Dynamic risk factors in the misuse of opioid analgesics

Journal of Psychosomatic Research 72 (2012) 443–451

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Journal of Psychosomatic Research

Review

Dynamic risk factors in the misuse of opioid analgesics Joseph V. Pergolizzi Jr. a, b, h, Christopher Gharibo c, Steven Passik d, Sumedha Labhsetwar e, Robert Taylor Jr. f,⁎, Jason S. Pergolizzi f, Gerhard Müller-Schwefe g a

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Anesthesiology, Georgetown University School of Medicine, Washington, DC, USA Department of Anesthesiology and Pain Medicine, New York University, New York, NY, USA d Department of Psychiatry and Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA e Division of Health Outcomes and Pharmacoeconomics, NEMA Research, Inc., Naples, FL, USA f Division Pharmaceutical Sciences, NEMA Research, Inc., Naples, FL, USA g Interdisciplinary Pain and Palliative Care Center, Göppingen, Germany h Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA b c

a r t i c l e

i n f o

Article history: Received 22 June 2011 Received in revised form 16 February 2012 Accepted 18 February 2012 Keywords: Chronic opioid therapy Nonmedical use of opioids Opioid abuse Opioid misuse Risk factors for opioid misuse Risk stratification for opioid misuse

a b s t r a c t Objective: Identify the risk factors for prescription opioid misuse among patients taking prescription opioids to deal with chronic pain. Methods: We examined the literature for a variety of dynamic risk factors associated with opioid misuse among the chronic pain population in order to present a narrative review. Considered were: taking single or multiple opioids, pain intensity, mental health disorders, including a history of preadolescent sexual abuse, personal and familial history of substance abuse, a history of legal problems, being a crime victim, drug-seeking behaviors, drug craving, and age. Results: A variety of risk factors have been studied in the literature. Risk factors in chronic opioid therapy patients are dynamic in that they can change with disease progression, tolerance, changes in pain quality, mental health, comorbidities, other drug therapies or drug interactions, and changes in the patient's lifestyle. Conclusion: Opioid analgesic therapy must be tailored to carefully monitor all patients in order to minimize misuse and abuse, since the risk is constant and dynamic and therefore every patient is at some degree of risk for opioid misuse. © 2012 Elsevier Inc. All rights reserved.

Introduction A total of 5.2 million American adults in 2006 reported that they had nonmedically used prescription painkillers in the prior month, an increase from 4.7 million adults who reported the same in 2005 [1]. The prevalence of inappropriate use of opioids among those with legitimate prescriptions is less well defined. Early studies reported that patients taking prescription opioid analgesics had substance abuse rates roughly equivalent to the rates among the general population [2,3], but more recent investigations suggest the rate of substance abuse among chronic pain patients receiving chronic opioid therapy may be higher, ranging from 14% to as high as 40% [4–10]. Risk factors for future misuse among those with a legitimate opioid prescription may be considered dynamic, in that they are impermanent. They will likely change, or at least vary, over the course of the patient's therapy as the patient's physical condition, mental health status, disease progression, comorbidity profile, social and

familial circumstances change and dosing level and type of opioid prescribed (long-acting/short-acting or combined therapy) changes. Furthermore, patient behaviors can be highly individual, subject to misinterpretation, and motivated by a wide range of intentions [11], thus making it difficult to identify potential opioid abusers and misusers. A number of instruments have been put forth to assess risk factors, but diagnostic accuracy of these monitoring tests may not be satisfactory [12]. Although attempts to synthesize risk factors from systematic analysis of the literature have been inconclusive, it should be noted that the one risk factor that was most predictive, based on this analysis, was a personal history of substance use disorder [13]. It is our intention not to study specific factors in-depth or establish a checklist instrument, but to set forth, from the literature, important dynamic risk factors and concepts that can help shape future understanding of why certain pain patients taking opioid analgesics will go on to misuse those drugs and other substances while other, seemingly similar patients, do not. Terminology

⁎ Corresponding author at: 840-111th Avenue No. Naples, FL, USA. + 1 239 597 3564. E-mail address: [email protected] (R. Taylor). 0022-3999/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2012.02.009

Discussions about the prevalence of opioid misuse are hindered by an inconsistent use of terminology [14]. Many clinicians are not

