Search Results (132)

Aim: There is an urgent need for systematic and well-designed studies to clarify the role of systemic inflammatory parameters, especially the neutrophil–lymphocyte-ratio (NLR), in the pathophysiology and clinical management of unregulated substance addiction. This review aims to synthesize current evidence on the relationship between unregulated substance addiction and systemic inflammatory parameters, focusing specifically on the NLR as a potential biomarker. Methods: To ensure a transparent approach in the collection of evidence, this review was carried out following the recommendations of the PRISMA 2020 guidelines and registered in PROSPERO (CRD420251151136). We searched the PubMed and Scopus databases in July2025 using combinations of MeSH terms and keywords related to unregulated substance use and inflammatory biomarkers. The strategy included terms such as “cocaine,” “cannabis,” “opioids,” “heroin,” “fentanyl,” “methadone,” “buprenorphine” “nitazene”, “MDMA”, and “methamphetamine,” combined with “neutrophil-to-lymphocyte ratio.” Filters were applied to limit results to human studies published between 2015 and 2025 in English. The methodological quality of the studies included was assessed using the STROBE 22-item checklist. Results: Fifteen studies were included in this review. Methamphetamine and opioid users showed higher NLR and MLR values. For cocaine abuse, although the evidence is limited to a single population-based study, a significant increase in NLR was reported. Controversial results were observed for cannabis use. Conclusions: Systemic inflammation markers are related to unregulated substance abuse disorders; however, the sparse available evidence encourages the need for well-designed large, prospective clinical trials. Full article

Criminal justice system (CJS) involvement is common among individuals with opioid use disorder (OUD), yet limited research examines retention in medications for OUD (MOUD) within community settings. This study assessed whether CJS involvement predicted retention on buprenorphine/naloxone and explored related demographic and clinical factors. A retrospective cohort included adults (n = 367) enrolled in a low-barrier outpatient MOUD program in Texas (January 2022–April 2024). CJS involvement was identified from program records. Retention was measured as the number of continuous days with buprenorphine/naloxone prescriptions. Analyses used univariate tests, logistic regression, and nonparametric kernel regression. Nearly one-quarter (24.8%) were CJS-involved. Retention at 180 days was similar between CJS and non-CJS groups (38%). CJS participants initiated substance use earlier and reported higher heroin and injection drug use. Behavioral health sessions were associated with both CJS involvement (OR = 1.10, p ≤ 0.001) and longer retention (β = 10.81 days/session, p = 0.001). With comprehensive, low-barrier services, individuals involved with CJS achieved MOUD retention comparable to their peers. Early behavioral health engagement was a strong predictor of retention, suggesting a key intervention point to enhance outcomes and advance equity for justice-involved populations. Full article

Sheep are routinely used as orthopedic models due to their similarities to human joints. Spinal anesthesia provides adequate analgesia for these procedures, and its duration can be enhanced with adjuvant drugs. Clonidine is commonly used in human spinal anesthesia, while dexmedetomidine is a newer and more selective α-2 agonist. This study compared the duration and analgesic effect of these two drugs as adjuvants in spinal anesthesia. Thirty-nine sheep undergoing experimental pelvic limb cartilage damage surgery were enrolled. Animals were sedated with diazepam (0.4 mg kg⁻¹) and buprenorphine (10 μg kg⁻¹) intravenously. Propofol was given as needed (0.5 mg kg⁻¹) and oxygen support via face mask was continuous. Animals were positioned with the treated limb in a dependent position for the lumbosacral spinal block. Sheep were divided into three groups (n = 13), receiving lidocaine 2% (L group), lidocaine 2% + clonidine 20 μg mL⁻¹ (CL group), or lidocaine 2% + dexmedetomidine 1 μg mL⁻¹ (LD group) for spinal block (1 mL every 10 kg). Recovery times (minute) from the spinal block were recorded: anal sphincter tone (AS), recovery of sensibility (RoS), first limb movements (FMov), time of standing (ToS), and first rescue analgesia; ataxia (ATA) was also measured after standing. Dexmedetomidine increased the duration of spinal anesthesia, affecting both motor and sensory functions. Full article

