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Addiction is a feel good or euphoria like condition which is commonly associated with drug abuse (opioid & non-opioid), alcohol and nicotine intake. There are many reasons behind a man gets addicted to these substances such as recreation purpose, drugs used for long time for treatment of any disorder and gets addicted, unemployment, stress, emotions, professional pressure and social status. It provides enjoyable feelings which results in creating a strong urge to use the substances again and again. These drugs can cause physical dependence or psychological dependence or both. Over time, drug tolerance is produced which means to get the same effect more quantity of the drug is needed. These substances are very harmful physically, mentally, financially and socially too. If someone suddenly terminates using these substances after heavy or long term use, the body needs time to recover and number of withdrawal symptoms arises. These withdrawal symptoms can’t be treated by medications only but it needs counselling and support as well. This article reviews i. the drug abuse (opioid & non-opioid), alcohol and nicotine addictions with their withdrawal symptoms and medications used to treat these symptoms ii. Rehabilitation centers running and other steps taken by Government of India to aware people especially the youths of the country about the harmful effects of these substances.

Benzodiazepines (BZDs) are among one of the most widely prescribed drug classes in the United States. BZDs are a class of psychoactive drugs known for their depressant effect on the central nervous system (CNS). They quickly diffuse through the blood–brain barrier to affect the inhibitory neurotransmitter GABA and exert sedative effects. Related to their rapid onset and immediate symptom relief, BZDs are used for those struggling with sleep, anxiety, spasticity due to CNS pathology, muscle relaxation, and epilepsy. One of the debilitating side effects of BZDs is their addictive potential. The dependence on BZDs generally leads to withdrawal symptoms, requiring careful tapering of the medication when prescribed. Regular use of BZDs has been shown to cause severe, harmful psychological and physical dependence, leading to withdrawal symptoms similar to that of alcohol withdrawal. Some of these withdrawal symptoms can be life threatening. The current treatment for withdrawal is through tapering with clonazepam. Many drugs have been tested as a treatment for withdrawal, with few proving efficacious in randomized control trials. Future research is warranted for further exploration into alternative methods of treating BZD withdrawal. This call to action proves especially relevant, as those seeking treatment for BZD dependence and withdrawal are on the rise in the United States.

Nociceptin opioid peptide (NOP) receptor modulates pain transmission and is considered a prospective target for pain management. Under acute pain conditions in rodents, however, no definitive conclusions about effects of systemically intervening NOP receptors on nociception, classical opioid-induced antinociception, tolerance and physical dependence have been drawn. Given that opioid analgesia has sex differences, and females experience greater pain and consume more opioids, clarifying these issues in females will help develop novel analgesics. To clarify the role of NOP receptors on the pharmacological profiles of µ-opioid receptor agonists, in this study, a selective agonist (SCH221510) and antagonist (SB612111) of the NOP receptor were subcutaneously administered in female mice in multiple animal models. In hot-plate test, neither SCH221510 (3 and 10 mg/kg, sc) nor SB612111 (10 mg/kg, sc) produced significant antinociception. SCH221510 (3 mg/kg, sc) attenuated but SB612111 (10 mg/kg, sc) enhanced morphine-induced antinociception, with rightward and leftward shift of morphine dose-response curves, respectively. SCH221510 (3 mg/kg, sc) combined with morphine (10 mg/kg, sc) accelerated the development of morphine antinociceptive tolerance. Conversely, SB612111 (10 mg/kg, sc) delayed morphine tolerance development. Neither SCH221510 (3 mg/kg, sc) nor SB612111 (10 mg/kg, sc) statistically significantly altered the development of morphine-induced physical dependence. Therefore, systemic activation of NOP receptors attenuated morphine antinociception to acute thermal stimuli, facilitated morphine-induced antinociceptive tolerance but did not robustly alter physical dependence in female mice. Systemic blockade of NOP receptors produced opposite actions. These findings demonstrate that N/OFQ-NOP receptor system plays diverse roles in modulating pharmacological profiles of µ-opioid receptor agonists.

Introduction Postoperative pain is often managed by opioid medications, even though they carry a risk of adverse effects such as vomiting, constipation, sedation, respiratory depression and physical dependence. Furthermore, opioid use in the healthcare setting has likely contributed to the epidemic. However, the mismanagement of postoperative pain can result in delayed recovery time, impaired physical function, increased risk of morbidity and mortality, chronic pain, and higher healthcare costs. Areas covered This review explores emerging therapeutic options and strategies in the management of acute postoperative pain and focuses on opioid-sparing, multimodal analgesia. This includes regional anesthetic techniques, non opioid pharmacotherapy, novel opioids and non-pharmacologic therapy. We have also discussed examples of novel analgesics and formulations which have potential benefits in reducing postoperative pain and opioid use after surgery. Expert opinion The development of novel regional anesthesia techniques allows for opioid minimization in increasing number of surgical procedures. This synergizes with the availability of novel non-opioid analgesic adjucts. In addition, several novel opioid drugs have been developed which may be pathway selective and associated with less adverse effect than conventional opioids.

Most conventional insomnia medications are gamma‐aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long‐term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta‐analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5‐ and 10‐mg lemborexant were superior to 20‐mg suvorexant because of the greater improvement in initiating sleep after 1‐week administration. Furthermore, 5‐mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5‐mg lemborexant as an initial treatment for insomnia, followed by 10‐mg lemborexant or suvorexant., A network meta‐analysis of the dual orexin receptor antagonists, suvorexant, and lemborexant, showed that 5‐ and 10‐mg lemborexant were superior to 20‐mg suvorexant, with greater improvement in sleep onset after 1 week of treatment. In addition, 5‐mg (but not 10‐mg) lemborexant and suvorexant were similarly well tolerated. We have overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical results, and recommended 5‐mg lemborexant as initial treatment for insomnia, followed by 10‐mg lemborexant or suvorexant.

Background: The more the cancer treatments progress, the more the needs increase to taper and discontinue opioids in cancer patients. Furthermore, opioid dependence of cancer survivors has become a bigger problem. However, a safe opioid tapering and discontinuation method has not yet been established in cancer patients. Objective: To suggest a safe opioid tapering and discontinuation method in cancer patients. Design: We reviewed opioid type, dose, administration route, administration duration, reason for tapering and discontinuation, and presence/absence of opioid withdrawal symptoms in cancer patients whose opioids needed to be tapered and discontinued. Setting/Subjects: We recruited cancer patients referred to the palliative care team of Kyoto University Hospital-Japan whose opioids were tapered and discontinued. Measurements: Opioid withdrawal symptoms were assessed by two physicians, one nurse, and one pharmacist of palliative care team. Results: Opioids were tapered and discontinued in 25 out of 145 cancer patients (17%). Opioid withdrawal symptoms were observed in 3 of the 25 cases (12%). In withdrawal symptom cases and nonwithdrawal symptom cases, the mean maximum oral morphine-equivalent doses of opioids were 352.0 and 55.7 mg/day, and the mean administration duration of opioid were 82.3 and 28.7 days, respectively. Withdrawal symptoms occurred in patients receiving higher-dose opioids with longer administration duration and their symptoms tended to appear at approximately 10% of the maximum dose. Conclusions: We suggest that withdrawal symptoms may be prevented by using a two-stage method rather than a monotonous tapering method in cancer patients whose higher-dose opioid with longer administration duration needed to be tapered and discontinued.