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trained in addiction or substance abuse disorders and may use some terms from that field differently from experts [15–18]. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) [19] sets forth substance abuse terminology from the perspective of substance abusers. The DSM-IV utilizes 7 criteria for substance dependence (addiction) with a stipulation that only 3 criteria are required to make the diagnosis and that 5 of these criteria are commonly seen in non-addicted pain patients utilizing opioids, thus limiting its relevance in describing the situation of patients taking opioids to control pain [20]. Because of the limitation of the DMS-IV definitions, we have chosen to present the reader with alternative terminology which may differ somewhat with terminology used by other respected colleagues in this field (Table 1). It should be noted that terminology in this field is constantly evolving and new DSM-V terms (May 2013) will likely help unify the language [21].

the patient history, physical examination, assessment of the patient's family history, psychosocial factors, personal and familial history of substance abuse (both drug and alcohol), patient age, and psychiatric comorbidities be considered when contemplating the prescription of or maintenance of chronic opioid therapy [27]. Many of these areas are subject to change during the course of opioid therapy due to the medical condition and life circumstances of the patient. For example, the emergence of a mental health condition, worsening pain syndrome, onset of a comorbid disease, or some sort of “loss,” e.g., death of a loved one, unemployment, divorce, would alter the patient's risk profile, possibly profoundly. This suggests that risk management for opioid misuse in chronic pain patients taking prescription opioids requires ongoing evaluation, careful monitoring, and frequent reassessments. From the literature, several constellations for potential opioid misuse could be identified.

Aberrant drug-related behaviors

Being prescribed opioids

Aberrant drug-related behaviors have been put forth in the literature as potential signs of current and future opioid misuse among chronic pain patients taking opioids [11,22–25]. Many of these behaviors can be categorized as prescription/drug seeking behaviors, nonprescribed uses, illegal acts and other unconventional behaviors (Table 2). Some individuals aberrant drug-taking behaviors may arise for a variety of reasons, including, but not limited to, the desire to misuse or abuse opioids. Others may exhibit aberrant drug-taking behaviors due to certain mental health conditions. Some so-called aberrant behaviors may be coincidental (auto accident, missed appointments) or idiosyncratic (excessive phone calls to the clinic). A differential diagnosis of aberrant drug-taking behaviors has been proposed to consider aberrant behaviors in light of addiction, pseudoaddiction, psychiatric disorders, chemical coping, depression or situational stressors, and criminal intentions [26]. As such, it is difficult to formulate any specific set of behaviors that describe ongoing misuse, much less predict elevated risk for opioid misuse in chronic pain patients on opioid therapy [13].

Evidence suggests that taking opioids may be considered a risk factor for developing misuse and abuse behaviors. A large populationbased study (n=9279) reported that patients who took prescription opioids to manage pain had significantly higher rates of any opioid misuse compared to individuals who did not take prescription opioids (OR=5.48, pb.001) [28]. In another study, Jameson et al. interviewed 248 patients at a methadone maintenance center and discovered that 61.3% of this population reported that they experience chronic pain as primary medical condition and that a large percentage of these patients with pain (44%) held the belief that the prescription opioids contributed to the development of their addictive disorder. Therefore, patients receiving long-term treatment of opioids for chronic pain should be monitored carefully due to the increased risk of developing abuse, misuse, or addictive behaviors [29]. An even greater risk is represented by multiple opioid prescriptions. A medical claims database retrospective study (n=632,000) from 2005 to 2006 found over a three-month period that among the biggest risk factors for prescription opioid abuse was taking four or more prescription opioids at one time or having opioid prescriptions from two or more pharmacies. Over a 12-month time period, these risk factors changed to 12 or more opioid prescriptions and opioid prescriptions from three or more pharmacies [30]. This lends support for state/nationwide drug monitoring programs and/or the unification

Risk factors for future opioid misuse The 2009 Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in patients with chronic non-cancer pain recommends that

Table 1 Terminology of inappropriate opioid analgesic use as used in this paper. Term Misuse

