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Comorbidity of opioid-related and anxiety-related symptoms and disorders
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ScienceDirect Comorbidity of opioid-related and anxiety-related symptoms and disorders Kirsten J Langdon1,2, Kathrine Dove3 and Susan Ramsey2,4,5 Opioid use disorder and anxiety disorders co-occur at strikingly high rates, and this comorbidity is marked by a more severe clinical presentation and poorer prognosis for treatment. Given the substantial morbidity and mortality associated with these two disorders, it is imperative to understand factors related to the high rates of co-occurrence in order to inform the development of specialized treatments for this population. Several lines of study suggest that simultaneously addressing opioid-related and anxiety-related symptoms and processes, particularly intolerance of distress and pain-related anxiety, may yield improved outcomes for this high risk, vulnerable population. Future work is needed to identify other novel mechanisms as well as develop specialized treatments to augment standard medication-assisted treatment. Addresses 1 Department of Psychiatry, Rhode Island Hospital, United States 2 Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States 3 Stonehill College, United States 4 Division of General Internal Medicine, Rhode Island Hospital, United States 5 Department of Medicine, Alpert Medical School of Brown University, United States Corresponding author: Langdon, Kirsten J ([email protected])
Current Opinion in Psychology 2019, 30:17–23 This review comes from a themed issue on Addiction Edited by Samantha Farris and Angelo Dibello
https://doi.org/10.1016/j.copsyc.2018.12.020 2352-250X/ã 2018 Elsevier Ltd. All rights reserved.
Anxiety-related symptoms and disorders are the most common psychiatric illness in the United States [5]. Approximately 19% of U.S. adults met criteria for a current (past year) anxiety disorder [6], and 31% of U. S. adults have experienced a lifetime anxiety disorder [7]. Opioid use disorder and anxiety disorders co-occur at strikingly high rates. Indeed, over 60% of individuals meeting criteria for an opioid use disorder also report the experience of a lifetime anxiety-related disorder [8]. This co-occurrence is marked by earlier onset for opioid use [9], more rapid transition from use to opioid use disorder [9], premature discontinuation of substance use treatment [10], and greater potential for the misuse of other substances, for example, benzodiazepines [11,12]. Historically, anxiety-related symptoms and disorders have received little scholarly attention in regard to opioid use compared to other psychiatric conditions such as depression. This neglect is unfortunate as opioid use frequently co-occurs with anxiety and its disorders, and furthermore, anxiety vulnerability and clinical disorders may play a key role in the onset and maintenance of opioid use disorder. Given the substantial morbidity and mortality associated with these two disorders, it is imperative to understand the nature of, and potential factors related to, the high rates of co-occurrence to inform the development of specialized treatments for this population. The overarching aims of this review are to review the rates of co-occurrence between opioid-related and anxiety-related symptoms and disorders, summarize the research focused on identifying mechanisms underlying these associations, discuss how opioid-related and anxiety-related comorbidities impact treatment outcomes, and discuss clinical implications and future directions.
Rates of co-occurrence
Introduction The prevalence of opioid use disorders has reached epidemic rates in the United States, and opioid-involved overdoses are now the country’s leading cause of injury deaths [1]. The number of fatal overdoses has quadrupled since 1999, and opioids accounted for 42 000 deaths in 2016 [1]. More than 2.1 million people meet criteria for opioid use disorder [2]. Opioid misuse carries tremendous economic burden, with costs exceeding $56 billion annually [3,4]. www.sciencedirect.com
Numerous studies have explored the patterns of cooccurrence between opioid-related and anxiety-related symptoms and disorders, with results generally supporting a strong association between these two disorders (see Ref. [13] for a review). Meta-analyses suggest that the pooled prevalence of an anxiety diagnosis among patients reporting non-medical prescription opioid use was 29% (95% CI: 14%–44%) [13]. Longitudinal work has attempted to clarify the temporal order of these relations. For example, data collected from the National Epidemiological Study on Alcohol and Related Conditions was used to examine potential pathways among non-medical prescription opioid use (defined as using a Current Opinion in Psychology 2019, 30:17–23
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prescription opioid without a prescription, in greater amounts, more often, or longer than prescribed, or for a reason other than a doctor said you should use them), opioid use disorder, and anxiety disorders in a large national sample completing two waves of data collection (wave 1 = 2001–2002, wave 2 = 2004–2005 [14]). Overall, bidirectional associations were observed between these two conditions with wave 1 lifetime non-medical prescription opioid use predicting incidence of anxiety disorders at wave 2 (OR = 1.7; CI = 1.3–2.1), and wave 1 lifetime anxiety disorders predicting incidence of nonmedical prescription opioid use/opioid use disorder at wave 2 (OR = 1.4; CI = 1.1–1.8) [14]. This pattern of findings has been documented in other populations exposed to prescription opioids. Among patients with chronic pain currently receiving prescription opioid medication, patients screening positive for clinical levels of anxiety were significantly more likely to also screen positive for misuse of prescription opioids [15 ]. Indeed, among the patients endorsing anxiety, nearly 50% screen positive for opioid misuse, compared to 10% of the patients denying current anxiety [15]. Consistent with a larger literature highlighting sex and gender role differences across substance use disorders more broadly (see Ref. [16] for a review), women with opioid use disorder may be particularly prone to psychiatric comorbidities, particularly anxiety-related symptoms and disorders. Among treatment-seeking injection opioid users [17], individuals with concurrent opioid and cocaine use disorders [18], and patients engaging in medication-assisted treatment for opioid use disorder [19], women, compared to men, are more likely to have a diagnosis of an anxiety disorder. Taken together, existing work in this area suggests that there are high rates of co-occurrence between opioidrelated and anxiety-related symptoms and disorders. Further, there appears to be a bidirectional pathway between these two conditions such that the experience of anxiety may confer risk for subsequent opioid use/misuse, and opioid misuse may further promote or exacerbate the development of anxiety. However, this work has primarily relied on self-report data or retrospective chart reviews, which limits the ability to make causal inferences or define temporal ordering. Future work, including multi-modal assessments of anxiety and opioid use in the context of longitudinal and experimental designs, is needed to more accurately capture proximal associations over time.