Dual orexin receptor antagonists (DORAs) represent a novel type of sleep medication that provide an alternative to the traditionally used positive allosteric gamma-aminobutyric acid (GABA)-A receptor modulators. Daridorexant is a new DORA that exhibited in phase 3 trials in insomnia not only a beneficial effect on sleep variables, measured objectively and assessed subjectively, but also an improvement in daytime functioning. Daridorexant was discovered through a tailored research program aimed at identifying an optimized sleep-promoting molecule with pharmacokinetic properties appropriate for covering the whole night while avoiding next-morning residual activity at efficacious doses. By specific binding to both orexin receptors, daridorexant inhibits the actions of the wake-promoting orexin (also called hypocretin) neuropeptides. This mechanism avoids a more widespread inhibition of neuronal pathways and associated side effects that are intrinsic to positive allosteric GABA-A receptor modulators. Here, we review the general pharmacology of daridorexant, based on nonclinical pharmacology studies of daridorexant, unpublished or already described, or based on work with other DORAs. Some unique features of daridorexant will be highlighted, such as the promotion of natural and surmountable sleep, the preservation of memory and cognition, the absence of tolerance development or risk of physical dependence, and how it can benefit daytime functioning. Supplementary Information The online version contains supplementary material available at 10.1007/s00213-021-05954-0.

Pregabalin is a drug that can cause psychiatric symptoms via pregabalin withdrawal. Prior reports on pregabalin withdrawal have mainly focused on cases with pregabalin dependence or abuse, and little attention has been paid to patients who are prescribed regular doses of pregabalin. Herein, we report three cases of pregabalin withdrawal in patients without psychiatric disorders, taking regular doses of pregabalin, who developed psychiatric symptoms such as insomnia and anxiety after abrupt discontinuation of pregabalin. In addition, we conducted a systematic review of six case reports (previous studies) of pregabalin withdrawal under regular doses of pregabalin. Among the six cases, three patients had no comorbid mental or substance use disorders, the dose of pregabalin ranged from 150 to 600 mg/d, and the duration of pregabalin use ranged from a few weeks to many years. Of these six cases of pregabalin withdrawal, five had psychopathological symptoms, three had vegetative symptoms, and three had neurologic and physical complications. We concluded that since pregabalin withdrawal can occur even with regular doses and short‐term use, clinicians must carefully reduce pregabalin doses when reducing or discontinuing treatment, paying close attention to withdrawal symptoms. Our case series sheds light on the scant evidence from previous research on physical dependence in patients who are taking regular doses of pregabalin. Furthermore, our cases were also valuable in demonstrating that pregabalin withdrawal can occur even after a relatively short period of 2 months., This case series shows pregabalin withdrawal in patients without psychiatric disorders taking a regular dose of pregabalin. Our cases demonstrated that pregabalin withdrawal can occur even after a relatively short period of 2 months following regular doses of pregabalin.

Drug addiction is a global health problem and continues to place an enormous financial burden on society. This addiction is characterized by drug dependence sensitization and craving. Morphine has been widely used for pain relief, but chronic administration of morphine causes analgesic tolerance, hyperalgesia, and addiction, all of which limit its clinical usage. Alterations of multiple molecular pathways have been reported to be involved in the development of drug addiction, including mitochondrial dysfunction, excessive oxidative stress and nitric oxide stress, and increased levels of apoptosis, autophagy, and neuroinflammation. Preclinical and clinical studies have shown that the co-administration of melatonin with morphine leads to a reversal of these affected pathways. In addition, murine models have shown that melatonin improves morphine-induced analgesic tolerance and addictive behaviors, such as behavioral sensitization, reward effect, and physical dependence. In this review, we attempt to summarize the recent findings about the beneficial effect and molecular mechanism of melatonin on mitochondrial dysfunction, uncontrolled autophagy, and neuroinflammation in morphine addiction and morphine analgesic tolerance. We propose that melatonin might be a useful supplement in the treatment opiate abuse.

AIMS: Intravenous (IV) misuse of the μ opioid analgesic oxymorphone has caused significant public health harms; however, no controlled data on its IV abuse potential are available. The primary aim of this pilot study was to directly compare IV oxymorphone to IV oxycodone, morphine and hydromorphone on a subjective measure of drug liking and to assess relative potency. METHODS: Participants (n=6) with opioid use disorder, physical dependence and current IV use completed this two-site, within-subject, double-blind, placebo-controlled, inpatient pilot study. During each session, one IV dose (mg/70 kg) was administered: oxymorphone (1.8, 3.2, 5.6, 10, 18, 32), hydromorphone (1.8, 3.2, 5.6, 10, 18), oxycodone (18, 32, 56), morphine (18, 32) and placebo. Data were collected before and for 6 h after dosing. Primary outcomes included safety/physiological effects, subjective reports of drug liking and relative potency estimates. RESULTS: All active test drugs produced prototypical, dose-related μ opioid agonist effects (e.g., miosis). Oxymorphone was more potent than the comparator opioids on several measures, including drug liking and respiratory depression (p

Preclinical studies demonstrate that the NK1 receptor is involved in opioid reinforcement and withdrawal expression. Few studies have examined the impact of treatment with NK1 antagonists on opioid response in humans. To explore the potential for a selective NK1 antagonist, tradipitant, to attenuate the abuse liability and reinforcing and analgesic effects of oxycodone in opioid-experienced individuals. Participants with recreational opioid use, but without opioid physical dependence, were enrolled as inpatients for ~6 weeks (n = 8). A within-subject, double-blind, randomized, placebo-controlled, crossover design was employed. The pharmacodynamic response to intranasal oxycodone across a range of doses (0 to 30 mg) was examined during two counterbalanced maintenance periods (tradipitant 0 or 85 mg/bid). Oxycodone self-administration was assessed with a modified progressive ratio procedure, and analgesia was assessed with the cold pressor test. Oxycodone produced significant and dose-related increases on a broad array of prototypic opioid measures, including subjective ratings related to abuse liability (e.g., liking) and physiological outcomes (i.e., expired CO2). Oxycodone self-administration increased with increasing dose, as did analgesia. Tradipitant largely did not alter any of these effects of oxycodone, with the exception of producing a reduction in ratings of desire for opioids. Given that the vast majority of oxycodone effects were unchanged by tradipitant, these data do not provide support for the utility of NK1 antagonists as a potential treatment for opioid use disorder.

