Association Between Harm Reduction Strategies and Healthcare Utilization and Outcomes in Patients on Long-term Prescribed Opioid Therapy Presenting to Acute Healthcare Settings: A Systematic Review and Meta-analysis

Background Long-term prescription of opioids by healthcare professionals has been linked to poor individual patient outcomes and high resource utilization. Harm reduction strategies in this population in regard to acute healthcare settings may have substantial impact. We performed a systematic review and meta-analysis of primary studies. The studies were included according to the following criteria: 1) age 18 and older; 2) long-term/chronic prescribed opioid therapy; 3) acute healthcare setting presentation from a complication of opioid therapy; 4) evaluating a harm reduction strategy; 5) comparing the effectiveness of different interventions; 6) addressing patient or healthcare related outcomes. We performed a qualitative analysis of harm reduction strategies identified. We pooled patient and system related outcome data for each harm reduction strategy. A total of 5664 studies were screened and 21 studies were included. A total of 11 broad categories of harm reduction strategies were identified. Meta-analysis was performed for the “supports for patients in pain” harm reduction strategy on two system-related outcomes using a ratio of means. The number of emergency department (ED) visits were significantly reduced for cohort studies (n=6, 0.36, 95% CI [0.20-0.62], I 2 = 87%) and randomized controlled trials (RCTs) (n=3, 0.71, 95% CI [0.61-0.82], I 2 = 0%). The number of opioid prescriptions at ED discharge was significantly reduced for RCTs (n=3, 0.34, 95% CI [0.14-0.82], I 2 = 78%). For the intervention with the most robust data is “supports pain”.


Abstract Background
Long-term prescription of opioids by healthcare professionals has been linked to poor individual patient outcomes and high resource utilization. Harm reduction strategies in this population in regard to acute healthcare settings may have substantial impact.

Methods
We performed a systematic review and meta-analysis of primary studies. The studies were included according to the following criteria: 1) age 18 and older; 2) long-term/chronic prescribed opioid therapy; 3) acute healthcare setting presentation from a complication of opioid therapy; 4) evaluating a harm reduction strategy; 5) comparing the effectiveness of different interventions; 6) addressing patient or healthcare related outcomes. We performed a qualitative analysis of harm reduction strategies identified. We pooled patient and system related outcome data for each harm reduction strategy.

Results
A total of 5664 studies were screened and 21 studies were included. A total of 11 broad categories of harm reduction strategies were identified. Meta-analysis was performed for the "supports for patients in pain" harm reduction strategy on two system-related outcomes using a ratio of means. The number of emergency department (ED) visits were significantly reduced for cohort studies (n=6, 0.36, 95% CI [0.20-0.62], I 2 = 87%) and randomized controlled trials (RCTs) (n=3, 0.71, 95% CI [0.61-0.82], I 2 = 0%). The number of opioid prescriptions at ED discharge was significantly reduced for RCTs (n=3, 0.34, 95% CI [0.14-0.82], I 2 = 78%).

Interpretation
For patients presenting to acute healthcare settings with complications related to long-term opioid therapy, the intervention with the most robust data is "supports for patients in pain".

Description of the condition
The opioid epidemic is a major public health problem across the world. While not initially recognized as a crisis, it has become a public health emergency that is largely believed to have begun in 1996 when OxyContin® was approved by the FDA (1). Opioid prescription was initially thought to be the crux of the problem and multiple interventions were implemented in response over the years. A majority of these interventions were focused on reducing access to opioid prescriptions. The results of these interventions have had unforeseen and paradoxical consequences. As an example, reducing in prescription rates in Ontario (Canada) lead to a doubling of opioid mortality due to an increase in street opioids (2). This shift in the nature of the opioid crisis to illicit opioid use has indeed been seen in multiple locations over the years and paralleled these interventions (3). In light of such findings, illicit drug use has become the focus of most current efforts to limit the impact of the opioid crisis and the impact of opioid prescriptions has taken a backseat. However, it remains that there are patients on longterm opioids for chronic painful conditions that are also at risk for complications. This group has ultimately been somewhat neglected amidst the extensive literature available on the more obvious high-risk populations. It is however quite clear that individuals on long-term opioid therapy are at risk of poor outcomes, including hospitalization, overdose and death from the use or management of their opioids (4,5). These poor outcomes invariably lead to acute healthcare presentations that have significant system level impacts on health services use including emergency department (ED) presentations, hospital and intensive care unit (ICU) admissions, as well important socio-economic consequences (6)(7)(8)(9)(10).