Impact of comorbidity on treatment outcomes Medication-assisted treatment, which involves the use of pharmacotherapy (methadone, buprenorphine, and injectable naltrexone) in combination with psychosocial support, is an evidence-based approach to treat opioid use Current Opinion in Psychology 2019, 30:17–23
disorder and reduce overdose risk [20,21]. Medicationassisted treatment is effective in reducing illicit opioid use and preventing incidence of overdose [22,23]; however, across the different medication options, there are varying rates of retention [22,24], highlighting the need to better understand which subgroups of patients do versus do not benefit from medication-assisted treatment [25]. By and large, it appears that the presence of anxietyrelated symptoms and disorders negatively impact the course of medication-assisted treatment, including methadone [26], buprenorphine [27], and injectable naltrexone [28]. Individuals experiencing elevated anxiety symptoms at treatment initiation may be more likely to relapse [27] or discontinue treatment prematurely [26]. Further, patients experiencing persistent anxiety symptoms throughout the course of treatment are more likely to drop out early [28]. For example, in a randomized controlled trial of voucher-based contingency management and support from a significant other to enhance retention on oral naltrexone, somatic and affective symptoms were assessed weekly among patients who were retained on naltrexone through the 12-week trial compared to those who dropped out [28]. Although there were no statistically significant differences between the groups at baseline, participants who prematurely discontinued treatment endorsed elevated rates of difficulty sleeping, nervousness, restlessness, feeling blah, depression, and anxiety in the weeks before dropout [28]. Similar findings have been observed in other clinical trials comparing extended release naltrexone to buprenorphine [29]. Specifically, higher mean anxiety scores across the study period were associated with greater illicit opioid and other substance use during treatment [29]. Consistent with a negative reinforcement model of substance use [30], individuals with co-occurring opioid use disorder and anxiety disorder may be particularly motivated to resume substance use following treatment initiation to manage or alleviate aversive physical or emotional symptoms that emerge as a result of ongoing stressors or in response to drug cues. Such data suggest that to optimize treatment outcomes for this vulnerable, high-risk, subset of the population, it is imperative to concurrently treat these two overlapping disorders [31]. A related, and emerging body of work, suggests that engagement in medication-assisted treatment may have added benefit for anxiety-related symptoms; however, this literature is mixed. For example, two recently randomized, controlled trials examining the efficacy of medication-assisted treatment found that symptoms of anxiety tended to improve across the study period among individuals who remained active in treatment [29,32]. Yet, another randomized controlled trial documented an increase in anxiety symptoms throughout the treatment period, and increased anxiety at earlier time-points was associated with lack of attendance at subsequent www.sciencedirect.com
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assessments [33]. Future research is needed to further parse apart if, and how, medication-assisted treatment may influence the trajectory of anxiety-related symptoms of disorders among individuals seeking treatment for opioid use disorder.
Mechanisms underlying the association between opioid-related and anxiety-related disorders Despite growing recognition that opioid-related and anxiety-related symptoms and disorders co-occur at high rates, far less scholarly attention has been devoted to understanding potential mechanisms underlying the etiology and maintenance of this comorbidity. Such a neglect is unfortunate as developing a greater understanding of factors associated with the opioid-anxiety comorbidity is a critical step in refining current theoretical models and empirically supported treatments. Although there are likely a variety of biopsychosocial mechanisms underlying this co-occurrence (e.g. neurobiological factors [34,35]), the current review focuses specifically on psychological mechanisms given the potential for therapeutic intervention. Distress intolerance
Existing work in this area has predominately focused on understanding the role of intolerance of distress. Distress intolerance, defined as the perceived or actual ability to handle aversive physical or emotional states, is a transdiagnostic vulnerability factor implicated in the development and maintenance of affective symptoms/disorders and substance use [36]. Distress intolerance is significantly related to a range of drug use outcomes, including frequency and severity of use [37] and early lapse/relapse [38,39]. Within the broader conceptualization of distress intolerance is the related construct of anxiety sensitivity. Anxiety sensitivity reflects the tendency to fear anxiety and related physical sensations due to the belief that these somatic sensations have negative physical, mental, and/or social consequences [40]. It has more recently been characterized as an amplifying factor that may enhance the perceived aversiveness of a particular emotional or somatic state, thus increasing the need or desire to escape/avoid these negative experiences [41,42]. Thus, distress intolerance, including anxiety sensitivity, may be particularly relevant to the co-occurrence of opioidrelated and anxiety-related symptoms and disorders. Consistent with this theoretical model, a growing body of work suggests that distress intolerance is linked to a variety of substance use processes among individuals with opioid use disorder. For example, in an experimental paradigm involving Quantitative Sensory Testing and a Cold Presser Task, the association between distress intolerance and opioid misuse was assessed among patients with chronic pain [43]. Results revealed that distress intolerance was associated with opioid misuse but was not www.sciencedirect.com
associated with pain severity, threshold, or tolerance as assessed through the laboratory tasks [43]. However, distress intolerance was also associated with self-reported anxiety and stress in response to noxious stimuli [43]. Other work has found that anxiety sensitivity moderates the effects of drug craving in response to a negative affect experimental induction, such that affect induction was only related to craving among individuals with high levels of anxiety sensitivity [44]. Anxiety sensitivity has also been shown to be related to fear of opioid withdrawal and greater subjective withdrawal severity [45], premature discontinuation of treatment [10], and frequency of past-month nonmedical benzodiazepine use among patients receiving inpatient treatment for opioid use disorder [46]. Regarding the latter, the most commonly cited reason for benzodiazepine misuse among individuals with opioid use disorder is to ‘manage anxiety;’ yet, paradoxically, participants using benzodiazepines primarily for anxiety did not endorse lower overall levels of anxiety [47]. Pain-related anxiety
Pain-related anxiety is another area of growing interest that may have applicability to opioid use disorder. Painrelated anxiety reflects worry about the negative consequences of pain [48]. Specifically, increased levels of anxiety about the experience of pain are posited to be related to avoidance of activities that promote pain which, in turn, is associated with physical deconditioning, behavioral problems (e.g. weight gain, mood disturbance), and impaired social functioning [49]. This pattern of responding is theorized to be cyclical, such that pain-related anxiety is linked to more severe pain and pain-related problems (e.g. physical deconditioning), which further promote and solidify worry-related beliefs about the nature of pain [50]. Additionally, pain-related anxiety is associated with several maladaptive coping tactics, such as substance use [51]. Regarding opioid use, specifically, several investigations have examined whether pain-related anxiety may serve as a risk factor for the development of opioid misuse. One study examined the role of pain-related anxiety in relation to opioid misuse among a racially/ethnically diverse young adult sample reporting moderate to severe bodily pain [52]. Results indicated that pain-related anxiety significantly predicted self-reported opioid addiction, family concerns due to opioid use, history of opioid detoxification, and number of opioid-related problems. Importantly, pain-related anxiety predicted each of these opioid misuse outcomes over and above relevant covariates, including gender, pain intensity, drug use, and alcohol use [52]. A second study investigated associations between pain-related anxiety, gender, and prescription opioid misuse among a sample of tobacco smokers living with HIV/AIDS who endorsed high levels of pain intensity and pain-related anxiety [53]. Pain-related anxiety Current Opinion in Psychology 2019, 30:17–23
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was found to be positively associated with current opioid misuse among male, but not female, participants [53]. Further, pain-related anxiety was positively associated with self-reported intention to misuse opioids in the future among all participants who were prescribed opioids [53]. Collectively, this work suggests that pain-related anxiety may be an important therapeutic target to prevent and address opioid use disorder among individuals living with chronic pain. Although distress intolerance and pain-related anxiety hold promise for better understanding and addressing opioid-related and anxiety-related symptoms and disorders, it would be fruitful to identify additional mechanisms of action to build multi-risk factor models. Doing so would allow for a more comprehensive and personalized approach to treatment.