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea “Kratom” and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined Kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n=10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), Kratom alkaloid extract (orally, p.o.), mitragynine (p.o.) or MP (subcutaneously, s.c.) for five days. Mice treated chronically with morphine, KAE or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically-dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine or MP given twice daily over the next three days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, Kratom, mitragynine and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

Rationale: The emergence of the consumption of highly potent synthetic cannabinoid receptor agonists (spice drugs) that produce important neurological symptoms has prompted the research on the consequences of acute and chronic use of these new psychoactive substances. Most studies on cannabinoid dependence have been performed in male animals, and there is a need of studies using female subjects. Objectives: In the present study, we evaluated only in female animals the role of dopamine D1 receptors in the behavioral responses induced by acute and repeated stimulation of cannabinoid CB1 receptors, including the development of physical dependence, since cannabinoid CB1 receptors are co-localized with dopamine D1 receptors on GABAergic neurons projecting to the substantia nigra. Methods: To this end, female dopamine D1 receptor-deficient mice and wild-type littermates were treated with HU-210, a potent synthetic cannabinoid agonist. Results: Mutant mice displayed an enhanced response to acute motor and hypothermic effects to HU-210 when compared with wild-type females. The administration of SR141716A precipitated behavioral signs of withdrawal in mice treated subchronically with HU-210. Severity of cannabinoid withdrawal syndrome was potentiated in dopamine D1-deficient female mice. Indeed, 4 of 6 abstinence signs were increased in mutant mice. Conclusions: These results support for a role of dopamine D1 receptors in the acute, chronic, and withdrawal actions of spice drugs., This work was supported by Red de Trastornos Adictivos, Instituto de Salud Carlos III and European Regional Development Funds-European Union (RD16/0017/001 to F.R.F); Ministerio de Economía y Competitividad, Instituto de Salud Carlos III and European Regional Development Funds-European Union (PI19/01755 to F.R.F and PI17/02026 to A.S); and Plan Nacional sobre Drogas and Ministerio de Sanidad, Servicios Sociales e Igualdad (PND2019/040, PND2018/044, PND2018/033, PND2017/043). AS, FJP and JS hold Miguel Servet research contracts funded by Instituto de Salud Carlos III and European Regional Development Funds-European Union (CP14/00173 to A.S, CP14/00212 to F.J.P and CPII17/00024 to J.S.).

Background and aim: Anxiety is one of the most common psychiatric disorders that lead to the disruption of daily life and also the quality of life. Routine medications have many side effects and cause physical dependence and psychosocial addiction. Diosgenin is a phytosteroid found in a number of herbs. The present study aimed to investigate the anxiolytic-like effect of diosgenin in the maternal separation model in male mice focusing on the role of NMDA receptors. Material and Methods: Maternal separation (MS) paradigm was performed daily (3 h) from postnatal day (PND) 2-14. Male mice were treated with different doses of diosgenin to find effective and sub-effective doses. In the next step, mice were treated with an effective dose of diosgenin plus NMDA and or a sub-effective dose of diosgenin plus ketamine (NMDA antagonist). Valid behavioral tests for the evaluation of anxiety-like behavior were performed. Then, mice were euthanized, the hippocampus was dissected out and gene expression of NMDA receptors (NR2a and NR2b subunits) was assessed. Results: MS provokes anxiety-like behaviors in the open field test (OFT) and elevated plus maze (EPM) test. Diosgenin significantly mitigated the negative effects of MS. Co-administration of NMDA attenuated anxiolyticlike effect of the effective dose of diosgenin, while ketamine potentiated the anxiolytic effect of sub-effective dose of diosgenin. Furthermore, MS increased the expression of the NMDA receptor in the hippocampus which to some extent modulated with diosgenin. Conclusion: Diosignin has an anxiolytic-like effect on MS mice which at least, in part, mediated through NMDA receptors.

On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines”. With this announcement, the FDA proclaimed that much more needs to be known about the initiation, continuation, and discontinuation of these widely-used drugs. Unfortunately, relevant information is lacking, since for many years, there has been a notable sparsity in the funding and conduct of basic and clinical research on these drugs. In order to begin to fill the void, it is valuable to (re)examine animal models. We here describe a model of conditioned place-preference (CPP) for rats and for the first time, to our knowledge, show that the representative benzodiazepine alprazolam induces positive place-preference in male rats.

The benzodiazepines were introduced into medical practice during the 1960s. At the time, they represented a safer alternative to extant therapies used for anxiety, such as the barbiturates. However, on September 23, 2020, the United States FDA indicated that more is needed to be known about the initiation, continuation, and discontinuation of the use of these widely-used drugs with publication of the announcement “to address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines.” Because for many years, there has been a sparsity of research on these drugs, relevant information is unfortunately lacking at this critical time. It is therefore valuable to (re)establish animal models and begin to collect relevant data. We here use a model of conditioned place preference (CPP) which suggests that the representative benzodiazepine alprazolam induces positive place preference in female rats.

After the identification of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) and its cognate receptor, the unique functional profiles of the N/OFQ-NOP receptor system have been uncovered. NOP receptors are distributed in the key regions that regulate pain and reward processing in the central nervous system. In non-human primates (NHPs), activation of the NOP receptor causes antinociception and anti-hypersensitivity via spinal and supraspinal effects. Moreover, activation of the NOP receptor attenuates dopaminergic transmission and potentiates mu-opioid peptide (MOP) receptor-mediated analgesia. Here, we highlight the functional profiles of bifunctional NOP and MOP receptor agonists based on their promising effects for the treatment of pain and drug abuse. Bifunctional NOP/MOP receptor "partial" agonists, such as AT-121, BU08028, and BU10038, exert potent analgesic effects without MOP receptor-related side effects such as abuse liability, respiratory depression, physical dependence, and itching in NHPs. These novel NOP/MOP receptor agonists reduce rewarding and the reinforcing effects of abused drugs. Furthermore, a mixed NOP/opioid receptor "full" agonist, cebranopadol, is undergoing several clinical trials, and the therapeutic advantage of the coactivation of NOP and MOP receptors has also been confirmed in humans. Therefore, this class of drugs that coactivate NOP and MOP receptors proposes a wide therapeutic range with fewer side effects, indicating a greater potential for the development of novel safer opioid analgesics.

Background: Several pharmaceutical treatments for chronic pain caused by osteoarthritis (OA) and chronic low back pain (CLBP) are available or currently under development, each associated with different adverse events (AEs) and efficacy profiles. It is therefore important to understand what trade-offs patients are willing to make when choosing between treatments. Methods: A discrete-choice experiment (DCE) was conducted with 437 adults with chronic pain caused by OA and/or CLBP. Respondents were presented with a series of scenarios and asked to choose between pairs of hypothetical treatments, each defined by six attributes: level of symptom control; risks of heart attack, rapidly progressive osteoarthritis and dependency; frequency and mode of administration and cost. Attributes were based on known profiles of oral nonsteroidal anti-inflammatory drugs, opioids and injected nerve growth factor inhibitors, the last of which were under clinical development at the time of the study. Data were analysed using a latent class (LC) model to explore preference heterogeneity. Results: Overall, respondents considered improving symptom control and reducing risk of physical dependency to be the most important attributes. The LC analysis identified four participant classes: an ‘efficacy-focused’ class (33.7%), a ‘cost-averse’ class (29.4%), a ‘physical-dependence–averse’ class (19.6%) and a ‘needle-averse’ class (17.3%). Subgroup membership was incompletely predicted by participant age and their responses to comprehension questions. Conclusions: Preference heterogeneity across respondents indicates a need for a personalized approach to offering treatment options. Symptom improvement, cost, physical dependence and route of administration might be important to different patients. Significance: Multiple treatment options that differ substantially in terms of efficacy and adverse events are available for the management of chronic pain. With a growing emphasis on a patient-centred care model that incorporates patients’ priorities and values into treatment decisions, there is a need to understand how individuals with chronic musculoskeletal pain balance the benefits and risks of treatment and how treatment priorities vary among individuals. This study was designed to identify patient preferences for different characteristics of treatments for the management of chronic pain and to investigate how preferences differ among respondents.

An increasing number of chronic pain patients presenting for surgery are chronic opioid users. Pain management in the postoperative period can be challenging in this population due to the development of tolerance, physical dependence, and hyperalgesia in long-term opioid users. It is common for postoperative pain to be undertreated in these patients, leading to an overall increase in length of hospital stays, health care costs, and decreased patient satisfaction. Identifying opioid-tolerant patients and developing a perioperative pain management plan are important components of a patient's overall recovery after any surgical procedure.

