A Narrative Literature Review of the Epidemiology, Etiology, and Treatment of Co-occurring Panic Disorder and Opioid Use Disorder

Abstract

Objective:

Panic disorder is a debilitating psychiatric disorder that often co-occurs with substance use disorders. Given the current opioid epidemic, the high reported rates of comorbid panic disorder and opioid use disorder are particularly concerning. In this narrative review, we describe the literature on panic disorder and opioid use disorder co-occurrence.

Methods:

86 studies, 26 reviews, 2 commentaries, and 5 guidelines pertaining to opioid use disorder, panic disorder, and their comorbidity were identified using all EBSCO databases, PubMed, and Google Scholar.

Results:

First, we review epidemiological literature on the prevalence of the comorbid condition above and beyond each disorder on its own. Additionally, we discuss the challenges that complicate the differential diagnosis of panic disorder and opioid use disorder and contribute to difficulties establishing rates of comorbidity. Second, we review three theoretical models that have been proposed to explain high rates of co-occurring panic disorder and opioid use disorder: the precipitation hypothesis, the self-medication hypothesis, and the shared vulnerability hypothesis. Third, we outline how co-occurring panic and opioid use disorder may impact treatment for each condition.

Conclusion:

Based on findings in the field, we provide recommendations for future research as well as treatment considerations for co-occurring panic and opioid use disorders.

Introduction

Panic disorder is a debilitating psychiatric disorder characterized by unexpected panic attacks that have rapid onset and are short in duration (American Psychiatric Association, 2013). To meet criteria for panic disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), individuals are required to have 4 of 13 symptoms, which can include fast heartbeat, shaking, shortness of breath, chest pain, nausea, and fears of dying. After experiencing a panic attack, an individual may worry about its re-occurrence or avoid situations they feel may result in another panic attack (American Psychiatric Association, 2013). Findings from national epidemiological studies indicate 2.1% of American adults endorse past 12-month panic disorder and 5.1% endorse lifetime panic disorder (Hasin & Grant, 2015). Although these rates of panic disorder may appear modest, they translate into a significant economic and societal burden. Panic and other anxiety disorders cost the United States as much as $46.6 billion per year (Devane et al., 2005; Greenberg et al., 1999) with panic disorder ranking as one of the costliest psychiatric conditions (Batelaan et al., 2007). Panic disorder also confers significant costs in terms of annual emergency room visits, as those with panic attacks commonly seek general medical care as opposed to psychiatric care due to the disorder being undiagnosed and symptoms mistaken for heart-related issues (Lynch & Galbraith, 2003).

Panic disorder also can co-occur with substance use disorder (SUD). Recent National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) data show that lifetime SUD is associated with a 30% increase in the odds of developing panic disorder (Grant et al., 2016). The consequences of these co-occurring disorders are significant, and SUD and anxiety may reciprocally affect one another, such that drug use negatively impacts treatment for anxiety disorders, and anxiety disorders in turn may exacerbate drug use (Bizzarri et al., 2007; Gajecki et al., 2014; for review, see McHugh et al., 2021). Studies that have looked specifically at panic disorder have found that the disorder confers greater risk for developing SUD than other anxiety disorders (Bolton et al., 2006), and that panic disorder for many develops prior to the onset of SUD (Marmorstein, 2012). Of central importance, persons with panic disorder are at increased risk to use opioids (Sullivan et al., 2005; Sullivan et al., 2006; Sareen et al., 2006), suggesting that some individuals may be uniquely positioned to progress from panic disorder to opioid use disorder (OUD).

The overlapping rates of panic disorder and OUD are particularly concerning. The United States is in the midst of an opioid epidemic in which rates of opioid use are steadily rising while increasingly burdening the health care and criminal justice systems (Florence et al., 2016; Lipari & Park-Lee, 2019). Given the high rates of comorbidity between panic disorder and OUD (Maremmani et al., 2010), it is important to understand the mechanisms driving this relationship in order to improve prevention efforts and tailor treatments for individuals with these clinical presentations. In this paper, we review the literature on panic disorder/OUD co-occurrence, including epidemiology, shared behavioral and biological mechanisms, and implications for their combined treatment.

Methods

Studies were first identified between September 2019 and January 2020 using all EBSCO databases, PubMed, and Google Scholar. Reference lists for the database-acquired publications were then examined, and a repeated search was conducted to find additional studies between September 2020 and February 2021. Studies were considered if they were published in peer-reviewed journals by February 2021 and were written in English. Literature reviews, commentaries, and published guidelines were also considered. Search terms included combinations of “opioid use disorder,” “opioid addiction,” “opioid dependence,” with “anxiety disorder,” “panic disorder,” and/or “comorbidity.” Results were sorted by relevance and were reviewed using titles, abstracts, and indexing fields until results became generally repetitive or no longer relevant. Studies providing information relevant to the relationship between panic disorder and OUD on a broader scale were also included. Studies with data describing “repeated panic attacks” or “panic symptoms” were included. Additionally, relevant studies detailing “anxiety disorders” and “substance use disorders” were also included in the review. Table 1 provides a list of all publications cited in the manuscript, the section they are found in, and the type of publication (review, study, guideline, or commentary). There were 86 studies, 26 reviews, 2 commentaries, and 5 guidelines cited in this review.

Table 1.

