Exploring the Interactions between Non-Medical Methamphetamine Use and Prescribed Buprenorphine or Naltrexone in Opioid Use Disorder Treatment Retention.

OBJECTIVES: Our objectives were to examine the impact of methamphetamine use on opioid use disorder (OUD) treatment retention in patients prescribed either buprenorphine/buprenorphine-naloxone (BUP-NX) or naltrexone/extended-release naltrexone (XR-NTX), while also exploring the role of other risk factors that may modify the impact of methamphetamine use. METHODS: We conducted an exploratory retrospective study examining OUD treatment retention in 127 patients in Ohio (USA). Patients were prescribed either BUP-NX or naltrexone/XR-NTX. Cox proportional hazard regression was used to compare time to dropout of treatment between patients positive and negative on screening for methamphetamines at intake, estimate the association between other risk factors and time to dropout, and test interactions between risk factors and methamphetamine status. RESULTS: Among patients prescribed naltrexone/XR-NTX, those positive for methamphetamines had almost three times the risk of treatment dropout (AHR = 2.89, 95% CI =1.11, 7.07), significantly greater (interaction p = .039) than the methamphetamine effect among those prescribed BUP-NX (AHR = 0.94, 95% CI = 0.51, 1.65). Early in treatment, being prescribed BUP-NX was strongly associated with a greater risk of treatment dropout (at baseline: AHR = 2.90, 95% CI = 1.33, 7.15), regardless of baseline methamphetamine use status. However, this effect decreased with time and shifted to greater risk of dropout among those prescribed naltrexone/XR-NTX (non-proportional hazard; interaction with time AHR = 0.66, 95% CI = 0.49, 0.86), with the shift occurring sooner among those positive for methamphetamine at baseline. CONCLUSIONS: Additional support should be provided to patients who use methamphetamines prior to starting OUD treatment.

Type I interferons regulate cytolytic activity of memory CD8(+) T cells in the lung airways during respiratory virus challenge.

Memory CD8(+) T cells in the lung airways provide protection from secondary respiratory virus challenge by limiting early viral replication. Here, we demonstrate that although airway-resident memory CD8(+) T cells were poorly cytolytic, memory CD8(+) T cells recruited to the airways early during a recall response showed markedly enhanced cytolytic ability. This enhanced lytic activity did not require cognate antigen stimulation, but rather was dependent on STAT1 transcription factor signaling through the interferon-alpha receptor (Ifnar1), resulting in the antigen-independent expression of granzyme B protein in both murine and human virus-specific T cells. Signaling through Ifnar1 was required for the enhanced lytic activity and control of early viral replication by memory CD8(+) T cells in the lung airways. These findings demonstrate that innate inflammatory signals act directly on memory T cells, enabling them to rapidly destroy infected host cells once they enter infected tissues.

The chemokine receptor CCR5 plays a key role in the early memory CD8+ T cell response to respiratory virus infections.

Innate recognition of invading pathogens in peripheral tissues results in the recruitment of circulating memory CD8(+) T cells to sites of localized inflammation during the early phase of a recall response. However, the mechanisms that control the rapid recruitment of these cells to peripheral sites are poorly understood, particularly in relation to influenza and parainfluenza infections of the respiratory tract. In this study, we demonstrate a crucial role for C-C chemokine receptor 5 (CCR5) in the accelerated recruitment of memory CD8(+) T cells to the lung airways during virus challenge. Most importantly, CCR5 deficiency resulted in decreased recruitment of memory T cells expressing key effector molecules and impaired control of virus replication during the initial stages of a secondary response. These data highlight the critical importance of early memory T cell recruitment for the efficacy of cellular immunity in the lung.

Risk for broad-spectrum neuropsychiatric disorders after mild traumatic brain injury in a cohort of US Air Force personnel.

BACKGROUND: Military personnel are at increased risk for traumatic brain injury (TBI) from combat and non-combat exposures. Sequelae of moderate-to-severe TBI are well described, but the literature remains conflicted regarding whether mild TBI (mTBI) results in lasting brain injury and functional impairments. This study assessed risk for a range of neuropsychiatric disorders presenting after mTBI while adjusting for the potential confounds of depression and post-traumatic stress disorder (PTSD). METHODS: A historical prospective association study was conducted utilising electronic demographic, medical and military-specific data for over 49,000 active duty US Air Force service members (Airmen). This study utilised diagnostic codes considered by an expert panel to be indicative of mTBI to identify cases. Cox proportional hazards modelling calculated HRs for neuropsychiatric outcomes while controlling for varying lengths of follow-up and potentially confounding variables. RESULTS: Airmen with mTBI were at increased risk for specific neuropsychiatric disorders compared with a similarly injured non-mTBI control group. HRs for memory loss/amnesia, cognitive disorders, schizophrenia, PTSD, and depression were significantly elevated and remained so for at least 6 months post-mTBI, even after eliminating those with previous neuropsychiatric diagnoses. CONCLUSIONS: mTBI was positively associated with neuropsychiatric disorders in this population of primarily young adult males; with increased HRs 6 months post-mTBI. The results support that mTBI is distinguished from moderate-to-severe TBI in terms of risk for developing neuropsychiatric disorders. Further, these findings suggest the importance of screening for psychiatric and cognitive disorders post-mTBI in general medical practice.

