Review Articles Prescription Opioid Misuse, Abuse, Morbidity, and Mortality: Balancing Effective Pain Management and Safety

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1 Pain Medicine 2015; 16: S3 S8 Wiley Periodicals, Inc. Review Articles Prescription Opioid Misuse, Abuse, Morbidity, and Mortality: Balancing Effective Pain Management and Safety Martin D. Cheatle, PhD Center for Studies of Addiction, Department of Psychiatry, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Reprint requests to: Martin D. Cheatle, PhD, Center for Studies of Addiction, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, 4th floor, Philadelphia, PA 19104, USA. Tel: ; Fax: ; Disclosures/Conflicts of Interest: Cordant Healthcare, Campbell Alliance, Zogenix, Nektar. Abstract Objective. The burgeoning rate of prescription opioid misuse, abuse, addiction, and opioid related overdose deaths has gained substantial professional and national media attention. This manuscript provides a narrative review and critique of the literature on prescription opioid misuse, abuse, addiction and opioid-related mortality and discusses future research needs in this area. Design. Current literature on misuse, abuse, addiction and opioid related fatalities was reviewed in patients with chronic noncancer pain receiving long-term prescription opioid therapy. Results. There have been inconclusive results on the efficacy of long-term opioid therapy in patients with chronic pain but moderate level evidence of dosedependent risk of harm. The estimated prevalence of prescription opioid abuse and opioid use disorders ranges from <1% to 40% due to the paucity of uniform definitions of what constitutes misuse, abuse, and addiction but several recent studies have developed unique methodology to more accurately assess these states in the pain population. The rate of opioidrelated overdose deaths is not inconsequential and a number of patient related and medication specific risk factors have been identified that may provide a basis for risk mitigation strategies. Conclusions. Accurately assessing the prevalence of misuse, abuse, and addiction in the pain population has been challenging due to inconsistent definitions between studies. Additional high-quality research is needed in this area utilizing consistent definitions and in reducing the risk of opioid-related overdose fatalities. Key Words. Chronic Pain; Opioids; Misuse; Abuse; Overdose; Opioid Use Disorder Introduction Over the past two decades opioid analgesics have become a cornerstone of what is considered as effective, balanced pain management. Historically, opioid analgesics were typically prescribed for acute pain and cancer related pain. In the early 1990s the undertreatment of pain including patients with chronic non cancer pain (CNCP) garnered national attention. There were publications asserting that the rate of addiction in patients receiving opioids was low and that patients were being deprived of adequate pain management [1 3]. By the late 1990s, healthcare providers were encouraged to be more proactive in treating all types of pain (acute, end-of-life, CNCP) to alleviate suffering, including prescribing of opioid analgesics often times long term and at high dosing. The potential adverse effects of chronic opioid use was minimized with an overriding belief that opioids were safe in patients with pain, and that there was no dosing threshold in the legitimate pain sufferer. This resulted in an exponential increase in opioid prescribing. There was a fourfold increase in the sales of S3

2 Cheatle prescription opioid analgesics from 1999 to 2010 [4] and as of % of adults reported using a prescription opioid in the last 30 days [5]. While a number of patients may benefit from access to opioid analgesics, there has been an alarming increase in opioid misuse, abuse, and opioid-related mortality and morbidity. In million persons aged 12 or older were current nonmedical users of pain relievers and only marijuana (2.4 million) surpassed nonmedical use of pain relievers (1.9 million) for first-time use among persons aged 12 years or older [6]. There were 488,004 emergency department visits related to nonmedical use of opioids in 2011 [7] and there were 186,986 admissions to treatment facilities for opioid use disorders [8]. In 2010 there were 38,329 pharmaceutical-related deaths in the United States, of which 16,651 of these deaths were related to opioids alone, or related to opioids in combination with other drugs, the most common being benzodiazepines [9]. Age-adjusted opioid poisoning deaths quadrupled from 1999 to 2011 [10]. Efficacy vs Risk There has been an ongoing debate regarding the longterm efficacy of opioid analgesics for CNCP. A 2010 Cochran systematic review identified 26 studies that evaluated the efficacy of chronic opioid therapy (COT) for CNCP (>6 months). Over 22% of patients discontinued opioids due to adverse effects and 10.3% due to insufficient pain relief. There was very weak evidence that patients who were maintained on opioids long-term (>6 months) experienced significant pain relief. Improvement in function or quality of life was not measured. Most of these studies were of poor scientific quality, being either case studies or long-term drug trial continuation