Author & Date	Title	Type	Section
Abadie, D., Essilini, A., Fulda, V., Gouraud, A., Yéléhé-Okouma, M., Micallef, J., Montastruc, F., & Montastruc, J. L. (2017).	Drug-induced panic attacks: Analysis of cases registered in the French pharmacovigilance database	Study	Behavioral Mechanisms
Akiyama, Y., Nishimura, M., Kobayashi, S., Yoshioka, A., Yamamoto, M., Miyamoto, K., & Kawakami, Y. (1993).	Effects of naloxone on the sensation of dyspnea during acute respiratory stress in normal adults	Study	Treatment Implications
Alanis-Hirsch, K., Croff, R., Ford, J. H., Johnson, K., Chalk, M., Schmidt, L., & McCarty, D. (2016).	Extended-Release Naltrexone: A Qualitative Analysis of Barriers to Routine Use	Study	Treatment Implications
Amato, L., Minozzi, S., Davoli, M., & Vecchi, S. (2011).	Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence	Study	Treatment Implications
American Psychiatric Association. (2009).	Practice guideline for the treatment of patients with panic disorder	Guideline	Treatment Implications
American Psychiatric Association. (2013).	Diagnostic and statistical manual of mental disorders (DSM-5®)	Guideline	Introduction; Epidemiology
Andraka-Christou, B., & Capone, M. J. (2018).	A qualitative study comparing physician-reported barriers to treating addiction using buprenorphine and extended-release naltrexone in U.S. office-based practices	Study	Treatment Implications
Ashton, H. (1994).	Guidelines for the Rational Use of Benzodiazepines	Guideline	Treatment Implications
Back, S. E., Dansky, B. S., Carroll, K. M., Foa, E. B., & Brady, K. T. (2001).	Exposure therapy in the treatment of PTSD among cocaine-dependent individuals: Description of procedures	Study	Treatment Implications
Back, S. E., Killeen, T., Badour, C. L., Flanagan, J. C., Allan, N. P., Ana, E. S., Lozano, B., Korte, K. J., Foa, E. B., & Brady, K. T. (2019).	Concurrent Treatment of Substance Use Disorders and PTSD using Prolonged Exposure: A Randomized Clinical Trial in Military Veterans	Study	Treatment Implications
Back, S. E., Killeen, T. K., Teer, A. P., Hartwell, E. E., Federline, A., Beylotte, F., & Cox, E. (2014).	Substance use disorders and PTSD: An exploratory study of treatment preferences among military veterans	Study	Treatment Implications
Bakken, K., Landheim, A. S., & Vaglum, P. (2007).	Axis I and II disorders as long-term predictors of mental distress: A six-year prospective follow-up of substance-dependent patients	Study	Epidemiology
Baldwin, D. S., Anderson, I. M., Nutt, D. J., Allgulander, C., Bandelow, B., den Boer, J. A., Christmas, D. M., Davies, S., Fineberg, N., Lidbetter, N., Malizia, A., McCrone, P., Nabarro, D., O’Neill, C., Scott, J., van der Wee, N., & Wittchen, H.-U. (2014).	Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British Association for Psychopharmacology	Guideline	Treatment Implications
Barry, D. T., Fazzino, T., Necrason, E., Ginn, J., Fiellin, L. E., Fiellin, D. A., & Moore, B. A. (2016).	The availability of ancillary counseling in the practices of physicians prescribing buprenorphine	Study	Treatment Implications
Batelaan, N., Smit, F., Graaf, R. de, Balkom, A. van, Vollebergh, W., & Beekman, A. (2007).	Economic costs of full-blown and subthreshold panic disorder	Study	Introduction
Battaglia, M., Pesenti-Gritti, P., Medland, S. E., Ogliari, A., Tambs, K., & Spatola, C. A. M. (2009).	A Genetically Informed Study of the Association Between Childhood Separation Anxiety, Sensitivity to CO2, Panic Disorder, and the Effect of Childhood Parental Loss	Study	Behavioral Mechanisms
Becker, W. C., Sullivan, L. E., Tetrault, J. M., Desai, R. A., & Fiellin, D. A. (2008).	Non-medical use, abuse and dependence on prescription opioids among U.S. adults: Psychiatric, medical and substance use correlates	Study	Epidemiology; Behavioral Mechanisms
Bizzarri, J. V., Rucci, P., Sbrana, A., Gonnelli, C., Massei, G. J., Ravani, L., Girelli, M., Dell’osso, L., & Cassano, G. B. (2007).	Reasons for substance use and vulnerability factors in patients with substance use disorder and anxiety or mood disorders	Study	Introduction; Epidemiology; Behavioral Mechanisms
Boettcher, H., & Barlow, D. H. (2019).	The unique and conditional effects of interoceptive exposure in the treatment of anxiety: A functional analysis	Study	Treatment Implications
Bolton, J., Cox, B., Clara, I., & Sareen, J. (2006).	Use of Alcohol and Drugs to Self-Medicate Anxiety Disorders in a Nationally Representative Sample	Study	Introduction; Epidemiology
Brady, K. T., Dansky, B. S., Back, S. E., Foa, E. B., & Carroll, K. M. (2001).	Exposure therapy in the treatment of PTSD among cocaine-dependent individuals: Preliminary findings	Study	Epidemiology; Treatment Implications
Brady, K. T., Haynes, L. F., Hartwell, K. J., & Killeen, T. K. (2013).	Substance Use Disorders and Anxiety: A Treatment Challenge for Social Workers	Review	Introduction
Center for Substance Abuse Treatment. (2004).	Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction	Guideline	Treatment Implications
Cohen, M. R., Cohen, R. M., Pickar, D., Weingartner, H., & Murphy, D. L. (1983).	High-Dose Naloxone Infusions in Normals: Dose-Dependent Behavioral, Hormonal, and Physiological Responses	Study	Treatment Implications
Connery, H. S. (2015).	Medication-Assisted Treatment of Opioid Use Disorder: Review of the Evidence and Future Directions	Review	Treatment Implications
Conway, K. P., Compton, W., Stinson, F. S., & Grant, B. F. (2006).	Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions	Study	Introduction; Epidemiology
Darke, S., & Ross, J. (1997).	Polydrug dependence and psychiatric comorbidity among heroin injectors	Study	Epidemiology
Deacon, B., Kemp, J. J., Dixon, L. J., Sy, J. T., Farrell, N. R., & Zhang, A. R. (2013).	Maximizing the efficacy of interoceptive exposure by optimizing inhibitory learning: A randomized controlled trial	Study	Treatment Implications
Deakin, J. F. W., & Graeff, F. G. (1991).	5-HT and mechanisms of defence	Review	Biological Mechanisms
Devane, C. L., Chiao, E., Franklin, M., & Kruep, E. J. (2005).	Anxiety disorders in the 21st century: Status, challenges, opportunities, and comorbidity with depression	Review	Introduction
Drake, R. E. (2007).	Dual diagnosis	Commentary	Future Directions
Dugosh, K., Abraham, A., Seymour, B., McLoyd, K., Chalk, M., & Festinger, D. (2016).	A Systematic Review on the Use of Psychosocial Interventions in Conjunction With Medications for the Treatment of Opioid Addiction	Review	Treatment Implications
Eidson, L. N., Inoue, K., Young, L. J., Tansey, M. G., & Murphy, A. Z. (2017).	Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling	Study	Biological Mechanisms
Esquivel, G., Fernández-Torre, O., Schruers, K., Wijnhoven, L., & Griez, E. (2009).	The effects of opioid receptor blockade on experimental panic provocation with CO 2	Study	Treatment Implications
Flanagan, J. C., Korte, K. J., Killeen, T. K., & Back, S. E. (2016).	Concurrent Treatment of Substance Use and PTSD	Review	Future Directions
Florence, C., Luo, F., Xu, L., & Zhou, C. (2016).	The Economic Burden of Prescription Opioid Overdose, Abuse and Dependence in the United States, 2013	Review	Introduction
Gajecki, M., Berman, A. H., Sinadinovic, K., Andersson, C., Ljótsson, B., Hedman, E., Rück, C., & Lindefors, N. (2014).	Effects of Baseline Problematic Alcohol and Drug Use on Internet-Based Cognitive Behavioral Therapy Outcomes for Depression, Panic Disorder and Social Anxiety Disorder	Study	Introduction
Bart G. (2012).	Maintenance Medication for Opiate Addiction: The Foundation of Recovery	Review	Treatment Implications
George, D. T., Ameli, R., & Koob, G. F. (2019).	Periaqueductal Gray Sheds Light on Dark Areas of Psychopathology	Review	Biological Mechanisms