Revisiting Preaddiction.

ABSTRACT: The directors of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism have proposed new efforts to enable earlier identification and intervention for harmful substance use and its consequences. As editors of The ASAM Principles of Addiction Medicine, we fully support this goal. The word "preaddiction" has been suggested as a diagnostic label to describe individuals who would be targeted for early intervention. In this commentary, we offer that "unhealthy substance use" would be a better descriptor than "preaddiction" and review several potential barriers to be addressed in order to maximize the impact of introducing this new paradigm.

CXCR3 directs antigen-specific effector CD4+ T cell migration to the lung during parainfluenza virus infection.

Effector T cells are a crucial component of the adaptive immune response to respiratory virus infections. Although it was previously reported that the chemokine receptors CCR5 and CXCR3 affect trafficking of respiratory virus-specific CD8+ T cells, it is unclear whether these receptors govern effector CD4+ T cell migration to the lungs. To assess the role of CCR5 and CXCR3 in vivo, we directly compared the migration of Ag-specific wild-type and chemokine receptor-deficient effector T cells in mixed bone marrow chimeric mice during a parainfluenza virus infection. CXCR3-deficient effector CD4+ T cells were 5- to 10-fold less efficient at migrating to the lung compared with wild-type cells, whereas CCR5-deficient effector T cells were not impaired in their migration to the lung. In contrast to its role in trafficking, CXCR3 had no impact on effector CD4+ T cell proliferation, phenotype, or function in any of the tissues examined. These findings demonstrate that CXCR3 controls virus-specific effector CD4+ T cell migration in vivo, and suggest that blocking CXCR3-mediated recruitment may limit T cell-induced immunopathology during respiratory virus infections.

Mental health impact of the Iraq and Afghanistan conflicts: a review of US research, service provision, and programmatic responses.

Although documentation that war inflicts psychological casualties dates back to the American Civil War and earlier, most research began after the Vietnam conflict, when studies focused on post-traumatic stress disorder (PTSD). With ongoing conflicts in Iraq and Afghanistan, there has been significant research to illuminate the epidemiology of war-related psychological casualties. Significant findings include an appreciation for the role combat plays in the development of mental disorders, including PTSD and traumatic brain injury (TBI). Recent research has endeavoured to understand and improve psychological resilience to temper potentially adverse mental health effects of military service in the theatre of combat operations. Over 2 million US service members have now deployed and returned over 3 million times to the Iraq and Afghanistan conflicts. Mental health providers in the Departments of Defense and Veterans Affairs healthcare systems have consequently observed steep increases in mental health service use among these personnel. The Departments have responded aggressively to bolster staffing levels, increase capacity, improve available services, and anticipate future needs. Scientists and clinicians continue efforts to understand the determinants, prevention, recognition, and treatment of combat-related mental disorders.

Differential antigen presentation regulates the changing patterns of CD8+ T cell immunodominance in primary and secondary influenza virus infections.

The specificity of CD8+ T cell responses can vary dramatically between primary and secondary infections. For example, NP366-374/Db- and PA224-233/Db-specific CD8+ T cells respond in approximately equal numbers to a primary influenza virus infection in C57BL/6 mice, whereas NP366-374/Db-specific CD8+ T cells dominate the secondary response. To investigate the mechanisms underlying this changing pattern of immunodominance, we analyzed the role of antigen presentation in regulating the specificity of the T cell response. The data show that both dendritic and nondendritic cells are able to present the NP366-374/Db epitope, whereas only dendritic cells effectively present the PA224-233/Db epitope after influenza virus infection, both in vitro and in vivo. This difference in epitope expression favored the activation and expansion of NP366-374/Db-specific CD8+ memory T cells during secondary infection. The data also show that the immune response to influenza virus infection may involve T cells specific for epitopes, such as PA224-233/Db, that are poorly expressed at the site of infection. In this regard, vaccination with the PA224-233 peptide actually had a detrimental effect on the clearance of a subsequent influenza virus infection. Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies.

