The opioid crisis continues to be a major public health concern in the United States (U.S.). Globally, 58 million people used opioids in 2018 accounting for the majority of disability-adjusted life years lost [41]. Compared to other regions in the world, pharmaceutical opioids are drivers of the opioid epidemic in North America [41]. In the same year in the U.S., 9.9 million people, representing 3.6% of the population, reported opioid misuse in the past year [40].

Addressing the opioid epidemic in the U.S. has focused heavily on reducing opioid prescribing with a notable effect: the national opioid prescribing rate was 51.4 prescriptions per 100 persons in 2018, the lowest in 13 years [5]. Even so, drug overdoses accounted for 67,367 overdose deaths in 2018 with 69.5% of these deaths involving opioids (n=46,802) [38]. Opioid-related adverse events are on the rise among patients without documented opioid prescriptions [25] along with increased use of illicit opioids like heroin or fentanyl [8].

Following publication of Centers for Disease Control (CDC) Prescribing Opioids for Chronic Pain in 2016 [13], some have raised concern about unintended consequences of aggressive or involuntary tapering of patients on chronic high-dose opioid therapy [24]. CDC Guideline calls for a collaborative approach between clinicians and patients to determine appropriate tapering plans. However, some may integrate elements of the CDC Guideline and reduce opioid prescribing in ways that are not sensitive to patient needs or preferences. In fact, some healthcare professionals have identified multilevel barriers to deprescribing (i.e. dose reduction and discontinuation) [26] while others have suggested opioid “stewardship” toolkits to reduce opioid harms especially in high prescribing settings (e.g. emergency departments) [33].

Few studies have examined unintended effects of abrupt discontinuation on patient outcomes. Patients on chronic opioid therapy in one primary care clinic who discontinued opioid prescriptions had nearly a three-fold increase in overdose risk [17]. Elevated overdose mortality risk remained high for 3 years following discontinuation of prescription opioids in a Massachusetts cohort [27]. Mark et al. found that many long-term opioid users are discontinued quickly and without prior dose reduction, a pattern that is associated with increased risk of adverse events [29]. This finding focused on the relationship between timing of discontinuation and the risk of an adverse opioid-related event among patients on chronic opioid therapy but did not examine the interaction between dose reduction and discontinuation, and did not assess opioid-related deaths or suicide as outcomes.

The aim of this study was to evaluate the association between dose reduction and risk of suicide, opioid overdose, and other opioid-related adverse events among patients with high-dose chronic opioid therapy.

The linked dataset contained 354,841 patients with Medicaid eligibility and an opioid prescription or opioid-related diagnoses between 2014 and 2017. Of these, 20,575 (5.8%) patients had at least one episode of high-dose COT that ended in 2014 or 2015 (Figure 1).

Of the 14,596 high-dose COT patients that met continuous enrollment criteria, 4,191 (28.7%) abruptly discontinued opioid prescriptions in the year after high-dose COT, 1,648 (11.3%) reduced opioid dose prior to discontinuing, 6,480 (44.4%) had a dose reduction but never discontinued, and 2,277 (15.6%) had a stable or increasing dose in the year following the COT episode (Figure 1).

Patients with an abrupt discontinuation had the highest daily average MME during the COT episode (mean 146.08, SD 735.53) while patients with a stable or increasing dose had the lowest average MME (mean 103.46, SD 76.49) (Table 1). Patients who discontinued opioid prescriptions (abruptly or with a preceding dose reduction) were younger and less likely to be female than patients who did not discontinue opioid prescriptions (with or without a dose reduction). Patients with a dose reduction and discontinuation were more likely to have a multiple prescriber or pharmacy episode during COT or diagnoses of chronic pain, depression, alcohol abuse, or any drug abuse in the 3-months prior to the end of the COT than patients in other groups (Table 1).

Overall, 625 (4.3%) patients had an opioid-related event (Table 2). Patients who discontinued opioid prescriptions (with or without a dose reduction) were more likely to have a suicide event (1.0% and 1.4% vs. 0.3% and 0.2%) or experience some other opioid-related harm (3.8% and 4.6% vs. 2.7% and 1.9%) than those who did not discontinue (p<0.0001). Patients with a stable or increasing dose were most likely to experience an opioid overdose (1.7%, p=0.0002) (Table 2).

Among patients with an opioid overdose, those who abruptly discontinued opioid prescriptions were more likely than patients in all other groups to overdose on heroin vs prescription opioids (n=8, 14.8%, p=0.0622) while patients with a stable or increasing dose were more likely to experience a fatal overdose (n=27, 67.5%, p<0.0001). Among patients with a suicide event, those with an abrupt discontinuation were more likely to experience a fatal event (n=23, 57.5%, p<0.0001) than patients in other dose change groups (Table 2).

Patients with an abrupt discontinuation (n=192, 4.6%) or dose reduction prior to discontinuation (n=83, 5.0%) were more likely to have filled at least one buprenorphine prescription during the follow-up period than patients in other dose change groups (p<0.0001) (Table 2).