Clinical implications Better understanding the role of anxiety-related symptoms and disorders in terms of opioid use disorder etiology and maintenance has the potential to inform the development of promising cognitive-behavioral interventions that complement standard medication-assisted treatment. Here, we highlight several promising treatments.
pain [52,53]. Acceptance and Commitment Therapy and Cognitive-Behavioral Therapy have demonstrated efficacy in the treatment of chronic pain [59,60] anxiety disorders [61,62], and substance use disorders [63,64]. Thus, future work could meaningfully build upon these treatments to tailor intervention content to more adequately address opioid use in the context of chronic pain and related anxieties. Integrated cognitive-behavioral therapy (I-CBT) for cooccurring opioid use disorder and anxiety disorders is a novel intervention approach that utilizes treatment elements that target the interaction of shared symptoms and processes underlying both disorders to facilitate overall recovery [46]. Unlike other treatment modalities that focus on each disorder in isolation, this approach emphasizes the interaction of overlapping symptoms and conceptualizes these conditions as a single disorder [46]. Skills training addresses the overarching theme of negative reinforcement to reduce reliance on maladaptive avoidance-based behaviors (e.g. drug use) that provide relief from distress in the short term. By targeting underlying processes of both disorders, I-CBT has the potential to improve both anxiety and opioid use outcomes.
Future directions As described above, distress intolerance may have particular relevance to the opioid–anxiety co-occurrence. Distress tolerance involves the ability to withstand negative reinforcement opportunities by exerting control over behavioral responding to opportunities that would provide immediate relief from distress, such as stress or anxiety [54]. Converging lines of evidence suggest that opioid users may be hypersensitive to interoceptive cues that occur in the context of early abstinence [55]; therefore, relapse is likely given that illicit opioid use potentially serves as way to avoid or manage negative internal states in the short term [56]. There may be merit to directly targeting distress tolerance to increase the ability to tolerate negative physical and emotional states that occur during the early phases of medication-assisted treatment in order to decrease the use of avoidance-based strategies such as substance use. Distress tolerance is an important aspect of emotional self-regulation, given that distress tolerance skills help to mitigate the impact of negative mood states [57]. Preliminary work suggests that targeting distress tolerance during substance use treatment may improve outcomes by promoting the ability to persist in goal directed activity (e.g. abstinence) even when experiencing high levels of distress [56,58]. Pain-related anxiety, which reflects worry about the negative consequences of pain [48], is another factor relevant to opioid misuse/disorder and anxiety disorders. A growing body of work suggests that pain-related anxiety may be an important therapeutic target to prevent and address opioid use disorder among individuals living with chronic Current Opinion in Psychology 2019, 30:17–23
While the work outlined in this review is promising, there remain several avenues in need of further investigation. First, future studies would benefit from inclusion of multi-modal assessments of anxiety and opioid use, in the context of longitudinal and experimental designs, to better understand the nature of this comorbidity and the facets involved in the etiology and maintenance of these disorders. Second, it would be fruitful to identify additional mechanisms of action to build multi-risk factor models. Explicating these explanatory mechanisms is essential to translating basic research knowledge to advances in specialized behavioral and pharmacologic interventions for this population. Finally, although medication-assisted treatment has revolutionized the treatment of opioid use disorders, there remain significant limitations in terms of facilitating long-term abstinence and retention among certain subgroups. Therefore, it is critical that we continue to expand upon this treatment to develop novel strategies to augment standard medicationassisted treatment to more fully meet the needs of individuals with co-occurring opioid-related and anxietyrelated symptoms or disorders.
Conclusions Opioid use disorder and anxiety disorders co-occur at strikingly high rates, and this comorbidity is marked by a more severe clinical presentation and poorer prognosis for treatment. Given the substantial morbidity and mortality associated with these two disorders, it is imperative to understand factors related to the high rates of cooccurrence in order to inform the development of www.sciencedirect.com
Opioid and anxiety disorders Langdon, Dove and Ramsey 21
specialized treatments for this population. Several lines of study suggest that simultaneously addressing opioidrelated and anxiety-related symptoms and processes, particularly intolerance of distress and pain-related anxiety, may yield improved outcomes for this high risk, vulnerable, population. Future work is needed to identify other novel mechanisms as well as develop specialized treatments to augment standard medication-assisted treatment.
Funding source This work was made possible, in part, by the AdvanceCTR supported by the IDeA-CTR grant, National Institute of General Medical Sciences, Grant #U54GM115677 awarded to Kirsten Langdon, PhD. The funding source had no further role in the analyses or presentation of these data.
Conflicts of interest statement Nothing declared.