Definition

The inappropriate use of the prescription opioid agent, whether intentional or unintentional, and regardless of motivation Abuse A maladaptive pattern of prescription opioid use leading to considerable impairment and/or distress Nonmedical The inappropriate use of a prescription opioid but without delineating the specific motivations for such use, use which may or may not include pain relief (self-medication). While “misuse” and “nonmedical use” may be used interchangeably in some contexts, we prefer to use “misuse” in this article, since our patients are under medical supervision and obtain opioids by prescription Tolerance State of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time Addiction Primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestation, characterized by one or more of the following behaviors: impaired control over drug use, compulsive drug use, continued drug use despite harm, and craving PseudoA syndrome in which patients display behaviors similar to those displayed by addicts but which are actually addiction associated with the under-treatment of their pain Dependence State of adaptation that often includes tolerance and is manifested by a drug class specific withdrawal syndrome that can be induced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of the antagonist Chemical A state observed in certain patients on chronic opioid therapy who have a mixed response to opioid therapy coping and in whom aberrant drug-related behaviors are sometimes (but not consistently) exhibited. Chemical coping has been described as a “middle ground” between compliance and addiction.

Source/comments Passik [128] Passik [128] National Survey on Drug Use and Health and the Drug Early Warning Network [109,132]

American Pain Society [133] American Pain Society[133]

Weissman and Haddox [134] American Pain Society[133]

Kirsh and colleagues [135]

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Table 2 Aberrant drug behaviors. Aberrant drug taking behaviors [22,84,129,136–137] Prescription requests ● demands for more medications or early refills ● lost prescriptions, lost pills ● “doctor shopping” or seeing multiple physicians ● visits to the emergency room to obtain opioids ● obtaining opioids from non-medical sources (including taking drugs prescribed to other people) ● canceled or missed appointments or showing up at the clinic without an appointment ● requesting refills rather than a clinic visit, excessive phone calls to the clinic Use of medications for non-prescribed purposes ● the use of prescription opioids to treat symptoms such as anxiety or depression ● illicit drug use ● patient's admitting that he or she desired euphoric effects from the opioids

Illegal behaviors ● stealing drugs, ● selling prescription drugs ● motor vehicle accident ● prescription forgery, theft or other tampering Other signs or behaviors ● multiple dose escalations without prior authorization or even despite physician warning ● concurrent use of alcohol ● resisting changes to prescribed medications despite adverse side effects, ● asking for drugs by brand name or street names ● hoarding drugs ● injecting an oral formulation ● escalating tolerance in the absence of objective signs of uncontrolled pain ● deteriorating ability to function at work, school, or home that seems related to the prescription opioid ● third party asked to manage the patient's medication, purposely over-sedating oneself, concern expressed by another party about the patient's opioid use

of physician and pharmacy prescription databases in order to prevent excessive opioid distribution among patients.

[49]. Overall, pain levels may be useful in assessing future patterns of opioid use.

Pain intensity

Mental health disorders

Some patients who display aberrant drug-related behaviors and misuse opioids are trying to manage uncontrolled pain [31]. While inadequate analgesia may contribute to aberrant drug-related behaviors, in some cases, effective analgesia also contributed led to aberrant drug behaviors [32]. Some of the behaviors that result from inadequate analgesia are described below. Inadequate analgesia may manifest in pseudoaddiction, a constellation of aberrant drug-related behaviors that mimic those of addiction but are actually driven by a desire to control pain [33]. Pseudoaddiction may be more prevalent than is generally appreciated by clinicians, and should be distinguished from tolerance and opioidinduced hyperalgesia [34]. Pseudoaddiction is difficult to diagnose contemporaneously as its symptoms mimic those of addiction.[35] Tolerance is a physiological response which is typically managed by judicious dose increases or, in some cases, opioid rotation [36]. Opioid-induced hyperalgesia occurs when chronic opioid patients develop increased sensitivity to pain through mechanisms which have not been thoroughly elucidated [37]. The role of pain intensity in shaping aberrant drug-related behaviors of opioid patients is still currently unclear. In a study of 110 chronic pain patients on opioid therapy, higher pain intensity scores at baseline as captured on the Screener and Opioid Assessment of Pain Patients scale (SOAPP) were associated with a significantly greater risk of opioid misuse at baseline (pb.05) and over time at 10 months later (pb.01) [38]. A retrospective study of electronic health records culminating in interviews with 705 patients on opioid therapy found that patients who reported higher pain impairment were significantly more likely to have experienced opioid dependence at some point over their lifetime (pb.01) [39]. However, in a study of 196 chronic non-cancer pain patients on opioid therapy, pain scores were not found to be associated with rates of opioid misuse [9]. It has been suggested that opioid abusers have lower pain thresholds than the general population or, at least, they perceive pain differently. Studies have found that opioid addicts had shorter pain latencies [40,41]. In animal [42] and human [43,44] models, some otherwise healthy individuals tolerate pain far less well than the mean. This aligns with the self-medication theory of addiction [45,46]. In addition, some studies have suggested that the perception of pain severity may be exacerbated in patients with mental health issues and/or substance abuse histories [47], pain may be heightened in patients who catastrophize [48] or have an exaggerated fear of pain