Goodwin, R. D., Stayner, D. A., Chinman, M. J., Wu, P., Tebes, J. K., & Davidson, L. (2002).	The relationship between anxiety and substance use disorders among individuals with severe affective disorders	Study	Epidemiology; Behavioral Mechanisms
Graeff, F. G. (2017).	Translational approach to the pathophysiology of panic disorder: Focus on serotonin and endogenous opioids	Study	Biological Mechanisms
Grant, B. F., Saha, T. D., Ruan, W. J., Goldstein, R. B., Chou, S. P., Jung, J., Zhang, H., Smith, S. M., Pickering, R. P., Huang, B., & Hasin, D. S. (2016).	Epidemiology of DSM-5 Drug Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III	Study	Introduction
Greenberg, P. E., Sisitsky, T., Kessler, R. C., Finkelstein, S. N., Berndt, E. R., Davidson, J. R. T., & Fyer, A. J. (1999).	The Economic Burden of Anxiety Disorders in the 1990s	Review	Introduction
Hasin, D. S., & Grant, B. F. (2015).	The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Waves 1 and 2: Review and summary of findings	Review	Introduction
Hassan, A. N., & Nunes, E. (2018).	Medication Treatments for Opioid Use Disorder: What Is the Impact on Mood and Mood Disorders?	Review	Treatment Implications
Hettema, J. M., Prescott, C. A., Myers, J. M., Neale, M. C., & Kendler, K. S. (2005).	The Structure of Genetic and Environmental Risk Factors for Anxiety Disorders in Men and Women	Study	Behavioral Mechanisms
Hien, D. A., Cohen, L. R., Miele, G. M., Litt, L. C., & Capstick, C. (2004).	Promising Treatments for Women With Comorbid PTSD and Substance Use Disorders	Study	Treatment Implications
Hien, D. A., Wells, E. A., Jiang, H., Suarez-Morales, L., Campbell, A. N. C., Cohen, L. R., Miele, G. M., Killeen, T., Brigham, G. S., Zhang, Y., Hansen, C., Hodgkins, C., Hatch-Maillette, M., Brown, C., Kulaga, A., Kristman-Valente, A., Chu, M., Sage, R., Robinson, J. A., … Nunes, E. V. (2009).	Multisite randomized trial of behavioral interventions for women with co-occurring PTSD and substance use disorders	Study	Treatment Implications
Iida, T., Yi, H., Liu, S., Ikegami, D., Zheng, W., Liu, Q., Takahashi, K., Kashiwagi, Y., Goins, W. F., Glorioso, J. C., & Hao, S. (2017).	MnSOD mediated by HSV vectors in the periaqueductal gray suppresses morphine withdrawal in rats	Study	Biological Mechanisms
Jann, M., Kennedy, W. K., & Lopez, G. (2014).	Benzodiazepines: A Major Component in Unintentional Prescription Drug Overdoses With Opioid Analgesics	Review	Treatment Implications
Jonge, P. de, Roest, A. M., Lim, C. C. W., Florescu, S. E., Bromet, E. J., Stein, D. J., Harris, M., Nakov, V., Caldas-de-Almeida, J. M., Levinson, D., Al-Hamzawi, A. O., Haro, J. M., Viana, M. C., Borges, G., O’Neill, S., Girolamo, G. de, Demyttenaere, K., Gureje, O., Iwata, N., … Scott, K. M. (2016).	Cross-national epidemiology of panic disorder and panic attacks in the world mental health surveys	Study	Epidemiology
Kendler, K. S., Neale, M. C., Kessler, R. C., Heath, A. C., & Eaves, L. J. (1992).	Childhood Parental Loss and Adult Psychopathology in Women: A Twin Study Perspective	Study	Behavioral Mechanisms
Kendler, K. S., Prescott, C. A., Myers, J., & Neale, M. C. (2003).	The Structure of Genetic and Environmental Risk Factors for Common Psychiatric and Substance Use Disorders in Men and Women	Study	Behavioral Mechanisms
Klein, E., Colin, V., Stolk, J., & Lenox, R. H. (1994).	Alprazolam withdrawal in patients with panic disorder and generalized anxiety disorder: Vulnerability and effect of carbamazepine	Study	Treatment Implications
Kok, T., de Haan, H. A., van der Meer, M., Najavits, L. M., & DeJong, C. A. (2013).	Efficacy of “seeking safety” in a Dutch population of traumatized substance-use disorder outpatients: Study protocol of a randomized controlled trial	Study	Treatment Implications
Krueger, R. F., McGue, M., & Iacono, W. G. (2001).	The higher-order structure of common DSM mental disorders: Internalization, externalization, and their connections to personality	Study	Behavioral Mechanisms
Kuch, K., Cox, B. J., Woszczyna, C. B., Swinson, R. P., & Shulman, I. (1991).	Chronic pain in panic disorder	Study	Behavioral Mechanisms
Lancaster, C. L., Gros, D. F., Mullarkey, M. C., Badour, C. L., Killeen, T. K., Brady, K. T., & Back, S. E. (2020).	Does trauma-focused exposure therapy exacerbate symptoms among patients with comorbid PTSD and substance use disorders?	Study	Treatment Implications
Latif, Z.-H., Šaltytė Benth, J., Solli, K. K., Opheim, A., Kunoe, N., Krajci, P., Sharma-Haase, K., & Tanum, L. (2019).	Anxiety, Depression, and Insomnia Among Adults With Opioid Dependence Treated With Extended-Release Naltrexone vs Buprenorphine-Naloxone: A Randomized Clinical Trial and Follow-up Study	Study	Treatment Implications
Lee, J. D., Nunes, E. V., Novo, P., Bachrach, K., Bailey, G. L., Bhatt, S., Farkas, S., Fishman, M., Gauthier, P., Hodgkins, C. C., King, J., Lindblad, R., Liu, D., Matthews, A. G., May, J., Peavy, K. M., Ross, S., Salazar, D., Schkolnik, P., … Rotrosen, J. (2018).	Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): A multicentre, open-label, randomised controlled trial	Study	Treatment Implications
Lejuez, C. W., Paulson, A., Daughters, S. B., Bornovalova, M. A., & Zvolensky, M. J. (2006).	The association between heroin use and anxiety sensitivity among inner-city individuals in residential drug use treatment	Study	Behavioral Mechanisms
Levis, S. C., Bentzley, B. S., Molet, J., Bolton, J. L., Perrone, C. R., Baram, T. Z., & Mahler, S. V. (2019).	On the early life origins of vulnerability to opioid addiction	Study	Behavioral Mechanisms
Lewinsohn, P. M., Holm-denoma, J. M., Small, J. W., Seeley, J. R., & Joiner, T. E. (2008).	Separation Anxiety Disorder in Childhood as a Risk Factor for Future Mental Illness	Study	Behavioral Mechanisms
Lipari, R. N., & Park-Lee, E. (2019).	Key substance use and mental health indicators in the United States: Results from the 2018 National Survey on Drug Use and Health	Study	Introduction
Lovallo, W. R., Acheson, A., Vincent, A. S., Sorocco, K. H., & Cohoon, A. J. (2018).	Early life adversity diminishes the cortisol response to opioid blockade in women: Studies from the Family Health Patterns project	Study	Behavioral Mechanisms
Lynch, P., & Galbraith, K. M. (2003).	Panic in the emergency room	Review	Introduction
Ma, J., Bao, Y.-P., Wang, R.-J., Su, M.-F., Liu, M.-X., Li, J.-Q., Degenhardt, L., Farrell, M., Blow, F. C., Ilgen, M., Shi, J., & Lu, L. (2019).	Effects of medication-assisted treatment on mortality among opioids users: A systematic review and meta-analysis	Review	Treatment Implications
Mangrum, L. F., Spence, R. T., & Lopez, M. (2006).	Integrated versus parallel treatment of co-occurring psychiatric and substance use disorders	Study	Future Directions
Maraschin, J. C., Rangel, M. P., Bonfim, A. J., Kitayama, M., Graeff, F. G., Zangrossi, H., & Audi, E. A. (2016).	Opiorphin causes a panicolytic-like effect in rat panic models mediated by μ-opioid receptors in the dorsal periaqueductal gray	Study	Biological Mechanisms
Maraschin, J. C., Sestile, C. C., Yabiku, C. T., Roncon, C. M., de Souza Fiaes, G. C., Graeff, F. G., Audi, E. A., & Zangrossi, H. (2020).	Effects of the adjunctive treatment of antidepressants with opiorphin on a panic-like defensive response in rats	Study	Biological Mechanisms
Maremmani, I., Pani, P. P., Pacini, M., Bizzarri, J. V., Trogu, E., Maremmani, A. G., Gerra, G., Perugi, G., & Dell’Osso, L. (2010).	Subtyping patients with heroin addiction at treatment entry: Factor derived from the Self-Report Symptom Inventory (SCL-90)	Study	Introduction; Epidemiology; Behavioral Mechanisms
Marmorstein, N. R. (2012).	Anxiety disorders and substance use disorders: Different associations by anxiety disorder	Study	Introduction
Martins, S. S., Fenton, M. C., Keyes, K. M., Blanco, C., Zhu, H., & Storr, C. L. (2012).	Mood/Anxiety disorders and their association with non-medical prescription opioid use and prescription opioid use disorder: Longitudinal evidence from the National Epidemiologic Study on Alcohol and Related Conditions	Study	Epidemiology; Behavioral Mechanisms
