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Rationale Consideration by the US Drug Enforcement Administration and Food and Drug Administration of placing kratom into Schedule I of the Controlled Substances Act (CSA) requires its evaluation of abuse potential in the context of public health. Objective The objective of the study is to provide a review of kratom abuse potential and its evaluation according to the 8 factors of the CSA. Results Kratom leaves and extracts have been used for centuries in Southeast Asia and elsewhere to manage pain and other disorders and, by mid-twentieth century, to manage opioid withdrawal. Kratom has some opioid effects but low respiratory depression and abuse potential compared to opioids of abuse. This appears due to its non-opioid-derived and resembling molecular structure recently referred to as biased agonists. By the early 2000s, kratom was increasingly used in the US as a natural remedy to improve mood and quality of life and as substitutes for prescription and illicit opioids for managing pain and opioid withdrawal by people seeking abstinence from opioids. There has been no documented threat to public health that would appear to warrant emergency scheduling of the products and placement in Schedule I of the CSA carries risks of creating serious public health problems. Conclusions Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist. Furthermore, appropriate regulation by FDA is vital to ensure appropriate and safe use.

Controlled substance lock-in programs are garnering increased attention from payers and policy makers seeking to combat the epidemic of opioid misuse. These programs require high-risk patients to visit a single prescriber and pharmacy for coverage of controlled substance medication services. Despite high prevalence of the programs in Medicaid, we know little about their effects on patients' behavior and outcomes aside from reducing controlled substance-related claims. Our study was the first rigorous investigation of lock-in programs' effects on out-of-pocket controlled substance prescription fills, which circumvent the programs' restrictions and mitigate their potential public health benefits. We linked claims data and prescription drug monitoring program data for the period 2009-12 for 1,647 enrollees in North Carolina Medicaid's lock-in program and found that enrollment was associated with a roughly fourfold increase in the likelihood and frequency of out-of-pocket controlled substance prescription fills. This finding illuminates weaknesses of lock-in programs and highlights the need for further scrutiny of the appropriate role, optimal design, and potential unintended consequences of the programs as tools to prevent opioid abuse.

The United States is facing an opioid epidemic that is virulent in its lethality and includes morbidity and mortality related to prescription opioids. Overuse of another class of drugs— benzodiazepines—has received less media attention, but also poses the threat of tolerance, dependence, and death, especially in combination with opioids or alcohol. These negative outcomes are not distributed evenly over the population but are especially prevalent in vulnerable populations. One such vulnerable population comprises individuals with serious mental illness. Professionals who serve this population are challenged by an often-fragmented health care system to collaborate with patients and other professionals to reduce risks and improve outcomes. This article examines strategies for addressing risks associated with the use of benzodiazepines and opioids in this population within the context of an integrated interprofessional team. Recommendations include (a) building consensus on the team, (b) providing education for all stakeholders, and (c) enhancing care coordination and patient access to effective treatments. [ Journal of Psychosocial Nursing and Mental Health Services, 56 (12), 11–15.]

The Deputy Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule three synthetic cannabinoids under the Controlled Substances Act (CSA) pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The substances are (1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (UR-144), [1-(5-fluoro-pentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (5-fluoro-UR-144, XLR11) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA, AKB48). This action is based on a finding by the Deputy Administrator that the placement of these synthetic cannabinoids and their salts, isomers and salts of isomers into Schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the full effect of the CSA and the Controlled Substances Import and Export Act (CSIEA) and their implementing regulations including criminal, civil and administrative penalties, sanctions and regulatory controls of Schedule I substances will be imposed on the manufacture, distribution, possession, importation, and exportation of these synthetic cannabinoids.

In this trial involving adult ex-prisoners who had a history of opioid dependence, extended-release naltrexone resulted in a lower rate of opioid relapse than did usual treatment (brief counseling and referrals). The drug did not reduce rates of reincarceration or unsafe sex. Opioid-use disorder is a chronic relapsing condition that has serious public health consequences. Opioid dependence disproportionately affects U.S. criminal justice system populations, and relapse and overdose deaths occur at high rates after release from incarceration. 1 Evidence-based opioid-agonist maintenance therapies for opioid dependence (methadone and buprenorphine) are effective in prison, jail, and community reentry (i.e., parole) settings 2 – 5 but have historically been unavailable or discouraged among criminal justice clients. 6 – 8 Extended-release naltrexone (Vivitrol, Alkermes), a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, was approved by the Food and Drug Administration in 2010 for the prevention of relapse to . . .