Description of the intervention
Harm reduction strategies are defined as "any policy or program designed to reduce drug-related harm without requiring the cessation of drug use; these interventions may be targeted at the individual, the family, community or society (11)(12)(13)(14)(15)(16)(17)(18)(19)." Harm reduction strategies are traditionally thought of and applied to patients demonstrating high risk behaviors and the term has not typically been applied in relation to individuals on longterm opioid therapy. These individuals may still benefit from harm reduction strategies as they require these medications for their well-being but may still suffer harmful consequences from their use. While evidence exists for harm reduction strategies in acute opioid overdoses, the evidence to support their impact in individuals on long-term opioid therapy is harder to discern but it may be substantial given the reported high risk of adverse events in these settings (7,(20)(21)(22). The most important complications as a result of opioid therapy most often lead to a presentation to an acute healthcare setting, defined as a setting in which "health system components, or care delivery platforms, are used to treat sudden, often unexpected, urgent or emergent episodes of injury and illness that can lead to death or disability without rapid intervention (23)." Examples of these include emergency departments, acute health care clinics, hospital inpatient units. Accordingly, this may be the healthcare setting in which the most impactful harm reduction strategies may lie, and how this population can best be captured in studies. As such, the primary objective of this study was to identify the most effective harm reduction strategies for patients on long-term prescribed opioids presenting to acute care settings to decrease complications attributable to opioid use, to reduce avoidable health services use, and to improve outcomes.

Study design and registration
We performed a systematic review using the guidelines from Cochrane and the Centre for Reviews and Dissemination (24,25), and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines for observational studies (26,27). The study was registered with the PROSPERO (CRD42018088962 on 2018/02/19) International Prospective Register of Systematic Reviews (http://ww.crd.york.ac.uk/prospero).

Types of studies
We considered primary studies (i.e., randomized controlled trials (RCT), cohort studies, case-control studies) and secondary analyses or evidence syntheses (i.e., systematic reviews, meta-analyses). There were no language restrictions. We considered studies published after 1996 as this is when OxyContin® was introduced, and the current prescription opioid epidemic is believed to have largely began(1). We excluded editorials, case series, case reports and narrative reviews.

Eligibility of individual studies
Studies were eligible for inclusion if they satisfied the following criteria: Patient related criteria: Age 18 years or older.
Long-term or chronic opioid therapy, reflecting prescribed opioid more than 70% of days for at least 3 months(28).
Presentation to acute healthcare setting secondary for a presumed or confirmed complication of prescribed opioid therapy.

Study-related criteria
Evaluating an intervention representing a harm reduction strategy.
Comparing the effectiveness of different interventions between each other or individual interventions compared to current care Addressing patient or healthcare system related outcomes (i.e. number of opioid prescriptions, repeat presentations to ED or acute healthcare, number of overdoses).
We excluded studies that specifically addressed patients with non-prescription opioid use, or prescription opioid use not obtained through healthcare professionals. We excluded studies of patients with opioid use disorder or misuse that was not attributable to an established chronic pain disorder or disease.

Search methods
The search strategy was developed and executed by an information specialist (RF) and was peer-reviewed by a second research librarian ( Figure 1). The information specialist searched electronic databases: Ovid MEDLINE (1946-), Ovid EMBASE (1996-), Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCOhost (1937-), and Wiley Cochrane Library (inception-), including the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL). We also searched reports from the National Information Center on Health Services Research and Health Care Technology (NICHSR) via the NICHSR ONESearch portal. Study records were also searched via the trial registry platform ClinicalTrials.gov, guidelines via the National Guidelines Clearinghouse, and meeting abstracts via the Conference Proceedings Citation Index database (Clarivate Analytics). The following search themes was used: 1) opioids; 2) long-term drug therapy; and 3) acute healthcare settings (emergency departments, acute care surgery, critical care, urgent care and short-term inpatient stabilization). We additionally scanned the reference list of relevant included studies for additional articles. Bibliographic records were exported to an EndNote X9 (Clarivate Analytics, Philadelphia, Pennsylvania). Databases were searched up to and including April 11, 2019.

Study assessment
Articles were identified through two phases. First, two authors (JD and JG) independently reviewed the titles and abstracts of all retrieved articles for study inclusion. Second, full texts of the selected articles were retrieved, reviewed and selected based on inclusion criteria. All steps were performed in duplicate, and in each phase, disagreements were resolved through discussion. In the case of unresolved matters, a third author (OGR) was involved. Reasons for exclusion of full text articles were recorded and displayed in a PRISMA diagram format.