Background: Local analgesia administered through a wound catheter is widely used for postoperative pain control, yet its effects on wound healing remain incompletely understood. This study examined how levobupivacaine alone or combined with meloxicam or buprenorphine influences inflammatory markers, angiogenesis, apoptosis, and transforming growth factor β1 (TGF-β1) expression during wound healing in rats. Methods: Thirty Sprague Dawley rats were assigned to five groups: control, saline, levobupivacaine (L), levobupivacaine/meloxicam (L/MEL), and levobupivacaine/buprenorphine (L/BUP). Treatments were administered via a wound catheter for three days. Blood and skin samples were collected before surgery and on days 3, 10, and 21. Results: Levobupivacaine combined with meloxicam or buprenorphine caused fluctuations in white blood cell counts, while albumin levels remained stable. Angiogenesis in the L/MEL group was markedly increased compared with the control, saline, and levobupivacaine-only groups, but the newly formed vessels exhibited consistently narrow lumina during the early healing phase. Caspase-3–positive cells were most numerous in L/MEL during inflammatory and proliferative phases, whereas delayed caspase-3 activation was observed in L/BUP. TGF-β1 expression peaked in both adjuvant groups on days 3 and 10. Conclusions: Meloxicam and buprenorphine increased TGF-β1 expression, but their vascular effects differed considerably. Meloxicam induced a marked increase in angiogenesis, but the newly formed vessels were structurally immature, displaying uniformly narrow lumina and poor architectural organisation, which led to their subsequent regression. In contrast, buprenorphine supported the formation of more mature vascular structures, characterised by wider vessel lumina and a more organised vascular network. These findings demonstrate that adjuvants used with levobupivacaine can significantly modify angiogenic and apoptotic responses and should be carefully considered when selecting multimodal local analgesia strategies after surgery. Full article

Background/Objectives: Recent studies have identified some concerns related to the occurrence of eye disorders in offspring of opioid-prescribed mothers, and especially so in those exposed to methadone. The aim here was to investigate, from a pharmacovigilance point of view, the association between opioid exposure during pregnancy and reported eye disorders in children. Methods: The FDA Adverse Event Reporting System (FAERS) was searched for the following: reports of eye disorders in children aged 0–17 years exposed during pregnancy to either methadone or buprenorphine; top 20 medications administered during pregnancy and associated with eventual occurrence of eye disorders in children; and reports of eye disorders in children from mothers prescribed with a range of psychotropics. Results: For 190 methadone and 79 buprenorphine cases, occurrence of eye disorders was registered as the consequence of having been exposed to these drugs in utero. After data cleaning, residual cases for methadone and buprenorphine were 17 and 15, respectively. Overall, in comparing the odds of eye disorders given methadone exposure to the odds of eye disorders given buprenorphine exposure, which represents a relative Reporting Odds Ratio (ROR) between two drugs, the relative ROR between methadone and buprenorphine was 0.59, suggesting lower odds of eye disorders for methadone compared to buprenorphine in children 0–17 years old antenatally exposed to either methadone or buprenorphine. Conversely, the ROR values resulting from a comparison of methadone- or buprenorphine-related data versus all other psychotropic drugs resulted in 0.27 (95% CI 0.16–0.48) and 0.47 (95% CI 0.26–0.85), respectively, indicating lower reporting odds of eye disorders for these molecules versus the pooled non-opioid comparator group. Medications prescribed during pregnancy which were most frequently related to the occurrence of eye disorders included the following: dupilumab (126 reports), valproate (69 reports), and ibuprofen (52 reports). Indeed, no opiates/opioids appeared among the top 20 drugs linked to eye disorders. A total of 25 and 11 unique cases were associated either with benzodiazepines or antipsychotics, respectively. Conclusions: No potential disproportionality safety signal for eye disorders associated with prenatal opioid exposure was identified. Specifically, the relative ROR indicated lower reporting odds for methadone compared to buprenorphine. The interpretation of these results is complicated by common co-exposures, polydrug interventions, and underlying maternal comorbidities, which introduce substantial confounding in real-world pharmacovigilance data. Overall, these findings highlight the importance of continued systematic post-marketing surveillance. Full article

The current pharmacological approach for the treatment of opioid use disorder (OUD), as a result of prescription misuse or illicit opioids, utilises opioid ligands that have either an agonist or antagonist profile. In this context, methadone and buprenorphine act as opioid agonists, whereas naltrexone functions as an opioid antagonist. To decrease the reinforcing effects of illicit opioids, higher doses of methadone and buprenorphine have been recommended, but this is associated with increased side effects. Therefore, several preclinical efforts have been carried out over the last decades to find drugs that act on receptors other than opioid receptors. A large body of preclinical evidence has shown the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists like ketamine to treat opioid addiction behaviours in animals. Indeed, ketamine by itself is an addictive drug; thus, the treatment of OUD is still a matter to be solved. Growing data position glycine transporter 1 as a possible therapeutic target for the treatment of substance use disorder. This transporter regulates the reuptake of glycine, which can modulate the function of both NMDARs and GPR158, a metabotropic glycine receptor (mGlyR); thus, it is worth investigating in the management of OUD. To gain insight into the role of glycinergic transmission in OUD, alongside NMDAR-mediated glutamatergic transmission, dopaminergic and GABAergic transmission were also reviewed. Full article