Martins, S. S., Keyes, K. M., Storr, C. L., Zhu, H., & Chilcoat, H. D. (2009).	Pathways between nonmedical opioid use/dependence and psychiatric disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions	Study	Epidemiology; Behavioral Mechanisms
McCrady, B., Witkiewitz, K., Venner, K., & Fokas, K. (2020).	Education and Training in Substance Use Disorders and Addictions: The University of New Mexico Integrated Training Model	Review	Future Directions
McHugh, R. K. (2015).	Treatment of Co-occurring Anxiety Disorders and Substance Use Disorders	Review	Epidemiology
McHugh, R. K., Votaw, V. R., Barlow, D. H., Fitzmaurice, G. M., Greenfield, S. F., & Weiss, R. D. (2017).	Development of an integrated cognitive behavioral therapy for anxiety and opioid use disorder: Study protocol and methods	Study	Epidemiology
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Najavits, L. M., Weiss, R. D., Shaw, S. R., & Muenz, L. R. (1998).	“Seeking safety”: Outcome of a new cognitive-behavioral psychotherapy for women with posttraumatic stress disorder and substance dependence	Study	Treatment Implications
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Otto, M. W., McHugh, R. K., & Kantak, K. M. (2010).	Combined pharmacotherapy and cognitive-behavioral therapy for anxiety disorders: Medication effects, glucocorticoids, and attenuated treatment outcomes.	Review	Treatment Implications
Pani, P. P., Maremmani, A. G., Trogu, E., Vigna-Taglianti, F., Mathis, F., Diecidue, R., Kirchmayer, U., Amato, L., Davoli, M., & Ghibaudi, J. (2016).	Psychic structure of opioid addiction: Impact of lifetime psychiatric problems on SCL-90-based psychopathologic dimensions in heroin-dependent patients	Study	Epidemiology; Behavioral Mechanisms
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Paul, E. D., Johnson, P. L., Shekhar, A., & Lowry, C. A. (2014).	The Deakin/Graeff hypothesis: Focus on serotonergic inhibition of panic	Review	Biological Mechanisms
Pedersen, S., & Sayette, M. (2020).	Education and Training in Substance Use Disorders: A Roadmap to Move Forward	Commentary	Future Directions
Persson, A., Back, S. E., Killeen, T. K., Brady, K. T., Schwandt, M. L., Heilig, M., & Magnusson, Å. (2017).	Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE): A Pilot Study in Alcohol-dependent Women	Study	Treatment Implications
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Popik, P., Kamysz, E., Kreczko, J., & Wróbel, M. (2010).	Human opiorphin: The lack of physiological dependence, tolerance to antinociceptive effects and abuse liability in laboratory mice	Study	Biological Mechanisms
Preter, M., Lee, S. H., Petkova, E., Vannucci, M., Kim, S., & Klein, D. F. (2011).	Controlled cross-over study in normal subjects of naloxone-preceding-lactate infusions; respiratory and subjective responses: Relationship to endogenous opioid system, suffocation false alarm theory and childhood parental loss	Study	Behavioral Mechanisms; Treatment Implications
Preter, Maurice, & Klein, D. F. (2014).	Lifelong opioidergic vulnerability through early life separation: A recent extension of the false suffocation alarm theory of panic disorder	Study	Behavioral Mechanisms; Biological Mechanisms
Priester, M. A., Browne, T., Iachini, A., Clone, S., DeHart, D., & Seay, K. D. (2016).	Treatment Access Barriers and Disparities Among Individuals with Co-Occurring Mental Health and Substance Use Disorders: An Integrative Literature Review	Review	Future Directions
Reiman, E. M., Raichle, M. E., Robins, E., Mintun, M. A., Fusselman, M. J., Fox, P. T., Price, J. L., & Hackman, K. A. (1989).	Neuroanatomical Correlates of a Lactate-Induced Anxiety Attack	Study	Biological Mechanisms
Rickels, K., Schweizer, E., Weiss, S., & Zavodnick, S. (1993).	Maintenance drug treatment for panic disorder: II. Short-and long-term outcome after drug taper	Study	Treatment Implications
Robinson, J. A., Sareen, J., Cox, B. J., & Bolton, J. M. (2009).	Correlates of self-medication for anxiety disorders: Results from the National Epidemiolgic Survey on Alcohol and Related Conditions	Study	Behavioral Mechanisms
Roncon, C. M, Biesdorf, C., Santana, R. G., Zangrossi, H., Graeff, F. G., & Audi, E. A. (2012).	The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey	Study	Biological Mechanisms
Roncon, C. M., Yamashita, P. S. de M., Frias, A. T., Audi, E. A., Graeff, F. G., Coimbra, N. C., & Zangrossi, H. (2017).	μ-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses	Study	Biological Mechanisms
Rosen, D., Smith, M. L., & Reynolds III, C. F. (2008).	The prevalence of mental and physical health disorders among older methadone patients	Study	Epidemiology
Rosenblatt, R. A., Andrilla, C. H. A., Catlin, M., & Larson, E. H. (2015).	Geographic and Specialty Distribution of US Physicians Trained to Treat Opioid Use Disorder	Study	Treatment Implications
Rosenblum, A., Cleland, C. M., Fong, C., Kayman, D. J., Tempalski, B., & Parrino, M. (2011).	Distance traveled and cross-state commuting to opioid treatment programs in the United States	Study	Treatment Implications
Sareen, J., Chartier, M., Paulus, M. P., & Stein, M. B. (2006).	Illicit drug use and anxiety disorders: Findings from two community surveys	Study	Epidemiology
Saxon, A. J., Oreskovich, M. R., & Brkanac, Z. (2005).	Genetic Determinants of Addiction to Opioids and Cocaine	Review	Behavioral Mechanisms
Sestile, C. C., Maraschin, J. C., Gama, V. S., Zangrossi, H., Graeff, F. G., & Audi, E. A. (2017).	Panicolytic-like action of bradykinin in the dorsal periaqueductal gray through μ-opioid and B2-kinin receptors	Study	Biological Mechanisms
Sigmon, S. C. (2014).	Access to treatment for opioid dependence in rural America: Challenges and future directions	Review	Treatment Implications
Sinha, S. S., Goetz, R. R., & Klein, D. F. (2007).	Physiological and behavioral effects of naloxone and lactate in normal volunteers with relevance to the pathophysiology of panic disorder	Study	Treatment Implications
Sordo, L., Barrio, G., Bravo, M. J., Indave, B. I., Degenhardt, L., Wiessing, L., Ferri, M., & Pastor-Barriuso, R. (2017).	Mortality risk during and after opioid substitution treatment: Systematic review and meta-analysis of cohort studies	Review	Treatment Implications
Sullivan, M. D., Edlund, M. J., Steffick, D., & Unützer, J. (2005).	Regular use of prescribed opioids: Association with common psychiatric disorders	Study	Epidemiology
Sullivan, M. D., Edlund, M. J., Zhang, L., Unützer, J., & Wells, K. B. (2006).	Association between mental health disorders, problem drug use, and regular prescription opioid use.	Study	Epidemiology
Turner, L., Kruszewski, S. P., & Alexander, G. C. (2015).	Trends in the use of buprenorphine by office-based physicians in the United States, 2003–2013	Study	Treatment Implications
Volkow, N. D., Frieden, T. R., Hyde, P. S., & Cha, S. S. (2014).	Medication-assisted therapies—Tackling the opioid-overdose epidemic	Review	Treatment Implications
Weiss, R. D., Potter, J. S., Fiellin, D. A., Byrne, M., Connery, H. S., Dickinson, W., Gardin, J., Griffin, M. L., Gourevitch, M. N., & Haller, D. L. (2011).	Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: A 2-phase randomized controlled trial	Study	Treatment Implications
Wilsey, B. L., Fishman, S. M., Tsodikov, A., Ogden, C., Symreng, I., & Ernst, A. (2008).	Psychological comorbidities predicting prescription opioid abuse among patients in chronic pain presenting to the emergency department	Study	Behavioral Mechanisms
Yi, H., Iida, T., Liu, S., Ikegami, D., Liu, Q., Iida, A., Lubarsky, D. A., & Hao, S. (2017).	IL-4 mediated by HSV vector suppresses morphine withdrawal response and decreases TNFα, NR2B, and pC/EBPβ in the periaqueductal gray in rats	Study	Biological Mechanisms

