A national study of clinical discussions about cannabis use among Veteran patients prescribed opioids.

BACKGROUND: The Veterans Health Administration tracks urine drug tests (UDTs) among patients on long-term opioid therapy (LTOT) and recommends discussing the health effects of cannabis use. OBJECTIVE: To determine the occurrence of cannabis-related discussions between providers and patients on LTOT during six months following UDT positive for cannabis, and examine factors associated with documenting cannabis use. DESIGN: We identified patients prescribed LTOT with a UDT positive for cannabis in 2019. We developed a text-processing tool to extract discussions around cannabis use from their charts. SUBJECTS: Twelve thousand seventy patients were included. Chart review was conducted on a random sample of 1,946 patients. MAIN MEASURES: The presence of a cannabis term in the chart suggesting documented cannabis use or cannabis-related discussions. Content of those discussions was extracted in a subset of patients. Logistic regression was used to examine the association between patient factors, including state of residence legal status, with documentation of cannabis use. KEY RESULTS: Among the 12,070 patients, 65.8% (N = 7,948) had a cannabis term, whereas 34.1% (N = 4,122) of patients lacked a cannabis term, suggesting that no documentation of cannabis use or discussion between provider and patient took place. Among the subset of patients who had a discussion documented, 47% related to cannabis use for medical reasons, 35% related to a discussion of VA policy or legal issues, and 17% related to a discussion specific to medical risks or harm reduction strategies. In adjusted analyses, residents of states with legalized recreational cannabis were less likely to have any cannabis-related discussion compared to patients in non-legal states [OR 0.73, 95% CI 0.64-0.82]. CONCLUSIONS: One-third of LTOT patients did not have documentation of cannabis use in the chart in the 6 months following a positive UDT for cannabis. Discussions related to the medical risks of cannabis use or harm reduction strategies were uncommon.

A national population-based study of cannabis use and correlates among U.S. veterans prescribed opioids in primary care.

BACKGROUND: Cannabis is marketed as a treatment for pain. There is limited data on the prevalence of cannabis use and its correlates among Veterans prescribed opioids. OBJECTIVE: To examine the prevalence and correlates of cannabis use among Veterans prescribed opioids. DESIGN: Cross-sectional study. PARTICIPANTS: Veterans with a urine drug test (UDT) from Primary Care 2014-2018, in 50 states, Washington, D.C., and Puerto Rico. A total of 1,182,779 patients were identified with an opioid prescription within 90 days prior to UDT. MAIN MEASURES: Annual prevalence of cannabis positive UDT by state. We used multivariable logistic regression to assess associations of demographic factors, mental health conditions, substance use disorders, and pain diagnoses with cannabis positive UDT. RESULTS: Annual prevalence of cannabis positive UDT ranged from 8.5% to 9.7% during the study period, and in 2018 was 18.15% in Washington, D.C. and 10 states with legalized medical and recreational cannabis, 6.1% in Puerto Rico and 25 states with legalized medical cannabis, and 4.5% in non-legal states. Younger age, male sex, being unmarried, and marginal housing were associated with use (p < 0.001). Post-traumatic stress disorder (adjusted odds ratio [AOR] 1.17; 95% confidence interval [CI] 1.13-1.22, p < 0.001), opioid use disorder (AOR 1.14; CI 1.07-1.22, p < 0.001), alcohol use disorder or positive AUDIT-C (AOR 1.34; 95% CI 1.28-1.39, p < 0.001), smoking (AOR 2.58; 95% CI 2.49-2.66, p < 0.001), and other drug use disorders (AOR 1.15; 95% CI 1.03-1.29, p = 0.02) were associated with cannabis use. Positive UDT for amphetamines AOR 1.41; 95% CI 1.26-1.58, p < 0.001), benzodiazepines (AOR 1.41; 95% CI 1.31-1.51, p < 0.001) and cocaine (AOR 2.04; 95% CI 1.75-2.36, p < 0.001) were associated with cannabis positive UDT. CONCLUSIONS: Cannabis use among Veterans prescribed opioids varied by state and by legalization status. Veterans with PTSD and substance use disorders were more likely to have cannabis positive UDT. Opioid-prescribed Veterans using cannabis may benefit from screening for these conditions, referral to treatment, and attention to opioid safety.

