116 Journal of Pain and Symptom Management Vol. 41 No. 1 January 2011

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1 116 Journal of Pain and Symptom Management Vol. 41 No. 1 January 2011 Original Article Aberrant Drug-Related Behavior Observed During Clinical Studies Involving Patients Taking Chronic Opioid Therapy for Persistent Pain and Fentanyl Buccal Tablet for Breakthrough Pain Steven D. Passik, PhD, John Messina, PharmD, Anthony Golsorkhi, MD, and Fang Xie, PhD Memorial Sloan-Kettering Cancer Center (S.D.P.), New York, New York; and Cephalon, Inc. (J.M., A.G., F.X.), Frazer, Pennsylvania, USA Abstract Context. Information on aberrant drug-related behaviors in the clinical study setting is limited. Objectives. This retrospective analysis was designed to identify the types and frequency of aberrant drug-related behaviors (including misuse and abuse) and associated patient characteristics in opioid-tolerant patients with chronic pain. Methods. Data from opioid-tolerant patients participating in clinical studies of fentanyl buccal tablet (FBT) for breakthrough pain (up to 18 months of clinical study case-report forms) were retrospectively reviewed and coded for abuse, overdose, and aberrant behavior. Aberrant behaviors were categorized as those involving FBT (overuse, lost or stolen study drug) and those not involving FBT (patients seeking prescriptions from other sources, not returning for follow-up). Results. Of the 1,160 patients evaluated, 10 (<1%) patients had an abuserelated event, 18 (<2%) had a positive urine drug screening (nonprescribed drug or illicit substance), and 12 (1%) had an event consistent with opioid overdose; 124 (11%) had aberrant behaviors related to FBT, and 68 (6%) had aberrant behaviors that were not. Aberrant behaviors were more frequent in men (odds ratio [OR]: 1.5; 95% confidence interval [CI]: 1.1, 2.1; P < 0.01), in patients 42 years or younger (OR: 2.5; 95% CI: 1.6, 4.0; P < 0.01), and in patients 43 years to 49 years (OR: 1.9; 95% CI: 1.2, 3.1; P < 0.01). Conclusion. The incidence of drug abuse events and aberrant drug-related behaviors was relatively low, probably because of the implementation of universal precautions and the controlled clinical study setting. Even in this setting, events occurred, highlighting the limits of screening and the need for ongoing This study was sponsored by Cephalon, Inc. Writing assistance was provided by Peloton Advantage, LLC, funded by Cephalon, Inc. Address correspondence to: Steven D. Passik, PhD, Memorial Sloan-Kettering Cancer Center, 641 Ó 2011 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. Lexington Avenue, 7th Floor, New York, NY 10022, USA. passiks@mskcc.org Accepted for publication: April 1, /$ - see front matter doi: /j.jpainsymman

2 Vol. 41 No. 1 January 2011 Aberrant Drug-Related Behavior 117 monitoring of aberrant behavior. J Pain Symptom Manage 2011;41:116e125. Ó 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Chronic pain, fentanyl buccal tablet (FBT), breakthrough pain (BTP), opioid, aberrant drug-related behavior, drug abuse Introduction Opioids are a mainstay of treatment for moderate to severe pain, and they are prescribed extensively for chronic and persistent pain. 1e3 Aberrant behavior is defined as drug-seeking behavior and/or problematic opioid use, 4 often associated with addictive disease. 5 Aberrant behavior (e.g., diversion of prescribed opioids, forging prescriptions, concomitant use of alcohol or illicit drugs, repeated unauthorized dose increases) may indicate loss of control or outright abuse and addiction. 6,7 Such behavior clearly complicates pain management for patients who are prescribed opioids. 8 Abuse and misuse of prescription opioids is a growing problem. 4,8,9 For example, in a sample of 185 patients with chronic pain, monitored for one year, 41% displayed at least one aberrant behavior indicative of abuse (e.g., took opioids other than or more than those prescribed, abnormal urine or blood screening, or requested early refills). 10 Opioid misuse occurred in 32% of patients monitored over a one-year period in another study. 