Results

Epidemiology of PD and OUD

General population studies.

Data from large-scale epidemiologic studies show alarmingly high rates of comorbidity between panic disorder and OUD (Becker et al., 2008; Martins et al., 2009, 2012). In a 2006 analysis of NESARC data, panic disorder with agoraphobia was more related to SUD than all other anxiety disorders (e.g., panic without agoraphobia, social phobia, specific phobia, and generalized anxiety disorder) and was associated with a 13.8-fold increase in odds of DSM-IV opioid dependence (Conway et al., 2006). In this sample, lifetime OUD was strongly associated with lifetime panic disorder both with and without agoraphobia (i.e., odds ratios > 4). Further, in a longitudinal study of two waves of more recent NESARC data, baseline lifetime panic disorder was associated with over two-times greater odds of incidence of opioid use disorder due to non-medical use at follow up (Martins et al., 2012).

Panic disorder in people with OUD.

Among individuals with OUD, a significant proportion also endorse symptoms of panic disorder (Darke & Ross, 1997; Pani et al., 2016), with lifetime rates as high as 13.7% in NESARC samples (Conway et al., 2006). Research on clinical samples of opioid users finds significant comorbidity. Maremmani and colleagues (2010) found that 22.3% of patients with opioid dependence exhibited panic symptoms. While experiencing symptoms of panic does not necessarily equate to having panic disorder, repeated and unexpected symptoms of panic may eventually lead to panic disorder if the subject becomes fearful of these symptoms to such an extent that subsequent behavior is altered. Another study of 140 patients on methadone maintenance found that 13.6% met for past-year panic disorder, and notably, rates of panic disorder in women in the sample (22.9%) nearly doubled that of men (12%; Rosen et al., 2008).

OUD in people with panic disorder.

Research has found that people reporting panic attacks are at least 6.9 times more likely to meet criteria for lifetime OUD than individuals with severe affective disorders with no panic features (Goodwin et al., 2002). Furthermore, those with panic disorder are 8.46 times more likely to use prescription opioids regularly (Sullivan et al., 2005) and 3.02 times more likely to have used heroin in their lifetime than people without panic disorder (Sareen et al., 2006). In past NESARC samples, between 4 – 6 % of individuals with panic disorder report lifetime OUD (Conway et al., 2006).

Factors that complicate differential diagnosis.

There are challenges that complicate the differential diagnosis of panic disorder and OUD and contribute to difficulties establishing rates of comorbidity. First, epidemiological studies commonly report on classes of disorders but not on specific types of disorders. While anxiety and substance use disorders are examined broadly, often data on specific disorders such as panic disorder and OUD are not reported. Conversely, whereas large-scale epidemiological studies often examine the more common anxiety disorders such as generalized anxiety or social anxiety disorder, panic disorder has received relatively little attention. Second, there is significant symptom overlap between SUD and anxiety disorders generally and between panic disorder and OUD specifically. When diagnosing SUD, assessors often conflate panic attacks and panic disorder with substance withdrawal due to overlapping symptom presentations and lack of measure specificity (Maremmani et al., 2010). More specifically, panic disorder and co-occurring opioid use also share similar features of withdrawal that include feelings of anxiety, nausea, accelerated heartbeat, and sweating (American Psychiatric Association, 2013). Therefore, opioid withdrawal may worsen pre-existing anxiety symptoms by mimicking the increased frequency or intensity of anxiety symptoms (McHugh et al., 2017).

Additionally, measures used to assess anxiety disorders have usually not been validated in populations with comorbid SUD; hence, differentiating panic symptoms from opioid withdrawal psychometrically may be particularly difficult considering the aforementioned shared symptomology (McHugh, 2015). Bakken and colleagues (2007) examined a large number of SUD treatment programs and found that 80% of those in treatment met criteria for least one anxiety disorder (Bakken et al., 2007). The discrepancy between the rate of anxiety disorders and OUD comorbidity in the general population and the rate reported by Bakken and colleagues (2007) suggests that acute or protracted withdrawal, even when facilitated by treatment, may closely mimic an anxiety disorder. Unfortunately, as Brady and colleagues (2013) note in their review, current methods fail to adequately determine whether these high rates of comorbidity in treatment samples are due to substance withdrawal that mimics an anxiety disorder or are true instances of co-occurring anxiety disorders (Brady et al., 2013).

Third, OUD is also associated with other comorbid anxiety and mood disorders, providing further complications in establishing rates of comorbidity of panic disorder and OUD (Becker et al., 2008). Social anxiety in particular is associated with opioid use. When investigating reasons that those with comorbid anxiety and OUD use opioids, one of the top responses was to feel more comfortable in social situations (Bizzarri et al., 2007). Symptoms associated with panic, such as trembling and profound fear, may be exclusive to performance situations and better explained by social anxiety. Agoraphobia, obsessive compulsive disorder, and social phobia all have symptom overlap with panic disorder and are all associated with an increased likelihood of a diagnosis of SUD (Bolton et al., 2006).

Lastly, establishing rates of panic disorder and OUD is complicated by a change in diagnostic criteria with the advent of the transdiagnostic panic attack specifier in DSM-5 (American Psychiatric Association, 2013). Panic attacks can now be a symptom specifier for other disorders, such as SUD, as opposed to being specific to panic disorder. This change was made after many studies revealed that panic attacks were sometimes associated with various disorders, such as SUD, but not panic disorder or agoraphobia (Jonge et al., 2016). It is therefore possible that prior to the publication of the DSM-5, recurrent panic attacks were diagnosed as panic disorder when the attacks may have been exclusive to the SUD, either brought on by withdrawal or effects of the substance itself. New epidemiological data is needed to assess whether the changes in panic disorder diagnostic criteria have affected rates of panic disorder and OUD comorbidity.