Quality assessment of studies
The methodological quality of each study was independently analyzed by two authors (JD and JG) using the Newcastle-Ottawa Quality Assessment Scale (NOS) for observational studies and the Cochrane Risk of Bias Tool for randomized controlled trials (24,29). Disagreements were resolved through discussion, and in the case of unresolved matters, a third author (OGR) was involved.

Data analysis and synthesis
An inventory of harm reduction strategies was developed from the included studies. Descriptive analysis and data extraction of patient and study characteristics, and of harm reduction strategies and their outcomes were performed using standardized electronic data forms (Supplementary Appendix 1 for variables extracted). We analyzed all available data qualitatively and, when possible, aggregate analysis was performed (30). For each study we extracted or computed the ratio of means between the intervention and usual care groups with 95% confidence interval (31). These ratios were then pooled using the DerSimonian-Laird random effects method with an inverse variance weighting. To minimize bias due to confounding, results for RCTs were pooled separately from results for cohort studies and the two were not combined in one meta-analysis. Heterogeneity was assessed using the I-squared statistic with values greater than 50% considered to be "substantial" heterogeneity.

Results
Our search yielded 5664 studies, of which 21 studies fulfilled our eligibility criteria (Figure 2, Supplementary Appendix 2). These included 19 full-text articles and 2 abstracts, of which 16 were cohort studies and 5 were randomized controlled trials (Table 1). No additional articles were identified for inclusion from the reference list of included articles. Study quality is reported in tables 2 and 3.
A total of 11 categories of harm reduction strategies were identified (Table 4). Most studies addressed multiple harm reduction strategies simultaneously making separation difficult. This is reflected and detailed in both Table  1 and Table 4. The 16 cohort studies included all assessed harm reduction strategies in a pre/post intervention model (Table 1). They either compared matched cohorts of different patients (n = 9) or cohorts of same patients before and after intervention (n = 7) in which each patient was his own control. Nearly all studies were performed in ED settings (n = 14). A single cohort study assessed mortality (11). The five RCTs (Table 1) were all performed in the ED, with the comparator being usual care. Outcomes assessed included ED opioid prescriptions, ED discharge opioid prescriptions, hospital length of stay (LOS), and overdose and opioid related ED visits. All cohort and RCT studies were conducted in the US other than the cohort study by Allen et al. in Canada (32).
Six cohort studies and three RCTs were suitable for meta-analysis (Figures 3 and 4). All studies included in the meta-analysis assessed outcomes for the "supports for patients in pain" harm reduction strategy. This strategy is characterized by the use of patient support groups, individual patient case management and pain clinic vetting and referrals. Two outcomes (number of ED visits and number of ED discharge opioid prescriptions) were metaanalyzed. The ED visits outcome refers to total number of visits to the ED after implementation of the strategy. The ED discharge opioid prescriptions outcome refers to the number of prescriptions dispensed at discharge of the patients from the ED. A significant reduction in number of ED visits for cohort studies (ratio of means 0.36, 95% CI [0.20-0.62], I 2 = 87%) and for RCTs (ratio of means 0.71, 95% CI [0.61-0.82], I 2 = 0%) was apparent. A significant reduction in number of ED discharge opioid prescriptions was noted for RCTs (ratio of means 0.34, 95% CI [0.14-0.82], I 2 = 78%). No patient-centered outcomes could be meta-analyzed. The studies duration ranged from 6 to 52 months.