8 The display of aberrant behaviors alone does not always indicate substance abuse or addiction; rather, it suggests that further evaluation may be warranted. Aberrant behavior also may reflect other conditions, such as uncontrolled pain or other psychiatric disorders resulting in self-medication. The increase in the nonmedical use of opioids has complicated pain management and has raised the ante for risk stratification and screening of all patients who will receive opioids. Physicians are faced with the task of weighing the essential medical role of opioids in pain relief against the potential of opioids for misuse, abuse, and diversion. They must take reasonable precautions to reduce the impact of these negative outcomes on the patient and the public at large. One potential strategy to mitigate the risks of abuse, addiction, and diversion is to stratify patients based on the risk factors before embarking on a particular treatment plan. 11 With effective risk stratification, treatment decisions and monitoring practices can be individually tailored to optimize the risk-benefit ratio. The data on aberrant drug-related behavior published to date are primarily from the clinical practice setting. There is very limited information available on abuse, addiction, or diversion of opioids in the clinical study setting. The few reports of abuse and addiction in clinical studies indicate that the incidence of abuse-related behavior ranges from less than 1% to 3% in studies involving longacting opioids. 12,13 A large database of five clinical studies in patients who were taking around-the-clock (ATC) opioids for persistent pain and fentanyl buccal tablet (FBT) for breakthrough pain (BTP) was retrospectively examined for behaviors that might be precursors or indicators of potential signs of loss of control or frank abuse and addiction. The objective of the analysis was to identify the types and frequency of aberrant drug-related behaviors and characteristics of patients that might be correlated with these behaviors. Methods Patient Populations This observational risk assessment analysis combined data from five previously completed studies that were designed to evaluate the efficacy, safety, and tolerability of FBT for the treatment of BTP in patients taking at least 60 mg of oral morphine or an equivalent ATC opioid for persistent pain and a shortacting oral opioid for BTP (Table 1). The database included information from a randomized, double-blind, placebo-controlled study in patients with chronic neuropathic pain (Study 1); 14 an identically designed study in patients with chronic low-back pain (Study 2); 15

3 118 Passik et al. Vol. 41 No. 1 January 2011 Table 1 Overview of Component Studies Study Population a Study Design Mean (Median) Duration of Study-Drug Exposure in Days b Study 1 14 BTP associated with chronic neuropathic Double-blind, placebo-controlled 18 (14) pain (n ¼ 102) Study 2 15 BTP associated with chronic low back pain Double-blind, placebo-controlled 15 (12) (n ¼ 104) Study 3 16 BTP associated with chronic pain (n ¼ 148) Double-blind, placebo-controlled 71 (97) Study 4 c BTP associated with chronic pain (n ¼ 218) Open-label 31 (35) Study 5 17 Patients who completed Studies 1 and 2 as well as new patients with chronic pain (n ¼ 728) Open-label 301 (329) a Protocols specified that all patients should be opioid tolerant (e.g., taking the equivalent of at least 60 mg/day of oral morphine for $1 week before study entry). b Duration of total study-drug exposure, mean (median) ¼ 207 (106). c Data on file, Cephalon, Inc., Frazer, PA. a randomized study with three within-patient double-blind treatment periods in patients with a variety of chronic pain diagnoses (Study 3); 16 an open-label study in patients with chronic pain (Study 4); and a long-term, open-label study in patients with chronic pain treated for up to 18 months (Study 5). 