The limits of innovation: directly addressing known challenges is necessary to improve the real-world experience of novel medications for opioid use disorder

Medication treatment for individuals with opioid use disorder (OUD) is an important tool to combat the opioid overdose epidemic. New medications – whether formulation, dose, or route of administration – improve efforts to offer patient-centered care and can reduce barriers to treatment. However, without concomitant measures to connect patients to care and improve retention, these new products might be associated with low uptake, limited real-world effectiveness, and high costs.

D’Onofrio et al. report findings that emerged from an ongoing clinical trial (ED INNOVATION) describing the pharmacokinetics and feasibility of a 7-day injectable extended-release buprenorphine (XR-BUP) formulation initiated in the emergency department (ED).¹ This important study represents a critical step to increase options for medications for opioid use disorder (MOUD). Injectable MOUD offer the potential for increased medication retention, where a once weekly or monthly dosing schedule may be easier to adhere to than a daily oral preparation. While 30-day formulations of XR-BUP (30-day XR-BUP, Sublocade®) are approved for administration after an initial lead-in period with an oral buprenorphine product,² D’Onofrio et al. evaluate omitting the lead-in step with the new 7-day product (CAM2038), potentially allowing for easier ED use. Authors found that the 7-day XR-BUP formulation was well tolerated and administration in the ED was feasible.¹ These findings are encouraging and provide an additional MOUD option, especially for administration in ED settings that are common touchpoints with the healthcare system for patients with OUD. However, any discussion of clinical trial efficacy should be paired with considerations for real-world implementation in order to realize the potential identified in clinical trials of lower barrier MOUD. The last ten years have seen several new MOUD come to market, and yet the overdose crisis remains intractable, claiming over 80,000 lives annually based on the most recent estimates.³ Clinical trial results as these should be framed with the real-world challenges necessary to overcome to best serve patients with OUD.

The first challenge is one of effectiveness, as a drug can only be effective if taken. D’Onofrio et al. note that evaluations of 7-day XR-BUP (BRIXADI^™) are in their infancy, and that further studies are necessary.¹ While clinical trials are important to isolate the clinical effect of a drug in a controlled setting, evidence from real-world early adopters of MOUD are underscoring the importance of efforts to enhance retention.⁴ These data revealed that additional support is needed to ensure that injectable forms become a potential solution to challenges related to initiation or retention.⁴ Only 1 in 5 individuals with OUD receives medication treatment,⁵ and this estimate has not improved in recent years.⁶ For those who do initiate, retention is often brief. First with injectable naltrexone,^6–8 and now with 30-day XR-BUP (Sublocade^®),^4,9 several studies have shown that real-world retention (and protection against overdose) on these products lagged behind oral buprenorphine. Additionally, emerging evidence suggests that patients generally prefer longer prescriptions of oral medication over injections.¹⁰ This does not imply that injectable formulations are not important options for patients, but demonstrates that new medications have not yet fulfilled the hope for improved real-world treatment effectiveness, and future efforts should ensure that patients receive the medication that best fits their individual needs.

The second challenge is one of cost. Particularly relevant in the United States context, high medication costs are often passed along to the consumer, which presents particular barriers to individuals with chronic conditions that affect their financial outlook, such as OUD. Prior work has documented the importance of costs on initiation and retention,¹¹ and revealed that even small differences in out-of-pocket payments present significant barriers to filling an MOUD prescription.¹² While the cost of drugs will vary based on insurance plan, the current monthly federal supply schedule cost for 30-day XR-BUP (Sublocade^®) is over $1,000 (the federal supply schedule is the contracted rate the government pays for pharmaceuticals and it is often used as a baseline cost in economic evaluations). This cost is in contrast to $50 or less for oral buprenorphine formulations, a considerable gap that is likely reflected to some degree in out-of-pocket payments for the consumer. The combination of high costs and low effectiveness translates to poor value for money. A forthcoming cost-effectiveness analysis of 30-day XR-BUP (Sublocade^®) relative to oral formulations found that because XR-BUP was more costly and less effective, it was not preferred,¹³ mirroring similar findings about injectable naltrexone.¹⁴ Of course, we do not yet know the cost of the investigational drug studied by D’Onofrio et al. However, unless the cost of this new medication is substantially lower than that of current injectable formulations of XR-BUP, cost will likely remain a barrier. The cost effectiveness analysis focusing on 30-day dosing for injectable XR-BUP (Sublocade^®) found that either the medication cost would need to decrease by 80%, or the 6-month retention would need to more than double, for the drug to be competitive with oral buprenorphine from a cost-effectiveness standpoint.¹³

The third challenge is one of linkage-to-care. D’Onofrio et al. note that one of the most important takeaways from their study was the feasibility of the 7-day XR-BUP (BRIXADI^™) product in the ED.¹ Engagement in care can be difficult for many patients with OUD, and the ED often serves as the sole contact with the medical system for some of the most ill patients. Nevertheless, initiation is just the first step, and an important component of the overall approach should include plans to increase retention on treatment after discharge from the ED, and attention to facilitating access to the drug in other settings. For example, short-term inpatient medically-managed withdrawal programs (detox) are another commonly used facility for individuals not engaged in the formal medical system. However, data show that shortly after release, when tolerance is low, individuals are at a particularly high risk for overdose.¹⁵

Framing the optimistic results of D’Onofrio et al. with a realistic picture of the challenges that need to be addressed in a real-world setting provides a roadmap to best leverage pharmaceutical innovation. For effectiveness, it is critical to develop strategies for patient-centered, targeted treatment. New medications are an important addition to our treatment toolkit, and to maximize their influence it is important to understand which drugs provide which patients the best chance for success. This is hard to do in a clinical trial setting, and funding agencies should strive to couple support of novel clinical trials with real-world research with adequate follow-up and a large, diverse patient sample. At the current cost of novel MOUD treatments, including XR-BUP, they are unlikely to prove cost-effective. The entrance of new medications onto the market (including the formulation described by D’Onofrio et al.) may represent an opportunity for lowering drug cost through competition. As time passes and new medications come to market, some of the currently branded products will move to generic, further decreasing their price. This may be similar to hepatitis C medications, where cost-effectiveness analyses demonstrated that while novel drugs were not cost-effective at the initially high launch price, they became acceptable when prices were lowered.^16,17 In the short term, however, cost may pose a barrier for many patients, and clinicians should consider a conversation about cost as essential to shared-decision making of MOUD choice. Both patients and policy-makers take cost into account when making decisions, and “non-inferiority” of two medications should not be the only axis of comparison if drug costs are severely mismatched. Finally, linkage-to-care needs to be a priority if novel treatments are to have a noticeable effect on the population health of individuals with OUD. Settings with either brief or short-term encounters with patients, including the ED, detox, and jails, represent an opportunity to reach some of the most at-risk individuals. Nevertheless, if these strategies are not coupled with effective linkage efforts, we may be putting patients at risk if they end up off medications and with a lower tolerance.

Novel therapeutics are necessary, but not sufficient, to reduce overdose and improve the lives of individuals with OUD. Directly tackling challenges, namely drug effectiveness, drug cost, linkage-to-care and engagement in care, and using lessons learned to inform the design, execution, and framing of clinical trial results provide an opportunity for meaningful progress related to the persistent opioid overdose crisis.