Association of a Positive Drug Screening for Cannabis With Mortality and Hospital Visits Among Veterans Affairs Enrollees Prescribed Opioids.

Importance: Cannabis has been proposed as a therapeutic with potential opioid-sparing properties in chronic pain, and its use could theoretically be associated with decreased amounts of opioids used and decreased risk of mortality among individuals prescribed opioids. Objective: To examine the risks associated with cannabis use among adults prescribed opioid analgesic medications. Design, Setting, and Participants: This cohort study was conducted among individuals aged 18 years and older who had urine drug screening in 2014 to 2019 and received any prescription opioid in the prior 90 days or long-term opioid therapy (LTOT), defined as more than 84 days of the prior 90 days, through the Veterans Affairs health system. Data were analyzed from November 2020 through March 2022. Exposures: Biologically verified cannabis use from a urine drug screen. Main Outcomes and Measures: The main outcomes were 90-day and 180-day all-cause mortality. A composite outcome of all-cause emergency department (ED) visits, all-cause hospitalization, or all-cause mortality was a secondary outcome. Weights based on the propensity score were used to reduce confounding, and hazard ratios [HRs] were estimated using Cox proportional hazards regression models. Analyses were conducted among the overall sample of patients who received any prescription opioid in the prior 90 days and were repeated among those who received LTOT. Analyses were repeated among adults aged 65 years and older. Results: Among 297 620 adults treated with opioids, 30 514 individuals used cannabis (mean [SE] age, 57.8 [10.5] years; 28 784 [94.3%] men) and 267 106 adults did not (mean [SE] age, 62.3 [12.3] years; P < .001; 247 684 [92.7%] men; P < .001). Among all patients, cannabis use was not associated with increased all-cause mortality at 90 days (HR, 1.07; 95% CI, 0.92-1.22) or 180 days (HR, 1.00; 95% CI, 0.90-1.10) but was associated with an increased hazard of the composite outcome at 90 days (HR, 1.05; 95% CI, 1.01-1.07) and 180 days (HR, 1.04; 95% CI, 1.01-1.06). Among 181 096 adults receiving LTOT, cannabis use was not associated with increased risk of all-cause mortality at 90 or 180 days but was associated with an increased hazard of the composite outcome at 90 days (HR, 1.05; 95% CI, 1.02-1.09) and 180 days (HR, 1.05; 95% CI, 1.02-1.09). Among 77 791 adults aged 65 years and older receiving LTOT, cannabis use was associated with increased 90-day mortality (HR, 1.55; 95% CI, 1.17-2.04). Conclusions and Relevance: This study found that cannabis use among adults receiving opioid analgesic medications was not associated with any change in mortality risk but was associated with a small increased risk of adverse outcomes and that short-term risks were higher among older adults receiving LTOT.

Management of opioid use disorder, opioid withdrawal, and opioid overdose prevention in hospitalized adults: A systematic review of existing guidelines.

BACKGROUND: Hospitalizations related to the consequences of opioid use are rising. National guidelines directing in-hospital opioid use disorder (OUD) management do not exist. OUD treatment guidelines intended for other treatment settings could inform in-hospital OUD management. OBJECTIVE: Evaluate the quality and content of existing guidelines for OUD treatment and management. DATA SOURCES: OVID MEDLINE, PubMed, Ovid PsychINFO, EBSCOhost CINHAL, ERCI Guidelines Trust, websites of relevant societies and advocacy organizations, and selected international search engines. STUDY SELECTION: Guidelines published between January 2010 to June 2020 addressing OUD treatment, opioid withdrawal management, opioid overdose prevention, and care transitions among adults. DATA EXTRACTION: We assessed quality using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. DATA SYNTHESIS: Nineteen guidelines met the selection criteria. Most recommendations were based on observational studies or expert consensus. Guidelines recommended the use of nonstigmatizing language among patients with OUD; to assess patients with unhealthy opioid use for OUD using the Diagnostic Statistical Manual of Diseases-5th Edition criteria; use of methadone or buprenorphine to treat OUD and opioid withdrawal; use of multimodal, nonopioid therapy, and when needed, short-acting opioid analgesics in addition to buprenorphine or methadone, for acute pain management; ensuring linkage to ongoing methadone or buprenorphine treatment; referring patients to psychosocial treatment; and ensuring access to naloxone for opioid overdose reversal. CONCLUSIONS: Included guidelines were informed by studies with various levels of rigor and quality. Future research should systematically study buprenorphine and methadone initiation and titration among people using fentanyl and people with pain, especially during hospitalization.