studies [11]. A subsequent Cochran review evaluated opioids as compared to placebo or other treatments for chronic low back pain (CLBP). Results indicated that there were low to moderate quality evidence that opioids provided short-term benefit for both pain and function as compared to placebo, but there were very few studies that evaluated the efficacy of opioids as compared to non-opioid medications, such as antidepressants or nonsteroidal anti-inflammatories. [12] Chou et al. examined the evidence for effectiveness and adverse effects of COT (>3 months) for CNCP. None of the studies reviewed evaluated the effectiveness or harm of opioids vs no opioids greater than 1 year with respect to pain, function, quality of life, opioid abuse or development of an opioid use disorder (OUD). There were a number of good to fair quality observational studies that suggested that opioid therapy in patients with CNCP has an increased association with risk for overdose, abuse, sexual dysfunction, fractures from falls, and some data suggesting that higher dosing of opioids is associated with increased risk. The authors concluded that there is insufficient evidence to fairly assess the effectiveness of COT, but there was some evidence suggesting a dose-dependent risk for significant harm [13]. There is a need for more, higher quality research to adequately assess the efficacy and risks of COT as compared to nonopioid therapies (NSAID, antidepressants, antiepileptic drugs, etc.). Prevalence of Prescription Opioid Misuse and Abuse: Diagnostic Issues There has been a great deal of scholarly activity devoted to assessing the prevalence of prescription opioid misuse, abuse, and OUD in patients with CNCP. Estimates of the rate of misuse and abuse has ranged from less than 1% up to 40% [14 16]. This wide range is related to the difficulty of diagnosing misuse, abuse and OUD in this patient population and inconsistent definitions of misuse and abuse between studies [17]. Defining Misuse, Abuse and Addiction in Patients with CNCP on COT Diagnosing abuse or addiction in patients with CNCP receiving COT is challenging. These patients tend to have multiple medical and psychological comorbidities and physical impairments. The persuasive Diagnostic and Statistical Manual of Mental Disorders-Fourth edition, Text Revision (DSM-IV-TR) [18] published in 2000 outlines seven criteria defining substance dependence (addiction) including tolerance and dependence/withdrawal. As tolerance and physical dependence commonly occur in patients on COT these signs may be misinterpreted as signs of abuse or addiction [17,19]. In 2001 a consensus document from the American Academy of Pain Medicine (AAPM), the American Pain Society (APS), and the Society of Addiction Medicine (ASAM) was published in response to concerns in the pain community regarding defining addiction in the pain population [20]. They defined addiction as characterized by one or more aberrant behaviors that included impaired control over drug use, continued use despite harm, compulsive use and craving for nonpain relief effect. Physical dependence and tolerance were not considered signs of addiction. There is some evidence that craving may be a key marker of addiction in patients on COT [21]. An expert panel from ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks) performed a systematic literature review and formulated recommendations regarding the classification and definition of misuse, abuse, and related events to guide prescription drug postmarketing adverse event surveillance and monitoring [22]. The expert panel concluded that there were many limitations to ICD-10 and DSM-IV-TR definitions related to misuse and abuse, and that there was a need to standardize the classification and definition of these terms to accurately assess efficacy and safety in clinical trials. Misuse was generally defined as an intentional therapeutic use of a drug in an inappropriate way. For example, this may be taking opioid analgesics to relieve pain in excess of what was prescribed by the treating clinician. Abuse, conversely, was defined as an intentional, nontherapeutic use S4

3 of a drug or substance for the purpose of achieving a desirable psychological or physiological effect. This could include the use of a substance to induce sleep, treat anxiety or depression; in other words, use of a prescribed medication for purposes for which it was not intended. Diversion was defined as an intentional act that results in transferring a drug product from lawful to unlawful distribution or possession. Lastly, addiction was defined as consisting of behavioral, cognitive, and physiological experiences that develops typically after repeated exposure to a substance that results in craving, poorly controlling drug use, persistent drug use despite negative consequences, and focusing on drug use over other activities and obligations such as school and work. This is similar to the AAPM, APS, ASAM definition of addiction. The Diagnostic and Statistical Manual of Mental Disorders- Fifth Edition (DSM-5) [23] was published in May of 2013 and several major changes were made in the Substance Use Disorders (SUD) diagnostic category including combining abuse and dependence into one single category of SUD and adding