FormalPara Key Points

Real-world evidence supporting the use of abuse-deterrent drug formulations is limited.

Xtampza ER demonstrates reduced odds of tampering in a treatment population.

Abuse-deterrent drugs could present an intervention against opioid use disorder.

1 Introduction

Opioid-use disorders (OUDs) continue to plague many individuals even as misuse of prescription opioids has decreased [1]. Although prescription opioid abuse in general remains high among those with OUD [2, 3], abuse of immediate-release (IR) and extended release (ER) formulations does not occur equally. Among poison-center calls, intentional abuse exposures involving IR formulations occurred at much higher rates, while the gap between IR and ER formulations was smaller among individuals with OUD [1]. Among individuals with OUD, use of IR formulations was preferred over ER formulations, where ease of tampering was cited as a chief reason for preferring the IR products [4]. Though IR formulations have had higher rates of misuse, ER formulations have historically been physically tampered with and used via unintended methods (e.g., chewing, smoking, snorting, or injecting) [5], and being exposed to a tampered opioid has been associated with more severe medical outcomes [6].

Those who use tampered prescription opioids do so to increase the speed of absorption and intensity of the euphoria [5]. Misuse by alternative routes remains a frequently discussed topic among people who use drugs [7]. One technique to impede tampering with prescription opioids has been the development of abuse-deterrent formulations (ADFs), currently only available in ER formulations. These formulations are designed to reduce a person’s ability to easily tamper with a drug, and they present a barrier against the person using a drug in a manner not intended by the drug manufacturer, which has been shown to dissuade some individuals from transitioning from oral use to non-oral use [5].

While all ER oxycodone drugs now utilize ADFs to reduce tampering, there is still information to be gathered about their real-world utility [8]. For example, there is evidence that different formulations of ADFs may have differing effects on the overall reduction of tampering despite using the same ADF technology [9]. This demonstrates that each ADF opioid should be assessed on its individual merits, despite the use of technology that has been established as successful. The Food and Drug Administration (FDA) also recommends that post-market studies be conducted on an ongoing basis to determine whether ADF opioids are having a consequential impact on the misuse and abuse of prescription opioids in a real-world setting [10]. Despite the recommendations, barriers for patients to use an ER ADF drug remain. Limited formulary coverage by health plans reduces the likelihood of an ADF being prescribed [11] and immediate-release (IR) opioid counterparts can be prescribed for longer than 90 days [12], when an ER analgesic might be better suited.

In an effort to expand the post-market research on ADF effects in the real world, this study aims to quantify differences in tampering between one abuse-deterrent oxycodone, Xtampza ER (oxycodone myristate), and comparable opioids on the market. Analyzing this unique formulation (designed as microspheres within a capsule, and been shown in vitro and clinically to reduce tampering [13, 14]), offers insight into how tailored formulations might affect real-world behaviors and support regulatory requirements [10]. Assessing the effectiveness at reducing tampering of a drug in the real-world setting requires informative counterfactual scenarios, so that the effectiveness might be contextualized against other treatment options [15]. This study compares oxycodone myristate against three active comparators and quantifies the difference in odds of tampering. These results will assist healthcare providers to make patient-centered decisions surrounding pain management and provide further information on the real-world utility of ADF ER opioid drugs.

2 Methods

This cross-sectional study utilized data from the Treatment Center Programs Combined, which are included in the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System. The RADARS® System is a mosaic of programs that collect and report on trends in drug use throughout the USA [16]. These data were collected between the third quarter of 2018 and the third quarter of 2021 from individuals upon entry into opioid treatment programs, and it included basic demographic data as well as drug history. The 163 treatment centers participating in the study are nationally distributed throughout 46 states and the District of Columbia. Both privately funded clinics and publicly funded opioid treatment programs participate. Surveys are self-administered and are anonymous. They are offered to individuals aged > 18 during the admissions process. In some clinics, the questionnaire can be filled out in private then returned to the treatment clinic personnel. In other clinics, the questionnaire can be taken home and filled out; it is then mailed directly to the researchers. Returned questionnaires undergo rigorous quality control steps. A sample of questionnaires is quality checked on a quarterly basis, and data entry must register a < 5% per questionnaire error rate. These data have been validated against other drugs surveillance programs and the Treatment Episodes Data Set (TEDS) [16, 17]. The questionnaire includes demographic questions, broad questions related to drug use, and specific questions related to use and route of use for 28 drug groups. Participants are asked about which drug products they used “to get high” in the past month and the route they used. For the purposes of these analyses, tampering was defined as chewing, smoking, snorting, or injecting an opioid. Respondents to the survey indicated which routes they have utilized within the past month for the list of opioids of interest. They were able to select as many opioids and routes of use as necessary. As a result, participants could have used more than one drug group during the study period.