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34. Koob GF: Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology 2009, 56:18-31. 35. Wilson MA, Junor L: The role of amygdalar mu-opioid receptors in anxiety-related responses in two rat models. Neuropharmacology 2008, 33:2957-2968. 36. Leyro TM, Zvolensky MJ, Bernstein A: Distress tolerance and psychopathological symptoms and disorders: a review of the empirical literature among adults. Psychol Bull 2010, 136:576-600. 37. McHugh RK, Otto MW: Profiles of distress intolerance in a substance-dependent sample. Am J Drug Alcohol Abuse 2012, 38:161-165. 38. Daughters SB, Lejuez CW, Kahler CW, Strong DR, Brown RA: Psychological distress tolerance and duration of most recent abstinence attempt among residential treatment-seeking substance abusers. Psychol Addict Behav 2005, 18:208-211. 39. Strong DR, Brown RA, Sims M, Herman DS, Anderson BJ, Stein MD: Persistence during stress-challenge predicts lapse to opiate use during buprenorphine treatment. J Addict Med 2012, 6:19-25. 40. McNally RJ: Anxiety sensitivity and panic disorder. Biol Psychiatry 2002, 52:938-946. 41. McHugh RK, Otto RW: Refining the measurement of distress intolerance. Behav Ther 2012, 43:641-651. 42. Otto MW, Eastman A, Lo S, Hearon BA, Bickel WK, Zvolensky M, Smits JA, Doan SN: Anxiety sensitivity and working memory capacity: risk factors and targets for health behavior promotion. Clin Psychol Rev 2016, 49:67-78. 43. McHugh RK, Weiss RD, Cornelius M, Martel MO, Jamison RN, Edwards RR: Distress intolerance and prescription opioid misuse among patients with chronic pain. J Pain 2016, 17:806-814. This study examined whether distress intolerance was associated with opioid misuse among participants (n = 51) recruited from a pain management clinic. Participants completed self-report measures followed by a behavioral measure of distress intolerance and a psychophysical testing battery. Specifically, participants completed the Computerized Mirror Tracing Persistence Task as well as Quantitative Sensory Testing. This work demonstrated that distress intolerance was associated with a greater likelihood of opioid misuse. Distress intolerance was not associated with pain severity, threshold or tolerance; however, distress intolerance was associated with affective response to pain (e.g. increased anxiety). 44. Stathopoulou G, Pollack MH, Otto MW: Anxiety sensitivity moderates drug cravings in response to induced negative affect in opioid dependent outpatients. Addict Behav 2018, 84:75-78. Seventy-six participants who had been engaged in a methadone maintenance treatment program for at least four months were recruited to participate in a laboratory study to experimentally induce negative affect. The negative affect induction procedures consisted of viewing two three-minute clips previously validated to induce sadness. Following presentation of these film clips, participants completed measures of negative affect and craving. Findings revealed that anxiety sensitivity moderated drug craving in response to the negative affect induction procedures such that negative affect was only associated with drug craving among individuals characterized by high levels of anxiety sensitivity. 45. Baxley C, Weinstock J, Lustman PJ, Garner AA: The influence of anxiety sensitivity on opioid use disorder treatment outcomes. Exp Clin Psychopharmacol 2018. Epub ahead of print. 46. McHugh RK, Votaw VR, Barlow DH, Fitzmaurice GM, Greenfield SF, Weiss RD: Development of an integrated cognitive behavioral therapy for anxiety and opioid use disorder: study protocol and methods. Contemp Clin Trials 2017, 60:105-112. This manuscript provides an overview of the rationale and methods for the development of a behavioral treatment designed to simultaneously address co-occurring opioid use disorder and anxiety disorders. This treatment emphasizes the interaction of these two disorders and the need to target both concurrently by conceptualizing these conditions as a single disorder. www.sciencedirect.com
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47. Stein MD, Anderson BJ, Kenney SR, Bailey GL: Beliefs about the consequences of using benzodiazepines among persons with opioid use disorder. J Subst Abuse Treat 2017, 77:67-71. 48. McCracken LM, Zayfert C, Gross RT: The Pain Anxiety Symptoms Scale: development and validation of a scale to measure fear of pain. Pain 1992, 50:67-73. 49. Hadjistavropoulos HD, LaChapelle DL: Extent and nature of anxiety experienced during physical examination of chronic low back pain. Behav Res Ther 2000, 38:13-29. 50. Asmundson GJG, Norton PJ, Norton GR: Beyond pain. Clin Psychol Rev 1999, 19:97-119. 51. Slade PD, Troup JDG, Lethem J, Bentley G: The fear-avoidance model of exaggerated pain perception—II. Behav Res Ther 1983, 21:409-416. 52. Rogers AH, Bakhshaie J, Lam H, Langdon KJ, Ditre JW, Zvolensky MJ: Pain-related anxiety and opioid misuse in a racially/ethnically diverse young adult sample with moderate/ severe pain. Cogn Behav Ther 2018, 47:372-382. The present study examined the role of pain-related anxiety in opioid misuse among a racially/ethnically diverse young adult sample (n = 256) reporting moderate to severe bodily pain. Results indicated that painrelated anxiety significantly predicted self-reported opioid addiction, family concerns due to opioid use, history of opioid detoxification, and number of opioid-related problems. Importantly, pain-related anxiety predicted each of these opioid misuse outcomes over and above relevant covariates, including gender, pain intensity, drug use, and alcohol use. 53. Larowe LR, Chilcott LN, Zvolensky MJ, Vanable PA, Flood K, Ditre JW: Associations between pain-related anxiety, gender, and prescription opioid misuse among tobacco smokers living with HIV/AIDS. Subst Use Misuse 2018, 53:2210-2219. 54. Trafton JA, Gifford EV: Behavioral reactivity and addiction: the adaptation of behavioral response to reward opportunities. J Neuropsychiatry Clin Neurosci 2008, 20:23-35. 55. Tull MT, Schulzinger D, Schmidt NB, Zvolensky MJ, Lejuez CW: Development and initial examination of a brief intervention for heightened anxiety sensitivity among heroin users. Behav Modif 2007, 31:220-242. 56. Brown RA, Bloom EL, Hecht J, Moitra E, Herman DS, Stein MD: A pilot study of stress tolerance treatment for opiate dependent
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patients initiating buprenorphine: rationale, methodology, and outcomes. Behav Modif 2016, 38:730-759. This manuscript describes the development and preliminary outcomes from a pilot evaluation of a novel distress tolerance treatment for individuals initiating buprenorphine. This treatment incorporates exposurebased and acceptance-based treatment approaches as an adjunct to standard outpatient buprenorphine treatment. The goal of this treatment is to provide participants with an opportunity to learn new skills or strategies to tolerate uncomfortable withdrawal symptoms, cravings, and negative affect states that occur during early periods of abstinence. 57. Simons JS, Gaher RM: The Distress Tolerance Scale: development and validation of a self-report measure. Motiv Emot 2005, 29:83-102. 58. Bornovalova MA, Gratz KL, Daughters SB, Hunt ED, Lejuez CW: Initial RCT of a distress tolerance treatment for individuals with substance use disorders. Drug Alcohol Depend 2012, 122:70-76. 59. Soler AF, Montesinos F, Gutie´rrez-Martı´nez O, Scott W, Mccracken L, Luciano J: Current status of acceptance and commitment therapy for chronic pain: a narrative review. J Pain Res 2018, 11:2145-2159. 60. Williams AC, Eccleston C, Morley S: Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev 2012. CD007407. 61. Carpenter JK, Andrews LA, Witcraft SM, Powers MB, Smits JAJ, Hofmann SG: Cognitive behavioral therapy for anxiety and related disorders: a meta-analysis of randomized placebocontrolled trials. Depress Anxiety 2018, 35:502-514. 62. Twohig MP, Levin ME: Acceptance and commitment therapy as a treatment for anxiety and depression: a review. Psychiatr Clin North Am 2017, 40:751-770. 63. Lee EB, An W, Levin ME, Twohig MP: An initial meta-analysis of acceptance and commitment therapy for treating substance use disorders. Drug Alcohol Depend 2015, 155:1-7. 64. McHugh RK, Hearon BA, Otto MW: Cognitive behavioral therapy for substance use disorders. Psychiatr Clin North Am 2010, 33:511-525.