Morphine is a potent analgesic agent used to control acute or chronic pain. Chronic administration of morphine results in analgesic tolerance, hyperalgesia, and other side effects including dependence, addiction, respiratory depression, and constipation, which limit its clinical usage. Therefore, identifying the new analgesics with fewer side effects which could increase the effect of morphine and reduce its side effects is crucial. Melatonin, a multifunctional molecule produced in the body, is known to play an important role in pain regulation. The strong anti-inflammatory effect of melatonin is suggested to be involved in the attenuation of the pain associated with inflammation. Melatonin also increases the anti-nociceptive actions of opioids, such as morphine, and reverses their tolerance through regulating several cellular signaling pathways. In this review, published articles evaluating the effect of the co-consumption of melatonin and morphine in different conditions were investigated. Our results show that melatonin has pain-killing properties when administered alone or in combination with other anti-nociceptive drugs. Melatonin decreases morphine consumption in different pathologies. Furthermore, attenuation of morphine intake can be accompanied by reduction of morphine-associated side-effects, including physical dependence, morphine tolerance, and morphine-related hyperalgesia. Therefore, it is reasonable to believe that the combination of melatonin with morphine could reduce morphine-induced tolerance and hyperalgesia, which may result from anti-inflammatory and antioxidant properties of melatonin. Overall, we underscore that, to further ameliorate patients' life quality and control their pain in various pathological conditions, melatonin deserves to be used with morphine by anesthesiologists in clinical practice.

Chronic use of opioids as morphine and tramadol to control pain is associated with several side effects and tolerance to their analgesic effect and dependence. Some of the side effects of opioids can be ameliorated by naloxone, however this is associated with decreased analgesia. Nalbuphine was shown to ameliorate morphine and tramadol psychological dependence. The current study aims to investigate the effect of co-administration of nalbuphine with morphine or tramadol on tolerance to analgesia and physical dependence and the possible involvement of norepinephrine in its effect.Co-admistration of nalbuphine with morphine or tramadol prevented tolerance to analgesia and physical dependence that was observed with each drug alone and this was associated with prevention of the elevation in norepinephrine in the locus coereulus (LC) following naloxone administration.These results emphasize the possible use of nalbuphine in combination with morphine or tramadol to preserve their analgesic effect and to prevent the development of dependence to their effect.

Following the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) as an endogenous ligand for the NOP receptor, ample evidence has revealed unique functional profiles of the N/OFQ-NOP receptor system. NOP receptors are expressed in key neural substrates involved in pain and reward modulation. In nonhuman primates (NHPs), NOP receptor activation effectively exerts antinociception and anti-hypersensitivity at the spinal and supraspinal levels. Moreover, NOP receptor activation inhibits dopaminergic transmission and synergistically enhances mu-opioid peptide (MOP) receptor-mediated analgesia. In this article, we have discussed the functional profiles of ligands with dual NOP and MOP receptor agonist activities and highlight their optimal functional efficacy for pain relief and drug abuse treatment. Through coactivation of NOP and MOP receptors, bifunctional NOP/MOP receptor "partial" agonists (e.g., AT-121, BU08028, and BU10038) reveal a wider therapeutic window with fewer side effects. These newly developed ligands potently induce antinociception without MOP receptor agonist-associated side effects such as abuse potential, respiratory depression, itching sensation, and physical dependence. In addition, in both rodent and NHP models, bifunctional NOP/MOP receptor agonists can attenuate reward processing and/or the reinforcing effects of opioids and other abused drugs. While a mixed NOP/opioid receptor "full" agonist cebranopadol is undergoing clinical trials, bifunctional NOP/MOP "partial" agonists exhibit promising therapeutic profiles in translational NHP models for the treatment of pain and opioid abuse. This class of drugs demonstrates the therapeutic advantage of NOP and MOP receptor coactivation, indicating a greater potential for future development.

RATIONALE: In order to understand mechanisms underlying tolerance and dependence following chronic benzodiazepine treatments, quantitative and reproducible behavioral models of these phenomena are required. OBJECTIVES: This research evaluated the ability of chronic treatment with a commonly-prescribed benzodiazepine, alprazolam, to induce tolerance to sedative effects and physical dependence using a novel set of behavioral measurements in rhesus monkeys. METHODS: Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered i.v. alprazolam (1.0 mg/kg every 4 h, 38 days total). Quantitative observation measures were obtained during the 38 days of treatment. Acute administration of the benzodiazepine receptor antagonist flumazenil (0.1, 0.3 mg/kg, i.v.) was given to assess precipitated withdrawal. On day 39, saline was substituted for alprazolam and withdrawal signs were assessed for 7 days. RESULTS: Maximal sedation (“deep sedation”) was evident on day 1 but was not significantly different from baseline levels by day 4 and was absent for the remainder of the 38 days of treatment. A milder form of sedation, “rest/sleep posture”, emerged by day 3 and did not decline over 38 days. Cessation of alprazolam treatment resulted in significant withdrawal signs (nose rub, vomit, procumbent posture, tremor/jerk, rigid posture) that dissipated by day 3. These signs also were observed with flumazenil (0.3 mg/kg). CONCLUSIONS: Chronic alprazolam treatment resulted in rapid tolerance to some behaviors (e.g., deep sedation) but no tolerance to others (e.g., rest/sleep posture). Physical dependence was observed via both spontaneous and precipitated withdrawal. Based on previous research, these phenomena may reflect differential plasticity at GABA(A) receptor subtypes.

PurposeTo determine which factors are associated with physical inactivity in hospitalized adults of all ages.MethodsA cross-sectional sample of 114 adults admitted to a gastrointestinal surgery, internal medicine or cardiology hospital ward (median age 60, length of stay 13 days) were observed during one random day from 8 am to 8 pm using wireless accelerometers and behavioral mapping protocols. Factors (e.g., comorbidities, self-efficacy, independence in mobility, functional restraints) were collected from medical records, surveys, and observations.ResultsPatients were physically active for median(IQR) 26 (13–52.3) min and were observed to lie in bed for 67.3%, sit for 25.2%, stand for 2.5%, and walk for 5.0% of the time. Multivariable regression analysis revealed that physical inactivity was 159.87% (CI = 89.84; 255.73) higher in patients dependent in basic mobility, and 58.88% (CI = 10.08; 129.33) higher in patients with a urinary catheter (adjusted R2 = 0.52). The fit of our multivariable regression analysis did not improve after adding hospital ward to the analysis (p > 0.05).ConclusionsIndependence in mobility and urine catheter presence are two important factors associated with physical inactivity in hospitalized adults of all ages, and these associations do not differ between hospital wards. Routine assessments of both factors may therefore help to identify physically inactive patients throughout the hospital.IMPLICATIONS FOR REHABILITATIONHealthcare professionals should be aware that physical inactivity during hospital stay may result into functional decline.Regardless of which hospital ward patients are admitted to, once patients require assistance in basic mobility or have a urinary catheter they are at risk of physical inactivity during hospital stay.Implementing routine assessments on the independence of basic mobility and urine catheter presence may therefore assist healthcare professionals in identifying physically inactive patients before they experience functional decline.