Discussion
This systematic review identified 11 harm reduction strategies for patients on long-term prescription opioids presenting to an ED with complications related to their opioid therapy. A pooled analysis of outcomes for "support for patients in pain" showed a clinically important decrease in the number of ED visits and ED discharge opioid prescriptions. Other harm reduction strategies could not be analyzed in a rigorous fashion and may be considered by healthcare providers until additional evidence becomes available.
Opioid use is an important and increasing problem in the US and Canada. Multiple harm reduction strategies for acute healthcare settings have been developed and studied, but the evidence had not been collated for an assessment of their impact. Most of the harm reduction strategies identified were from small, single center studies, were too heterogeneous to be meta-analyzed, or were infrequently studied (Table 4). While most reported positive results, a number of these are single-center studies with a small number of patients. These small studies often lack the scientific rigor or external validity to allow meaningful interpretation in a larger context, and to support widespread changes in practice (33).
We identified multiple studies with enough data to perform a meta-analysis for outcomes of the "supports for patient in pain" strategy (Table 4 for definitions). These studies were chosen due to their similarity in the coordinated care models used and the target populations. There was a clinically important decrease in systemrelated outcomes of ED visits and ED discharge opioid prescriptions for this strategy. For both outcomes, 3 RCTs were included, with the most compelling data for ED visits due statistical significance and uniform data (I 2 0%), while ED discharge opioid prescriptions were significant but showed substantial heterogeneity (I 2 87%). The ED visits outcome was also supported by the meta-analysis of cohort studies that all trended in the same direction despite substantial heterogeneity (I 2 87%). Across all studies, there were only four instances of patient-related outcomes being evaluated. In these cases, the decrease in system-related outcomes were associated with unfavorable patient-related outcomes. Faryar et al. and Fulton-Kehoe respectively showed an increase in heroin use and methadone poisonings as the number of opioid prescriptions and poisonings decreased (34,35). Alexandridis et al. was the only study with a favourable patient-related outcome, demonstrating lower overdose mortality related to healthcare professional education, but as a whole did not change the rate of ED visits (11). This highlights concerns by experts that harm reduction strategies that focus on decreasing opioid prescriptions might actually contributed to unanticipated increases in avoidable deaths and overdoses (36) as patients seek out non-prescribed opioids to replace the previously prescribed opioids. The outcomes meta-analyzed may thus represent a poor proxy for appropriately impactful harm reduction strategies.
The other harm reduction strategies listed in Table 4 represent a combination of frequently recurring well-defined harm reduction strategies as well as composite terms representing harm reduction strategies referred to with different names across studies. This was determined through careful review of the detailed intervention performed in each study in order to reclassify them under umbrella headings. Unfortunately, precise definitions for each harm reduction strategy identified were not present in most studies. This limits our ability to both have homogeneous interventions under each harm reduction strategy. As such, based on the analysis of the interventions performed, most studies have multiple simultaneous harm reductions strategies employed. Accordingly, this limits the rigorous analysis of each harm reduction strategy independently.
In a similar fashion, there are no comparative studies of harm reduction strategies to inform which strategies may be superior, in which specific context, and where to direct organization and resources. Alexandridis et al. was the only study to include multiple well-differentiated strategies but analyzed them as independent variables despite a simultaneous implementation (11). However, identifying a superior strategy may be of limited importance, as statistical superiority does not necessarily reflect the clinical reality in these complex patients. Indeed, the most appropriate strategy depends on multiple local factors such as individual patient's specific needs and availability as well as access to resources. This highlights the complexity of assessing these process of care interventions for successful implementation and effectiveness of intervention. Such interventions may not lead to statistical or clinical significance in traditional outcomes (i.e., mortality) but have wider ranging benefits in care processes, workflow and resource optimization, as in the case and wide adoption of medical emergency teams (MET) (37).

Strengths and limitations
While this study had several important strengths (i.e., breadth of scope, rigorously pre-defined methodology stretching across several medical domains, presence of patient advisors), several important limitations warrant discussion. First, important terms (i.e., long-term medical opioid therapy, opioid 'abuse' and misuse, harm reduction strategies) were heterogeneously defined across studies and may have been a barrier to study identification. Most importantly, the harm reduction strategies were overall poorly defined across studies. Despite a careful analysis of the interventions in order to regroup or reclassify them under umbrella terms, it was difficult to clearly identify separate harm reduction strategies in some studies. Accordingly, these studies then often used multiple harm reduction strategies simultaneously, which significantly limited our ability to have a rigorous analysis. This is reflected in the meta-analysis where the most important harm reduction strategy was analyzed, acknowledging that it may not be fully separated from other minor elements of the intervention that may be classified under another umbrella term. We attempted to mitigate these factors by independent screening by two authors to ensure the inclusion of all relevant studies and appropriately classify the harm reduction strategies. Second, the rate of study inclusion was only 0.4%. This was secondary to most identified studies either studied illicit drug use or did not adequately differentiate between illicit drug use and opioid misuse, or poorly defined their population. When unclear following full-text review of the relevant publications, we erred to exclude studies from this review, hence focusing the findings of this review to those patients on prescribed opioid therapy. Third, the wide scope of some harm reduction strategies lead to difficult decisions for study inclusion. Indeed, a number of harm reductions were part of a package organized at a state level. It was difficult to separate the specific impact of each strategy, the impact on acute versus non-acute healthcare settings and to discern which studies dealt with patients on appropriate long-term opioid therapy. In these situations, we opted to include these state level studies if there was a well-described significant proportion of long-term opioid users, and if number of acute healthcare presentations was an outcome of interest. We do acknowledge that these studies reflect a very heterogeneous group in a lot of instances and limit the validity of the findings. This is not reflected well in the quality assessment of the cohort study who are technically for the most part of moderate to high methodological quality. The RCTs are for their part paradoxically at moderate to high risk of bias due to their design but represent a more homogeneous population. Fourth, most identified studies were from the US, limiting the generalizability of our findings to other jurisdictions that may have different policies and context that affect the outcomes of the identified harm reduction strategies. This is not surprising as the opioid epidemic was first recognized in the US, and many findings in the US are applicable across Canada and other high-income countries (1). Finally, while we decided to include studies from 1996, all of the studies included are from the last 15 years. This is likely explained by the delayed recognition of the public health crisis from the opioid epidemic.