17 Study 5 included patients who completed Studies 1 and 2 as well as patients naive to FBT treatment. Study participants were opioid-tolerant adults aged 18e80 years, with persistent pain of greater than or equal to three months duration, who were taking ATC opioids (opioid therapy equivalent to at least 60 mg of oral morphine per day at a stable dose for at least one week before study entry). In addition, patients had an average pain intensity score of 6 or less for chronic pain during the previous 24 hours, were experiencing an average of one to four BTP episodes daily (each lasting less than four hours) while taking supplemental opioids for BTP, and were achieving at least partial relief of their BTP. Patients were excluded from the studies if they had a recent history (i.e. within five years) of alcohol or substance abuse or a positive urine drug screening (UDS) for illicit substances or medications without legitimate medical explanation. All participants underwent a UDS at the screening visit. Although no other scheduled UDS samples were required by the study protocols, the investigators were permitted to conduct a UDS anytime at their discretion. Patients also were excluded if they had a psychiatric condition that could compromise study data, had unstable or uncontrolled pain, or had participated in an earlier FBT study (except as noted in Study 5). Conduct of Component Studies All patients who met the inclusion criteria entered an open-label dose titration period. The purpose of the dose titration period was to determine a successful dose for each patient. A successful dose was defined as the single dose of FBT (100, 200, 400, 600, or 800 mg) that provided adequate analgesia for at least two of three BTP episodes without the need for a second dose or supplemental medication and without unacceptable adverse events. Once a successful dose was identified, patients were treated with open-label FBT, except for brief double-blind periods in Studies 1, 2, and 3 to assess efficacy. 14e16 During the studies, patients continued their prestudy, fixedschedule, ATC opioid regimens, and the supplemental opioid taken for BTP was replaced with FBT, taken on an as-needed basis. Adjustments to dose and type of ATC medication were allowed as clinically indicated, and administration of the prestudy supplemental opioid was allowed if relief with FBT was occasionally unsatisfactory. During open-label treatment periods, if adequate pain relief was not achieved 30 minutes after the first dose was administered, a second tablet (of the same dose strength) could be administered to treat the same episode. Patients were instructed to treat no more than six BTP episodes per day and to take no more than eight doses of FBT in a single day. Patients were asked to report in their diaries the number of tablets taken and the number

4 Vol. 41 No. 1 January 2011 Aberrant Drug-Related Behavior 119 of BTP episodes experienced and treated each day. Study visits occurred each month. Patients were instructed to return all unused study drug and packaging at each visit, and drug accountability was monitored at each visit. Aberrant Behavior and Risk Factors Aberrant Behavior. Currently, no definitive lists of aberrant drug-related behaviors are widely accepted in the pain community. However, a number of authors have published what they consider to be aberrant behaviors in patients with chronic pain. 4e6,8,10,18 For the purposes of this analysis, a list of aberrant drug-related behaviors was compiled through a review of the published literature (Table 2). 4e6,8,10,18 The meaning of aberrant behavior has not been well defined within the structure of a clinical study. Nevertheless, based on this list of aberrant behaviors from the published literature, a list of target terms was compiled and used to conduct text string searches within the data sets from the five FBT component studies. Manual review of the relevant data listings was also performed by the study medical monitor to identify possible aberrant behaviors. Results from the string searches, together with the results from the medical monitor review, were further reviewed for false-positive and duplicate results. The identified behaviors were then classified into categories consistent with those reported in the literature and were further reviewed to identify those that might have face validity for potentially predicting abuse and/or addiction in a clinical study setting. Patients in the database were stratified for analysis based on the presence or absence of any aberrant behavior. They were then grouped according to behaviors possibly involving and not involving the administration of the study drug (Table 3). Baseline Factors. Baseline factors evaluated as possibly associated with aberrant behavior included the following: 1) age (grouped by quartile); 2) gender; 3) race; 4) body mass index (grouped by quartile); 5) pain diagnosis; 6) pathophysiology of BTP; 