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The number of older adults who had medical encounters for treatment of opioid misuse, dependence, and poisoning has increased disproportionately over the past decade [1]. The opioid-related adverse events (ORAEs) defined by the United States (US) government agencies [1–3] contain diagnostic codes commonly used for opioid use disorder (OUD) and overdose from use of illicit opioids (i.e., heroin) or incorrect use of prescribed opioids, as well as E codes for severe adverse effects from use of heroin or correct use of prescribed opioids that lead to hospital or emergency department visits. The rate of hospital stays and emergency department visits due to ORAEs rose by 34% (from 199.3 stays to 267.6 stays per 100,000 persons) and 74% (from 44.7 visits to 77.9 visits per 100,000 persons), respectively, among older patients between 2010 and 2015 [1]. A study of a commercially insured population also indicated a marked increase (14.2-fold from 2.05 to 31.12 per 10,000 persons) in the incidence of OUD or overdose among older adults aged 65 and older between 2006 and 2016 [4]. These alarming statistics have prompted questions of what might have predisposed older patients to be at risk for ORAEs [2].

Of the known risk factors, prescription opioid dose is one of the strong predictors of ORAEs [5–9]. Studies of nonelderly or mixed populations of young and older populations showed that use of prescription opioids at a dose of 90 morphine milligram equivalent (MME) or above per day was associated with an increased risk for opioid overdose and deaths [10–13]. Built on this evidence, the 2016 Centers for Disease Control and Prevention (CDC)’s Guidance for Opioid Prescribing for Chronic Pain recommends avoidance of prescribing daily opioid doses at 90 mg MME or greater [14]. Since then, some medical societies’ guidelines [15], state regulations [16], and health insurance payers [17] have adapted the CDC-recommended dose threshold and limited prescribing doses of opioids to 90 mg MME per day [18,19].

The Centers for Medicare and Medicaid Services (CMS), the largest insurer of older adults in the US, has utilized 90 daily MME as one of the criteria for flagging high-risk beneficiaries for OUD or overdose and required its Part D plan sponsors to adjudicate the appropriateness of opioid prescribing of these high-risk patients [20]. However, our prior study has shown that the CMS’s opioid overutilization criteria missed the majority of patients with OUD or overdose and flagged more than half of opioid prescription users as high risk who were not diagnosed with OUD or overdose [21]. The finding challenges the use of 90 daily MME as a risky threshold for Medicare beneficiaries, the vast majority of whom are aged 65 years or older. Literature has primarily focused on establishing the high-risk prescription opioid dose thresholds using healthcare data among young (aged 18 to 64) individuals, which may not be applicable to older individuals who may have different thresholds for adverse opioid outcomes due to declined renal and hepatic function, multiple comorbidities, and polypharmacy.

A cohort of 380,272 Medicare older patients with CNCP (mean [SD] age, 76.2 [7.9] years; 65.4% female; and 81.4% White) were new users of prescription opioids between 2011 and 2018 (Table 1). Fig 1 describes the cohort inclusion and exclusion criteria. During the year before cohort entry, 9.0% had a diagnosis of tobacco or alcohol use disorder, 28.3% had mental health disorders, 44.7% had diabetes, and 59.3% had cardiovascular diseases. The majority (80.9%) had polypharmacy. Musculoskeletal pain was the most prevalent pain condition experienced in these older adults.

Table 1. Characteristics of the total cohort, cases who had an incident ORAE encounter, and matched controls of older adults with CNCP who were new users of prescription opioids between 2011 and 2018.

https://doi.org/10.1371/journal.pmed.1003947.t001

From this opioid new user cohort, we identified 6,176 patients who had an incident ORAE encounter during follow-up, yielding an incidence rate of 7.17 per 1,000 person-years. Of the 6,176 ORAE cases, 1,800 (29.1%) had the encounter within the first 6 months after prescription opioid initiation, and 1,273 (20.6%) had no prescription opioid fill in the 6 months preceding the ORAE diagnosis. This resulted in 3,103 cases with a 6-month follow-up preceding the ORAE, during which at least one opioid prescription was dispensed for dose trajectory analysis. Of 3,103 cases, 55.5% had a diagnosis of opioid misuse or dependence, 45.1% had a diagnosis of opioid poisoning, and only 0.06% had a diagnosis of adverse effects of opioids. Table 1 gives the characteristics of the 3,103 cases and 3,103 matched control patients.