Three active comparators were selected to present a range of contrasts between oxycodone myristate and other potential drug exposures scenarios [15]. Primarily, comparators must be plausible exposure alternatives [18]. The first comparison is between oxycodone myristate and immediate release (IR) single entity (SE) oxycodone. This comparison highlights the use of an ADF when compared to non-ADF IR formulations, which is an alternative treatment for chronic pain [19] and historically has a very similar abuse risk in the population to ER oxycodone [20]. The second comparison investigates the differences in oxycodone myristate and other ER oxycodone opioids. All ER oxycodone opioids are similarly indicated and have potential for abuse, making other ER oxycodone a suitable exposure alternative. The final comparison is between oxycodone myristate and ER oxymorphone, which examines the differences between oxycodone myristate and an ER opioid that is often tampered with before use [21]. Extended-release oxymorphone is similarly indicated as oxycodone myristate, although has a lower abuse risk [20]. Other differences and similarities between oxycodone myristate and comparators should be considered when interpreting results. All drugs included in this study are formulated for use via the oral route. Immediate-release SE oxycodone is prescribed more frequently than ER formulations [1], making them generally more available for abuse than ER formulations. No IR oxycodone formulation currently has abuse-deterrent labelling. All current formulations of ER oxycodone, which includes OxyContin and other licensed generic drugs, are labelled as abuse deterrent. Finally, ER oxymorphone has high abuse potential via tampering [21] and tampering has historically produced adverse health events [22].

Individuals were included in this study sample if they indicated past month use by any route of any of the drug groups listed above. If route of use was not indicated, then those individuals were removed from the sample. In the logistic regression model, for each pair of comparisons, the odds of tampering with Xtampza ER (the exposure category) was compared to the odds of tampering with the comparison category. The logistic model was fit with a random intercept allowing for multiple drugs in each subject. Within-subject correlation was assumed to have a compound symmetric relationship. Demographics by drug group were conducted to examine potential confounders. Only age and sex within Xtampza ER subjects appeared to differ from the comparator drugs. Odds ratios (ORs) were adjusted for age and sex; however, neither was significantly associated with tampering with Xtampza ER and therefore removed from the final model. Analyses were conducted using SAS software, Version 9.4 (Cary, NC, USA) and figure creation was conducted using RStudio Team, version 4.1.1 (2021-08-10)—“Kick Things” [23].

3 Results

As seen in Table 1, the participants in this study were 57.6% male and predominantly White (78.4%). The mean age was 36.7 years (SD = 9.9 years). Of the 2273 participants, 35.2% had previously overdosed on an opioid, and 33.9% had never previously been in a substance abuse treatment program. Health care professionals made up 5.6% of the sample, and 3.1% were former active-duty armed forces personnel. For those who tampered with oxycodone myristate, the mean age was 38.9 years (SD 11.0 years), 51.3% were male, and 38.5% had never been in a treatment program. An additional breakdown of the demographic characteristics stratified by drug group can be seen in Table 1.

Table 1 Sample demographics of the study population
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The highest percent of tampering was seen in IR SE oxycodone (72.5%, 95% CI 69.9, 74.9). Extended-release oxymorphone had the next highest rate at 66.7% (95% CI 62.1, 71.2), followed by ER oxycodone with 56.4% (95% CI 53.9, 58.8) and oxycodone myristate with the lowest tampering rate at 38.5% (95% CI 23.4, 55.4) (Fig. 1). Overlap among the categories of drug tampering was high. Only 16 individuals (≤ 1%) tampered with oxycodone myristate alone, while 941 (41%) tampered with ER oxycodone alone. Those who tampered with both IR SE oxycodone and ER oxycodone made up 14% (N = 328) of the sample (Supplemental Table 1).

Fig. 1
figure 1

Percent of tampering and 95% CIs in each drug category. CIs confidence intervals, ER extended release, IR immediate release, SE single ingredient

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Odds of tampering with oxycodone myristate were generally smaller than either of the non-abuse deterrent comparators, but they were not significantly smaller than other ER oxycodone products, which are also abuse deterrents. Shown in Table 2, odds of tampering with oxycodone myristate were 77% lower than tampering with IR SE oxycodone (OR = 0.23 [95% CI 0.11, 0.50], p = 0.0002) and 70% lower than ER oxymorphone (OR = 0.30 [95% CI 0.14, 0.67], p = 0.0038). In contrast, there was no significant difference in the odds of tampering between oxycodone myristate and other ER oxycodone, which also has abuse-deterrent properties (OR = 0.5 [95% CI 0.24, 1.03], p = 0.0612). The ORs between drug groups did not demonstrate a notable difference against the unadjusted values when age and sex were included in the model (Table 2).