An electronic intervention to improve safety for pain patients co-prescribed chronic opioids and benzodiazepines.

BACKGROUND: Co-prescribing opioids and benzodiazepines increases overdose risk. A paucity of literature exists evaluating strategies to improve safety of co-prescribing. This study evaluated an electronic intervention to improve safety for patients co-prescribed chronic opioids for pain and benzodiazepines at 3 and 6 months. METHODS: A prospective cohort study was conducted from December 2015 through May 2016 at San Francisco Veterans Affairs Health Care System. A clinical dashboard identified 145 eligible patients prescribed chronic opioids and benzodiazepines. Individualized taper and safety recommendations were communicated to prescribers via electronic medical record progress note and encrypted e-mail at baseline. Primary outcome was number of patients co-prescribed chronic opioids and benzodiazepines. Secondary outcomes included daily dose of opioids and benzodiazepines and number prescribed ≥100 mg morphine equivalent daily dose. Safety outcomes included number with opioid overdose education and naloxone distribution, annual urine drug screening, annual prescription drug monitoring program review, and signed opioid informed consent. Linear mixed models and generalized estimating equations were used to examine within-group change in outcomes between baseline and 3 and 6 months. RESULTS: Among the 145 patients, mean (standard deviation) age was 62 (11) years and 91.7% (133/145) were male. Number co-prescribed significantly decreased from 145/145 (100%) at baseline to 93/139 (67%) at 6-month follow-up (odds ratio [OR] = 0.53, 95% confidence interval [CI]: 0.34-0.81, P = .003). Mean opioid and benzodiazepine doses significantly decreased from 84.61 to 65.63 mg (95% CI: 8.32-27.86, P < .001) and from 16.10 to 13.45 mg (95% CI: 1.6-3.9, P < .001), respectively, from baseline to 6-month follow-up. Patients prescribed ≥100 mg morphine equivalent daily dose significantly decreased from 39/145 (26.8%) at baseline to 26/139 (18.7%) at end of study (OR = 0.59, 95% CI: 0.44-0.78, P < .001), and patients with opioid overdose education and naloxone distribution significantly increased from 3/145 (2.1%) at baseline to 46/139 (33.1%; OR = 23.4, 95% CI: 7.61-71.99, P < .001) by the end of study. Number of patients with annual urine drug screening tended to increase from 123/145 (84.8%) at baseline to 132/145 (91.4%) by the end of study (OR = 1.89, 95% CI: 0.95-3.76, P = .07), and there were no significant changes across time in numbers of patients with annual prescription drug monitoring program review or signed opioid informed consent. CONCLUSIONS: Electronic interventions may provide an effective strategy to improve safety for patients co-prescribed chronic opioids for pain and benzodiazepines.

Co-Occurrence of Substance-Related and Other Mental Health Disorders Among Adolescent Cannabis Users.