We identified distinct opioid dose trajectories before an incident ORAE encounter or matched date in controls (Fig 2). Four trajectories, categorized based on their mean daily MME use of prescription opioids per month, included patients with gradual dose discontinuation (from ≤3 to 0 daily MME, consisting of 23.5% of the study sample), gradual dose increase (from 0 to >3 daily MME, 30.3%), consistent low-dose use (between 3 and 5 daily MME, 24.3%), and consistent moderate-dose use (>20 daily MME, 22.0%). The dose trajectory groups differed significantly for most demographics as well as select pain and clinical conditions (Table 2).

Fig 2. Trajectories of mean daily MME dose prescribed in each month for the 6 months preceding an incident encounter of ORAE for cases or matched controls of older adults.

Lines represent types of dose trajectory group, and for each line, each point represents the mean daily MME of prescription opioids per month. The scale on the left and right side of the figure is the natural logarithm of MME and actual MME, respectively. The error bar represents the standard deviation of the natural logarithm transformed MME. MME, morphine milligram equivalent; ORAE, opioid-related adverse event.

https://doi.org/10.1371/journal.pmed.1003947.g002

Compared with controls, cases had a lower proportion of patients with gradual dose discontinuation (11.8% versus 35.2%, P < 0.001) but a higher proportion with consistent moderate dose (31.6% versus 12.3%, P < 0.001) (Table 3). Overall, only 2.4% of older patients were prescribed a mean daily dose of 90 mg MME or more during any month of the 6 months before the index date. Sensitivity analysis with mean daily MME use of prescription opioids calculated at the biweekly interval showed similar dose trajectories (S1 Fig). We found similar prescription opioid dose trajectories among cases with opioid misuse or dependence encounters and their controls (S2 Fig) and among cases with opioid poisoning encounters and their controls (S3 Fig).

In adjusted multivariable conditional logistic regression analysis, prescription opioid dose trajectories were independently associated with risk for an ORAE encounter (Table 4). Compared to patients with gradual dose discontinuation, those with graduate dose increase had a 3.4-fold (95% CI 2.8 to 4.0; P < 0.001), those with consistent low dose had a 3.8-fold (95% CI 3.2 to 4.6; P < 0.001), and those with consistent moderate dose had an 8.5-fold (95% CI 6.8 to 10.7; P < 0.001) increased risk for having an incident ORAE encounter, after adjustment for covariates. Stratification analysis by specific types of opioid encounters showed similar results, with the gradual dose increase, consistent low dose, and consistent moderate dose group having an increased risk for opioid misuse/dependence or poisoning when compared to the group with decreasing dose trajectory (S4 Table).

Our main findings remained robust in the sensitivity analysis using a cohort study design. The increased risk of ORAE among patients with the gradual dose increase (adjusted hazard ratio [HR] = 4.4; 95% CI 3.8 to 5.1; P < 0.001), consistent low dose (aHR = 1.9; 95% CI 1.6 to 2.1; P < 0.001), and consistent moderate dose (aHR = 5.7; 95% CI 5.0 to 6.5; P < 0.001), as compared to those with the gradual dose discontinuation, persisted in a cohort design (S7 Table). Further stratification by the duration of follow-up revealed a higher risk of ORAE in the earlier months (i.e., first or second month) of the follow-up defined in the cohort design as a sensitivity analysis (S7 Table).

Across the 4 identified groups, we observed a low dose range (mean daily dose between 0 to 20 daily MME) of prescribed opioids and less than 5% of older patients, the majority of whom were among the cases, receiving doses at or above the dose threshold of 90 daily MME. Compared to evidence observed in younger adults with ORAE [25], a lower dose range (0 to 20 daily MME versus 3 to 150 daily MME) and a lower proportion with ≥90 daily MME (2.4% versus 28.8%) was observed among older adults with a similar diagnosis of ORAE, suggesting that there is a unique opioid dosage pattern preceding the incident ORAE encounter in the older population.