7) baseline ATC daily opioid dose (grouped by quartile); and 8) history of depressive disorder, anxiety disorder, psychotic symptoms or mania, or alcohol or drug abuse (more than five years prior; each separately). Statistical Analysis In this post hoc exploratory analysis, baseline characteristics, including demographics and Table 2 Aberrant Drug-Related Behaviors Identified Through Literature Review 4e6,8,10,18 Multiple dose escalations or other noncompliance with therapy despite warnings Unsanctioned dose escalations or other noncompliance with therapy on 1 or 2 occasions Requesting early renewals Aggressive complaining about the need for more drug Repeated resistance to changes in the therapy despite clear evidence of adverse physical or psychological effects from the drug Drug hoarding during periods of reduced symptoms Openly acquiring similar drugs from other medical sources Repeatedly seeking prescriptions from other clinicians or from emergency rooms without informing prescriber or after warnings to desist Missed doctor appointment Requested refills instead of clinic visit Multiple episodes of prescription loss No show or no follow-up Third party required to manage patient s medication Excessive phone calls Was discharged from practice Involvement in motor vehicle accident Abnormal urine/blood screening Abnormal urine/blood positive for $2 substances Unanticipated positive results in urine toxicology tests Negative UDS (when it is expected to be positive) Positive UDS for stimulant Injection of oral formulations Injected drug Abused prescribed drug Overdose and death Frequency of drug intoxication Concurrent abuse of alcohol or illicit drugs Purposely oversedating oneself Concern expressed by a significant other about the patient s use of opioids Evidence of deterioration in the ability to function at work, in the family, or socially that appears to be related to drug use Unapproved use of the drug to treat another symptom Reporting psychic effects not intended by the clinician Admitted to seeking euphoria from opioids Admitted to wanting opioids for anxiety Resistance to a change in the therapy associated with tolerable adverse events with expression of anxiety related to the return of severe symptoms Selling prescription drugs Stealing or borrowing drugs from others Obtaining prescription drugs from nonmedical sources Requesting specific drugs Prescription forgery

5 120 Passik et al. Vol. 41 No. 1 January 2011 Events Indicating Substance Abuse or Overdose Table 3 Aberrant Drug-Related Behavior Categories Aberrant Behaviors Possibly Involving the Study Drug Aberrant Behaviors Not Involving the Study Drug Abuse/dependence (described by Fear of addiction Discharged from pain management practice investigator) Report of study-drug theft Use of nonprescribed medication Positive urine drug screening Report of lost study drug Lost to follow-up Overdose Overadministration of study drug Seeking prescriptions from other sources Unapproved administration of study drug for another symptom Unreliability Motor vehicle accident relevant medical history, were summarized by the presence or absence of aberrant behavior using descriptive statistics. A Kaplan-Meier curve was used to illustrate the time to the first onset of any aberrant behavior. The logistic regression model was used to quantify the relationship between the incidence rate of aberrant behavior and the baseline characteristics. Relative risks, as measured by odds ratios (ORs), were estimated along with the 95% confidence interval from the logistic regression models. Results Patients and Pain Characteristics A total of 1,160 opioid-tolerant patients with chronic pain and BTP, who received at least one dose of FBT during the five clinical studies, made up the analysis group. The mean age of the cohort was 48.9 years (range 20.0e77.0 years). Most patients were white (93%) women (57%), aged 65 years or younger (94%). Mean body mass index was 30.1 kg/m 2 (range 14.3e76.3 kg/m 2 ). Back pain was the most common pain diagnosis (57%), followed by traumatic injury (9%), osteoarthritis (6%), and complex regional pain syndrome (5%). The pathophysiological basis for pain was fairly evenly distributed among predominantly neuropathic pain (28%), predominantly nociceptive pain (29%), or a mixture of the two (34%). The mean