degrees of severity: mild (2-3 symptoms), moderate (4-5 symptoms) and severe (6 or greater symptoms). The illegal acts criterion was deleted and a craving criterion added. In rendering a diagnosis of OUD the criteria tolerance and withdrawal are not considered met if the individual is prescribed an opioid by a licensed clinician. Theoretically these changes in diagnostic criteria should improve sensitivity and specificity in making a diagnosis of OUD in patients prescribed COT. Prevalence of Prescription Opioid Misuse and Abuse In spite of these concerted efforts to refine the definitions of misuse, abuse, and addiction there is still a substantial variation in estimates of these states in patients with CNCP on COT. Boscarino evaluated 705 patients on COT, using both DSM-IV-TR and DSM-5 criteria for abuse and found that the prevalence of lifetime OUD, based on DSM-5 criteria was 34.9%, which was similar to the DSM-IV-TR criteria (35.5%). Based on the more sensitive DSM-5 criteria, 21.7% of this patient population met criteria for moderate OUD, and 13.2% met criteria for severe OUD [24]. There has been more recent literature utilizing electronic medical health records (EMHR) to accurately assess prevalence of problematic opioid use in patients on COT. A study by Palmer et al. [25] utilized natural language processing (NLP) techniques to identify clinical care notes containing any text indicating problematic opioid use. Data was extracted from eight million EMHRs from 2006 to 2012 of which 22,142 adult patients were receiving COT. There was moderate agreement between the NLP methodology and ICD-9 coding of problematic opioid use (Kappa ). Results indicated that 9.4% of the patients receiving COT displayed evidence of problematic opioid use based on the computer assisted manual review of NLP. There were 14 risk factors identified for problematic opioid use. Forty-seven percentage of patients on COT had three or more risk factors. Younger age, use of opioids greater than one year and patients on higher doses of opioids had higher rates of problematic opioid use. Vowles et al. [26] conducted a systematic review of the rates of opioid misuse, abuse and addiction in patients with chronic pain. Data from 38 studies were included in the review. They discovered a wide range of estimates of misuse and abuse with significant differences in study methodology. Results indicated that the rate of problematic opioid use ranged from <1% to 81% across the studies. Rates of misuse averaged between 21 and 29% (95% CI: 13 38%) and rates of addiction averaged between 8 and 12% (95% CI: 3 17%) and abuse was reported in only one study. To address the variability of assessed rate of misuse and addiction in these studies the authors coded problematic use (misuse, abuse, addiction) according to definitions offered by the IMMPACT and ACTTION guidelines and calculated several weighted separate means for high and low quality studies. They estimated that misuse occurred in the range of % and OUDs in % of patients. High quality studies had less variability. Interestingly, 52.6% of the studies were conducted within a chronic pain clinic and only 26.3% of the data collected was from a primary care setting. This is relevant as, most likely, patients who are more problematic in nature are referred to specialty pain clinics thus possible skewing the results. These studies emphasize that there is a sufficient void in standardized approaches to assessing misuse and abuse in this patient population, but underscore that the rate is not inconsequential. Further work is needed in conducting high-quality research that utilizes measures of misuse, abuse and addiction that are adequately sensitive and specific, corroborative information and include samples from diverse clinical settings (pain clinics, primary care clinics, etc.) to accurately determine the prevalence of misuse, abuse and OUD in the pain population. Opioid-Related Overdoses There has been an increasing trend in opioid-related fatal overdoses [9,10]. It is critical to identify patient related and medication specific risk factors to develop preemptive mitigation strategies. Methadone Prescription Opioids An expert panel evaluated the potential causes of opioidrelated overdose fatalities utilizing data from a literature search on PubMed and state and federal sources [27]. They were able to identify risk factors attributable to both human error and system/organization protocols. There was a high proportion of methadone-related deaths as compared to other classes of opioid analgesics due in part to the unique pharmacokinetics and pharmacodynamics of methadone. Physician errors contributing to methadone related deaths included: starting methadone S5

