Hormone Replacement Therapy for Restoring the HPG Axis in Pain Patients Treated with Long-Term Opioid Analgesics

Opioids are a treatment option for a variety of chronic pain conditions. But long-term opioid use can be associated with side effects, including hypogonadism. Opioid-induced hypogonadism (OIhG) is associated with the alteration of the hypothalamic-pituitary-gonadal axis (HPG). In males, hypogonadism can result in erectile dysfunction, reduced libido, fatigue, worsening mood, and increased risk of osteoporosis;in females, it can result in changes in the menstrual cycle and reduced libido, among other effects. A current treatment option for these patients is hormone replacement therapy. In this report, we discuss the problem of opioid-induced hypogonadism, and the therapeutic approach and the potential complications of treating pain patients using hormone replacement therapy.

The Effectiveness of Ketamine Compared to Opioid Analgesics for Management of Acute Pain in Children in the Emergency Department: Systematic Review

Background: Ketamine is increasingly being used as an alternative to opioids in the management of acute pain in the emergency department. In turn, there is increasing research attention to prove the efficacy of ketamine as an analgesic in children presenting in the emergency department. Objective: The first objective of this systematic review was to investigate the effectiveness of ketamine compared to opioid analgesics for pain management in children aged two months to 18 years who have acute pain in the emergency department. The second objective was to compare the adverse events and side effects associated with ketamine with those associated with opioids used for pain management. Methods: A systematic review, using the JBI systematic review was completed. A computerised search from five databases;CINAHL, EMBASE, EMCARE and PubMed, and Cochrane. The included studies were appraised by JBI critical appraisal tool for randomised controlled trials and the study results analysed. Findings: Four randomised control trial studies were included in this systematic review. All the included studies compared ketamine with opioids (morphine and fentanyl) for the management of severe pain in children. The studies were of high methodological quality based on JBI critical appraisal outcome. Meta-analysis was not possible because of the heterogeneity of the studies, especially in terms of different outcome measures, and the approaches (pain assessment tool) used to measure the pain outcomes. The review identified that ketamine demonstrated a non-inferior analgesia effect compared to opioid medication (morphine or fentanyl) as determined by various pain scores used in different studies. However, ketamine use was associated with increased frequency of occurrence of temporary adverse effects that do not require clinical attention. Conclusion: Based on the findings from the review, ketamine is a suitable alternative for opioid analgesics for the management of acute and severe pain in children in ED. The minor transient side effects associated with ketamine should not limit the use of ketamine. Future studies should investigate the appropriate dosage and route of administration of ketamine to be used while managing pain among children with acute and severe pain in the emergency department.

Fentanyl and xylazine crisis:Crafting coherent strategies for opioid overdose prevention

The United States is in the throes of a severe opioid overdose epidemic,primarily fueled by the pervasive use of fentanyl and the emerging threat of xylazine,a veterinary sedative often mixed with fentanyl.The high potency and long duration of fentanyl is compounded by the added risks from xylazine,heightening the lethal danger faced by opioid users.Measures such as enhanced surveillance,public awareness campaigns,and the distribution of fentanylxylazine test kits,and naloxone have been undertaken to mitigate this crisis.Fentanyl-related overdose deaths persist despite these efforts,partly due to inconsistent policies across states and resistance towards adopting harm reduction strategies.A multifaceted approach is imperative in effectively combating the opioid overdose epidemic.This approach should include expansion of treatment access,broadening the availability of medications for opioid use disorder,implementation of harm reduction strategies,and enaction of legislative reforms and diminishing stigma associated with opioid use disorder.

Exploring the Contribution of Pharmacists in Addressing the Opioid Crisis through Naloxone Prescriptions and Pharmacist-Led Interventions

The opioid epidemic in the United States continues to take the lives of many individuals, with overdoses continuing to rise every year. Naloxone is an opioid antagonist that is efficacious in temporarily reversing opioid overdoses. Pharmacists play an important role in the accessibility and education of naloxone in both the community and health system settings. Recent efforts, such as co-dispensing naloxone with opioid prescriptions, naloxone training programs, and approval of naloxone to be over-the-counter, have been implemented in hopes to better control the opioid epidemic. Despite the efforts to make naloxone more accessible, there are still some barriers to overcome such as lack of training, cost, stigma, and patient refusal. This review aims to explore the contributions pharmacists have made thus far and define the barriers that still have to be resolved.