Introduction: Cannabis is the most widely used illicit drug in the US, and cannabis use among young adults continues to rise. Previous studies have shown that chronic administration of delta 9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, induces dependence in animal models. Because smoking is the most frequent route of THC self-administration, it is critical to investigate the effects of cannabis smoke inhalation. The goal of the current study was to develop a rat model to characterize the pharmacokinetics (PKs) of THC after cannabis smoke inhalation, and to determine if chronic cannabis smoke inhalation leads to the development of cannabis dependence. Materials and Methods: For the PK study, male Wistar rats were administered THC intravenously (1 mg/kg) or exposed to smoke from 5 or 10 sequentially smoked cannabis cigarettes (5.3% THC) in an automated smoking machine. Plasma samples were collected from 10 min to 10 hours post smoke exposure (or intravenous administration) and analyzed using liquid chromatography–mass spectrometry to characterize the PK of THC. A three-compartment PK model was used to characterize the PKs. In a separate study, three groups of male Wistar rats were trained in an intracranial self-stimulation (ICSS) procedure, and exposed to smoke from burning 5 or 10 cannabis cigarettes (or clean air control conditions), 5 days/week for 4 weeks. Discussion and Conclusions: Across exposure days, the change from baseline in ICSS thresholds for cannabis smoke-exposed groups was significantly lower and response latencies were significantly faster in the cannabis smoke-exposed groups compared to controls, suggesting that chronic cannabis smoke exposure has rewarding properties. Acute administration of the CB1 receptor antagonist rimonabant (0.3, 1.0, 3.0 mg/kg) induced a dose-dependent increase in ICSS thresholds in the smoke-exposed rats, suggestive of dependence and withdrawal. Finally, an effect compartment PK-pharmacodynamic model was used to describe the relationship between THC concentrations and changes in ICSS thresholds after cannabis smoke exposure.

Benzodiazepine and related sedative use has been increasing. There has been a growing number of unregulated novel psychoactive substances, including designer benzodiazepines. Benzodiazepines have neurobiological and pharmacologic properties that result in a high potential for misuse and physical dependence. Options for discontinuing long-term benzodiazepine use include an outpatient benzodiazepine taper or inpatient withdrawal management at a hospital or detoxification facility. The quality of evidence on medications for benzodiazepine discontinuation is overall low, whereas cognitive behavioral therapy has shown the most benefit in terms of behavioral treatments. Benzodiazepines may also have significant adverse effects, increasing the risk of overdose and death.

Because of increased opioid misuse, there is a need to identify new targets for minimizing opioid tolerance, and physical and psychological dependence. Previous studies showed that fibroblast growth factor 21 (FGF21) decreased alcohol and sweet preference in mice. In this study, FGF21-transgenic (FGF21-Tg) mice, expressing high FGF21 serum levels, and wildtype (WT) C57BL/6J littermates were treated with morphine and saline to determine if differences exist in their physiological and behavioral responses to opioids. FGF21-Tg mice displayed reduced preference for morphine in the conditioned place preference assay compared to WT littermates. Similarly, FGF21-Tg mice had an attenuation of the magnitude and rate of acute morphine antinociceptive tolerance development, and acute and chronic morphine physical dependence, but exhibited no change in chronic morphine antinociceptive tolerance. The ED50 values for morphine-induced antinociception in the 55°C hot plate and the 55°C warm-water tail withdrawal assays were similar in both strains of mice. Likewise, FGF21-Tg and WT littermates had comparable responses to morphine-induced respiratory depression. Overall, FGF21-Tg mice had a decrease in the development of acute analgesic tolerance, and the development of physical dependence, and morphine preference. FGF21 and its receptor have therapeutic potential for reducing opioid withdrawal symptoms and craving, and augmenting opioid therapeutics for acute pain patients to minimize tolerance development.

The opioid epidemic was triggered by an overprescription of opioid analgesics. In the treatment of chronic pain, repeated opioid administrations are required which ultimately lead to tolerance, physical dependence, and addiction. A possible way to overcome this conundrum consists of a co-medication that maintains the analgesic benefits of opioids while preventing their adverse liabilities. YHS, the extract of the plant Corydalis yanhusuo, has been used as analgesic in traditional Chinese medicine for centuries. More recently, it has been shown to promote analgesia in animal models of acute, inflammatory, and neuropathic pain. It acts, at least in part, by inhibiting the dopamine D2 receptor, suggesting that it may be advantageous to manage addiction. We first show that, in animals, YHS can increase the efficacy of morphine antinociceptive and, as such, decrease the need of the opioid. We then show that YHS, when coadministered with morphine, inhibits morphine tolerance, dependence, and addiction. Finally, we show that, in animals treated for several days with morphine, YHS can reverse morphine dependence and addiction. Together, these data indicate that YHS may be useful as a co-medication in morphine therapies to limit adverse morphine effects. Because YHS is readily available and safe, it may have an immediate positive impact to curb the opioid epidemic.

Alcohol use is associated with a significant variety of harms to both the individual and society. Screening for alcohol use disorders should be part of most clinical assessments. It is particularly important to identify people with features of physical dependence as they can be at risk of complications on alcohol withdrawal. Identification and brief advice can be effective at targeting drinking in low-risk individuals, but higher risk individuals with more severe alcohol use disorders may require specialist interventions. Alcohol withdrawal should be treated with long-acting benzodiazepines, ideally in a planned way as part of a comprehensive treatment plan including psychosocial intervention. There is a risk of neurotoxicity associated with repeated alcohol withdrawal and detoxification, so the relative risks and benefits to patient should always be weighed up. Wernicke–Korsakoff's syndrome should be considered in all individuals with a significant alcohol use disorder and the presence of a single suggestive symptom should be sufficient to prompt treatment. Alcohol use disorders are relapsing and remitting conditions; therefore it is important that health professionals convey a sense of hope and optimism to promote a patient's sense of self-efficacy as they work towards recovery.

Aims Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting μ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol. Main methods Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine. Key findings Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α2-adrenoceptor (α2-AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment. Significance Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI.

Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

Best practice guidelines for the safe and compassionate care of critically ill children necessitates the use of sedation to ensure adequate ventilation, patient safety and comfort. Prolonged use of sedation can result in tolerance, physical dependence and iatrogenic withdrawal syndrome if medications are weaned too quickly.In the context of medication errors related to parent administration of outpatient sedation weans, we set out to improve the safety of children weaning from sedatives.A retrospective analysis was completed. Quality improvement was guided by using Plan-Do-Study-Act cycles.An evidence-based post PICU sedation weaning guideline was created and implemented over time with ongoing education, and review of progress with staff members with pre-post evaluation.Post intervention, there were significant differences in the numbers of patients discharged on home weaning from both opioids and benzodiazepines (11%, n = 24/219 pre; 3%, n = 7/233 post; p 0.005). The number of patients discharged with a methadone wean decreased (7%, n = 16/219 pre; 0%, 0/233 post; p = 0.03). Despite these differences, there were no significant differences in the median hospital length of stay (42 pre; 39 post; p = 0.35). Post implementation more children had mild to moderate symptoms of withdrawal (11% pre; 21% post; p 0.005) as compared to pre-implementation, however, the percentage of severe symptoms remained consistently low (0.6% pre; 1% post; p = 0.11).Implementation of an evidence-based post PICU weaning guideline significantly reduced the number of patients discharged on potentially dangerous medications with modest increases in mild-moderate symptoms of withdrawal and no significant change in length of stay or the incidence of severe symptoms of withdrawal.