4 Cheatle at too high of a dose; over-relying on conversion tables when converting from another opioid to methadone; rapid dose titration; not assessing for co-occurring SUD; and overestimating the tolerance to respiratory depression in patients previously on other opioids. Patient related errors included escalating doses without the permission of the treating physician (to obtain euphoria, self-medicate for a mental disorder, obtain pain relief) or combining methadone with alcohol, benzodiazepines or other substances. System contributors to opioid-related fatalities revolve around insurance companies and other payers mandating that methadone be the first line opioid in managing chronic pain. This is related to the low cost of methadone as compared to other long acting opioids. This would require clinicians unfamiliar with the unique properties of methadone to prescribe it. Other factors increasing the risk of methadone related overdose deaths included unanticipated mental health (in particular depression, SUD) and medical comorbidities (sleep disordered breathing, cardiac effects). The authors noted that while methadone is implicated in one third of opioid related deaths, all opioids should be prescribed cautiously. Opioids in Combination with Other Prescription and Nonprescription Substances Opioids combined with other prescription or nonprescription substances substantially increase the risk for unintentional overdose fatalities. A number of studies have demonstrated a relationship between opioids combined with benzodiazepines. Park et al. [28] evaluated a large cohort of US veterans who received opioid analgesics from 2004 to Of this study population, 2,400 died from a drug-related overdose while receiving opioid analgesics and this was compared to a random sample of veterans (n 5 420,386) who received opioid analgesics. Results indicated that 27% of veterans that received opioid analgesics also received benzodiazepines. Approximately, 50% of the deaths from drug overdoses occurred when the veterans were prescribed benzodiazepines and opioids concurrently. A study by Jones et al. [29] discovered that alcohol was significantly involved in opioid analgesic and benzodiazepines drug-related emergency department visits and drug-related deaths. Turner and Liang [30] performed a retrospective review of patients with CNCP treated with opioids, antidepressants and/or sedative hypnotics and the interaction with depression. A total of 1,385 subjects in a cohort had a drug overdose. An adjusted odds ratio for overdose of all subjects increased with daily opioid dosing, but was highest for persons with depression and a high opioid dose (>100 mg MED) vs no depression or opioid use. Antidepressant use was protective for individuals with depression. The authors concluded that opioids and long-term benzodiazepine use were associated with drug overdose among the entire cohort, but that opioid risk was greatest for persons with depression and that antidepressant use greater than 90 days reduced the odds of overdose for persons with depression, but all antidepressant use increased risk for persons without depression. These studies highlight the need to focus on not only the use of opioids but also screening for medical and nonmedical use of benzodiazepines, antidepressants, and also concurrent other SUD and mental health disorders. Opioid Dosing and Duration of Action Miller et al. [31] reviewed opioid preparation (long-acting vs short-acting) and risk of unintentional overdose. They conducted a population-based healthcare utilization review of the Veteran s Administration Healthcare System. A total of 319 unintentional overdose events were discovered and patients commencing long-acting opioid therapy were more than twice as likely to overdose compared with persons initiating therapy with short-acting opioid preparations. Risk of overdose was associated with longacting opioid agents, particularly in the first 2 weeks after initiation of treatment (HR 5.25; ). There have been a number of studies investigating the relationship between opioid dosing and risk of overdose. Bohnert et al. [32] evaluated the association of maximum prescribed daily opioid dosing. Data was reviewed from a random sample of 154,684 patients extracted from the Veteran s Health Administration database from 2004 to They identified 750 cases of unintentional prescription opioid overdose fatalities. Results revealed that the risk of opioid related overdose death was directly related to the maximum prescribed daily opioid dose. They compared dosing of 1 to <20 MEDs and found that the adjusted hazard ratios increased with dosing. Patients on 20 to <50 MEDs the HR was 1.9 ( ); 50 to <100 MEDs HR was 4.6 ( ) and in dosing greater than 100 MEDs HR was 7.2 (4.8 11). Many states have enacted opioid prescribing guidelines recommending limiting upper dosing thresholds in patients with CNCP to help reduce the risk of misuse, abuse and overdose fatalities. Opioid Overdose and Suicide Suicidal ideation and behavior is highly prevalent in patients with CNCP with estimates ranging from 20 to greater than 50%. The majority of opioid-related overdoses have been classified as unintentional in nature, but most likely a subgroup of these individuals intentionally overdosed for purposes of committing suicide [33]. Further research is needed to accurately assess intentionality in opioid related deaths. Discussion Preserving the rights of patients to receive adequate pain management, which may include access to opioids, needs to be balanced with the risks associated with therapeutic agents both to the individual and society. This requires further high quality research utilizing consistent definitions of what constitutes prescription opioid misuse, S6

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