This systematic review identified 11 supportive 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 supportive 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 supportive 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 supportive strategies identified were from small, single center studies, and 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 (34).
We identified multiple studies with enough data to perform a meta-analysis for outcomes of the “support for patient in pain” strategy (Table 4). 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 system-related 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 (I2 0%), while ED discharge opioid prescriptions were significant but showed substantial heterogeneity (I2 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 (I2 87%). As discussed above, “support for patients in pain” represent an aggregation of strategies individualized to a specific patient’s needs, which is widely different from other supportive interventions. These types of interventions are of course more resource intensive. Overall, the evidence demonstrates that the costs of treatment for opioid misuse and abuse are offset by the reduced health care costs (35,36). Murphy et al. provides the only economic analysis that indicates similar findings (37) and may support an economic incentive to their use in long-term opioid users without opioid use disorder. Furthermore, these interventions have clear evidence and support for patients with chronic non-cancer pain and opioid use disorder (38–40). They are accordingly recommended by different international guidelines with recommendations (41). Unfortunately, our findings are more complex in terms of interpretation by the nature of the outcomes used. Indeed, 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. Fulton-Kehoe indeed showed an increase in methadone poisonings as the number of opioid prescriptions and poisonings decreased (42) Alexandridis et al. was the only study with a favorable 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 (43) 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 supportive strategies.
The other supportive strategies listed in Table 4 represent a combination of frequently recurring well-defined supportive strategies as well as composite terms representing supportive 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 supportive 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) (44).
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 supportive strategies were overall poorly defined across studies. Despite a careful analysis of the interventions to regroup or reclassify them under umbrella terms, it was difficult to clearly identify separate supportive strategies in some studies. Accordingly, these studies then often used multiple supportive 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 supportive strategies. Second, the rate of study inclusion was only 0.4%. This was secondary to most identified studies either studied illicit drug use or poorly differentiated long-term opioid use without opioid disorder from opioid use disorder. We aimed to exclude opioid use disorder or abuse but were faced with a high degree of uncertainty in some cases. We thus decided to include studies only if they specifically referred to acute pain presentation in long-term opioid users even if there was mention of prescription opioid misuse, as long as there was some clear distinction between the groups. Given that there is a degree of conversion from appropriate use to abuse, we believe that this captures well this evolution in patients. Similarly, identifying what constitutes harm or complications from long-term opioid use proved challenging. Presentations other than overdose or without the attached opioid misuse label are often unrecognized as related to opioids. We had to assume that in the selected papers, the focus on patients being on opioid therapy means that there is a reasonable expectation that their presentation is related to opioid in some way. In our opinion, acute on chronic pain qualified as such, as it either represents hyperalgesia or under-treatment, both of which require a measured treatment approach. Third, the wide scope of some supportive 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 supportive 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.
Our systematic review revealed that most of the studies have targeted patients presenting to the ED, with very little data on inpatient supportive 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 (41). 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.