Table 2 Odds ratios of tampering
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4 Discussion

The results of this study provide community-based, real-world evidence of the abuse deterrence of the oxycodone myristate formulation. These findings demonstrate that, in a sample of individuals entering a treatment program, oxycodone myristate is less likely to be tampered with than IR SE oxycodone and ER oxymorphone but was statistically no different than other abuse-deterrent oxycodone drugs. These findings indicate that ADFs can deter individuals from tampering with opioids in the community setting.

Although mortality involving prescription opioids declined slightly through 2019 [24], mortality rates involving prescription drugs remain much higher than historic levels and 2.3 million individuals aged ≥ 12 years had a prescription pain reliever use disorder in 2020 [25]. Severtson et al. [26] found a reduction in abuse, misuse, and diversion of oxycodone myristate when compared to other opioids across many real-world data sources in the USA. It follows that the reduction in tampering seen in this study may also extend to other real-world settings, such as those abusing, but not seeking treatment. These findings also provide additional post-market evidence of the real-world utility of ADF opioids in reducing tampering [27, 28]. Although the estimated OR was notable, no significant difference was observed between the two types of abuse-deterrent oxycodone products. This suggests that individual abuse-deterrent technologies could result in different reductions in abuse, but, due to the rarity of tampering with Xtampza ER, the study was insufficiently powered to detect smaller effects. This highlights a need to evaluate each individual ADF technology separately.

In 2020, the number of individuals misusing specific opioid drugs varied widely [25]. This study indicates that use patterns differ even within products using the same active ingredient, as evidenced by the different likelihoods of tampering between oxycodone formulations. Differentiating product or formulation usage, while challenging, provides critical nuance when evaluating the effectiveness at reducing tampering of prescription drug use interventions. Cicero and colleagues [9] enhanced our knowledge of the variability that can occur between different ADF opioids when investigating specific routes of use. Even though two opioids may have the same ADF technology, the drugs may not have similar deterrent effects on the populations that use them. This is a driving reason for the need for extensive real-world data on specific drugs. This study’s findings contribute to the body of knowledge regarding ADF real-world usefulness by confirming the success of oxycodone myristate at reducing tampering when compared to non-ADF opioids. In addition, the lack of significant difference between oxycodone myristate and other ADF ER oxycodone demonstrates that ADFs are likely successful at deterring tampering overall, and additional differences between the two groups may be uncovered in a larger dataset.

The primary limitation of the study was that additional confounding effects were not controlled due to infrequent endorsement of the drug of interest, limiting the causal implications of the study. Other relevant confounders such as mental health history, past treatment history, and acquisition through peer networks should be included once more data are collected. However, two demographic confounders, age, and sex, were included, and no substantial adjustment in ORs was observed. A second limitation is the lack of route information from all participants. Excluding these individuals could have introduced bias. Imputation approaches may address this bias [26]. In addition, the sample of individuals with opioid use disorder reflect those who personally sought and had access to treatment for their opioid use disorder and may not be reflective of the entire population of people who use opioids. There is also a need to consider the fundamental differences in abuse rates for IR and ER oxycodone, which primarily result from ease of tampering. Finally, given low market penetration of abuse-deterrent opioids, these data may not reflect trends if there were increases in the widespread adoption of ADFs, which should be closely and continuously monitored.

However, the strengths of this study include product-level post-marketing surveillance from a reasonably large, nationally representative sample of individuals with opioid use disorder, a population that would be most likely to seek and tamper with prescription opioids due to advanced addiction. In addition, the ability to collect data on a variety of comparator opioids provides crucial information needed to understand the role of abuse-deterrent formulations in the larger culture of opioid prescribing and pain management.

5 Conclusions

Despite an increased focus on illicit opioids in mitigating the US opioid crisis, and reductions in opioid prescribing, non-medical use of prescription opioids remains ubiquitous and continues to play an important role in pathways to opioid use disorder. Government agencies, professional organizations, and healthcare organizations have identified abuse-deterrent formulations as a key strategy in combating the extra-medical use of prescription opioids by presenting barriers to non-oral use. However, variability in individual preference, ADF technology, and access, may lead to differences in ADF-related outcomes, as has been noted in prior research. These real-world data suggest that tampering of a specific ADF formulation, oxycodone myristate, is comparable to that of other ER oxycodone (ADF) products, and significantly less than that of non-ADF formulations. These data support the utility of ADFs overall in discouraging non-oral use among individuals with opioid addiction. As such, disseminating information and research into ADF technology and outcomes, particularly among clinicians managing chronic pain, would add to the range of options clinicians have to combat misuse, abuse, and opioid use disorder.