Behavioral Mechanisms of PD/OUD Comorbidity

Three models have been identified to explain high rates of co-occurring OUD and anxiety disorders, including panic disorder. Martins and colleagues (2012) summarize the three leading models of psychopathology in the context of panic disorder and OUD: (1) precipitation hypothesis: OUD leads to anxiety disorders, with side effects of opioid use or symptoms of opioid withdrawal causing anxiety and panic, (2) self-medication hypothesis: panic disorder leads to OUD, with opioid use an attempt to relieve anxiety symptoms, or (3) shared vulnerability hypothesis: a third factor leads to a susceptibility to both OUD and panic disorder.

There are several lines of research that support the precipitation hypothesis. Individuals who reported lifetime non-medical use of opioids and those with a pre-existing OUD were more than three and eight times more likely, respectively, to subsequently develop panic disorder (Martins et al., 2009). While it is possible that side effects of opioids themselves lead to anxiety or panic symptoms, it is more likely that panic generates from the onset of acute opioid withdrawal because of the acute depressant and anxiolytic actions of opioids (Goodwin et al., 2002; Lejuez et al., 2006). Despite unpleasant withdrawal symptoms from many classes of drugs, withdrawal from opioids specifically may be more likely to be panicogenic than withdrawal from other drugs. In a study of 623,000 cases of adverse drug reactions, panic attacks only occurred during withdrawal from two drug classes: benzodiazepines and opioids (Abadie et al., 2017). While benzodiazepines are often used as anxiolytics to treat panic disorder and therefore withdrawal-induced panic is not unexpected, the relationship between panic disorder and opioid withdrawal is less clear and may be rooted in complex biological mechanisms discussed below (Maremmani et al., 2010; Pani et al., 2016). It should also be noted that anxiety disorders may mediate the relationship between pain and OUD. Individuals experiencing chronic pain may develop an anxiety disorder and subsequently develop OUD after non-medical use of the pain medications they were prescribed in order to relieve symptoms of anxiety (Martins et al., 2012). In the National Comorbidity Survey (N = 5,877), presence of panic disorder within the last 12-month had the strongest association with experience of chronic pain of all anxiety disorders (McWilliams et al., 2003). In a study of individuals seeking an opioid refill at an emergency room or urgent care, it was found that 12% met criteria for panic disorder, and panic disorder diagnosis strongly predicted likelihood of prescription opioid abuse (Wilsey et al., 2008).

Other research provides support for the self-medication hypothesis of OUD and panic disorder comorbidity. Self-medication has long been a framework to explain general SUD and anxiety disorder comorbidity (Bizzarri et al., 2007; Robinson et al., 2009) and has been applied to OUD and panic disorder comorbidity specifically. The reasoning behind why one may use opioids to self-medicate is varied. One theory suggests that because panic disorder is linked to elevated somatic preoccupation, opioids may relieve somatic complaints such as pain or other bodily discomfort and arousal. In a study of 141 participants with panic disorder, nearly 40% reported chronic pain and 8% reported daily analgesic use (Kuch et al., 1991). Therefore, those with pre-existing panic may be vulnerable to seeking opioids for pain relief.

Another theory proposes that those with anxiety self-medicate using opioids for their anxiolytic properties. However, it is unclear as to why one would choose opioids to self-medicate with as opposed to more common anxiolytic substances such as benzodiazepines or alcohol. One explanation is that those with panic disorder often use more than a single substance, combining multiple anxiolytic drugs such as alcohol, sedatives, and opioids (Goodwin et al., 2002). Use of multiple substances is particularly prevalent in those with panic disorder with an agoraphobia specifier, possibly suggesting that disorder severity may positively predict whether opioids are added to a self-medication routine (Robinson et al., 2009).

Anxiety sensitivity, which refers to the fear of the physical sensations associated with anxiety or the fear of fear, is closely correlated with panic disorder and may also be related to substance use. In a sample of 172 treatment seeking drug users, anxiety sensitivity was highest in primary heroin users (Lejuez et al., 2006). Those who scored high on anxiety sensitivity measures also tended to use substances, particularly with heroin, to reduce negative affective symptoms. A combination of self-medication and withdrawal may create a cycle in those with high anxiety sensitivity: those with high anxiety sensitivity may use opioids to regulate negative affect but will also be more fearful of unpleasant bodily sensations associated with withdrawal from opioids, thereby creating a self-perpetuating negative reinforcement cycle (Becker et al., 2008; Lejuez et al., 2006).

Lastly, several factors have been identified that support a theory of shared vulnerability to explain OUD/panic disorder comorbidity. Panic disorder and OUD are both moderately heritable disorders (Hettema et al., 2005; Kendler et al., 2003; Saxon et al., 2005), but their shared genetic vulnerability is less clear. Large behavioral genetic studies suggest a moderate and small shared genetic vulnerability between 1) general anxiety factors and substance use disorders (Kendler et al., 2003) and 2) panic disorder and substance use disorders, respectively (Krueger et al., 2001). Specific genes, gene clusters, and signaling pathways have not been identified. Regarding environmental influences, there is evidence that early life adversity is a risk factor for both disorders, and such environmental stressors produce shared biological vulnerabilities that may converge on the endogenous opioid system (Kendler et al., 1992; Levis et al., 2019; Lewinsohn et al., 2008). Studies suggest that early life adversity is associated with endogenous opioid deficits (Lovallo et al., 2018; M. Preter et al., 2011), and this dysfunction may predispose early life adversity-exposed individuals to heightened sensitivity to physiological symptoms of panic attacks [for review, see (Maurice Preter & Klein, 2014)]. Interestingly, 90% of the path from early life adversity to endogenous opioid dysfunction to panic disorder is explain by shared genetic and environmental factors (Battaglia et al., 2009). These examples of shared vulnerability to OUD and panic disorder suggest a substantial overlap in neurobiological etiology. Indeed, as described below, the biological basis of panic disorder and OUD converges in several brain areas and neurotransmitter systems.

Biological Mechanisms of PD/OUD Comorbidity

Over the past 30 years, there have been two predominant and competing hypotheses of the biological basis of panic disorder. The first hypothesis proposes that individuals with panic disorder have reduced serotonergic levels and/or transmission in the periaqueductal gray (PAG; (Deakin & Graeff, 1991; Paul et al., 2014). This serotonin deficiency in the PAG disinhibits circuits that are responsible for physiological reactivity to acute threats, giving rise to autonomic nervous system activation and panic-like symptoms. The second suggests that endogenous opioids have anxiolytic properties, and their systemic deficit produces a heightened sensitivity to signals of suffocation, i.e., a “false suffocation alarm,” in individuals with panic disorder (Maurice Preter & Klein, 2014). Interestingly, recent evidence suggests that both theories are synergistic and converge via serotonin and opioid signaling in the PAG, which ultimately may have important ramifications for preventing and treating comorbid panic disorder and OUD.

The PAG is a midbrain nucleus that, while predominantly known for its role in nociception, has numerous, critical functions outside the scope of this review (for review, see (George et al., 2019; Motta et al., 2017). It has the densest localization of mu-opioid receptors in the brain and contains neurons and glia that mediate both the development of tolerance to opioids as well as the physical and subjective experience of their withdrawal (Eidson et al., 2017; Iida et al., 2017; Yi et al., 2017). A long and substantial body of work has supported the involvement of the PAG in panic disorder. Administration of a panicogenic substance, sodium lactate, during a PET scan produced increased blood flow to the PAG and surrounding areas in both individuals who experience panic symptoms and controls (Reiman et al., 1989). During stereotaxic surgery in humans, stimulation of the PAG produced reports of numerous panic-like symptoms, including hyperventilation, apnea, dread/terror, urge to flee, sweating, tachycardia, and chest pains (Nashold et al., 1969; Nashold et al., 1974). Lastly, as measured by functional magnetic resonance imaging, PAG activation during a virtual escape task was associated with increased subjective feelings of dread and decreased confidence of escape in healthy controls (Mobbs et al., 2007).