A patients mental health is not static and its dynamic nature can create a condition where the patient may become more prone to opioid abuse. Mental health disorders including mood disorders and various types of depressed states are common in those with chronic pain [50], whether or not they take opioid analgesics, and in those who misuse opioids [51]. In addition, it should be noted that accurate prevalence of depression and anxiety in pain populations is subject to the population sampled (e.g., pain clinic, sports medicine, primary care). Patients that are referred to integrated pain management may have more psychiatric comorbidities than patients from a community sample. In a single-center study of 500 consecutive chronic pain patients receiving stable doses of opioid analgesics, 59% had depression, 64% anxiety disorders, and 30% somatization at baseline [52]. Drug misuse was significantly higher in depressed patients than those without depression (12% vs. 5%). In another study of chronic pain patients on opioid analgesic therapy (n=228), patients were grouped into “high” and “low” psychiatric morbidity categories based on the psychiatric subscale of the Prescription Drug Use Questionnaire (PDUQ). Patients in the “high” psychiatric morbidity group were significantly more likely to have abnormal urine tests (pb.01) and higher scores on the Drug Misuse Index (pb.001) than similar patients in the “low” psychiatric morbidity group [53]. Mood disorders have been associated with substance abuse, including, but not limited to opioid misuse [9,22,54–62]. In addition, mental disorders that have an increased risk of substance abuse include dissociative disorders [63], schizophrenia [64], and bipolar disorders [65,66]; depression [67,68], borderline personality disorder [66,69], suicidal ideation [67,70], post-traumatic stress disorder [30], gambling addiction [71], panic and anxiety disorders [72,73], body dysmorphic disorder [74], social phobia and agoraphobia [75], and a recently described state of emotional distress known as hyperkatifeia [76]. In a study (n=288) of outpatients on chronic opioid therapy for pain of various etiologies, a history of psychiatric disorders was associated with an elevated risk for opioid misuse [32]. It is not clear if or to what extent there is a causal relationship between mental health disorders and opioid misuse or whether these conditions merely overlap [47]. Depression, in particular, seems linked to opioid misuse. In a study of 500 consecutive pain patients who received chronic opioid analgesic therapy, depression was diagnosed in 59% of patients at baseline [52]. In this study, depressed patients were significantly more likely to abuse drugs (12% vs. 5%) and depressed women were significantly