Discontinuation significantly increased risk of suicide compared to those with stable or increasing dose (abrupt, adjusted hazard ratio (aHR) 3.63; 95% CI 1.42–9.25 or with dose reduction, aHR 4.47, 95% CI 1.68–11.88), while discontinuation or dose reduction reduced the risk of overdose compared to those with a stable or increasing dose (aHR 0.36 – 0.62, 95% CI 0.20 – 0.94) (Table 3).

Those with an abrupt discontinuation (aOR 15.07, 95% CI 7.28–38.38), dose reduction and discontinuation (aOR 14.83, 95% CI 7.00–38.33), or dose reduction without discontinuation (aOR 2.47, 95% CI 1.14–6.46) all had higher odds of filling a buprenorphine prescription relative to those with a stable or increasing dose (Table 3). Full models with adjusted covariates and survival curves can be found in Table 1, Appendix B.

In this cohort of Medicaid beneficiaries with an episode of chronic opioid therapy (COT), discontinuation of opioid prescriptions (abrupt or with dose reduction) increased the patient’s risk of suicide or opioid related adverse events in the following year. Patients with an abrupt discontinuation were more likely to overdose on heroin (vs. prescription opioids) or experience a fatal suicide than those in all other dose change groups. Patients on a stable or increasing dose were more likely to experience an overdose event. Patients who discontinued opioid prescriptions had higher odds of filling a buprenorphine prescription.

This study broadens our understanding of the potential risks of opioid discontinuation among individuals using high-dose COT. Similar to Mark et al [29], we find that individuals with an abrupt discontinuation face increased risk for some harms, but we also find increased risk of overdose among those with a stable or increasing dose. Our findings extend these observations to a cohort of individuals with COT at a lower average dose (50 versus 120 MME daily) and highlight specific risks.

There has recently been a shift in deaths from prescription opioids to heroin and synthetic opioid overdose deaths [34]. Prescription opioid use or misuse is common among individuals who initiate heroin [31]; one study suggests that restrictive policies on prescription opioids, sometimes leading to opioid discontinuation, may precipitate heroin use [25]. Moreover, the combination of prescription opioid use prior to injection drug use is associated with increased overdose risk [1]. Consistent with these observations, we find that heroin-related overdose was more common among individuals who abruptly discontinued opioid prescriptions. We also found that fatal overdose was more common among individuals with a stable or increasing dose, though individuals in this group were also more likely to overdose on prescription opioids than heroin.

Growing evidence suggests the use of sublingual buprenorphine may confer analgesic effects in patients with chronic non-cancer pain. In addition, opioid-dependent patients with chronic pain may benefit from reversal of opioid-induced hyperalgesia and improvement in opioid tolerance [6; 7; 10]. In this study, patients who discontinued opioid prescriptions or reduced their dose without ever discontinuing had higher odds of filling a buprenorphine prescription than those who had a stable or increasing dose, suggesting that some patients may be transitioned to buprenorphine. However, the degree to which people were switched to buprenorphine for opioid use disorder, chronic pain management, or both is unclear.

This study raises several important issues. Discontinuation after COT may increase risks of heroin overdose, suicide, or other adverse events, so discontinuation should be carefully considered in partnership with the patient. We found that opioid harms were most common among those with a dose reduction prior to discontinuation, so even when dose reduction is the best identified clinical course, clinical caution is merited [28]. Certain conditions may favor rapid tapering or discontinuation [3], yet in general, the CDC guideline recommends slow dose reductions over a longer time period for patients with COT [4]. We found that stable or increasing dose of opioids carries a notable risk of fatal overdose, and emphasize the importance of patient education and co-prescriptions for naloxone [9]. Lastly, after end of COT, patients had characteristics similar to patients with opioid use disorder (OUD) [15; 23; 39] as well as a high proportion of health services utilization for OUD (opioid misuse and opioid dependence) after opioid discontinuation or reduction [43]. Wei et al, found that 50% of patients on chronic opioid therapy developed OUD within a year [42]; therefore, tapering decisions should account for presence or risk of OUD in patients on COT to reduce any potential harms.

This study has several limitations. First, the observational design does not permit us to disentangle issues related to temporality and causation; we do not know why prescriptions were interrupted. Patients who were incarcerated or hospitalized may have erroneously appeared to discontinue use. The length of COT may be underestimated and we cannot ascertain any differences in the length of COT across the four cohorts because we were limited by the start of our study period [35].

The patient cohort is comprised entirely of Oregon Medicaid members, so may not represent national patterns [16]. We also could not determine clinical indication for COT, thus, we could not evaluate the appropriateness of any opioid use, nor could we determine the appropriateness of the identified dose reductions or discontinuations. As with all studies using claims data, we may underestimate risk if there was not a billed medical visit as a result of an overdose, suicide attempt, or other adverse event. To mitigate this limitation we applied a continuous enrollment criterion and used PDMP data instead of pharmacy claims to ensure that we captured all opioid prescriptions including those paid with cash, and we used vital statistics data to identify fatal events that may not have been identified in claims.

In summary, discontinuation of prescription opioid dose after a period of high-dose long-term use is associated with an increased risk of suicide or other opioid-related harms, while a stable or increasing opioid dose is associated with an increased risk of opioid overdose. Our study suggests that patients on COT require careful risk assessment and supportive interventions when considering opioid discontinuation or continuation at a high dose.