Most recently, models of panic in rodents have demonstrated that serotonin and endogenous opioids interact in the PAG (and hypothalamus) through 5-HT1A and mu-opioid receptor heterodimers to suppress panic-like behaviors (Maraschin et al., 2016; Roncon et al., 2012; Roncon et al., 2017). As both serotonergic and opioidergic activity in the PAG and hypothalamus produces anxiolytic and panicolytic effects, all three of the aforementioned theoretical models of the etiology of comorbid panic disorder and OUD have a strong biological basis. In support of the precipitation hypothesis, in which OUD precedes and leads to the development of panic disorder, a reduction of endogenous opioid levels in the PAG and hypothalamus, as would be observed during acute opioid withdrawal, is sufficient to produce panic-like behaviors in animals (Maraschin et al., 2016; see Graeff, 2017 for discussion). In support of the self-medication hypothesis, in which panic disorder precedes and leads to OUD, opioids have been shown to have potent panicolytic and anxiolytic effects in rodents (Maraschin et al., 2016; see Graeff, 2017 for discussion); chronic self-medication of panic disorder symptoms could lead to OUD, which would then be compounded by the probable experience of exacerbated panic symptoms during acute and protracted opioid withdrawal. Lastly, in support of the shared vulnerability hypothesis, naturally deficient levels of serotonin and/or endogenous opioids in the PAG and/or hypothalamus could feasibly predispose an individual to panic symptoms and high trait and state anxiety, which would in turn increase susceptibility to OUD and other SUD. Furthermore, low basal levels of both neurotransmitters in the PAG could feasibly augment the severity of opioid withdrawal.

Although the shared biological basis for OUD and panic disorder point to a heightened risk for the development of a comorbid disorder, it may also provide a roadmap for novel pharmacological targets to treat both conditions. Recent evidence suggests that two peptides may be promising pharmacological targets for treatment of each OUD and panic disorder. In rodents, increasing levels of the peptides bradykinin and opiorphin in the PAG produces panicolytic effects (bradykinin – Sestile et al., 2017; opiorphin – Maraschin et al., 2016) and augments the panicolytic effects of tricyclic antidepressants (opiorphin – Maraschin et al., 2020). Furthermore, the antidepressant and analgesic effects of opiorphin, without abuse liability, suggest promise as a pharmacological target for chronic pain and opioid withdrawal (Popik et al., 2010).

Treatment Implications

Panic Disorder

A cognitive behavioral therapy called exposure therapy is a well-established treatment for panic disorder and focuses on exposing patients to unpleasant physical sensations of panic (Boettcher & Barlow, 2019). In panic disorder, patients tend to interpret unpleasant physical symptoms of anxiety ruinously, creating a cycle of fear of the symptoms themselves. When a patient’s expectations of catastrophic outcomes are repeatedly not confirmed during a session of exposure therapy, physiological symptoms of panic gradually decrease. Cognitions that maintain fear and avoidance are restructured through repeated exposures and the modified patient perceptions of physiological symptoms leads to less fear and avoidance (Deacon et al., 2013). There is risk, however, of the exposure session leading to exacerbated panic if the patient does not remain exposed to the stimuli for the duration of the panic attack, which can lead to subsequent treatment dropout (Norton et al., 2011). Medicinally, benzodiazepines, beta blockers, and anti-depressants have all shown efficacy in reducing panic disorder symptoms (American Psychiatric Association, 2009; Baldwin et al., 2014). Benzodiazepines and/or beta blockers are commonly prescribed in the short term to offer quick relief from attacks. Selective serotonin reuptake inhibitors (SSRIs) are the preferred short- and long-term pharmacological treatment strategy due to other anti-depressant classes producing more adverse effects and the abuse liability of benzodiazepines. However, both benzodiazepines and antidepressants may inhibit the memory formation and extinction learning upon which exposure therapy relies (Otto et al., 2010). For this reason, combined pharmacological and exposure therapies may not facilitate treatment for panic disorder.

Opioid Use Disorder

Medication Assisted Treatment (MAT) is an evidence-based treatment for OUD that includes the use of medications and psychosocial interventions. Three medications are approved by the FDA for the treatment of OUD: methadone, buprenorphine, and naltrexone. All three have demonstrated greater efficacy than counseling alone in decreasing opioid use, increasing retention in substance use treatment, and decreasing the risk of overdose and death (Connery, 2015; Bart, 2012; Ma et al., 2019; Sordo et al., 2017; Volkow et al., 2014). However, the systems of providing these treatments differ in important ways.

Methadone is strictly regulated by the federal government and can only be dispensed by certified opioid treatment programs. Approximately 1500 active methadone treatment programs exist in the country. The majority are geographically clustered in large urban centers (Sigmon, 2014). One benefit of providing methadone treatment in such programs is that patients have ready access to psychosocial interventions, including group and individual counseling that support their reduction or abstinence from substance use. In contrast, buprenorphine and naltrexone are generally delivered in office settings, such as primary care, with less regulatory oversight compared to methadone (Rosenblum et al., 2011). Current guidelines require buprenorphine prescribers to provide or refer patients to psychosocial counseling as part of office-based service delivery (Center for Substance Abuse Treatment, 2004, p. 40). Most family or internal medicine doctors who prescribe buprenorphine (the fastest growing group of prescribers; Turner et al., 2015) refer patients to counseling at other locations (Barry et al., 2016). Naltrexone has the advantage of being available in oral and injectable, long-acting formulations; it also requires no license or oversight to prescribe and can therefore be provided by anyone with a medical license. However, there is little guidance for prescribers or patients in selecting which counseling or psychosocial interventions will be most beneficial and scarce availability of evidence-based counseling alongside office-based buprenorphine treatment (Amato et al., 2011; Dugosh et al., 2016). Despite the effectiveness of all three medications and the high availability of naltrexone and buprenorphine, these medications are rarely prescribed due to a variety of barriers, explained elsewhere (Alanis-Hirsch et al., 2016; Andraka-Christou & Capone, 2018; Rosenblatt et al., 2015).

Comorbid PD and OUD

Past guidelines for treating patients with co-occurring anxiety disorders and SUD recommended addressing the SUD first without consideration of the ways that anxiety symptoms support ongoing substance use (as discussed in Brady et al., 2013). This is especially important to consider in panic disorder: substance use can perpetuate a cycle of avoided negative sensations which further aggravates the cycle of panic, exacerbates substance use, and impedes treatment progress for each disorder. Current treatment guidelines are in line with the majority of findings: treating comorbid anxiety disorder and SUD concurrently is feasible, safe, effective, and thus preferred to treating each disorder sequentially (Back et al., 2001, 2019; Brady et al., 2001, 2001; Mills et al., 2012).