Current Opinion in Psychology 2019, 30:17–23
ScienceDirect Comorbidity of opioid-related and anxiety-related symptoms and disorders Kirsten J Langdon1,2, Kathrine Dove3 and Susan Ramsey2,4,5 Opioid use disorder and anxiety disorders co-occur at strikingly high rates, and this comorbidity is marked by a more severe clinical presentation and poorer prognosis for treatment. Given the substantial morbidity and mortality associated with these two disorders, it is imperative to understand factors related to the high rates of co-occurrence in order to inform the development of specialized treatments for this population. Several lines of study suggest that simultaneously addressing opioid-related and anxiety-related symptoms and processes, particularly intolerance of distress and pain-related anxiety, may yield improved outcomes for this high risk, vulnerable population. Future work is needed to identify other novel mechanisms as well as develop specialized treatments to augment standard medication-assisted treatment. Addresses 1 Department of Psychiatry, Rhode Island Hospital, United States 2 Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States 3 Stonehill College, United States 4 Division of General Internal Medicine, Rhode Island Hospital, United States 5 Department of Medicine, Alpert Medical School of Brown University, United States Corresponding author: Langdon, Kirsten J ([email protected])
Current Opinion in Psychology 2019, 30:17–23 This review comes from a themed issue on Addiction Edited by Samantha Farris and Angelo Dibello
https://doi.org/10.1016/j.copsyc.2018.12.020 2352-250X/ã 2018 Elsevier Ltd. All rights reserved.
Anxiety-related symptoms and disorders are the most common psychiatric illness in the United States [5]. Approximately 19% of U.S. adults met criteria for a current (past year) anxiety disorder [6], and 31% of U. S. adults have experienced a lifetime anxiety disorder [7]. Opioid use disorder and anxiety disorders co-occur at strikingly high rates. Indeed, over 60% of individuals meeting criteria for an opioid use disorder also report the experience of a lifetime anxiety-related disorder [8]. This co-occurrence is marked by earlier onset for opioid use [9], more rapid transition from use to opioid use disorder [9], premature discontinuation of substance use treatment [10], and greater potential for the misuse of other substances, for example, benzodiazepines [11,12]. Historically, anxiety-related symptoms and disorders have received little scholarly attention in regard to opioid use compared to other psychiatric conditions such as depression. This neglect is unfortunate as opioid use frequently co-occurs with anxiety and its disorders, and furthermore, anxiety vulnerability and clinical disorders may play a key role in the onset and maintenance of opioid use disorder. Given the substantial morbidity and mortality associated with these two disorders, it is imperative to understand the nature of, and potential factors related to, the high rates of co-occurrence to inform the development of specialized treatments for this population. The overarching aims of this review are to review the rates of co-occurrence between opioid-related and anxiety-related symptoms and disorders, summarize the research focused on identifying mechanisms underlying these associations, discuss how opioid-related and anxiety-related comorbidities impact treatment outcomes, and discuss clinical implications and future directions.
Rates of co-occurrence
Introduction The prevalence of opioid use disorders has reached epidemic rates in the United States, and opioid-involved overdoses are now the country’s leading cause of injury deaths [1]. The number of fatal overdoses has quadrupled since 1999, and opioids accounted for 42 000 deaths in 2016 [1]. More than 2.1 million people meet criteria for opioid use disorder [2]. Opioid misuse carries tremendous economic burden, with costs exceeding $56 billion annually [3,4]. www.sciencedirect.com
Numerous studies have explored the patterns of cooccurrence between opioid-related and anxiety-related symptoms and disorders, with results generally supporting a strong association between these two disorders (see Ref. [13] for a review). Meta-analyses suggest that the pooled prevalence of an anxiety diagnosis among patients reporting non-medical prescription opioid use was 29% (95% CI: 14%–44%) [13]. Longitudinal work has attempted to clarify the temporal order of these relations. For example, data collected from the National Epidemiological Study on Alcohol and Related Conditions was used to examine potential pathways among non-medical prescription opioid use (defined as using a Current Opinion in Psychology 2019, 30:17–23
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prescription opioid without a prescription, in greater amounts, more often, or longer than prescribed, or for a reason other than a doctor said you should use them), opioid use disorder, and anxiety disorders in a large national sample completing two waves of data collection (wave 1 = 2001–2002, wave 2 = 2004–2005 [14]). Overall, bidirectional associations were observed between these two conditions with wave 1 lifetime non-medical prescription opioid use predicting incidence of anxiety disorders at wave 2 (OR = 1.7; CI = 1.3–2.1), and wave 1 lifetime anxiety disorders predicting incidence of nonmedical prescription opioid use/opioid use disorder at wave 2 (OR = 1.4; CI = 1.1–1.8) [14]. This pattern of findings has been documented in other populations exposed to prescription opioids. Among patients with chronic pain currently receiving prescription opioid medication, patients screening positive for clinical levels of anxiety were significantly more likely to also screen positive for misuse of prescription opioids [15 ]. Indeed, among the patients endorsing anxiety, nearly 50% screen positive for opioid misuse, compared to 10% of the patients denying current anxiety [15]. Consistent with a larger literature highlighting sex and gender role differences across substance use disorders more broadly (see Ref. [16] for a review), women with opioid use disorder may be particularly prone to psychiatric comorbidities, particularly anxiety-related symptoms and disorders. Among treatment-seeking injection opioid users [17], individuals with concurrent opioid and cocaine use disorders [18], and patients engaging in medication-assisted treatment for opioid use disorder [19], women, compared to men, are more likely to have a diagnosis of an anxiety disorder. Taken together, existing work in this area suggests that there are high rates of co-occurrence between opioidrelated and anxiety-related symptoms and disorders. Further, there appears to be a bidirectional pathway between these two conditions such that the experience of anxiety may confer risk for subsequent opioid use/misuse, and opioid misuse may further promote or exacerbate the development of anxiety. However, this work has primarily relied on self-report data or retrospective chart reviews, which limits the ability to make causal inferences or define temporal ordering. Future work, including multi-modal assessments of anxiety and opioid use in the context of longitudinal and experimental designs, is needed to more accurately capture proximal associations over time.