Background: Insomnia is strongly associated with stimulant use across various populations and for a wide range of substances. It represents a significant clinical problem among individuals with stimulant use disorders, yet treatment guidelines for this specific population are limited. This gap underscores the need for a systematic review to analyze the pharmacological and non-pharmacological treatments for insomnia in individuals with stimulant use disorders. The aim of this review is to determine the efficacy, safety, and limitations of these approaches and their impact on psychiatric symptoms, stimulant use, and adverse events. Methodology: A systematic review was conducted through January–July 2025 using PubMed, Scopus, and Web of Science. The review focused on the management of chronic insomnia associated with stimulant use, including substances such as amphetamines, methylphenidate, nicotine, caffeine, and cocaine. The systematic review was structured in accordance with the PRISMA guidelines, and identified studies were assessed by title/abstract and full-text evaluation. Results: A total of twenty studies were included in the systematic review. Seven studies examined pharmacological interventions, including modafinil, naltrexone/buprenorphine-naloxone, varenicline, combination NRT, and ramelteon. Thirteen studies investigated non-pharmacological approaches, including Cognitive Behavioral Therapy (CBT), Repetitive Transcranial Magnetic Stimulation (rTMS), Electrical Vestibular Nerve Stimulation (VeNS), maximal strength training, electroacupuncture (EA), and probiotics. The majority of interventions demonstrated positive outcomes in reducing insomnia severity, with some participants achieving non-clinical levels. Commonly reported clinical symptoms related to insomnia included difficulty initiating or maintaining sleep, early morning awakening, and sleep dissatisfaction. Conclusions: Both pharmacological and non-pharmacological interventions showed promise. However, the lack of validated guidelines underscores the need for integrated therapeutic approaches that address the complex comorbidity of insomnia, stimulant use, and co-occurring psychiatric conditions. Full article

Introduction: Chronic low-back pain (CLBP) is a leading cause of disability, often requiring opioid therapy when conservative treatments fail. Transdermal buprenorphine and oral oxycodone/naloxone are commonly used, but their comparative effectiveness and safety remain underexplored. Materials and Methods: In this retrospective cohort study, 173 patients with CLBP treated at our center between June 2022 and May 2024 were analyzed. Group A (n = 88) received transdermal buprenorphine (5–15 μg/h), while Group B (n = 85) was treated with oral oxycodone/naloxone (10/5–20/10 mg/day). Treatment lasted four weeks, with dose titration after one week if pain was uncontrolled. Pain intensity (VAS), functional status (ODI), rescue medication use, and adverse effects were assessed at baseline and during follow-up. Results: Both groups showed significant reductions in VAS and ODI scores. Buprenorphine led to a greater functional improvement (ODI reduction p = 0.04) and a trend toward greater pain reduction (VAS p = 0.08). Rescue drug use was significantly lower in Group A (53.4%) compared to Group B (78.8%, p = 0.003). Adverse events were more frequent in the oxycodone group, particularly nausea and constipation. Conclusions: Transdermal buprenorphine provided comparable or superior analgesia with better tolerability and reduced reliance on rescue medication. It represents a safer, effective alternative for CLBP management in routine clinical practice. Full article

Background and Objectives: This systematic review and network meta-analysis evaluated the effects of postoperative opioid use on nausea and vomiting in women undergoing laparoscopic hysterectomy. Materials and Methods: A systematic search of PubMed, EMBASE, the Cochrane Library, and RISS was conducted to identify randomized controlled trials that met the eligibility criteria. The Cochrane Risk of Bias 2 tool was used to assess the quality of the included studies. A frequentist network meta-analysis was performed to compare the risks of opioid-associated postoperative nausea and vomiting (O-PONV). Quantitative statistics were presented in forest plots, and the ranking of treatments was determined using the P-score. Results: Seventeen studies involving 1315 participants and 18 postoperative analgesic interventions were included. No significant differences were found among the opioid monotherapies—buprenorphine, butorphanol, fentanyl, oxycodone, sufentanil, and tapentadol. However, among the combination therapies, oxycodone/ketorolac therapy was associated with a significantly higher risk of O-PONV than other ketorolac-containing regimens, including dexmedetomidine, remifentanil, and fentanyl. Conclusions: No significant differences in O-PONV risk were observed among the six opioid monotherapy groups. An opioid-sparing regimen, such as dexmedetomidine/ketorolac, showed a lower risk of O-PONV than an oxycodone-based regimen, underscoring the importance of incorporating patient-centered considerations, such as patient preference and route of administration, into postoperative pain management. Full article