The prevalence of insomnia, depression and anxiety have recently been increasing (Kessler et al., 2005) with approximately 18.4% of the Brazilian population having experienced depression at least once during their lifetimes. These data characterize Brazil as the developing country with the largest number of people suffering from this disease (WHO, 2018). Depression is commonly accompanied by anxiety disorders and chronic psychiatric conditions with an estimated prevalence of approximately 29% (Kessler et al., 2005), which results in functional impairment that is associated with significant social costs. Treatment of these conditions includes psychological therapy and antidepressants. These drugs, such as benzodiazepines (BZDs), have been widely studied since the 1960s (Llorente et al., 2000) (WHO, 2018). BZDs are used by 9–25% of the elderly population aged 65 years of age and over, mainly among women (15–21.7% in Brazil, 9.9% in the United States, 24% in Canada and 25% in Sweden) (Jorm et al., 2000, Alvarenga et al., 2008, Johnell and Fastbom, 2009, Leggett et al., 2015). BZDs can be divided into two categories, anxiolytics and hypnotics, and can be used as anticonvulsants due to their muscle relaxant effects (De Almeida et al., 2008). As with all central-acting drugs, BZDs have side effects, such as decreased psychomotor activity, memory loss, physical dependence on long-term treatments, (Longo et al., 2000, Uzun et al., 2010) and hyposalivation and/or xerostomia, which is one of the main adverse effects described in the literature (Guggenheimer and Moore, 2003, Lambrecht et al., 2013, Raghavan et al., 2014). BZDs are among the drugs with the highest rates of complaints by patients in dental offices (Smith and Burtner, 1994) where these drugs are prescribed to reduce anxiety related to dental treatments of non-cooperative patients (Zaclikevis et al., 2009). Among the licensed BZDs, Lorazepam is one of the most widely used drugs for both insomnia and anxiety (Amato et al., 2010), particularly among elderly individuals with anxiety disorders and related conditions (Pomara et al., 2015). Previous studies, by our research group, demonstrated the damage Lorazepam and midazolam, another BDZ commonly prescribed for anxiety, caused to the acinar cells of parotid glands (Rinaldi et al., 2015, Mattioli et al., 2016, Rinaldi et al., 2018). We observed that the chronic use of BZDs significantly decreased the number and proliferation of acinar cells, reduced salivary flow and increased cell volume. In light of this, we hypothesize that the reduction in the number of acinar cells caused by Lorazepam in the salivary glands is possibly due to an apoptotic effect on these cells of the parotid glands of rats caused by the chronic use of this drug. Apoptosis plays a fundamental role in the elimination of unwanted, damaged or infected cells in multicellular organisms and serves as an important biological process in cellular development, differentiation and proliferation (So et al., 2016). The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) (Tilly, 1996) technique is the gold standard test employed to detect apoptotic cells (Burattini et al., 2009, Heisler-Taylor et al., 2018). Because of the its wide-spread use of TUNEL, there is no need to use another technique to detect apoptotic cells. The literature lacks studies demonstrating Lorazepam-induced apoptosis in acinar cells. The aim of this study was to evaluate the apoptotic action of a BZD on the acinar cells of the parotid glands of rats by quantification of the number of apoptotic cell nuclei (NCA), the number of acinar cells (N) and the immunoexpression of nuclear proliferation cell proliferation (PCNA) protein.

Introduction The major aim of this study was to test whether abstinence from e-cigarettes causes withdrawal symptoms in former smokers. Methods We conducted an unblinded, within-participants, pre–post clinical trial in which 109 former smokers who were current daily electronic cigarette (e-cigarette) users used their own e-cigarette for 7 days followed by 6 days of biologically confirmed abstinence engendered via an escalating contingency payment system. Participants monitored symptoms of nicotine withdrawal daily via an Interactive Voice Response system. They also attended three laboratory visits per week for carbon monoxide and cotinine testing to verify abstinence. Results Half of participants completely abstained for a week. All the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) tobacco withdrawal symptoms, craving for e-cigarettes, craving for tobacco cigarettes, and the four possible new withdrawal symptoms (anhedonia, impulsivity, mood swings, and positive affect) increased during abstinence. Weight increased and heart rate decreased with abstinence. Symptoms showed the prototypical inverted U time pattern of a withdrawal state. The magnitude of withdrawal appeared to be somewhat less than that in a prior study of abstinent daily tobacco cigarette smokers. More severe withdrawal on the first 2 days of abstinence did not predict abstinence on the last day of the study. Conclusions Former smokers who are daily e-cigarette users transfer physical dependence on tobacco cigarettes to dependence on e-cigarettes. The severity of withdrawal from e-cigarettes appears to be only somewhat less than that from daily tobacco cigarette use. Replication tests that include placebo controls, testing for pharmacological specificity, and including never-smokers, non-daily e-cigarette users and dual users are indicated. Implications Our results indicate e-cigarettes can maintain physical dependence. This adverse effect should be included in any risk vs. benefit calculation. Also, potential and current e-cigarette users should be informed that abrupt cessation of e-cigarettes can cause withdrawal symptoms. Trial registration NCT02825459.

Most of the sedative drugs cause dose-dependent depression of the central nervous system (CNS) leading to hypnosis and possibly anaesthesia, however, these agents are associated with some side effects ranging from digestive, respiratory, immune system dysfunctions, cognitive function deterioration, tolerance, and physical dependence, hence investigations of newer and safer agents is therefore imperative. The current study sought to investigate the sedative-hypnotic effects of methanolic stem bark extract of Ficus abutilifolia in mice. Phytochemical constituents and sedative-hypnotic activity of the extract were investigated. Twenty Swiss albino mice were used for the experiment, the animals were randomly divided into four groups of five mice each. The mice in groups 1 and 2 were injected with the extract at the dose of 100 and 200 mg/kg, respectively, those in group 3 were injected with xylazine at the dose rate of 10 mg/kg, while the control group 4 mice received nothing at the beginning of the experiment. All the four experimental groups were injected with ketamine at the dose rate of 100 mg/kg after 30 min, all the treatments during the experimental trial were administered intraperitoneally (IP). Phytochemical analysis of the stem bark extract revealed the presence of carbohydrates, reducing sugars, cardiac glycosides, cardinolides, steroids and triterpenes, saponins, tannins, condensed tannins and flavonoids, while, anthraquinones, anthracene derivates and alkaloids were absent. The results show no significant difference (P ≥ 0.05) on the sleep onset time between the four groups, however, statistically significant difference (P

Background The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. Methods A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. Results After systemic administration, BU10038 (0.001–0.01 mg kg−1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10–30-fold higher dose (0.01–0.1 mg kg−1). After intrathecal administration, BU10038 (3 μg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. Conclusions These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.