Impact of comorbidity on treatment outcomes Medication-assisted treatment, which involves the use of pharmacotherapy (methadone, buprenorphine, and injectable naltrexone) in combination with psychosocial support, is an evidence-based approach to treat opioid use Current Opinion in Psychology 2019, 30:17–23
disorder and reduce overdose risk [20,21]. Medicationassisted treatment is effective in reducing illicit opioid use and preventing incidence of overdose [22,23]; however, across the different medication options, there are varying rates of retention [22,24], highlighting the need to better understand which subgroups of patients do versus do not benefit from medication-assisted treatment [25]. By and large, it appears that the presence of anxietyrelated symptoms and disorders negatively impact the course of medication-assisted treatment, including methadone [26], buprenorphine [27], and injectable naltrexone [28]. Individuals experiencing elevated anxiety symptoms at treatment initiation may be more likely to relapse [27] or discontinue treatment prematurely [26]. Further, patients experiencing persistent anxiety symptoms throughout the course of treatment are more likely to drop out early [28]. For example, in a randomized controlled trial of voucher-based contingency management and support from a significant other to enhance retention on oral naltrexone, somatic and affective symptoms were assessed weekly among patients who were retained on naltrexone through the 12-week trial compared to those who dropped out [28]. Although there were no statistically significant differences between the groups at baseline, participants who prematurely discontinued treatment endorsed elevated rates of difficulty sleeping, nervousness, restlessness, feeling blah, depression, and anxiety in the weeks before dropout [28]. Similar findings have been observed in other clinical trials comparing extended release naltrexone to buprenorphine [29]. Specifically, higher mean anxiety scores across the study period were associated with greater illicit opioid and other substance use during treatment [29]. Consistent with a negative reinforcement model of substance use [30], individuals with co-occurring opioid use disorder and anxiety disorder may be particularly motivated to resume substance use following treatment initiation to manage or alleviate aversive physical or emotional symptoms that emerge as a result of ongoing stressors or in response to drug cues. Such data suggest that to optimize treatment outcomes for this vulnerable, high-risk, subset of the population, it is imperative to concurrently treat these two overlapping disorders [31]. A related, and emerging body of work, suggests that engagement in medication-assisted treatment may have added benefit for anxiety-related symptoms; however, this literature is mixed. For example, two recently randomized, controlled trials examining the efficacy of medication-assisted treatment found that symptoms of anxiety tended to improve across the study period among individuals who remained active in treatment [29,32]. Yet, another randomized controlled trial documented an increase in anxiety symptoms throughout the treatment period, and increased anxiety at earlier time-points was associated with lack of attendance at subsequent www.sciencedirect.com
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assessments [33]. Future research is needed to further parse apart if, and how, medication-assisted treatment may influence the trajectory of anxiety-related symptoms of disorders among individuals seeking treatment for opioid use disorder.
Mechanisms underlying the association between opioid-related and anxiety-related disorders Despite growing recognition that opioid-related and anxiety-related symptoms and disorders co-occur at high rates, far less scholarly attention has been devoted to understanding potential mechanisms underlying the etiology and maintenance of this comorbidity. Such a neglect is unfortunate as developing a greater understanding of factors associated with the opioid-anxiety comorbidity is a critical step in refining current theoretical models and empirically supported treatments. Although there are likely a variety of biopsychosocial mechanisms underlying this co-occurrence (e.g. neurobiological factors [34,35]), the current review focuses specifically on psychological mechanisms given the potential for therapeutic intervention. Distress intolerance
Existing work in this area has predominately focused on understanding the role of intolerance of distress. Distress intolerance, defined as the perceived or actual ability to handle aversive physical or emotional states, is a transdiagnostic vulnerability factor implicated in the development and maintenance of affective symptoms/disorders and substance use [36]. Distress intolerance is significantly related to a range of drug use outcomes, including frequency and severity of use [37] and early lapse/relapse [38,39]. Within the broader conceptualization of distress intolerance is the related construct of anxiety sensitivity. Anxiety sensitivity reflects the tendency to fear anxiety and related physical sensations due to the belief that these somatic sensations have negative physical, mental, and/or social consequences [40]. It has more recently been characterized as an amplifying factor that may enhance the perceived aversiveness of a particular emotional or somatic state, thus increasing the need or desire to escape/avoid these negative experiences [41,42]. Thus, distress intolerance, including anxiety sensitivity, may be particularly relevant to the co-occurrence of opioidrelated and anxiety-related symptoms and disorders. Consistent with this theoretical model, a growing body of work suggests that distress intolerance is linked to a variety of substance use processes among individuals with opioid use disorder. For example, in an experimental paradigm involving Quantitative Sensory Testing and a Cold Presser Task, the association between distress intolerance and opioid misuse was assessed among patients with chronic pain [43]. Results revealed that distress intolerance was associated with opioid misuse but was not www.sciencedirect.com
associated with pain severity, threshold, or tolerance as assessed through the laboratory tasks [43]. However, distress intolerance was also associated with self-reported anxiety and stress in response to noxious stimuli [43]. Other work has found that anxiety sensitivity moderates the effects of drug craving in response to a negative affect experimental induction, such that affect induction was only related to craving among individuals with high levels of anxiety sensitivity [44]. Anxiety sensitivity has also been shown to be related to fear of opioid withdrawal and greater subjective withdrawal severity [45], premature discontinuation of treatment [10], and frequency of past-month nonmedical benzodiazepine use among patients receiving inpatient treatment for opioid use disorder [46]. Regarding the latter, the most commonly cited reason for benzodiazepine misuse among individuals with opioid use disorder is to ‘manage anxiety;’ yet, paradoxically, participants using benzodiazepines primarily for anxiety did not endorse lower overall levels of anxiety [47]. Pain-related anxiety
Pain-related anxiety is another area of growing interest that may have applicability to opioid use disorder. Painrelated anxiety reflects worry about the negative consequences of pain [48]. Specifically, increased levels of anxiety about the experience of pain are posited to be related to avoidance of activities that promote pain which, in turn, is associated with physical deconditioning, behavioral problems (e.g. weight gain, mood disturbance), and impaired social functioning [49]. This pattern of responding is theorized to be cyclical, such that pain-related anxiety is linked to more severe pain and pain-related problems (e.g. physical deconditioning), which further promote and solidify worry-related beliefs about the nature of pain [50]. Additionally, pain-related anxiety is associated with several maladaptive coping tactics, such as substance use [51]. Regarding opioid use, specifically, several investigations have examined whether pain-related anxiety may serve as a risk factor for the development of opioid misuse. One study examined the role of pain-related anxiety in relation to opioid misuse among a racially/ethnically diverse young adult sample reporting moderate to severe bodily pain [52]. Results indicated that pain-related anxiety significantly predicted self-reported opioid addiction, family concerns due to opioid use, history of opioid detoxification, and number of opioid-related problems. Importantly, pain-related anxiety predicted each of these opioid misuse outcomes over and above relevant covariates, including gender, pain intensity, drug use, and alcohol use [52]. A second study investigated associations between pain-related anxiety, gender, and prescription opioid misuse among a sample of tobacco smokers living with HIV/AIDS who endorsed high levels of pain intensity and pain-related anxiety [53]. Pain-related anxiety Current Opinion in Psychology 2019, 30:17–23
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was found to be positively associated with current opioid misuse among male, but not female, participants [53]. Further, pain-related anxiety was positively associated with self-reported intention to misuse opioids in the future among all participants who were prescribed opioids [53]. Collectively, this work suggests that pain-related anxiety may be an important therapeutic target to prevent and address opioid use disorder among individuals living with chronic pain. Although distress intolerance and pain-related anxiety hold promise for better understanding and addressing opioid-related and anxiety-related symptoms and disorders, it would be fruitful to identify additional mechanisms of action to build multi-risk factor models. Doing so would allow for a more comprehensive and personalized approach to treatment.
