Risks for opioid abuse and dependence among recipients of chronic opioid therapy: Results from the TROUP Study
Introduction
Prescription opioids are increasingly used long-term to manage chronic non-cancer pain (CNCP) (Gilson et al., 2004, Gureje et al., 1998, Zacny et al., 2003). Initial enthusiasm for the use of opioids in CNCP was based on low rates of addiction reported in cancer pain patients, but the largest study focused on inpatient use of opioids (Porter and Jick, 1980). Low addiction rates were also initially reported for CNCP patients, but these were small, selected, and uncontrolled case series (Portenoy and Foley, 1986). Recent marked increased use of opioids for CNCP, often of 50–100% in the last decade (Boudreau et al., 2009, Caudill-Slosberg et al., 2004, Gilson et al., 2004, Sullivan et al., 2008), has been accompanied by a parallel increase in opioid abuse/dependence and accidental overdose (Chabal et al., 1997, Chelminski et al., 2005, Compton and Volkow, 2006, Cowan et al., 2003, Department of Health and Human Services, 2005, Gilson et al., 2004, Jonasson et al., 1998, Michna et al., 2004, Schieffer et al., 2005, Warner et al., 2009) in both clinical and population samples, making opioid abuse/dependence among individuals using opioids for CNCP a significant public health concern. Further, there is misuse of opioids that does not rise to the level of DSM-IV abuse or dependence. Estimates of rates of opioid abuse, dependence, and misuse vary, and risk factors for (i.e., the factors associated with) opioid abuse/dependence and misuse have varied according to the population studied (Chabal et al., 1997, Chelminski et al., 2005, Cowan et al., 2003, Jonasson et al., 1998, Michna et al., 2004, Reid et al., 2002, Schieffer et al., 2005). For example, a recent review of clinical surveys of patients on COT found widely varying (3–62%) estimates of the prevalence of opioid misuse (Turk et al., 2008).
A key issue in prescribing opioids for CNCP is balancing the possible benefits of pain relief and improved quality of life with the risks of addiction, overdose, reduced quality of life, and other negative outcomes. Reflecting the importance of balancing benefits and risks, the Food and Drug Administration recently indicated that manufacturers of some long-acting opioid formulations will be required to have a Risk Evaluation and Mitigation Strategy to “ensure that the benefits of the drugs continue to outweigh the risks” (Food and Drug Administration, 2009).
To achieve this balance, researchers, clinicians, and policy makers need better information on the prevalence of, and risk factors for, opioid abuse/dependence among those using chronic opioid therapy (COT) for CNCP. The existing literature on risk factors for opioid abuse/dependence among COT recipients must be interpreted with caution since studies have generally been conducted in small clinical samples from specialty pain clinics with unknown generalizability. We do know that treatment of acute or cancer pain is rarely associated with development of opioid abuse/dependence, but COT for CNCP may result in opioid abuse/dependence in 3–19% of patients (Compton and Volkow, 2006, Cowan et al., 2003, Fishbain et al., 1992, Porter and Jick, 1980).
The literature describing which classes of opioids have the greatest abuse potential is limited, generally not evidence-based, and sometimes conflicting. Most treatment guidelines for chronic pain recommend use of long-acting U.S. Drug Enforcement Administration (DEA) Schedule II opioids, based on the assumption that long-acting Schedule II opioids are best able to provide stable pain relief and are less prone to abuse (Kalso et al., 2003), but evidence that long-acting opioids limit abuse is limited. (For examples of types of opioids, their strength relative to morphine and their U.S. DEA schedule, see Table 1.) Further, Schedule III opioids, for example, hydrocodone with acetaminophen (Vicodin®), are defined in Chapter 21, Section 812, of the U.S. Code as having “a potential for abuse less than the drugs or other substances in Schedules I and II,” but again this has not been demonstrated in chronic pain populations. Moreover, it is not known if co-administration of long and short-acting opioids for ‘breakthrough pain’ is protective or harmful (Vallerand, 2003).