duration of exposure to FBT during the studies was (standard error: 211.8) days, with a median of (range 1.0e638.0) days. Aberrant Behavior Rates In this analysis, 124 patients (11%) had an aberrant behavior possibly involving the study drug, and 68 (6%) had an aberrant behavior that was not related to the study drug. In most of the patients with aberrant behaviors (84%), only one aberrant behavior was identified (Table 4). Ten patients (<1%) had an abuse-related event, 18 (<2%) had a positive UDS, and 12 (1%) experienced an event consistent with opioid overdose (all patients recovered). The most commonly reported aberrant behaviors involving study drug were overadministration of study medication (i.e., >8 tablets per day; 79 events) and medication theft (45 events). By contrast, the most commonly reported aberrant behaviors that did Table 4 Aberrant Behaviors and Relationship to Study Medication Aberrant Behavior Category Patients, n (%) Aberrant Behavior Events, n Aberrant behaviors possibly involving study medication Overadministration of study 58 (5) 79 medication Medication theft 43 (4) 45 Overdose 8 (1) a 9 Motor vehicle accident 7 (1) 7 Abuse/dependence 6 (<1) 6 Fear of addiction 6 (<1) 6 Loss of study medication 5 (<1) 5 Unapproved administration of drug to treat another symptom 2(<1) 2 Aberrant behaviors not involving study medication Lost to follow-up 36 (3) 36 Positive UDS test 18 (2) 18 Taking nonprescribed 7 (1) 7 medications Overdose 5 (<1) a 5 Abuse/dependence 4 (<1) 4 Sought prescriptions from other 3(<1) 3 sources Discharged from pain management practice 3(<1) 3 a One patient had two events of overdose, one possibly involving FBT and the other not; this patient is counted twice in this table (n ¼ 1,160).

6 Vol. 41 No. 1 January 2011 Aberrant Drug-Related Behavior 121 Table 5 Rates of Aberrant Drug-Related Behavior by Baseline Characteristics Aberrant Behavior (Total n ¼ 1,160) Characteristic All a (n ¼ 192) None (n ¼ 968) OR b (95% CI) Age, years Mean d SD d Age group (years), n (%) #42 68 (35) c 232 (24) (1.6, 4.0) >42 to #49 57 (30) c 250 (26) (1.2, 3.1) >49 to #55 36 (19) 223 (23) (0.8, 2.3) >55 (reference) 31 (16) 263 (27) Gender, n (%) Women 92 (48) 566 (58) Men 100 (52) c 402 (42) (1.1, 2.1) Race group, n (%) White 179 (93) 904 (93) (0.3, 3.3) Black 9 (5) 45 (5) (0.3, 3.8) Other (reference) 4 (2) 19 (2) Primary pain diagnosis, n (%) Back pain 109 (57) 548 (57) d Traumatic injury 17 (9) 85 (9) d Osteoarthritis 10 (5) 55 (6) d Complex regional pain syndrome 8 (4) 54 (6) d Diabetic peripheral neuropathy 9 (5) 33 (3) d Chronic headache 12 (6) 22 (2) d Neck pain 0 30 (3) d Fibromyalgia 0 25 (3) d Postherpetic neuralgia 0 5 (<1) d Chronic pancreatitis 0 2 (<1) d Other 27 (14) 106 (11) d Primary pain diagnosis group, n (%) Neuropathic pain (reference) 38 (20) 175 (18) Back pain 109 (57) 548 (57) (0.6, 1.4) Other 45 (23) 245 (25) (0.5, 1.4) Pathophysiology of BTP, n (%) Predominantly neuropathic 62 (32) 258 (27) (1.0, 2.1) Predominantly nociceptive 54 (28) 280 (29) (0.8, 1.7) Mixed (reference) 57 (30) 343 (35) Baseline ATC daily opioid dose (mg), d n (%) #90 47 (24) 267 (28) (0.7, 9.0) >90 to # (30) 234 (24) (1.0, 12.6) >160 to # (19) 232 (24) (0.6, 8.2) > (24) 199 (21) (1.0, 12.1) Intrathecal (reference) 3 (2) 36 (4) a Includes patients with $1 aberrant behavior (i.e., abuse/dependence, overdose, positive urine drug screening, motor vehicle accident, fear of addiction, discharged from practice, unreliability, taking nonprescribed medication, study-drug theft, lost to follow-up, seeking prescriptions from other sources, lost study drug, overadministration of study drug, or unapproved administration of a medication to treat another symptom). b OR measures the relative risk of aberrant behaviors for one subgroup compared with the reference group. c P < d Before summarization, all oral opioid doses were converted to oral morphine-equivalent doses using predetermined conversion factors. not involve study medication were patients being lost to follow-up (36 events) and positive UDS tests (18 events). Patient demographic information and other baseline characteristics are summarized by aberrant drug-related behavior incidence in Table 5. The occurrence of aberrant drug-related behaviors was more frequent among younger patients. The mean age of patients with aberrant drug-related behaviors was 46.1 years compared with a mean age of 49.5 years for patients with no aberrant drug-related behaviors. The distribution of patients among the age categories showed that the occurrence of aberrant drugrelated behaviors was skewed toward the lower age (#49 years) categories compared with older age categories (P < 0.01), which is consistent with the differences in mean ages. Men were