IntroductionData suggest that micronised progesterone (mP) in menopausal hormone therapy is safer for the breast than synthetic progestins, while protection of the endometrium appears to be less effective. However, comparative randomised trial data are lacking. The objective of the Progesterone Breast Endometrial Safety Study is to investigate breast and endometrial safety of mP versus norethisterone acetate (NETA) in continuous combination with oral oestrogen.Methods and analysisThis multicentre trial, conducted at three University Hospitals in Stockholm and Uppsala, Sweden, consists of two phases: part 1 focuses on breast safety and is designed as a double-blind, randomised controlled trial. 260 postmenopausal women will be randomised to 100 mg mP or 0.5 mg NETA per day in continuous combination with 1 mg oestradiol. The primary objective is to compare the treatments with respect to percentage change in mammographic breast density after 12-month treatment. Secondary outcomes are breast proliferation, endometrial histology and proliferation, bleeding pattern, gut and vaginal microbiome, hormone levels and coagulation and metabolic factors, mood, and health-related quality of life. Part 2 features an open, single-arm design to study endometrial safety of 1-year treatment with mP in continuous combination with oestradiol on endometrial pathology (hyperplasia and cancer). We will treat 260 additional women with 100 mg mP/1 mg oestradiol resulting in an endometrial safety population of 390 women. The total number of participants in part 1 and part 2 will be 520.Ethics and disseminationThe study protocol was approved by the Swedish Ethical Review Authority (2021-03033) on 29 June 2021 with amendment (2023-01480-02, protocol version 3.1) on 14 March 2023. Results of the study will be published in peer-reviewed journals and presented at scientific meetings.Trial registration numberNCT05586724.

Background: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation. Methods: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: “duloxetine” OR “venlafaxine” OR “desvenlafaxine” OR “milnacipran” OR “levomilnacipran” OR “SNRI” OR “second generation antidepressant” OR “serotonin norepinephrine reuptake inhibitor” AND “discontinuation” OR “withdrawal” OR “rebound.” Only published trials in the English language were included. Results: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well. Conclusions: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.

Prescription drug abuse and illicit drug use are common in chronic pain patients. Adherence monitoring with screening tests, and urine drug testing, periodic monitoring with prescription monitoring programs, has become a common practice in recent years. Random drug testing for appropriate use of opioids and use of illicit drugs is often used in pain management practices. Thus, it is expected that random urine drug testing will deter use of illicit drugs, and also improve compliance. To study the prevalence of illicit drug use in patients receiving opioids for chronic pain management and to compare the results of illicit drug use with the results from a previous study. A prospective, consecutive study. Interventional pain management practice setting in the United States. A total of 500 consecutive patients on opioids, considered to be receiving stable doses of opioids supplemental to their interventional techniques, were studied by random drug testing. Testing was performed by rapid drug screen. Results were considered positive if one or more of the monitored illicit drugs including cocaine, marijuana (THC), methamphetamine or amphetamines were present. Illicit drug use was evident in 80 patients, or 16%, with marijuana in 11%, cocaine in 5%, and methamphetamine and/or amphetamines in 2%. When compared with previous data, the overall illicit drug use was significantly less. Illicit drug use in elderly patients was absent. The prevalence of illicit drug abuse in patients with chronic pain receiving opioids continues to be a common occurence. This study showed significant reductions in overall illicit drug use with adherence monitoring combined with random urine drug testing.