The Trends and Risks of Opioid Use for Pain (TROUP) study was designed to assess trends in (years 2000–2005) and risks of opioid therapy for CNCP in two disparate populations, a national commercially insured population (HealthCore) and a state-based publicly insured population (Arkansas Medicaid) (Braden et al., 2008, Braden et al., in press, Edlund et al., 2010a, Edlund et al., 2010b, Sullivan et al., 2008, Thielke et al., 2010). Our primary objective in this report was to estimate the prevalence of and risk factors for opioid abuse/dependence in COT recipients, including both non-modifiable (e.g., age) risk factors that may be useful for risk stratification and risk factors that can potentially be modified (e.g., characteristics of the opioid regimen) to decrease the likelihood of opioid abuse/dependence. As possible risk factors we investigated patient characteristics, including physical health, mental health and substance abuse diagnoses, and sociodemographic factors, along with pharmacological risk factors. Our previous work suggests that individuals with mental health and substance abuse disorders are more likely to be prescribed opioids, at higher doses, and for longer periods of time, than individuals without such disorders (Braden et al., 2008, Braden et al., in press, Edlund et al., 2010a, Edlund et al., 2010b, Sullivan et al., 2008, Sullivan et al., 2006, Thielke et al., 2010). In the current paper, we hypothesized that individuals with a mental health or substance abuse disorder would also be more likely to abuse opioids. We also hypothesized that long-acting Schedule II opioids would have the weakest association with opioid abuse/dependence, that short-acting Schedule II opioids would have the strongest association, and that the association for Schedule III opioids would be intermediate.
A secondary objective was to estimate the prevalence of and risk factors for non-opioid substance abuse/dependence (e.g., alcohol abuse or dependence, or methamphetamine abuse or dependence) in COT recipients. Fatal overdoses involving opioid analgesics increased three fold between 1999 and 2006 (Warner et al., 2009). Risk of fatal overdose is increased when opioids are taken with other drugs or alcohol, and the majority of fatal opioid overdoses involve at least one other drug (Warner et al., 2009). Our previous research suggests that COT recipients have elevated rates of non-opioid substance abuse/dependence (Edlund et al., 2007b). Thus it is important that we understand risk factors for both opioid abuse/dependence, and for non-opioid substance abuse/dependence.
Section snippets
Arkansas Medicaid
Arkansas Medicaid serves a disadvantaged and vulnerable population in the geographic region with the highest prescription opioid use in the country (Sullivan et al., 2006). Arkansas Medicaid covers all federally mandated services and nearly all optional services, including prescription drug services. Most Arkansas Medicaid enrollees participate in the primary care physician program where recipients utilize a primary care provider to coordinate care. Arkansas Medicaid imposes some benefit
Results
The samples tended to be predominantly female, especially Arkansas Medicaid, whose adult enrollees are mainly female. The Arkansas sample tended to be sicker than the commercial sample, with higher rates of pain conditions, higher Charlson scores, and higher rates of mental health and substance use disorders (Table 2). In the pre-index period the claims-based diagnosis rates of opioid abuse/dependence were 0.7% and 0.6% for HealthCore and Arkansas Medicaid, respectively. In both samples the
Discussion
To our knowledge, this is the largest study to date of risk factors for opioid abuse/dependence and non-opioid substance abuse/dependence among COT users. The sample is sociodemographically diverse, and we utilized 5 years of “real world” data from health care plans covering multiple states and regions of the country. For these reasons we believe our results enjoy good generalizability.
In a sample with at least 90 days of continuous opioid use, we found that opioid abuse/dependence was
Limitations
Our work should be interpreted in light of several limitations. First, although we utilized pre-index variables to predict post-index opioid abuse/dependence so that the independent variables temporally preceded the outcomes, the study is observational, so we are describing associations, and not necessarily causal relationships. Further, to the extent that these relationships are causal, they may be bi-directional in many cases (Martins et al., 2009). Second, our sample was extremely large and
Conclusions
Opioid and non-opioid substance abuse and dependence are diagnosed in only a small minority of COT recipients. We found similar risk factors for receiving opioid and non-opioid abuse/dependence diagnoses among individuals receiving COT. We believe that the robustness of the results across dissimilar samples enhances the validity and generalizability of our findings. In terms of risk factors that cannot be modified, there was a strong inverse relationship between age and receiving a diagnosis of
Conflict of interest
There are no conflicts of interest for any authors.
Acknowledgements
Role of funding source: Funding for this study was provided by NIH grant DA022560-01; the NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors: All authors obtained funding for the study and participated in the revision of the manuscript. Drs. Edlund and Sullivan designed the study and drafted the manuscript. Drs. Martin and DeVries acquired the data.
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