literature limitations

Study limitations

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Kyoung-Sae Na

Roles

Author response to Decision Letter 0

Decision Letter 1

Kyoung-Sae Na

Roles

Author response to Decision Letter 1

Decision Letter 2

Kyoung-Sae Na

Roles

Author response to Decision Letter 2

Decision Letter 3

Adam Todd

Roles

Acceptance letter

Adam Todd

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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