The mechanisms by which low to moderate doses of prescribed opioids were associated with increased risk of ORAEs among older patients may be complex and can possibly be explained by 2 major pathways. First, older patients may be more susceptible to opioid side effects at lower doses. While no empirical data or clinical consensus exists on a dose threshold above which opioids are considered harmful for older patients, evidence from the general population has suggested that increased risk of OD may occur at a dose as low as 20 mg/day MME [30]. The other pathway that may explain our observed associations is the use of illicit opioids, which cannot be captured with our data sources, to supplement the low-to-moderate dose of prescribed opioids. Recent reports suggest an emerging transition from prescription opioids to illicit opioids owing to increasingly restricted access to prescription opioids [31–33]. It is possible that the gradual dose discontinuation group identified in this study might have sought illicit opioids to achieve pain control or to enhance euphoric effects, putting them at higher risk for ORAEs, compared to other groups of prescription opioid dose. Yet, this assumption was not supported by our data where a lower risk of ORAEs was observed in the group with gradual dose discontinuation versus other identified prescription opioid dose groups. Further studies that examine whether illicit opioid use varies across the 4 identified prescribed opioid dose trajectories are needed to assist interpretations of our study findings.

Of note is our finding that over 1 in 4 (28.3%) older patients gradually discontinued their prescription opioids in 6 months before an ORAE or matched date for controls. The opioid discontinuation was much higher in the matched controls (35.2%) than in cases (11.8%). Reasons for more controls undergoing opioid discontinuation are unclear but could be because of improved pain control, opioid ineffectiveness, or adverse opioid side effects [34]. Opioid discontinuation or dose reduction, particularly among long-term users, is among the recommendations from the 2016 CDC opioid guidance [14]. While the CDC guideline did not support abrupt tapering and sudden discontinuation of prescription opioid dose, these clinical practices were reported for patients with chronic pain and have been implicated as a contributor to unintended consequences, including ORAEs [2], OD and deaths [35], and suicidal ideation or attempts [35,36]. The US Department of Health and Human Services in 2019 issued a new clinical guide on how to appropriately reduce dose or discontinue long-term opioid analgesics, emphasizing the importance of assessing the risks and benefits of such practices [37]. In the present study, we focused on opioid-naïve older adults and found that those with gradual dose discontinuation (versus those with gradual dose increase or those with low-to-moderate dose use) had decreased risk for ORAE. It is worth noting that the gradual dose discontinuation group identified in the present study was named based on the trajectory shape, and the definition of our gradual dose discontinuation is not the same as that defined by the CDC, which involves opioid dose reduction of 10% per week after opioid use for weeks to months and 10% per month following opioid use for >1 year [37]. Whether our association findings can be seen for older adults with long-term opioid therapy requires further investigations to understand the benefits and harms of discontinuation of long-term opioid analgesics.

There are also several limitations to note. First, this study allows for establishing an association but not causation between prescription opioid dose trajectories and risk for ORAEs. Second, illicit opioid use, a growing concern in the opioid epidemic, was not captured in our data, limiting our ability to clarify the safe dose threshold of prescribed opioids for older adults. Third, our analysis of prescription dispensing data confirms receipt of medications and not medication use. Fourth, Medicare administrative claims data lack information on pain severity, which is the key factor associated with selection into opioid treatment. Fifth, while several opioid endpoints defined in claims data have been validated against medical chart review [38–40], the validity of ORAE is unclear and warrants further research. Sixth, the present study did not measure the risk of adverse events associated with opioid tapering such as increased pain, insomnia, mental and physical function, and suicide. Seventh, our findings can only be generalized to Medicare fee-for-service beneficiaries with CNCP. Finally, our study excluded patients who had an incident diagnosis of ORAEs but had no prescription opioid fill during the 6 months before the diagnosis. This group may present different opioid risk profiles, and understanding risk factors beyond prescription opioid use is important to identify this high-risk subgroup of older patients.

Our findings have important clinical implications. The CDC-recommended 90 mg/day MME as the high-risk opioid dose threshold may be impractical to detect older adults at risk for ORAE. Only 5% of cases received prescribed opioid doses at or above 90 daily MME before diagnosis, leaving most cases undetected. Since 2013, the CMS required its Medicare Part D sponsors to closely monitor high-risk beneficiaries whose prescribed opioid dose was at or above 120 daily MME, and in recent years, they aligned the risky dose threshold to be consistent with the CDC-recommended 90 daily MME [41]. Prior studies have questioned the utility of using 90 daily MME in detecting patients at risk of ORAEs [21]. Echoing this finding, our study suggests that additional clinical markers to predict illicit opioid use are needed to identify older adult patients at high risk for ORAEs, particularly during the new era of increasingly restricted access to prescription opioids.