Clinical implications Better understanding the role of anxiety-related symptoms and disorders in terms of opioid use disorder etiology and maintenance has the potential to inform the development of promising cognitive-behavioral interventions that complement standard medication-assisted treatment. Here, we highlight several promising treatments.
pain [52,53]. Acceptance and Commitment Therapy and Cognitive-Behavioral Therapy have demonstrated efficacy in the treatment of chronic pain [59,60] anxiety disorders [61,62], and substance use disorders [63,64]. Thus, future work could meaningfully build upon these treatments to tailor intervention content to more adequately address opioid use in the context of chronic pain and related anxieties. Integrated cognitive-behavioral therapy (I-CBT) for cooccurring opioid use disorder and anxiety disorders is a novel intervention approach that utilizes treatment elements that target the interaction of shared symptoms and processes underlying both disorders to facilitate overall recovery [46]. Unlike other treatment modalities that focus on each disorder in isolation, this approach emphasizes the interaction of overlapping symptoms and conceptualizes these conditions as a single disorder [46]. Skills training addresses the overarching theme of negative reinforcement to reduce reliance on maladaptive avoidance-based behaviors (e.g. drug use) that provide relief from distress in the short term. By targeting underlying processes of both disorders, I-CBT has the potential to improve both anxiety and opioid use outcomes.
Future directions As described above, distress intolerance may have particular relevance to the opioid–anxiety co-occurrence. Distress tolerance involves the ability to withstand negative reinforcement opportunities by exerting control over behavioral responding to opportunities that would provide immediate relief from distress, such as stress or anxiety [54]. Converging lines of evidence suggest that opioid users may be hypersensitive to interoceptive cues that occur in the context of early abstinence [55]; therefore, relapse is likely given that illicit opioid use potentially serves as way to avoid or manage negative internal states in the short term [56]. There may be merit to directly targeting distress tolerance to increase the ability to tolerate negative physical and emotional states that occur during the early phases of medication-assisted treatment in order to decrease the use of avoidance-based strategies such as substance use. Distress tolerance is an important aspect of emotional self-regulation, given that distress tolerance skills help to mitigate the impact of negative mood states [57]. Preliminary work suggests that targeting distress tolerance during substance use treatment may improve outcomes by promoting the ability to persist in goal directed activity (e.g. abstinence) even when experiencing high levels of distress [56,58]. Pain-related anxiety, which reflects worry about the negative consequences of pain [48], is another factor relevant to opioid misuse/disorder and anxiety disorders. A growing body of work suggests that pain-related anxiety may be an important therapeutic target to prevent and address opioid use disorder among individuals living with chronic Current Opinion in Psychology 2019, 30:17–23
While the work outlined in this review is promising, there remain several avenues in need of further investigation. First, future studies would benefit from inclusion of multi-modal assessments of anxiety and opioid use, in the context of longitudinal and experimental designs, to better understand the nature of this comorbidity and the facets involved in the etiology and maintenance of these disorders. Second, it would be fruitful to identify additional mechanisms of action to build multi-risk factor models. Explicating these explanatory mechanisms is essential to translating basic research knowledge to advances in specialized behavioral and pharmacologic interventions for this population. Finally, although medication-assisted treatment has revolutionized the treatment of opioid use disorders, there remain significant limitations in terms of facilitating long-term abstinence and retention among certain subgroups. Therefore, it is critical that we continue to expand upon this treatment to develop novel strategies to augment standard medicationassisted treatment to more fully meet the needs of individuals with co-occurring opioid-related and anxietyrelated symptoms or disorders.
Conclusions Opioid use disorder and anxiety disorders co-occur at strikingly high rates, and this comorbidity is marked by a more severe clinical presentation and poorer prognosis for treatment. Given the substantial morbidity and mortality associated with these two disorders, it is imperative to understand factors related to the high rates of cooccurrence in order to inform the development of www.sciencedirect.com
Opioid and anxiety disorders Langdon, Dove and Ramsey 21
specialized treatments for this population. Several lines of study suggest that simultaneously addressing opioidrelated and anxiety-related symptoms and processes, particularly intolerance of distress and pain-related anxiety, may yield improved outcomes for this high risk, vulnerable, population. Future work is needed to identify other novel mechanisms as well as develop specialized treatments to augment standard medication-assisted treatment.
Funding source This work was made possible, in part, by the AdvanceCTR supported by the IDeA-CTR grant, National Institute of General Medical Sciences, Grant #U54GM115677 awarded to Kirsten Langdon, PhD. The funding source had no further role in the analyses or presentation of these data.
Conflicts of interest statement Nothing declared.