OBJECTIVE: Cannabis is the most commonly used illicit substance in the United States and is increasingly being legalized throughout the United States. Many believe that cannabis is relatively harmless, and some believe that cannabis is not addictive. We wondered what the rates of cannabis abuse and dependence might be among adolescents referred for substance use evaluations and also about the incidence of co-occurring psychiatric illnesses and substance use disorders among those individuals. METHODS: Herein, we analyze intake data from 483 adolescents referred for evaluation at an adolescent substance abuse clinic, with information gleaned from the adolescents and their parents or caregivers. RESULTS: Forty-seven percent of our sample met the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria for cannabis dependence and another 32% for cannabis abuse. Among adolescents with cannabis use disorders, the co-occurrence of alcohol and opioid abuse or dependence was high. These individuals also suffered from significant psychiatric comorbidities otherwise. CONCLUSIONS: Our results show that cannabis use carries the risk of dependence and also carries with it significant risk of comorbidities, both with respect to other substance use disorders and other psychiatric illness. Given the growing body of research linking cannabis use with addiction and other psychiatric illness, public health efforts ought to center on the potential dangers of cannabis use.

Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients.

Elevated plasma lipopolysaccharide (LPS), an indicator of microbial translocation from the gut, is a likely cause of systemic immune activation in chronic HIV infection. LPS induces monocyte activation and trafficking into brain, which are key mechanisms in the pathogenesis of HIV-associated dementia (HAD). To determine whether high LPS levels are associated with increased monocyte activation and HAD, we obtained peripheral blood samples from AIDS patients and examined plasma LPS by Limulus amebocyte lysate (LAL) assay, peripheral blood monocytes by FACS, and soluble markers of monocyte activation by ELISA. Purified monocytes were isolated by FACS sorting, and HIV DNA and RNA levels were quantified by real time PCR. Circulating monocytes expressed high levels of the activation markers CD69 and HLA-DR, and harbored low levels of HIV compared to CD4(+) T-cells. High plasma LPS levels were associated with increased plasma sCD14 and LPS-binding protein (LBP) levels, and low endotoxin core antibody levels. LPS levels were higher in HAD patients compared to control groups, and were associated with HAD independently of plasma viral load and CD4 counts. LPS levels were higher in AIDS patients using intravenous heroin and/or ethanol, or with Hepatitis C virus (HCV) co-infection, compared to control groups. These results suggest a role for elevated LPS levels in driving monocyte activation in AIDS, thereby contributing to the pathogenesis of HAD, and provide evidence that cofactors linked to substance abuse and HCV co-infection influence these processes.

Lytic and latent antigens of the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus induce T-cell responses with similar functional properties and memory phenotypes.

The cellular immunity against Kaposi's sarcoma-associated herpesvirus (KSHV) is poorly characterized and has not been compared to T-cell responses against other human herpesviruses. Here, novel and dominant targets of KSHV-specific cellular immunity are identified and compared to T cells specific for lytic and latent antigens in a second human gammaherpesvirus, Epstein-Barr virus. The data identify a novel HLA-B57- and HLA-B58-restricted epitope in the Orf57 protein and show consistently close parallels in immune phenotypes and functional response patterns between cells targeting lytic or latent KSHV- and EBV-encoded antigens, suggesting common mechanisms in the induction of these responses.

CD16+ monocyte-derived macrophages activate resting T cells for HIV infection by producing CCR3 and CCR4 ligands.

The CD16(+) monocyte (Mo) subset produces proinflammatory cytokines and is expanded in peripheral blood during progression to AIDS, but its contribution to HIV pathogenesis is unclear. In this study, we investigate the capacity of human CD16(+) and CD16(-) Mo subsets to render resting CD4(+) T cells permissive for HIV replication. We demonstrate that CD16(+) Mo preferentially differentiate into macrophages (Mphi) that activate resting T cells for productive HIV infection by producing the CCR3 and CCR4 ligands CCL24, CCL2, CCL22, and CCL17. CD16(+), but not CD16(-), Mo-derived Mphi from HIV-infected and -uninfected individuals constitutively produce CCL24 and CCL2. Furthermore, these chemokines stimulate HIV replication in CD16(-) Mo:T cell cocultures. Engagement of CCR3 and CCR4 by CCL24 and CCL2, respectively, along with stimulation via CD3/CD28, renders T cells highly permissive for productive HIV infection. Moreover, HIV replicates preferentially in CCR3(+) and CCR4(+) T cells. These findings reveal a new pathway of T cell costimulation for increased susceptibility to HIV infection via engagement of CCR3 and CCR4 by chemokines constitutively produced by CD16(+) Mo/Mphi. Thus, expansion of CD16(+) Mo in peripheral blood of HIV-infected patients and their subsequent recruitment into tissues may contribute to chronic immune activation and establishment of viral reservoirs in resting T cells.