Background The high recurrence rate after liver resection emphasizes the urgent need for neoadjuvant therapy in hepatocellular carcinoma (HCC) to enhance the overall prognosis for patients. Immune checkpoint inhibitors, camrelizumab combined with an anti-angiogenic tyrosine kinase inhibitor (TKI) apatinib, have emerged as a first-line treatment option for patients with unresectable HCC, yet its neoadjuvant application in combination with transarterial chemoembolization (TACE) in HCC remains unexplored. Therefore, this study aims to investigate the efficacy and safety of sequential TACE, camrelizumab, and apatinib as a neoadjuvant therapy for single, huge HCC. Methods This multi-center, open-label randomized phase 3 trial will be conducted at 7 tertiary hospitals. Patients with single huge (≥ 10 cm in diameter), resectable HCC will be randomly assigned in a 1:1 ratio to arm of surgery alone or arm of neoadjuvant therapy followed by surgery. In the neoadjuvant therapy group, patients will receive TACE within 1 week after randomization, followed by camrelizumab (200 mg q2w, 4 cycles), along with apatinib (250 mg qd, 2 months). Patients will receive liver resection after neoadjuvant therapy unless the disease is assessed as progressive. The primary outcome is recurrence-free survival (RFS) at 1 year. The planned sample size of 60 patients will be calculated to permit the accumulation of sufficient RFS events in 1 year to achieve 80% power for the RFS primary endpoint. Discussion Synergistic effects provided by multimodality therapy of locoregional treatment, TKI, and anti-programmed cell death 1 inhibitor significantly improved overall survival for patients with unresectable HCC. Our trial will investigate the efficacy and safety of the triple combination of TACE, camrelizumab, and apatinib as a neoadjuvant strategy for huge, resectable HCC. Trial registration www.chitr.org.cn ChiCTR2300078086. Registered on November 28, 2023. Start recruitment: 1st January 2024. Expected completion of recruitment: 15th June 2025.

Background Reducing opioid use is challenging due to limited evidence-based weaning methods and a lack of interventions to mitigate withdrawal symptoms. An emerging intervention using transcutaneous auricular neurostimulation (tAN) is being developed to reduce opioid withdrawal symptoms, but its mechanisms of action are not yet well understood. This is a clinical trial performed to investigate the mechanisms of tAN in managing pain and opioid withdrawal during opioid taper in adults with chronic pain. Methods This is a single-site, randomized, double-blind, and sham-controlled superiority framework trial during an inpatient opioid taper for participants on long-term opioid therapy for chronic pain. Participants are recruited for an inpatient stay at a large, academic medical center in the United States. Included participants are adults between 18 and 75 years of age who have the presence of pain more than half of the days in the past 6 months, are prescribed opioid medication, have a willingness to taper the opioid dose by at least 10%, and have a urine drug screen positive for the prescribed opioid but negative for illicit drugs and nonprescribed opioids. Participants are excluded with a condition affecting their safety of participation (e.g., epileptic seizures, current suicidal ideation, current abuse of illicit drugs or alcohol, pregnancy), a condition that precludes fMRI assessment (implanted medical device, claustrophobia), or a status affecting pain medication intake (e.g., surgery in the past month, opioid prescription dose > 200 morphine milligram equivalents per day, history of neurological diseases or traumatic brain injury, active treatment for cancer). Participants are randomized to receive either active tAN ( n  = 20) or sham tAN ( n  = 20). Both groups undergo a mild-to-moderate opioid taper on day 1 and are maintained at the reduced level for 4 days under inpatient medical supervision. The primary outcome measure, brain functional magnetic resonance imaging (fMRI), is used to measure BOLD signals and resting functional connectivity ( z -value) of pain networks. Secondary outcome measures are self- and clinician-observed opioid withdrawal scales, behavioral assessment questionnaires, and quantitative sensory testing (QST) data. The first subject enrollment was completed from July 25 to 28, 2023. The total enrollment count was set to 40 with two arms of equal ratios. Randomization stratification by gender at birth was performed. The study physician, intervention-providing staff member, and outcome-assessing study coordinator each perform recruitment, and each is blinded to treatment group assignment. Safety and harm measures of opioid withdrawal will be assessed with the Clinical and Subject-reported Opiate Withdrawal Scores. Vital signs will be assessed three times per day, and adverse events will be recorded and reported as necessary. Discussion Understanding the mechanisms of action of tAN will lead to the development of more effective future non-pharmacologic treatments in mitigating withdrawal while gradually tapering participants off prescription opioid management. Trial registration Clinicaltrials.gov, NCT05555485. Registered on 15 September 2022.