Opioid-use disorder (OUD) poses a growing global health crisis, with chronic opioid exposure linked not only to addiction but also to enduring neurological impairments. While traditional research has focused primarily on neuronal alterations, emerging evidence underscores the pivotal role of astrocytes, abundant glial cells in the central nervous system, and their secreted extracellular vesicles (EVs) in opioid-mediated neuropathology. This review delineates the mechanistic roles of astrocytes and astrocyte-derived EVs (ADEVs) across a spectrum of opioids, including morphine, heroin, fentanyl, codeine, tramadol, buprenorphine, and methadone. Opioids disrupt astrocytic homeostasis by impairing glutamate regulation, altering the redox balance, and activating pro-inflammatory signaling pathways. In response, astrocytes release EVs enriched with neurotoxic cargo, including amyloidogenic proteins, cytokines, microRNAs, and long non-coding RNAs, that propagate neuroinflammation, compromise blood–brain barrier (BBB) integrity, and exacerbate synaptic dysfunction. Preclinical models and in vitro studies reveal drug-specific astrocytic responses and ADEV profiles, implicating these vesicles in modulating microglial function, neuroimmune signaling, and neuronal viability. Notably, morphine-induced ADEVs promote amyloidosis and inflammatory signaling, while heroin and fentanyl affect glutamatergic and inflammasome pathways. Even opioids used in therapy, such as buprenorphine and methadone, alter astrocyte morphology and EV cargo, particularly during neurodevelopment. Collectively, these findings advance a neuro-glial paradigm for understanding opioid-induced brain injury and highlight ADEVs as both biomarkers and mediators of neuropathology. Targeting astrocyte-EV signaling pathways represents a promising therapeutic avenue to mitigate long-term neurological consequences of opioid exposure and improve outcomes in OUD. Full article

Substance use during pregnancy is an increasingly important yet under-recognized threat to maternal and child health. This narrative review synthesizes the current evidence available on the epidemiology, pathophysiology, clinical management, and policy landscape of prenatal exposure to alcohol, tobacco, opioids, benzodiazepines, cocaine, cannabis, methamphetamines, and other synthetic drugs. All major psychoactive substances readily cross the placenta and can remain detectable in breast milk, leading to a shared cascade of obstetric complications (hypertensive disorders, placental abruption, pre-term labor), fetal consequences (growth restriction, structural malformations), and neonatal morbidities such as neonatal abstinence syndrome and sudden infant death. Mechanistically, trans-placental diffusion, oxidative stress, inflammatory signaling, and placental vascular dysfunction converge to disrupt critical neuro- and cardiovascular developmental windows. Early identification hinges on the combined use of validated screening questionnaires (4 P’s Plus, CRAFFT, T-ACE, AUDIT-C, TWEAK) and matrix-specific biomarkers (PEth, EtG, FAEE, CDT), while effective treatment requires integrated obstetric, addiction, and mental health services. Medication for opioid use disorders, particularly buprenorphine, alone or with naloxone, confers superior neonatal outcomes compared to methadone and underscores the value of harm-reducing non-punitive care models. Public-health strategies, such as Mexico’s “first 1 000 days” framework, wrap-around clinics, and home-visiting programs, demonstrate the potential of multisectoral interventions, but are hampered by structural inequities and punitive legislation that deter care-seeking. Research gaps persist in polysubstance exposure, culturally tailored therapies, and long-term neurodevelopmental trajectories. Multigenerational, omics-enabled cohorts, and digital longitudinal-care platforms represent promising avenues for closing these gaps and informing truly preventive perinatal health policies. Full article