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more likely than women without depression to use illicit drugs (22% vs. 14%). Depression in men did not affect rates of drug abuse (12% in men with or without depression) [52]. While mental health disorders are potential risk factors for opioid misuse in chronic pain patients, there are some important issues. • Mental health disorders may not be recognized by patients, their families, or the physicians treating pain syndromes. • Patients, for any number of reasons, may fail to mention or actively conceal a history of mental health disorders. Oftentimes patients with chronic pain will underreport mental health disorders or symptoms as they are fearful that their pain will not be taken seriously. • More study is warranted to help prescribing physicians understand different types of mental health conditions and their relationships to substance misuse and abuse. • Some patients with psychiatric comorbidities may preferentially misuse prescription opioids rather than take appropriately prescribed psychiatric drugs because of the stigma associated with psychiatric drugs [77]. One study showed that women patients are more likely to exhibit this behavior than men. Compromised mental health may be a risk factor for opioid misuse in chronic opioid patients, and it must be periodically re-evaluated in that anxiety, depression, and other mental comorbidities may occur in chronic pain patients over time, possibly secondary to chronic pain syndromes. Personal history of substance abuse A history of substance abuse has been advanced as a reasonably reliable predictor of future opioid misuse in patients taking prescription opioids [9,32,57,62,78]. This leads clinicians to some open questions. For example, is the abuse of certain substances more or less predictive of potential opioid misuse in chronic pain patients taking opioids? Edlund and colleagues reported that non-opioid abuse was a predictor of opioid dependence (OR=2.34, 95% CI, 1.74–3.14 range) [57]. Ives and colleagues found strong associations between opioid misuse and prior alcohol abuse (OR=2.6, 95% CI, 1.12–6.26 range) and cocaine abuse (OR=4.30, 95% CI, 1.76–10.4 range) [9]. A 20-year study found a strong association between the use of benzodiazepines and the frequency of opioid prescriptions [79]. A follow-up study by the same investigators found the probability that a patient will be prescribed an opioid analgesic is associated with prior use of benzodiazepines (even four or more years in the past), independent of the patient's reported pain [80]. In fact, a history of benzodiazepine use was a stronger predictor of a subsequent opioid prescription than chronic pain [80]. In a study of patients entering an opioid abuse treatment program, a continuum of progressive drug use could be identified [34]. This led investigators to suggest that certain “gateway” drugs may be risk stratifiers for opioid abuse. It was found that the excessive use of alcohol, nicotine, and the use of marijuana, stimulants, licit and illicit drugs generally preceded opioid use and opioid abuse may be the next step in that particular sequence. Heroin use, if it occurs at all, typically occurs only after opioid abuse. Just 8% of patients in this study took heroin prior to prescription opioid abuse, but 90% of those who used heroin previously took prescription opioid opioids. This study described two main types of opioid abuser: those whose first exposure to opioids was an appropriate prescription for managing chronic pain and those whose first exposure to opioids was recreational. These two groups exhibited important differences. Those who started taking opioids with an appropriate prescription to manage pain but went on to misuse opioids were more often women and more often in worse physical condition than those opioid abusers who took the drugs recreationally. On the other hand, recreational users who never had a legitimate opioid prescription were more

likely to use other licit and illicit drugs than those who first took opioids to treat chronic pain. Recent substance abuse may be associated with altered pain perception and, plausibly, to altered responses to opioid analgesics. A study of pain responses in opioid addicts entering a detoxification program versus healthy controls found significant differences in cold pressor tests (latency, visual analog scale score, tolerance) both at baseline and 28 days after opioid detoxification, indicating that pain differences persisted even after opioids were discontinued [81]. Another study of 54 opioid addicts who had discontinued opioids compared to 46 health subjects revealed former opioid addicts had hyperalgesic responses to pain that persisted at least 5 months after opioid abstinence [82]. A history of opioid abuse correlated with increased risk for opioid misuse and dependence in a study of 705 chronic opioid therapy patients (OR=3.81, pb.001) [39]. Many individuals who misuse prescription opioids misuse or abuse other substances. A history of alcohol abuse is a risk factor for polysubstance abuse [83] and has been associated specifically with opioid misuse [9]. In a study of chronic pain patients treated for at least 3 months with opioid analgesics (n=196), those who abused alcohol were significantly more likely to misuse opioids than similar patients who did not abuse alcohol (p=.004). In this same study, those with a prior driving under the influence (DUI) conviction were significantly more likely to misuse opioids (pb.001) [9]. Intriguingly, a history of substance abuse more than 5 years in the past does not appear to be associated with opioid misuse in patients taking prescription opioids. In a study of 1160 patients taking chronic opioid analgesics to treat chronic pain, those who had a substance abuse problem 5 years in the past or more were less likely to exhibit aberrant drug-related behaviors than similar patients with no history of drug abuse (OR=0.33, not significant, p=.2879) [84]. This finding suggests that a patient who has successfully overcome a substance abuse problem in the past and remains “clean” for five or more years may be at less risk for opioid misuse than a patient with no history of substance abuse. Based on this finding, a history of substance abuse should be contextualized in terms of when it occurred and how it was managed. A history of substance abuse may have limited practicality in risk stratification of chronic pain patients taking opioid analgesics in that patients may attempt to conceal their substance abuse [13,53,85–87]. In a study of 100 chronic pain patients presenting for an initial evaluation at a pain clinic, 27% of patients misreported their current use of opioids (16% under-reported and 11% overreported) when patient interviews and questionnaires were compared to results from a urine test [88]. Twelve percent (12%) of patients tested positive for opioids although they denied having used opioids [88]. Misrepresentations in this study included both underand overstating substance abuse. In a study of Veterans Administration (VA) clinics, patients appropriately prescribed opioids for pain were more likely than similar pain patients not prescribed opioids to have a history of substance abuse disorders [89]. Another VA study found patients taking longterm oxycodone/acetaminophen were more likely to have a history of substance abuse than similar patients taking the drug shorter term [90]. It is unclear from these studies why those with a history of substance abuse disorders would be more likely to get an appropriate opioid prescription or take opioids longer-term. Several possible explanations have been offered:

• Prior substance abuse may have been an attempt at self-medication for chronic but untreated pain. • Patients with a history of substance abuse may have lower pain thresholds or other characteristics that makes them more likely to get legitimate prescriptions for opioids.

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• Patients with a history of substance abuse may seek prescription opioids and are skilful at manipulating the system to obtain them, possibly by being dishonest about their physical symptom Familial history of substance abuse Often considered a static risk, familial substance abuse has the ability to create a dynamic for polysubstance abuse and thus present the opportunity for opioid abuse to occur at any point in a patient's life. One hundred forty-five (145) patients who were taking opioids for their pain were classified as high or low risk for opioid abuse based on their responses to questions about substance abuse history in their family. Patients who admitted to a family history of substance abuse were prone to engage in more aberrant drug-related behaviors, including a higher incidence of lost or stolen prescriptions and the presence of illicit substances in their urine (pb.05) [78]. When an analysis was conducted of 50 opiate-dependent patients, 50 surgical patients (not opiate-dependent), and 50 psychiatric patients, it was found that first-degree relatives of opiate-dependent individuals had significantly higher rates of drug use and antisocial personality disorders compared to the first-degree relatives of surgical patients and psychiatric patients [91]. In another study (n=254), firstdegree relatives of opioid-dependent men were more likely to have opioid use disorders than similar non-opioid-dependent controls (OR=6.55, 95% CI, 1.44–29.88, p=.015) [92]. Thus, first-degree relatives of opiate-dependent individuals appear to be at increased risk for developing a drug-use disorder. This suggests a hereditary link that remains speculative. Legal problems A history of legal problems has been advanced as a risk stratifier for opioid misuse among chronic pain patients taking opioid analgesics [13]. A history of DUI, drug convictions, and motor vehicle collision has been associated with opioid misuse in chronic pain patients [9,93,94]. Victimization Victimization can occur at any point in life and thus it is important for physicians to communicate with patients throughout their opioid treatment. People who have been exposed to traumatic events in life, whether during childhood or adulthood, have a higher incidence of illicit drug use [95]. A controlled multivariate analysis based on the National Epidemiologic Survey on Alcohol and Related Conditions (2001–2002, n=43,093) found that having been a victim of a crime was associated with significantly elevated rates of opioid use disorders (as well as cocaine and alcohol abuse) [96]. Crime victimization occurs more frequently among individuals with mental health disorders than those without [96], so it is possible that being a crime victim is not directly related to potential opioid misuse but rather serves as a marker for mental health disorders which, in turn, are associated with risks of opioid misuse. Childhood sexual abuse has recently been recognized as risk factor for drug and alcohol abuse in both men and women [97], but women with a history of preadolescent abuse are at particularly high risk for substance abuse [98]. An analysis of adolescents found that a history of physical or sexual abuse occurred more often in subjects with substance abuse problems than those with no such history [99]. While childhood sexual abuse has not been evaluated as a risk factor for opioid misuse specifically among those taking prescription opioids to treat chronic pain, it appears worthy of future study. Age Opioids in our society are consumed by people of all ages, but opioid misuse is more common in younger patients, while opioid use in