The presence of OUD may complicate exposure therapy for panic disorder. Exposure therapy is particularly stress-inducing, especially if the patient does not complete the full session or treatment regimen. Historically, well-controlled studies of exposure therapy in comorbid populations have been sparse due the concern of acutely augmented stress and negative affect contributing to opioid relapse and treatment dropout. Indeed, those with OUD may be especially vulnerable to stress-induced relapse (Panlilio et al., 2019), and approximately 50% of treatment-seeking individuals with OUD relapse or drop out of substance use treatment (Lee et al., 2018; Weiss et al., 2011). Research examining the effects of exposure therapy on populations with comorbid panic disorder and SUD are still lacking, but there is research on the effects of exposure-based interventions in samples with comorbid posttraumatic stress disorder (PTSD) and SUD that may be informative.

Like with panic disorder, there is concern that exposure therapy in patients with comorbid PTSD and SUD may lead to relapse to substance use. To reduce this risk, two interventions of note have been developed. The first, Seeking Safety, a group intervention that focuses on affect regulation without any component of exposure (Hien et al., 2004, 2009; Najavits et al., 1998), has been found to reduce PTSD symptoms and substance use in samples with PTSD and SUD (Kok et al., 2013). The second, Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE) combines substance use disorder treatment with a highly monitored exposure protocol (Back et al., 2014; Persson et al., 2017; see Brady et al., 2013 for review). Studies of COPE have shown dramatic reductions in PTSD and SUD with no symptom exacerbation (Lancaster et al., 2020; Mills et al., 2012); however, dropout rates in some COPE studies have been high with one reporting that less than 40% of patients completed treatment (Brady et al., 2001). Seeking Safety and COPE could potentially serve as models for treating comorbid panic disorder and SUD given the similarities in how panic disorder and PTSD are treated, but well-controlled studies in this population are still needed.

Comorbid OUD and panic disorder may also complicate the pharmacological treatment of each condition. Although benzodiazepines can be prescribed for panic disorder, they may not be a safe long-term strategy for comorbid OUD and panic disorder given their high dependence liability and additive overdose risk when combined with opioids (Jann et al., 2014). Additionally, in any anxiety disorder the use of chronic use of benzodiazepines runs the risk of tolerance development and exacerbation of anxiety symptoms during acute and protracted withdrawal. However, this may be a particular concern in the treatment of panic disorder, as individuals with this disorder have shown particular difficulty in tapering off benzodiazepines due to exacerbation of panic symptoms (Klein et al., 1994; Rickels et al., 1993). The return or escalation of panic symptoms during concurrent treatment may increase the likelihood of dropout and relapse to opioid use. On one hand, not prescribing benzodiazepines could complicate treatment of patients with OUD who also have severe panic or an agoraphobia specifier; the fast-acting anxiolytic properties of this class of drugs may be critical for improving daily functioning in these individuals. While antidepressants, particularly SSRIs, are the gold standard in treating panic disorder (American Psychiatric Association, 2009), they lack the fast-acting benefits of benzodiazepines and accordingly cannot be used to alleviate an acute panic-related episode (Ashton, 1994). On the other hand, both benzodiazepines and opioids may acutely interfere with the exposure process, as the goal of exposure is to feel the unpleasant physical symptoms and learn that they can be tolerated (American Psychiatric Association, 2009; Boettcher & Barlow, 2019). This evidence suggests patients with comorbid OUD and panic disorder should be assessed individually and assigned individualized treatment plans based on need and presentation of symptoms. Factors such as severity of panic, the presence of an agoraphobia specifier, history of non-medical benzodiazepine use, and current status of OUD should be evaluated before the implementation of pharmacological treatment. If pharmacological treatments for panic disorder that may inhibit the effectiveness of exposure therapy are prescribed, alternative cognitive behavioral therapies without an exposure component, such as Seeking Safety, should be explored.

While is unclear whether methadone or buprenorphine could interfere with treatment for panic disorder due to a lack of pertinent studies, acute opioid receptor blockade, as produced by naltrexone, appears to increase susceptibility to panic-related symptoms due to the involvement of the endogenous opioid system in respiration. Naloxone, an opioid receptor antagonist with a similar pharmacological profile to naltrexone, has traditionally been used to acutely induce symptoms of panic attacks in human lab studies of panic disorder (Akiyama et al., 1993; Cohen et al., 1983; Preter et al., 2011; Sinha et al., 2007). Most concerningly, an acute dose of naltrexone (50 mg) increased panic-related symptoms in healthy controls (Esquivel et al., 2009). However, clinical trials generally suggest that chronic dosing with naltrexone and buprenorphine across a variety of populations improves mood and anxiety symptoms (for review, see Hassan & Nunes, 2018). In study of 254 treatment-seeking participants with comorbid alcohol use disorder and a mood disorder, naltrexone demonstrated a reduction in anxiety symptoms (Petrakis et al., 2005). One study of 159 adults with OUD found that naltrexone and buprenorphine each reduced anxiety symptoms over the course of treatment (Latif et al., 2019). Thus, providers prescribing naltrexone to individuals with co-occurring OUD and panic disorder may want to pay special care to acute adverse effects during initial dosing and titration due to risk of aggravating panic symptoms; however, there appears to be no risk, and potentially a benefit, to long term dosing with buprenorphine and naltrexone on panic and anxiety symptoms. More research is needed on the effects of MAT on panic symptoms in individuals with comorbid OUD and panic disorder before additional recommendations can be confidently made.

Summary and Future Directions

This paper reviews what is known about the co-occurrence of panic disorder and OUD, their shared behavioral and biological mechanisms, and implications for their combined treatment. More research on this comorbidity is needed at every level. In terms of epidemiology, there are few studies that specifically examine rates of panic disorder and OUD comorbidity. This dearth obscures the precision of base rates and has direct public health implications that may create barriers to successfully identifying, diagnosing, and treating persons vulnerable for co-occurring panic disorder and OUD. This may be especially needed considering the change in classification of panic disorder and panic attack specifiers in the DSM-5. As discussed earlier, a panic attack specifier is now included in the DSM-5 the diagnosis of SUD that was not available in the DSM-IV; as a result of this change, it is possible that what was once diagnosed as comorbid panic disorder and OUD using the DSM-IV may be now labeled as SUD with a panic specifier. However, it is presently unclear whether changes in diagnostic criterion have affected disorder prevalence, and future research is needed. In addition, given the complex nature of interacting factors may that contribute to this comorbidity, more research is needed to better understand how these disorders develop and influence the etiology of the other.

Additional research is needed that examines issues related to the combination of medication treatment for panic disorder in patients receiving MAT for OUD, the timing of interventions in patients with both disorders, and whether any tailoring of cognitive-behavioral therapeutic approaches would be needed in patients with OUD. More specifically, studies are urgently needed to determine whether MAT, particularly naltrexone, acutely increases panic symptoms in individuals with the comorbid disorders. Lastly, due to their overlapping neurobiology, promising pharmacological targets have been identified that could address symptoms of both disorders; additional translational studies pursuing development of these targets is warranted.

Treatment philosophies and intervention training may also need to be modified so that panic disorder and OUD can be assessed and treated simultaneously. While strides have been made over the last two decades to provide greater integration between addiction and mental health treatment (Drake, 2007; Mangrum et al., 2006; McKee, 2017), our diagnostic nosology and corresponding treatment systems are still imperfect. Patients with OUD who enter the addiction treatment system may not be offered evidence-based interventions for panic disorder, while patients who enter the mental health treatment system may have barriers to care due to requirements that patients have their SUD treatment first (Flanagan et al., 2016; Priester et al., 2016). Initiatives to train a multidisciplinary workforce across mental health and OUD service systems has the potential to support the needs of patients presenting for care with comorbid mental health and substance use disorders such as panic disorder and OUD (McCrady et al., 2020; Pedersen & Sayette, 2020).