In this review, our intention was to shed some light on the history of sublingual and buccal delivery over the past 75 years. By searching the query sublingual and buccal, we noticed four steady growth periods in the number of publications between 1950 and 2025. The early phase of sublingual and buccal drug delivery (1950–1982) saw limited attempts to explore this delivery route. The exploratory growth phase (1983–1993) was marked by the use of nitroglycerin to treat angina, calcium channel blockers to treat hypertension, ACE inhibitors to treat heart conditions, the use of opioids in pain management therapy, and peptide and hormonal therapy. The diversification and discovery phase (1994–2009) was marked by the introduction of small molecules for the treatment of opioid use disorder and analgesia, the use of animal models to enhance the pharmacokinetic understanding of the sublingual and buccal route, the use of penetration enhancers, peptide and hormonal therapy, and few marked FDA drug approvals in this area. The innovation and integration phase (2010–2025) was marked by the use of nanoparticles, multilayered mucoadhesive systems, pediatric formulations (fast-dissolving films and tablets), immunotherapy and vaccine delivery, and a broad spectrum of therapeutic agents, such as steroids, antifungals, cannabinoids, antidepressants, antipsychotics, and narcotics (e.g., buprenorphine and apomorphine), novel formulations of fentanyl and diazepam for pain and seizure control, and the introduction of buccal vitamin D3 sprays. Understanding the history of sublingual and buccal delivery demonstrates a growing area of research focused on enhancing mucosal drug delivery for achieving local and systemic therapeutic benefits. Full article

Substance-induced psychosis is a recognized clinical entity, commonly linked to cannabinoids, stimulants, hallucinogens, alcohol, and polysubstance use. These agents may provoke transient or persistent psychotic symptoms during intoxication or withdrawal. Opioids, however, constitute a noteworthy exception: psychosis is rarely observed during opioid intoxication, and emerging data suggest that opioid agonists might even exert antipsychotic-like effects. This article examines the paradoxical interaction between opioids and psychosis, with attention to clinical reports of psychotic symptoms arising following abrupt discontinuation of methadone or buprenorphine. In numerous cases, symptoms resolved swiftly after reintroduction of the opioid agonist, implying a neuromodulatory role. Opioids, unlike other substances of abuse, seem to lack intrinsic psychotogenic effects and may influence dopaminergic activity via kappa-opioid receptor antagonism and endorphinergic mechanisms. This challenges standard models of substance-induced psychosis and calls for a refined understanding of opioid pharmacodynamics in psychiatric contexts. In psychotic presentations among polysubstance users who also use opioids, restoring opioid agonist therapy should be prioritized, with antipsychotics reserved as second-line options—preferably agents with favorable receptor profiles. Where opioids are not involved, antipsychotics remain first-line, but should be applied judiciously, with efforts to taper when clinically appropriate. Full article

The use of opioids for cancer-related pain is essential but poses significant challenges due to the risk of misuse and the development of opioid use disorder (OUD). This review takes a multidisciplinary perspective based on the current scientific literature to analyze the pharmacological mechanisms, classification, and therapeutic roles of opioids in oncology. Key risk factors for opioid misuse—including psychiatric comorbidities, prior substance use, and insufficient clinical monitoring—are discussed in conjunction with validated tools for pain assessment and international guidelines. The review emphasizes the importance of integrating toxicological, pharmacological, physiological, and public health perspectives to promote rational opioid use. Pharmacogenetic variability is explored as a determinant of treatment response and addiction risk, underscoring the value of personalized medicine. Evidence-based strategies such as early screening, psychosocial interventions, and the use of buprenorphine-naloxone are presented as effective measures for managing OUD in cancer patients. Ultimately, this work advocates for safe, patient-centered opioid prescribing practices that ensure effective pain relief without compromising safety or quality of life. Full article

Opioid use disorder (OUD) is a chronic disease that remains difficult to treat, even with significant improvements in available medications. While current treatments work well for some, they often do not account for the unique needs of individual patients, leading to less-than-ideal results. Precision medicine offers a new path forward by tailoring treatments to fit each person’s genetic, psychological, and social needs. This review takes a close look at medications for OUD, including methadone, buprenorphine, and naltrexone, as well as long-acting options that may improve adherence and convenience. Beyond medications, the review highlights the importance of addressing mental health co-morbidities, trauma histories, and social factors like housing or support systems to create personalized care plans. The review also explores how emerging technologies, including artificial intelligence and digital health tools, can enhance how care is delivered. By identifying research gaps and challenges in implementing precision medicine into practice, this review emphasizes the potential to transform OUD treatment. A more individualized approach could improve outcomes, reduce relapse, and establish a new standard of care focused on recovery and patient well-being. Full article