Impact of HLA-B alleles, epitope binding affinity, functional avidity, and viral coinfection on the immunodominance of virus-specific CTL responses.

Immunodominance is variably used to describe either the most frequently detectable response among tested individuals or the strongest response within a single individual, yet factors determining either inter- or intraindividual immunodominance are still poorly understood. More than 90 individuals were tested against 184 HIV- and 92 EBV-derived, previously defined CTL epitopes. The data show that HLA-B-restricted epitopes were significantly more frequently recognized than HLA-A- or HLA-C-restricted epitopes. HLA-B-restricted epitopes also induced responses of higher magnitude than did either HLA-A- or HLA-C-restricted epitopes, although this comparison only reached statistical significance for EBV epitopes. For both viruses, the magnitude and frequency of recognition were correlated with each other, but not with the epitope binding affinity to the restricting HLA allele. The presence or absence of HIV coinfection did not impact EBV epitope immunodominance patterns significantly. Peptide titration studies showed that the magnitude of responses was associated with high functional avidity, requiring low concentration of cognate peptide to respond in in vitro assays. The data support the important role of HLA-B alleles in antiviral immunity and afford a better understanding of the factors contributing to inter- and intraindividual immunodominance.

CD16+ monocytes exposed to HIV promote highly efficient viral replication upon differentiation into macrophages and interaction with T cells.

The CD16+ subset of monocytes is dramatically expanded in peripheral blood during progression to AIDS, but its contribution to HIV pathogenesis is unknown. Here, we demonstrate that CD16+ but not CD16- monocytes promote high levels of HIV replication upon differentiation into macrophages and interaction with T cells. Conjugates formed between CD16+ monocyte-derived macrophages and T cells are major sites of viral replication. Furthermore, similar monocyte-T cell conjugates detected in peripheral blood of HIV-infected patients harbor HIV DNA. Thus, expansion of CD16+ monocytes during HIV infection and their subsequent recruitment into tissues such as lymph nodes, brain, and intestine may contribute to HIV dissemination and establishment of productive infection in T cells.

Acceptance of HIV antibody testing among inpatients and outpatients at a public health hospital: a study of rapid versus standard testing.

Patients of unknown HIV status who were admitted to the inpatient unit or who were undergoing evaluation in the outpatient clinic of a public health hospital were randomized to receive either the standard HIV test or a rapid HIV test. Patients ranged from 21-71 years of age, and 71% were male. Eleven percent were Hispanic, 36% black, and 48% Caucasian. 35% were injection drug users (IVDU) and 3% men who have sex with men (MSM). The waiting period for the standard test was 2 weeks, and that for rapid testing was approximately 20 minutes. Patients were provided with a telephone number and told to call and schedule a follow-up appointment to receive their standard test results. We found no statistical difference in the acceptance rates of either testing modality overall or with respect to age or gender. We did find a significantly greater percentage of Hispanic patients accepting rapid testing over standard testing (p = 0.04). The overall acceptance rates of rapid and standard testing were 60% and 41%, respectively. This was far lower than expected, and was due in part to the 40% of patients who refused testing because of their having a previous HIV test. All patients who had received previous testing had tested HIV negative, and we did not discover any new cases of HIV in the 103 patients tested during the study. Of those we tested, 95% of those receiving the rapid test and 43% of those receiving the standard test were informed of their status (p < 0.001). Failure of patients to return for follow-up visits accounts for the low percentage of individuals successfully informed of their standard test results. The study suggests that rapid HIV testing is at least as palatable as standard testing in our population. In addition, a far greater percentage of patients are informed of their status using the rapid HIV test. HIV testing programs at our hospital may not be cost effective as our population appears to have been heavily tested previously. Prior to initiating an HIV testing program within a hospital setting, it is imperative to determine the percentage of patients previously tested for HIV.