On my own terms: Motivations for self-treating opioid-use disorder with non-prescribed buprenorphine.

INTRODUCTION: The opioid overdose crisis in the United States has prompted an expansion of treatment services, including pharmacotherapy with buprenorphine. However, many people who use illicit opioids (PWUIO) self-treat their opioid-use disorder (OUD) with non-prescribed buprenorphine (NPB) in lieu of attending formal treatment. The present study aims to qualitatively understand motivations of people who are self-treating their OUD with NPB. METHODS: Qualitative study designed to supplement and contextualize quantitative findings from natural history study of buprenorphine diversion, self-treatment, and use of substance use disorder treatment services. Interviews were audio-recorded, transcribed, systematically coded and analyzed via Iterative Categorization. STUDY SETTING: The Dayton, Ohio metropolitan area in the midwestern United States; a site previously characterized as high impact in the national opioid overdose crisis. PARTICIPANTS: Sixty-five individuals (35 men and 30 women) who met the DSM-5 criteria for OUD (moderate or severe) and had used NPB at least one time in the six months prior to their intake interview. RESULTS: Participants described four key motivators for self-treating with NPB: perceived demands of formal treatment, the desire to utilize non-prescribed buprenorphine in combination with a geographic relocation, to self-initiate treatment while preparing for formal services, and to bolster a sense of self-determination and agency in their recovery trajectory. CONCLUSIONS: Use of NPB is a recognized self-treatment modality among PWUIO, with some PWUIO transitioning into sustained recovery episodes or enrollment in formal treatment. Understanding the motivations for opting out of treatment is crucial for improving forms of care for people with OUD.

Impact of implementing a tobacco and recreational nicotine-free policy and enhanced treatments on programmatic and patient-level outcomes within a residential substance use disorder treatment program.

BACKGROUND: Recent estimates are that 30% of military veterans use tobacco or recreational nicotine products, and rates significantly increase for veterans with co-occurring substance use disorder (SUD). Despite emerging literature that indicate better outcomes when SUD and tobacco use disorder (TUD) are treated simultaneously (in parallel), most SUD programs fail to address tobacco use. This can prove catastrophic, as perhaps the most likely cause of death lifetime for patients admitted to a SUD treatment program is tobacco/nicotine-related. Studies suggest that residential SUD treatment programs can improve the screening, diagnosis, documentation, and treatment of TUD. Perceived barriers among staff include fear of causing patients to leave early. There are few studies evaluating the accuracy of these perceived barriers to programmatic and patient-level outcomes in the residential SUD treatment setting when TUD services are provided along with a nicotine/tobacco-free therapeutic milieu. OBJECTIVE: In the fall of 2015, a SUD treatment program at a large midwestern Veteran. Affairs Medical Center fully implemented a tobacco-free residential unit. The current study investigates the programmatic and patient-level outcomes among cohorts treated before versus after the tobacco-free policy was implemented. PARTICIPANTS & PROCEDURES: This study utilized archival data and all participants were enrolled in the residential program with 117 veterans enrolled pre and 92 post tobacco-free policy. The final sample consisted of 194 males (92.8%), 14 females (6.7%), and 1 transgendered (0.5%) with a mean age of 47.80 (SD = 12.65). Most of the participants were Caucasian (69.4%) and divorced (43.1%). The majority (167, 79.9%) reported current tobacco use, with cigarettes (118, 56.5%) being the most frequently reported type. In addition, 17.59 (SD = 6.51) years old is the average start age of tobacco use. RESULTS: Veterans in the pre-policy cohort did not differ from post-policy cohort on age, gender, ethnicity, and marital status. Preliminary results related to programmatic outcomes indicate improved rates of TUD diagnosis during intake (28.4% to 75.0%). Similar rates were observed in veterans who reported tobacco quit goal during treatment planning (37.4% to 56.8%). However, while there were no significant differences in the total rates of infractions; tobacco-related infractions significantly increased from one to eight. Finally, there were no significant differences in the number of against medical advice discharges or irregular discharges. Examination of patient-level outcomes revealed similar rates of veterans enrolling in the program as it relates to rates of current tobacco use, admission expired breath carbon monoxide (CO) measured in parts per million (ppm), longest period of tobacco abstinence, and self-reported primary preferred substance/drug. Of note, there were also no differences in reported importance and confidence of quitting tobacco. Rates of veterans prescribed nicotine replacement therapy during residential stay more than doubled. CONCLUSIONS: Our data suggest that implementing a tobacco-free policy within a residential SUD treatment program would not deter veterans from staying engaged in the program as evident by similar rates of irregular and AMA discharges. In addition, the prevalence of Veterans wishing to quit tobacco was higher in the post-policy cohort, as was NRT utilization, and without the addition of staff. Specific treatment recommendations will be discussed along with other implications.