Future directions
Our systematic review revealed that most of the studies have targeted patients presenting to the ED, with very little data on inpatient harm reduction strategies. This knowledge gap is reflected in the most recent Canadian guidelines for opioid use for chronic non-cancer pain, which do not address acute admissions in this population (38). These guidelines do reflect the importance of a multidisciplinary approach in the chronic non-cancer pain population, which would be similar to the "supports for patient in pain" harm reductions strategy. Studying this harm reduction strategy for non-ED acute healthcare settings would strengthen the current body of evidence. Importantly, studying these strategies using patient-related outcomes such as mortality, quality of life and pain is of paramount importance, as opioid prescriptions and ED visits appear to be poor or misleading surrogate endpoints. Future policy work informed by these results would lead to better resource utilization through a shift from reactionary processes (i.e., ED visits) to preventative strategies that prevent acute healthcare presentations.

Conclusion
We identified 11 harm reduction strategies for patients chronically prescribed opioids presenting to acute healthcare. The only harm reduction strategy that showed evidence of efficacy what "support for patients in pain" with clinically important decrease in the number of ED visits and ED discharge opioid prescriptions. Unfortunately, other harm reduction strategies were not evaluated in a rigorous fashion and may be considered by healthcare providers until additional evidence becomes available. These strategies have been studied almost exclusively in ED patients, and data on inpatient harm reduction is lacking and requires further study. Availability of data and materials:

List Of Abbreviations
All data generated or analysed during this study are included in this published article.
Author contributions JD was responsible for the manuscript preparation. JD and OGR were responsible for finalizing the manuscript. RF developed the search strategy in consultation with JD and OGR and conducted the search. SMB and OGR conceived the project, and all authors provided critical revision of the final manuscript. OGR will guarantee the content of the review. All authors read and approved the final manuscript.   A maximum score of 9 is possible. A score of 0 to 3 represent low quality; 4 to 6 represent moderate quality; 7 to 9 represent high quality. Table 3. Quality assessment of randomized controlled trials using the Cochrane Risk of Bias Tool. Hospital ED policy Local practices to limit ED or inpatient OA prescribing and checking prescription drugs monitoring programs prior to prescribing 5

Provider education
Education of medical professionals in chronic pain treatment 4

Statewide prescription policies
Practices or wide-ranging regulations to limit OA prescription within a legislative territory 3

Addiction treatment
Opioid agonist therapies and policies supporting their use 4 Electronic alert system Systems that alert providers to possible opioid abuse situations without mandating their use 2

Community education
Promotion of public awareness of prescription opioid overdose 2

Diversion control
Removal of unused medications and training of local law enforcement with OA diversion 2 At-risk patient education Tailored preventative interventions targeted at patients currently on opioid therapy 0 1

Naloxone policies
Promotion of the adoption of policies to disseminate the opioid antagonist naloxone to opioid users 2

Multimodal
Composite approach that encompasses multiple elements of the previous harm reduction strategies as a combined package 2 Figure 1 Search strategy Figure 2 Flow diagram for study assessment Figure 3 Meta-analysis of support for patients in pain harm reduction strategy for number of ED visits outcome.

Figure 4
Meta-analysis of supports for patients in pain harm reduction for ED discharge opioid prescriptions outcome.

Supplementary Files
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