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34. Koob GF: Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology 2009, 56:18-31. 35. Wilson MA, Junor L: The role of amygdalar mu-opioid receptors in anxiety-related responses in two rat models. Neuropharmacology 2008, 33:2957-2968. 36. Leyro TM, Zvolensky MJ, Bernstein A: Distress tolerance and psychopathological symptoms and disorders: a review of the empirical literature among adults. Psychol Bull 2010, 136:576-600. 37. McHugh RK, Otto MW: Profiles of distress intolerance in a substance-dependent sample. Am J Drug Alcohol Abuse 2012, 38:161-165. 38. Daughters SB, Lejuez CW, Kahler CW, Strong DR, Brown RA: Psychological distress tolerance and duration of most recent abstinence attempt among residential treatment-seeking substance abusers. Psychol Addict Behav 2005, 18:208-211. 39. Strong DR, Brown RA, Sims M, Herman DS, Anderson BJ, Stein MD: Persistence during stress-challenge predicts lapse to opiate use during buprenorphine treatment. J Addict Med 2012, 6:19-25. 40. McNally RJ: Anxiety sensitivity and panic disorder. Biol Psychiatry 2002, 52:938-946. 41. McHugh RK, Otto RW: Refining the measurement of distress intolerance. Behav Ther 2012, 43:641-651. 42. Otto MW, Eastman A, Lo S, Hearon BA, Bickel WK, Zvolensky M, Smits JA, Doan SN: Anxiety sensitivity and working memory capacity: risk factors and targets for health behavior promotion. Clin Psychol Rev 2016, 49:67-78. 43. McHugh RK, Weiss RD, Cornelius M, Martel MO, Jamison RN, Edwards RR: Distress intolerance and prescription opioid misuse among patients with chronic pain. J Pain 2016, 17:806-814. This study examined whether distress intolerance was associated with opioid misuse among participants (n = 51) recruited from a pain management clinic. Participants completed self-report measures followed by a behavioral measure of distress intolerance and a psychophysical testing battery. Specifically, participants completed the Computerized Mirror Tracing Persistence Task as well as Quantitative Sensory Testing. This work demonstrated that distress intolerance was associated with a greater likelihood of opioid misuse. Distress intolerance was not associated with pain severity, threshold or tolerance; however, distress intolerance was associated with affective response to pain (e.g. increased anxiety). 44. Stathopoulou G, Pollack MH, Otto MW: Anxiety sensitivity moderates drug cravings in response to induced negative affect in opioid dependent outpatients. Addict Behav 2018, 84:75-78. Seventy-six participants who had been engaged in a methadone maintenance treatment program for at least four months were recruited to participate in a laboratory study to experimentally induce negative affect. The negative affect induction procedures consisted of viewing two three-minute clips previously validated to induce sadness. Following presentation of these film clips, participants completed measures of negative affect and craving. Findings revealed that anxiety sensitivity moderated drug craving in response to the negative affect induction procedures such that negative affect was only associated with drug craving among individuals characterized by high levels of anxiety sensitivity. 45. Baxley C, Weinstock J, Lustman PJ, Garner AA: The influence of anxiety sensitivity on opioid use disorder treatment outcomes. Exp Clin Psychopharmacol 2018. Epub ahead of print. 46. McHugh RK, Votaw VR, Barlow DH, Fitzmaurice GM, Greenfield SF, Weiss RD: Development of an integrated cognitive behavioral therapy for anxiety and opioid use disorder: study protocol and methods. Contemp Clin Trials 2017, 60:105-112. This manuscript provides an overview of the rationale and methods for the development of a behavioral treatment designed to simultaneously address co-occurring opioid use disorder and anxiety disorders. This treatment emphasizes the interaction of these two disorders and the need to target both concurrently by conceptualizing these conditions as a single disorder. www.sciencedirect.com
Opioid and anxiety disorders Langdon, Dove and Ramsey 23
47. Stein MD, Anderson BJ, Kenney SR, Bailey GL: Beliefs about the consequences of using benzodiazepines among persons with opioid use disorder. J Subst Abuse Treat 2017, 77:67-71. 48. McCracken LM, Zayfert C, Gross RT: The Pain Anxiety Symptoms Scale: development and validation of a scale to measure fear of pain. Pain 1992, 50:67-73. 49. Hadjistavropoulos HD, LaChapelle DL: Extent and nature of anxiety experienced during physical examination of chronic low back pain. Behav Res Ther 2000, 38:13-29. 50. Asmundson GJG, Norton PJ, Norton GR: Beyond pain. Clin Psychol Rev 1999, 19:97-119. 51. Slade PD, Troup JDG, Lethem J, Bentley G: The fear-avoidance model of exaggerated pain perception—II. Behav Res Ther 1983, 21:409-416. 52. Rogers AH, Bakhshaie J, Lam H, Langdon KJ, Ditre JW, Zvolensky MJ: Pain-related anxiety and opioid misuse in a racially/ethnically diverse young adult sample with moderate/ severe pain. Cogn Behav Ther 2018, 47:372-382. The present study examined the role of pain-related anxiety in opioid misuse among a racially/ethnically diverse young adult sample (n = 256) reporting moderate to severe bodily pain. Results indicated that painrelated anxiety significantly predicted self-reported opioid addiction, family concerns due to opioid use, history of opioid detoxification, and number of opioid-related problems. Importantly, pain-related anxiety predicted each of these opioid misuse outcomes over and above relevant covariates, including gender, pain intensity, drug use, and alcohol use. 53. Larowe LR, Chilcott LN, Zvolensky MJ, Vanable PA, Flood K, Ditre JW: Associations between pain-related anxiety, gender, and prescription opioid misuse among tobacco smokers living with HIV/AIDS. Subst Use Misuse 2018, 53:2210-2219. 54. Trafton JA, Gifford EV: Behavioral reactivity and addiction: the adaptation of behavioral response to reward opportunities. J Neuropsychiatry Clin Neurosci 2008, 20:23-35. 55. Tull MT, Schulzinger D, Schmidt NB, Zvolensky MJ, Lejuez CW: Development and initial examination of a brief intervention for heightened anxiety sensitivity among heroin users. Behav Modif 2007, 31:220-242. 56. Brown RA, Bloom EL, Hecht J, Moitra E, Herman DS, Stein MD: A pilot study of stress tolerance treatment for opiate dependent
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patients initiating buprenorphine: rationale, methodology, and outcomes. Behav Modif 2016, 38:730-759. This manuscript describes the development and preliminary outcomes from a pilot evaluation of a novel distress tolerance treatment for individuals initiating buprenorphine. This treatment incorporates exposurebased and acceptance-based treatment approaches as an adjunct to standard outpatient buprenorphine treatment. The goal of this treatment is to provide participants with an opportunity to learn new skills or strategies to tolerate uncomfortable withdrawal symptoms, cravings, and negative affect states that occur during early periods of abstinence. 57. Simons JS, Gaher RM: The Distress Tolerance Scale: development and validation of a self-report measure. Motiv Emot 2005, 29:83-102. 58. Bornovalova MA, Gratz KL, Daughters SB, Hunt ED, Lejuez CW: Initial RCT of a distress tolerance treatment for individuals with substance use disorders. Drug Alcohol Depend 2012, 122:70-76. 59. Soler AF, Montesinos F, Gutie´rrez-Martı´nez O, Scott W, Mccracken L, Luciano J: Current status of acceptance and commitment therapy for chronic pain: a narrative review. J Pain Res 2018, 11:2145-2159. 60. Williams AC, Eccleston C, Morley S: Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev 2012. CD007407. 61. Carpenter JK, Andrews LA, Witcraft SM, Powers MB, Smits JAJ, Hofmann SG: Cognitive behavioral therapy for anxiety and related disorders: a meta-analysis of randomized placebocontrolled trials. Depress Anxiety 2018, 35:502-514. 62. Twohig MP, Levin ME: Acceptance and commitment therapy as a treatment for anxiety and depression: a review. Psychiatr Clin North Am 2017, 40:751-770. 63. Lee EB, An W, Levin ME, Twohig MP: An initial meta-analysis of acceptance and commitment therapy for treating substance use disorders. Drug Alcohol Depend 2015, 155:1-7. 64. McHugh RK, Hearon BA, Otto MW: Cognitive behavioral therapy for substance use disorders. Psychiatr Clin North Am 2010, 33:511-525.
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