"Everything is not right anymore": Buprenorphine experiences in an era of illicit fentanyl.

BACKGROUND: Conducted in the Dayton Metropolitan area of Southwestern Ohio, this qualitative study explores the self-treatment practices of people who use illicit opioids (PWUIO) amidst the new risk environment produced by illicit, non-pharmaceutical fentanyl (NPF). We explore local perceptions of the presence of NPF in the Dayton area, and how this has both positively and negatively impacted practices of non-prescribed buprenorphine use among PWUIO. METHODS: This study analyzes qualitative data from 63 interviews conducted between October 2018 and June 2019. Participants were selected from a larger longitudinal study on non-prescribed buprenorphine use among individuals with opioid use disorder. Qualitative interviews were transcribed in their entirety, and their transcriptions were analyzed using NVivo software, drawing on a mix of thematic and inductive coding. RESULTS: Interview respondents ranged from 19 to 70 years old, with a mean age of 38.9 years. 54% of them were male, and 85.7% identified as non-Hispanic White. 98.4% of the sample had used heroin, and 93.7% of the sample reported use of NPF. Participants agreed NPF dominated the illicit opioids market in the area, and was perceived as both dangerous and desirable. The domination of NPF and associated overdose experiences prompted some to seek positive change and initiate self-treatment with non-prescribed buprenorphine. For others, NPF sabotaged established practices of harm reduction, as unanticipated experiences of precipitated withdrawals prompted some participants to give up non-prescribed buprenorphine use as a tactic of self-treatment. DISCUSSION: The changing nature of heroin/NPF necessarily gives rise to new beliefs surrounding self-treatment attempts, treatment seeking behaviors, and harm reduction practices. While buprenorphine treatment continues to offer promising results for treating opioid use disorders, it is urgent to reconsider how the unpredictable biochemical mixture of NPFs circulating on the streets today may impact the initiation and success of treatment.

Risk factors for opioid overdose and awareness of overdose risk among veterans prescribed chronic opioids for addiction or pain.

Rising overdose fatalities among U.S. veterans suggest veterans taking prescription opioids may be at risk for overdose. However, it is unclear whether veterans prescribed chronic opioids are aware of this risk. The objective of this study was to identify risk factors and determine awareness of risk for opioid overdose in veterans treated with opioids for chronic pain, using veterans treated with methadone or buprenorphine for opioid use disorder as a high-risk comparator group. In the current study, 90 veterans on chronic opioid medication, for either opioid use disorder or pain management, completed a questionnaire assessing risk factors, knowledge, and self-estimate of risk for overdose. Nearly all veterans in both groups had multiple overdose risk factors, although individuals in the pain management group had on average a significantly lower total number of risk factors than did individuals in the opioid use disorder group (5.9 versus 8.5, p < .0001). On average, participants treated for pain management scored slightly but significantly lower on knowledge of opioid overdose risk factors (12.1 versus 13.5, p < .01). About 70% of participants, regardless of group, believed their overdose risk was below that of the average American adult. There was no significant relationship between self-estimate of overdose risk and either number or knowledge of opioid overdose risk factors. Our results suggest that veterans in both groups underestimated their risk for opioid overdose. Expansion of overdose education to include individuals on chronic opioids for pain management and a shift in educational approaches to overdose prevention may be indicated.

Pathologic gambling disorder. How to help patients curb risky behavior when the future is at stake.

Pathologic gambling disorder and problem gambling are becoming increasingly common in the United States as more states legalize gambling. Although gambling-related disorders can cause devastating consequences, well-studied treatments are few. Fortunately, clinical experience suggests that pathologic gambling disorder is highly treatable. In this article, Drs Sumitra and Miller briefly summarize gambling-related disorders and discuss available, effective treatments.

Longitudinal assessment of mental disorders, smoking, and hazardous drinking among a population-based cohort of US service members.