7 122 Passik et al. Vol. 41 No. 1 January 2011 Table 6 Rates of Aberrant Drug-Related Behavior by Medical History Number (%) of Patients With Aberrant Drug-Related Behavior (Total n ¼ 1,160) Medical History All a (n ¼ 192) None (n ¼ 968) OR b (95% CI) Anxiety Yes 70 (36) 352 (36) (0.7, 1.4) No (reference) 122 (64) 616 (64) Depression Yes 97 (51) 553 (57) (0.6, 1.0) No (reference) 95 (49) 415 (43) Psychosis/mania Yes 10 (5) 31 (3) (0.8, 3.3) No (reference) 182 (95) 937 (97) Alcohol or drug abuse Yes 1 (<1) 15 (2) (0.0, 1.7) No (reference) 191 (>99) 953 (98) a Includes patients with $1 aberrant behavior (i.e., abuse/dependence, overdose, positive urine drug screening, motor vehicle accident, fear of addiction, discharged from practice, unreliability, taking nonprescribed medication, study-drug theft, lost to follow-up, seeking prescriptions from other sources, lost study drug, overadministration of study drug, or unapproved administration of a medication to treat another symptom). b OR measures the relative risk of aberrant behaviors for one subgroup compared with the reference group. 50% more likely than women to have aberrant drug-related behaviors (OR: women, 1.000; men, ; P ¼ ). Aberrant drugrelated behaviors were twice as likely to occur in patients taking ATC oral or transdermal opioids than in those receiving ATC intrathecal opioids, but this difference was not statistically significant (P > 0.09 for each comparison). No apparent relationship was found between daily dose of ATC opioid at baseline and aberrant drug-related behavior (i.e., higher opioid doses were not associated with higher risk of aberrant behavior). The relationship between patients history of selected medical conditions and aberrant drug-related behavior is presented in Table 6. Patients with psychiatric conditions associated with psychosis or mania (e.g., bipolar disorder) were somewhat more likely to exhibit an aberrant behavior than patients without (OR: 1.66), although the difference was not statistically significant (P ¼ ). Patients with a history of substance abuse (only patients with a history of substance abuse more than five years before enrollment were eligible) were less likely to display aberrant drugrelated behaviors than those without a similar history (OR: 0.33), but again, this was not statistically significant (P ¼ ). The time to first onset of aberrant drugrelated behavior is shown in Fig. 1 using the Kaplan-Meier method. The survival probability curve appeared to be approximately linear over time, indicating that the risk of exhibiting an aberrant drug-related behavior per unit of time was relatively constant. This implies that the risk of aberrant behavior onset was not associated with the duration of treatment. Discussion The current analysis evaluated aberrant drug-related behavior in a large database of patients using at least 60 mg of oral morphine or equivalent for persistent pain and FBT for BTP episodes during clinical studies. Despite the exclusion from the studies of patients with a positive UDS or with a recent history of substance abuse (i.e. within the past five years), this was an excellent opportunity to examine the frequency and type of aberrant drugrelated behavior during extended opioid therapy in patients with chronic pain. The mean duration of study participation was 207 days, which allowed for an adequate observation period. Abuse-related events occurred at a rate of 2% in this analysis, which is consistent with the findings of abuse-related events in previously reported studies involving chronic opioid therapy, where the rate of abuse-related events ranged from less than 1% to 3%. 12,13 There is also no sufficient evidence of a difference in abuse liability among different formulations of oral opioids. 11 Although this rate of aberrant behavior is lower than that reported previously, 5,8 this population was highly select.