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the form of analgesic therapy is more common among seniors [100]. When younger patients require chronic opioid therapy, they are significantly more likely to abuse opioids (pb.001) [9] and use illicit substances than older patients [101]. Younger age (b42 years) was associated with a greater risk for aberrant drug-related behaviors (OR=2.5, 95% CI, 1.6–4.0 range, pb.01) in a study of 48 patients, which excluded patients with a history of substance abuse [84]. It is not clear whether results would have been affected had patients with substance abuse histories been included. It should be noted that not all studies have found younger age to be associated with potential opioid misuse in chronic pain patients taking opioid analgesics [102]. The patient's age upon first exposure to opioids may be a risk factor for opioid misuse. A survey based on the 2002–2004 National Survey on Drug Use and Health (n=91,823) reports an association between individuals who experiment with prescription opioids before the age of 13 and those who develop prescription opioid abuse/ addiction [75]. This may have limited clinical practicality in that it is unlikely that a patient would freely disclose youthful drug abuse, even if he or she was appropriately seeking pain relief. Older age (≥65 years) has been negatively associated with opioid misuse and abuse [103]. A three-year study of chronic opioid patients with osteoarthritis (mean age=63 years) found that 3% of patients exhibited aberrant behaviors related to opioid abuse [104]. A prospective study (n=196) of chronic pain patients on opioid therapy found that older age was associated with a lower likelihood of opioid misuse and abuse (OR=0.95, 95% CI, 0.90–0.99) [9]. A retrospective study of chronic pain patients treated in primary care (n=98) found older age was associated with reduced likelihood of opioid misuse or abuse (OR=0.94, 95% CI, 0.89–0.99) [4]. Gender Gender has been suggested to play a role in different types of abuse and misuse behaviors [34,84,102,105–110]. Some studies have shown women to be more likely than men to report using or abusing prescription opioids (pb.001) [77], which is not the same thing as having higher rates of opioid misuse. Men who take prescription opioids are significantly more likely than similar women to receive alcohol or drug treatment (p=.001) [111]. Women report pain more frequently and describe more severe types of pain than men [112,113]. In a study of 610 chronic pain patients taking opioid analgesics, women and men both misused opioids at similar rates but for different reasons: women tended to have higher degrees of psychological distress while men exhibited more legal and behavioral problems [114]. Even though gender may be an inconsistent predictor, it should still be evaluated with other risk factors in chronic pain patients. Craving opioids It has been suggested that craving is a primary symptom of opioid addiction and it is a good way to differentiate chronic pain patients who are tolerant/dependent [115]. More than half of patients on chronic opioid therapy (55%) report some degree of opioid craving [116]. In a study of 613 chronic pain patients taking opioid analgesics, those who reported some degree of craving opioids were significantly more likely at 6 months to have a higher Prescription Drug Use Questionnaire (PDUQ) [47] score (pb.001), higher incidence of physician-rated aberrant drug behaviors (pb.004), and a higher rate of abnormal urine toxicology tests compared to those who never craved opioids [116]. While this study related craving with aberrant drug-related behaviors, it is unclear what craving actually is. Craving may be an urge to avoid dysphoria and achieve euphoria from the drug or it may be a symptom of tolerance or addiction [117]. Craving may be a difficult risk stratifier to employ, in that patients may conceal such feelings from their physician.

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Genetic factors It has been hypothesized in growing body of research that there are possible genetic factors involved in opioid misuse and abuse [118–124]. It is beyond the scope of this review to evaluate these findings, and prescribing clinicians cannot at this time readily use genetic information to help guide prescribing and treatment decisions. In addition, there are currently no reliable biomarkers to identify patients with an opioid addiction. Patient malaise A study of chronic pain patients on opioid analgesics (n=1144) found that many patients had uneasy or unsettled feelings regarding their drug therapy [125]. Concerns ranged from bothersome side effects, interference with clear thinking, inability to work or limitations about lifestyle, depression, concern about their inability to control their use of the drug, and worry about what friends and family might think. About 45% of these patients reported “high” or “intermediate” levels of concern. Interestingly, patients concerned about their inability to control their drug use did not have higher levels of opioid misuse. Thus, patients who express concerns about becoming addicted or fears about chronic opioid therapy may not be more likely to misuse or abuse opioids than similar patients who do not voice such concerns. Geographical setting While illicit drug use may seem to be an urban phenomenon, rural patterns of prescription opioid abuse in the United States have been described in the literature [126,127]. Speculations as to why this geographical distinction emerges have been put forth: limited availability of street drugs in some areas, social acceptance of prescription opioids in rural communities, and possible prevalence of chronic pain in rural areas where many jobs require manual labor and there may be fewer physicians and limited pain treatment options. Ethnicity Ethnicity has not been investigated thoroughly in terms of potential misuse of prescription opioids, but findings from the 2002–2004 National Survey on Drug Use and Health (n=91,823) reported that Hispanic ethnicity was associated with the non-medical use of prescription opioids; however, its relevance to Hispanic chronic pain patients is limited [75]. The literature contains very little information about opioid misuse by specific cultures or ethnicities. Discussion In order to evaluate risk factors for potential opioid misuse in chronic pain patients who are candidates for opioid analgesics, screening tools for both psychological and aberrant drug-related behaviors, treatment strategies, and urine or salvia drug testing are useful. It has been proposed that patients be stratified by high, moderate, and low risk for opioid misuse, so that more intensive scrutiny can be placed on those at higher risk [128,129]. However, it is our contention that all chronic pain patients who take prescription opioid pain relievers are at some degree of risk for opioid misuse and abuse and that this risk can change course during physician treatment due to the conditions in the patient's life, such as, emotional well-being,, disease progression, comorbid conditions, mental health conditions, and so on. Busy clinicians are not always cognizant of the subtle shifts in a patient's condition, and patients – for a variety of reasons – may not be forthcoming with details. However, clinicians who treat chronic pain patients with opioid analgesics must recognize that:

• all patients are at some degree of risk • risk is dynamic • risk factors should be periodically re-assessed. In particular, emerging mental health problems (episodes of cutting, suicide attempts, depression), recent legal battles, worsening physical condition, deteriorating quality of life, and development of comorbidities should be seriously evaluated by the prescribing physician in light of their potential effect on opioid misuse. However, worsening risk factors for opioid abuse need not preclude the patient from treatment. The literature reports that even patients with an active opioid addiction may be successfully treated with opioid analgesics—but under closely monitored conditions [129]. Chronic pain patients taking opioid analgesics should be carefully supervised and educated. Examples of patient monitoring and education may be through the use of testing measures such as urine toxicology screening tests and/or treatment agreements. Abnormal findings should be followed with more detailed testing, such as mass spectrometer gas chromatography testing. Urine drug testing is an important tool, but must be appropriately deployed. For instance, one abnormal urine test is not necessarily a cause for alarm [130]. By the same token, there are some reasons why a patient misusing opioids may still be able to pass a urine test. Treatment agreements can also be valuable, as is patient education. Patients should be educated that drug therapy may never eliminate their pain, but only reduce it. Patients who can be engaged in multimodal approaches, combining exercise, diet, better sleep hygiene, relaxation, massage, physical therapy, and other treatments may be less focused on deriving all of their pain relief from a prescription drug. However, it should be noted that there is insufficient evidence that urine toxicology screening and treatment agreements reduce misuse [131]. Owing to dynamic risk factors, the opioid formulation should be periodically reviewed in that its pharmacokinetics, its release time, lipophilicity, and dose may all play a role in possibly tempting patients to greater drug use and potential misuse. Abusedeterrent formulations may play an important role here in discouraging product tampering and early misuse, regardless of the motivations. Conclusion Misuse and abuse of opioids is a serious problem that places a huge burden on patients, their families, their employers, the healthcare system, and even society at large. Patients who are prescribed opioids appropriately to treat chronic pain are at some degree of potential risk for opioid misuse and that risk can be enhanced or lessened by any number of factors, including mental health, disease progression, family circumstances, and so on. Physicians prescribing opioid therapy are urged to rely on consistent patient monitoring, clinical judgment, and insight into the current literature to help assess risk for their patients rather than relying on any one formula or screening test. Physicians should pay close attention to many risk factors including a patient's mental health, history of substance abuse, pain intensity, past traumatic experiences, age, gender, genetics, ethnicity, and even family history. Opioid misuse is a complex subject that is made even more complex by inconsistent use of terminology and concepts. More study is needed to better define risk factors in specific, even if highly limited, subpopulations of patients who take opioids to manage chronic pain.

Acknowledgments Dr. Pergolizzi is a consultant for Grünenthal, Johnson and Johnson, Baxter, Kirax Corporation, and Endo Pharmaceuticals. Dr. Gharibo is a consultant for Endo, King, and Neurogesx. Dr. Passik is a consultant

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