OBJECTIVES: Combat exposure is known to increase the risk for mental disorders; however, less is known about the temporal relationship between mental disorders and alcohol misuse or smoking. To better understand these interrelationships, this study investigated mental disorders in association with hazardous drinking and cigarette smoking. METHODS: Using data from a large population-based military cohort, standardized instruments were used to screen for posttraumatic stress disorder, depression, panic, and other anxiety syndromes. Self-reported use of cigarettes and hazardous drinking was also assessed. Subjects were classified as having "new-onset," "persistent," or "resolved" mental disorders and health risk behaviors on the basis of screening results from baseline to follow-up (n = 50,028). Multivariable logistic regression models were used to investigate temporal patterns between the development of mental disorders and the uptake of smoking or hazardous drinking. RESULTS: The strongest associations of new-onset mental disorders were among those who newly reported smoking or hazardous drinking (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.28-2.59 and OR, 2.49; 95% CI, 2.15-2.89, respectively), even after adjustment for combat deployment experience. In addition, persistent smokers and hazardous drinkers had elevated odds for developing a mental disorder at follow-up. CONCLUSIONS: This study demonstrates a positive association between the onset of mental disorders with the uptake of smoking and hazardous drinking and the likelihood that multiple temporal sequence patterns exist to explain the relationship between mental disorders and hazardous drinking and smoking. Clinical approaches to mitigate deployment-related mental disorders should include alcohol and tobacco-related assessments and interventions.

Risk for addiction-related disorders following mild traumatic brain injury in a large cohort of active-duty U.S. airmen.

OBJECTIVE: Military personnel are at increased risk for traumatic brain injury (TBI) from combat and noncombat exposures. The sequelae of moderate to severe TBI are well described, but little is known regarding long-term performance decrements associated with mild TBI. Furthermore, while alcohol and drug use are well known to increase risk for TBI, little is known regarding the reverse pattern. The authors sought to assess possible associations between mild TBI and addiction-related disorders in active-duty U.S. military personnel. METHOD: A historical prospective study was conducted using electronically recorded demographic, medical, and military data for more than a half million active-duty U.S. Air Force service members. Cases were identified by ICD-9-CM codes considered by an expert panel to be indicative of mild TBI. Outcomes included ICD-9-CM diagnoses of selected addiction-related disorders. Cox proportional hazards modeling was used to calculate hazard ratios while controlling for varying lengths of follow-up and potential confounding variables. RESULTS: Airmen with mild TBI were at increased risk for certain addiction-related disorders compared with a similarly injured non-mild TBI comparison group. Hazards for alcohol dependence, nicotine dependence, and nondependent abuse of drugs or alcohol were significantly elevated, with a consistent decrease over time. CONCLUSIONS: A novel finding of this study was the initial increased risk for addiction-related disorders that decreased with time, thus eroding war fighter performance in a military population. Moreover, these results suggest that mild TBI is distinguished from moderate to severe TBI in terms of timing of the risk, indicating that there is a need for screening and prevention of addiction-related disorders in mild TBI. Screening may be warranted in military troops as well as civilians at both short- and long-term milestones following mild TBI.

Smokeless tobacco use related to military deployment, cigarettes and mental health symptoms in a large, prospective cohort study among US service members.

AIMS: To characterize smokeless tobacco initiation and persistence in relation to deployment, combat, occupation, smoking and mental health symptoms. DESIGN: Prospective cohort, utilizing self-reported survey data from the Millennium Cohort Study. SETTING: US military service members in all branches including active duty, reserve and National Guard. PARTICIPANTS: Population-based sample of 45,272 participants completing both baseline (July 2001-June 2003; n = 77,047) and follow-up (June 2004-January 2006; n = 55,021) questionnaires (follow-up response rate = 71.4%). MEASUREMENTS: Self-reported smokeless tobacco initiation and persistence. FINDINGS: Over the study period, 72.4% did not deploy, 13.7% deployed without combat exposures and 13.9% deployed with combat exposures, while 1.9% were smokeless tobacco initiators and 8.9% were persistent users. The odds of initiation were greater for deployers with combat exposure [odds ratio (OR), 1.76; 95% confidence interval (CI), 1.49-2.09], deployers without combat exposure (OR, 1.31; 95% CI, 1.07-1.60) and those who deployed multiple times (OR, 1.67; 95% CI, 1.31-2.14), as well as in smoking recidivists/initiators (OR, 4.65; 95% CI, 3.82-5.66) and those reporting post-traumatic stress disorder symptoms (OR, 1.54; CI, 1.15-2.07). A similar pattern for higher odds of persistent use was observed for deployment and combat exposure, but not for smoking and mental health symptoms. Military occupation was not significantly associated with initiation or persistence. CONCLUSIONS: Deployment and combat exposure in the US military are associated with increased risk of smokeless tobacco initiation and persistence while smoking and symptoms of post-traumatic stress disorder increase the odds for initiation. Research is needed on aspects of military service amenable to the reduction or prevention of tobacco consumption.