Background and Aim: Sedative drugs mostly cause dose-dependent depression of the central nervous system which results in hypnosis and anesthesia possibly; however, these agents are associated with some side effects ranging respiratory, digestive, immune system dysfunctions, tolerance, cognitive function deterioration, and physical dependence; hence, investigations of newer and safer agents are, therefore, imperative. The current study was aimed at investigating the sedative-hypnotic (S-H) effects of the methanol leaf extract of Ficus exasperata in mice. Materials and Methods: Phytochemical screening of the leaf extract was conducted, and S-H activity of the plant extract was evaluated. Twenty Swiss Albino mice were randomly divided into four groups of five mice each. The mice in Groups A and B were injected with the extract intraperitoneally (IP) at the dose rate of 100 and 200 mg/kg, respectively, those in Group C were injected with xylazine at the dose rate of 10 mg/kg, while Group D mice received distilled water at the dose rate of 2 ml/kg. All the four experimental groups were injected with ketamine (IP) at the dose rate of 100 mg/kg after 30 min. Results: Phytochemical analysis of the extract revealed the presence of carbohydrates, cardiac glycosides, reducing sugars, steroids and triterpenes, saponins, tannins, condensed tannins, and flavonoids, while anthraquinones, anthracene derivatives, and alkaloids were absent. Results from the S-H evaluation show no significant difference (p≥0.05) on the onset of sleep time between the four experimental groups; however, statistically significant difference (p≤0.05) was recorded in the sleep duration time between the groups treated with only ketamine and the other experimental groups pre-treated with either the extract or xylazine before ketamine administration. The group pre-treated with a high dose of the plant extract (200 mg/kg) and the treated with ketamine after 30 min exhibited longer sleeping duration time. The plant extract, xylazine and ketamine, sedated the mice for some period of time after arousal from sleep. Conclusion: Our finding suggests that methanol leaf extract of F. exasperata possesses S-H potential that may require further scientific investigations.

Nicotine has well known long term neurovegetative effects but their relationship to tobacco dependence is unknown. We study the change in the neurovegetative tone induced after sprayed nicotine, equivalent to one cigarette in smokers and non-smokers, and its relationship of this change with smoking addiction.

Objectives: Recently, opioid abuse and related overdoses have increased warranting the need for research directed against the opioid epidemic. Previous studies identified that patients on opioid therapy may become zinc deficient and that zinc, in a murine model, may antagonistically affect the opioid receptor. 13 Further understanding the relationship between opioid use and zinc deficiency may mitigate the opioid epidemic. Methods: A retrospective study was conducted to identify zinc (Zn2+) deficiencies among post-operative total hip arthroplasty (THA) patients. On post-operative day one, patients had routine blood tests, including Zn2+ plasma levels. Patients were considered Zn2+-deficient if their Zn2+ plasma was < 56 μg/dL (Reference: 56-134 μg/dL). Upon discharge from the hospital, the patients’ inpatient opioid medication consumption per day was determined by dividing total morphine milligram equivalents (MMEs) by length of stay. A Student's t-test was performed to compare the total MMEs for Zn2+-deficient patients versus Zn2+-normal patients. A univariate analysis followed by multiple linear regression was performed to identify demographic or surgical predictors of MMEs/day. Results: For Zn2+-deficient patients, the total MMEs/day was 33.62 ( ± 27.06), as compared to Zn2+-normal patients who consumed 16.22 ( ±16.01) MMEs/day (p = 0.031). The univariate analysis and multiple linear regression showed that patients’ Zn2+ status had a significant contribution toward predicting MMEs/day, with p = 0.022 and p = 0.04, respectively. Conclusion: The results of this study suggest that Zn2+ deficiency may potentiate opioid consumption. Thus, Zn2+ supplementation may be a simple approach to reducing opioid addiction and dependence.

The boxed warning for drugs in the benzodiazepine class has been strengthened to further emphasize the risk of overdose and death, especially if combined with opioids, alcohol, or illicit drugs, and the risk of abuse, misuse, addiction, physical dependence, and withdrawal.

Bulleyaconitine A (BAA), a C19-diterpenoid alkaloid, has been prescribed as a nonnarcotic analgesic to treat chronic pain over four decades in China. The present study investigated its inhibition in morphine-induced withdrawal symptoms, conditioned place preference (CPP) and locomotor sensitization, and then explored the underlying mechanisms of actions. Multiple daily injections of morphine but not BAA up to 300 μg/kg/day into mice evoked naloxone-induced withdrawal symptoms (i.e., shakes, jumps, genital licks, fecal excretion and body weight loss), CPP expression, and locomotor sensitization. Single subcutaneous BAA injection (30–300 μg/kg) dose-dependently and completely attenuated morphine-induced withdrawal symptoms, with ED50 values of 74.4 and 105.8 μg/kg in shakes and body weight loss, respectively. Subcutaneous BAA (300 μg/kg) also totally alleviated morphine-induced CPP acquisition and expression and locomotor sensitization. Furthermore, subcutaneous BAA injection also specifically stimulated dynorphin A expression in microglia but not astrocytes or neurons in nucleus accumbens (NAc) and hippocampal, measured for gene and protein expression and double immunofluorescence staining. In addition, subcutaneous BAA-inhibited morphine-induced withdrawal symptoms and CPP expression were totally blocked by the microglial metabolic inhibitor minocycline, dynorphin A antiserum, or specific KOR antagonist GNTI, given intracerebroventricularly. These results, for the first time, illustrate that BAA attenuates morphine-induced withdrawal symptoms, CPP expression, and locomotor sensitization by stimulation of microglial dynorphin A expression in the brain, suggesting that BAA may be a potential candidate for treatment of opioids-induced physical dependence and addiction.

Background: Caffeine is from methyl xanthine class which mainly stimulates the central nervous system. Caffeine is one of the most widely used psychoactive drugs in the world. It is commonly found in beverages, chocolates, cocoa containing products and in medications. Caffeine is recognized as legal and its consumption is unregulated all over of the world. Objectives: The objective of this study is to summarize the impact of caffeine on behavioral and health alterations, in both controlled and overdose conditions. Moreover, the specifics of caffeine withdrawal and a number of guidelines on how to handle reducing or quitting caffeine intake altogether is also highlighted. Methodology: To compose this review, more than seventy research and review articles were overviewed that were published over a period of last twenty years, using Google Scholar search engines. Results: Caffeine regular use causes physical dependence which may become the caffeine withdrawal sign that can consequently harm normal working. The most important function of caffeine is that it can reversibly blocks the adenosine performance on its receptor and as a result which prevent the beginning of drowsiness encouraged by adenosine. Caffeine also stimulates certain portions of the autonomic nervous system symptom including fatigue, drowsiness, depressed mood, headache, difficulty concentrating, decreased energy, decreased contentedness, decreased alertness, irritability and unclear headed. Conclusion: It is concluded that utilization of caffeine in a prescribed dose can have good impact on health and may decrease addictive symptoms. Additionally, reducing caffeine dosage over a six week period guides to successful, long-term caffeine cessation with very few side effects.

Preclinical opioid research using animal models not only provides mechanistic insights into the modulation of opioid analgesia and its associated side effects, but also validates drug candidates for improved treatment options for opioid use disorder. Non-human primates (NHPs) have served as a surrogate species for humans in opioid research for more than five decades. The translational value of NHP models is supported by the documented species differences between rodents and primates regarding their behavioral and physiological responses to opioid-related ligands and that NHP studies have provided more concordant results with human studies. This review highlights the utilization of NHP models in five aspects of opioid research, i.e., analgesia, abuse liability, respiratory depression, physical dependence, and pruritus. Recent NHP studies have found that (1) mixed mu opioid and nociceptin/orphanin FQ peptide receptor partial agonists appear to be safe, non-addictive analgesics and (2) mu opioid receptor- and mixed opioid receptor subtype-based medications remain the only two classes of drugs that are effective in alleviating opioid-induced adverse effects. Given the recent advances in pharmaceutical sciences and discoveries of novel targets, NHP studies are posed to identify the translational gap and validate therapeutic targets for the treatment of opioid use disorder. Pharmacological studies using NHPs along with multiple outcome measures (e.g., behavior, physiologic function, and neuroimaging) will continue to facilitate the research and development of improved medications to curb the opioid epidemic.

Abuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.

One of the main challenges in contemporary medicinal chemistry is the development of safer analgesics, used in the treatment of pain. Currently, moderate to severe pain is still treated with the “gold standard” opioids whose long-term often leads to severe side effects. With the discovery of biased agonism, the importance of this area of pharmacology has grown exponentially over the past decade. Of these side effects, tolerance, opioid misuse, physical dependence and substance use disorder (SUD) stand out, since these have led to many deaths over the past decades in both USA and Europe. New therapeutic molecules that induce a biased response at the opioid receptors (MOR, DOR, KOR and NOP receptor) are able to circumvent these side effects and, consequently, serve as more advantageous therapies with great promise. The concept of biased signaling extends far beyond the already sizeable field of GPCR pharmacology and covering everything would be vastly outside the scope of this review which consequently covers the biased ligands acting at the opioid family of receptors. The limitation of quantifying bias, however, makes this a controversial subject, where it is dependent on the reference ligand, the equation or the assay used for the quantification. Hence, the major issue in the field of biased ligands remains the translation of the in vitro profiles of biased signaling, with corresponding bias factors to in vivo profiles showing the presence or the lack of specific side effects. This review comprises a comprehensive overview of biased ligands in addition to their bias factors at individual members of the opioid family of receptors, as well as bifunctional ligands.

Physical dependence and addiction differ in that addiction causes activation of certain dopaminergic pathways in the mesolimbic system. Addiction occurs when this reward circuit is stimulated by drugs which are absorbed rapidly into the body, cross blood–brain barrier and for which tolerance develops. Ethanol is a commonly abused drug and causes greater mortality than several chronic diseases combined. Ethanol is a CNS stimulant at initial doses, it causes depression at higher doses, death occurring by coma. Acute withdrawal or delirium tremens can be life threatening and is treated by benzodiazepines. Disulfiram, acamprosate, and naltrexone help sustain abstinence. Methanol toxicity results from accumulation of formic acid and is treated by inhibiting the enzyme aldehyde dehydrogenase. The most addictive agent, nicotine works by stimulating nicotinic cholinergic receptors. To prevent withdrawal, nicotine substitutes such as patches and gums are used. Vaping poses dangers of its own and its entry has been made illegal in India. Varenicline and bupropion help sustain abstinence. Cannabis has been made legal to consume in some countries, given its low chances of causing tolerance and withdrawal. Nabilone and dronabinol are used medically and act on CB1 receptors.

Substance Use Disorder (SUD) is a chronic and relapsing disease characterized by craving, loss of control, tolerance and physical dependence. At present, the combination of pharmacotherapy and psychosocial intervention is the most effective management strategy in preventing relapse to reduce dropout rates and promote abstinence in SUD patients. However, only few effective medications are available. Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique that modulates the cellular activity of the cerebral cortex through a magnetic pulse applied on selected brain areas. Recently, the efficacy of TMS has been investigated in various categories of SUD patients. The present review analyzes the application of repetitive TMS in patients with alcohol, tobacco, and cocaine use disorder. Although the number of clinical studies is still limited, repetitive TMS yields encouraging results in these patients, suggesting a possible role of TMS in the treatment of SUD.

Opioid use, misuse, and risky use contribute to a critically important and complex crisis in current healthcare. Consequences of long-term opioid use, including opioid induced hyperalgesia, physical dependence, and opioid use disorder, can be considered iatrogenic, or partially iatrogenic, in cases where therapeutic opioid exposures were contributory. Research investigation and presumptive clinical action are needed to attenuate the iatrogenic component of the opioid crisis; treatment of individuals already suffering from opioid use disorder will not prevent incident cases. This work will be challenged by a remarkably high degree of complexity involving myriad and highly variable factors along the continuum from initial opioid exposure to long-term opioid use. An organized view of this complex problem should accelerate the pace of innovation and facilitate clinical implementation of research findings. Herein, we propose a theoretical framework and modern nomenclature for characterizing therapeutic opioid exposure and the degree to which it contributes iatrogenically to adverse outcomes. In doing so, we separate the role of exposure from other factors contributing to long-term opioid use, clarify the relationship between opioid exposure and outcomes, emphasize that exposure source is an important consideration for health services research and practice in the areas of pain treatment and opioid prevention, and recommend terminology necessary to quantify therapeutic opioid exposure separately from nonmedical exposure.

Summary Objective To quantify preferences for attributes of potential analgesic treatments for moderate-to-severe pain associated with osteoarthritis (OA) and/or chronic low back pain (CLBP) as relevant to injectable nerve growth factor (NGF)–inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Methods We used a discrete-choice experiment (DCE) to elicit preferences for attributes of OA and CLBP pharmaceutical treatments, and a best-worst scaling (BWS) exercise to further characterize the relative importance of treatment-related side-effect risks. The survey was completed online by 602 US residents with self-reported chronic, moderate-to-severe OA pain and/or CLBP who had tried, had contraindications for, or were unwilling to take currently available pharmaceutical therapies. In the DCE, respondents repeatedly chose between two hypothetical treatments defined by six attributes (symptom control; treatment-related risks of (1) severe joint problems, (2) heart attack, and (3) physical dependence; mode/frequency of administration; and cost). In the BWS exercise, respondents evaluated ten side-effect risks. Random-parameters logit models were estimated; conditional relative attribute importance, maximum acceptable risks, and willingness to pay were calculated. Results The most important DCE attributes were improving symptom control (scaled conditional relative importance, 10.00) and reducing risk of physical dependence (6.99). The three most important BWS attributes were, in rank order, risks of stroke, physical dependence, and heart attack. Respondents were willing to accept a > 4% treatment-related risk of severe joint problems for even modest symptom improvement. Conclusion A pharmaceutical treatment with a risk of severe joint problems was viewed as an acceptable alternative to other treatments with comparable efficacy but risks associated with NSAIDs or opioids.

Some opioid use disorder (OUD) patients attempt to self-treat using herbal remedies such as kratom. However, kratom use itself can paradoxically cause physical dependence and OUD. Currently, there are no guidelines for treating patients with OUD stemming from kratom use. Our empirically-based hypothesis was that there would be a correlation between the amount of kratom used and the amount of buprenorphine-naloxone required for opioid agonist therapy.This study includes a systematic review assessing treatment of kratom-dependent patients with buprenorphine-naloxone; a case series of our kratom-dependent patients; calculation of the correlation between the kratom dose and the buprenorphine-naloxone dose required to treat kratom-associated OUD; and our proposed starting doses for using buprenorphine-naloxone to treat kratom OUD.The OVID MEDLINE (1946-2020) database was searched using the terms "kratom," "buprenorphine," and "case report." This search yielded 3 relevant cases of patients having kratom OUD who were treated with buprenorphine-naloxone with the amounts of all substances reported. Review of the bibliographies, citing articles, and Google Scholar turned up three additional cases, yielding 6 literature cases that were analyzed. We also analyzed 2 patients from our clinic, giving a total of 8 patients included in the Pearson correlation coefficient calculation. We found a strong correlation of 0.84 between these variables, consistent with our hypothesis.Based on our analysis, patients using20 g of kratom/d could be initiated on opioid agonist therapy with 4/1 mg-8/2 mg buprenorphine-naloxone/d, while patients using kratom doses40 g/d could be initiated with 12/3 mg-16/4 mg of buprenorphine-naloxone/day.