8 Vol. 41 No. 1 January 2011 Aberrant Drug-Related Behavior 123 Fig. 1. Time to first onset of aberrant drug-related behavior. Demographic risk factors for aberrant drugrelated behavior in the current analysis included younger age and male gender, a finding consistent with the general literature. 8,11 Interestingly, patients with a history of substance abuse (more than five years before the study) were less likely to display aberrant drugrelated behavior than those without such a history. This finding suggests that a remote history of substance abuse may not necessarily predict future aberrant behavior during opioid therapy administered under highly structured conditions. Moreover, it is reasonable to think that a person with a history of substance abuse, who has remained stable for five years or more, might be less susceptible to aberrant drugrelated behavior than someone who has never received a drug that may be abused and whose susceptibility is unknown. There were no differences in the risk of aberrant behavior when comparing different pain diagnostic groups, including patients with low back pain. The published literature is limited with regard to the development or display of aberrant behaviors compared with the duration of treatment with opioids. In a study of chronic opioid therapy in 20 patients with a history of substance abuse, it was reported that aberrant behaviors were likely to surface early in the course of opioid therapy (i.e., in the first three months) in these high-risk patients. 19 By contrast, the occurrence of aberrant behavior was relatively constant over time in our highly select study population being treated for chronic BTP. It should be noted that, even though the clinical study setting was highly controlled, drug abuse events and aberrant drug-related behaviors still occurred. This observation highlights the limitations of current screening methods and the need for active monitoring. As a retrospective assessment, information on aberrant behavior was not defined a priori in the studies and, therefore, the case-report forms did not capture all of the information that may have been needed to confirm an aberrant behavior. As a result, a conservative approach was taken by assigning the occurrence of an aberrant behavior based on any suggestion of one within a comment field or in an adverse event report. The list of aberrant behaviors was compiled from the literature and was not validated as predictive of abuse or addiction in the clinical study setting. UDS testing after screening was not mandatory, which probably resulted in an underestimation of positive UDS results. This clinical study setting was controlled with specified eligibility criteria for ATC opioid therapy, BTP, and BTP therapy, meaning that the patient population probably does fully reflect the general population and that the clinical study setting may not adequately reflect real-world practice. For example, in contrast to typical clinical practice settings, patients in the studies

9 124 Passik et al. Vol. 41 No. 1 January 2011 underwent screening, leading to the exclusion of the highest-risk patient groups. Furthermore, close monitoring of the study population resulted in the discontinuation of patients with serious aberrant behaviors at the time of their detection, probably limiting the observation of additional aberrant behavior. The data presented here are in no way meant to be a definitive statement of the risk of aberrant behavior within the general, opioidtreated, chronic pain population, nor are they a reflection of the abuse liability of FBT. However, the incorporation of some clinical study methodologies (e.g., specified patient selection criteria, risk stratification, monitoring) into routine clinical practice may allow clinicians to aspire to the rates of aberrant behaviors observed within the analysis. Correspondingly, clinical study results might be more applicable to clinical practice with the integration of relevant aberrant behavior-monitoring tools, such as the Addiction Behaviors Checklist 20 and the Current Opioid Misuse Measure. 21 Considering the limited information available about aberrant behavior in a clinical study setting, the analysis and extent of these clinical study data are informative. The findings have important clinical implications for the management and monitoring of patients taking opioids for chronic pain and suggest that universal precautions (screening, monitoring, and recognizing behaviors) can minimize the incidence of aberrant behavior. References 1. Ballantyne JC. Chronic pain following treatment for cancer: the role of opioids. Oncologist 2003;8:567e Trescot AM, Boswell MV, Atluri SL, et al. Opioid guidelines in the management of chronic non-cancer pain. Pain Physician 2006;9:1e World Health Organization. Cancer pain relief and palliative care. Geneva, Switzerland: World Health Organization, Chabal C, Erjavec MK, Jacobson L, Mariano A, Chaney E. Prescription opiate abuse in chronic pain patients: clinical criteria, incidence, and predictors. Clin J Pain 1997;13:150e Michna E, Ross EL, Hynes WL, et al. Predicting aberrant drug behavior in patients treated for chronic pain: importance of abuse history. J Pain Symptom Manage 2004;28:250e Passik SD, Kirsh KL, Whitcomb L, Dickerson PK, Theobald DE. Pain clinicians rankings of aberrant drug-taking behaviors. J Pain Palliat Care Pharmacother 2002;16:39e Gourlay DL, Heit HA. Pain and addiction: managing risk through comprehensive care. J Addict Dis 2008;27:23e Ives TJ, Chelminski PR, Hammett-Stabler CA, et al. Predictors of opioid misuse in patients with chronic pain: a prospective cohort study. BMC Health Serv Res 2006;6: Gilson AM, Ryan KM, Joranson DE, Dahl JL. A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: J Pain Symptom Manage 2004; 28:176e Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med 2005;6: 432e Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10:113e Portenoy RK, Farrar JT, Backonja MM, et al. Long-term use of controlled-release oxycodone for noncancer pain: results of a 3-year registry study. Clin J Pain 2007;23:287e Cicero TJ, Wong G, Tian Y, et al. Co-morbidity and utilization of medical services by pain patients receiving opioid medications: data from an insurance claims database. Pain 2009;144:20e Simpson DM, Messina J, Xie F, Hale M. Fentanyl buccal tablet for the relief of breakthrough pain in opioid-tolerant adult patients with chronic neuropathic pain: a multicenter, randomized, doubleblind, placebo-controlled study. Clin Ther 2007;29: 588e Portenoy RK, Messina J, Xie F, Peppin J. Fentanyl buccal tablet (FBT) for relief of breakthrough pain in opioid-treated patients with chronic low back pain: a randomized, placebo-controlled study. Curr Med Res Opin 2007;23:223e Farrar JT, Michna E, Messina J, Xie F. Fentanyl buccal tablet (FBT) in opioid-tolerant patients with non-cancer-related breakthrough pain (BTP) on around-the-clock opioids: a 12-week study using a novel double-blind, placebo-controlled design. [abstract 130]. Pain Med 2008; 9: Fine PG, Messina J, Xie F, Rathmell J. Long-term safety and tolerability of fentanyl buccal tablet for the treatment of breakthrough pain in opioid-tolerant patients with chronic pain: an 18-month study. J Pain Symptom Manage XXeXX [In press]. 18. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage 1996;11:203e217.

10 Vol. 41 No. 1 January 2011 Aberrant Drug-Related Behavior Dunbar SA, Katz NP. Chronic opioid therapy for nonmalignant pain in patients with a history of substance abuse: report of 20 cases. J Pain Symptom Manage 1996;11:163e Wu SM, Compton P, Bolus R, et al. The addiction behaviors checklist: validation of a new clinician-based measure of inappropriate opioid use in chronic pain. J Pain Symptom Manage 2006;32:342e Butler SF, Budman SH, Fernandez KC, et al. Development and validation of the current opioid misuse measure. Pain 2007;130:144e156.