The Impact of Opioid Drugs on Memory and Other Cognitive Functions: A Review

Background and Purpose: Opioids, used for centuries to alleviate pain, have become a double-edged sword. While effective, they come with a host of adverse effects, including memory and cognition impairment. This review delves into the impact of opioid drugs on cognitive functions, explores underlying mechanisms, and investigates their prevalence in both medical care and illicit drug use. The ultimate goal is to find ways to mitigate their potential harm and address the ongoing opioid crisis. Methods: We sourced data from PubMed and Google Scholar, employing search combinations like “opioids,” “memory,” “cognition,” “amnesia,” “cognitive function,” “executive function,” and “inhibition.” Our focus was on English-language articles spanning from the inception of these databases up to the present. Results: The literature consistently reveals that opioid use, particularly at high doses, adversely affects memory and other cognitive functions. Longer deliberation times, impaired decision-making, impulsivity, and behavioral disorders are common consequences. Chronic high-dose opioid use is associated with conditions such as amnesiac syndrome (OAS), post-operative cognitive dysfunction (POCD), neonatal abstinence syndrome (NAS), depression, anxiety, sedation, and addiction. Alarming trends show increased opioid use over recent decades, amplifying the risk of these outcomes. Conclusion: Opioids cast a shadow over memory and cognitive function. These effects range from amnesiac effects, lessened cognitive function, depression, and more. Contributing factors include over-prescription, misuse, misinformation, and prohibition policies. Focusing on correct informational campaigns, removing punitive policies, and focusing on harm reduction strategies have been shown to lessen the abuse and use of opioids and thus helping to mitigate the adverse effects of these drugs. Further research into the impacts of opioids on cognitive abilities is also needed as they are well demonstrated in the literature, but the mechanism is not often completely understood.

Cardiovascular Risk of Opioids: A Real-World Study Based on FAERS

Objective:This research utilizes the FAERS for data mining to identify heart-related side effects caused by opioids,ensuring the safe use of these medications.Methods:Data from 79 quarters(Q12004 to Q32023)involving adverse event(AE)reports for opioids like morphine and oxycodone was reviewed.We applied the MedDRA system to categorize events and used statistical tools,ROR and BCPNN,for signal detection.These findings were cross-checked with drug labels and SIDER 4.1 for accuracy.Identified risks were then categorized by severity using DME and IME classifications.Results:Analysis of adverse events(AEs)for the five examined drugs(35359,14367,144441,10592,and 28848)identified 33,6,12,37,and 34 cardiovascular AEs,and 16,5,7,25,and 21 instances of important medical events(IMEs)respectively.Each drug was linked to cases of cardiac and cardiopulmonary arrest.The cardiovascular AEs varied widely in occurrence and severity,with methadone notably presenting diverse and potent risks,including sudden cardiac death as a distinct medical event(DME).A comparison with SIDER 4.1 showed 11 opioid-related cardiovascular AEs in line with our findings.Standardized MedDRA Queries(SMQs)confirmed these results,indicating stronger signals for methadone and tramadol,while morphine,hydromorphone,and oxycodone exhibited fewer and weaker signals.Conclusion:The study revealed numerous heart-related adverse effects(AEs)not listed on drug labels and identified new AE patterns.Recognizing these differences in AE profiles and risks across different opioids is crucial for safer prescription practices to minimize cardiac complications.

Expert consensus of Chinese Association for the Study of Pain on the non-opioid analgesics for chronic musculoskeletal pain

Chronic musculoskeletal pain(CMP)is a common occurrence in clinical practice and there are a variety of options for the treatment of it.However,the pharmacological therapy is still considered to be a primary treatment.The recent years have witnessed the emergence of opioid crisis,yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly.The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics.The purpose of this consensus is to present the application of nonsteroidal antiinflammatory drugs,serotonin norepinephrine reuptake inhibitors,serotonin and norepinephrine reuptake inhibitors,muscle relaxants,ion channel drugs and topical drugs in CMP.

Connectome-based predictive modelling can predict follow-up craving after abstinence in individuals with opioid use disorders

Background Individual differences have been detected in individuals with opioid use disorders(OUD)in rehabilitation following protracted abstinence.Recent studies suggested that prediction models were effective for individual-level prognosis based on neuroimage data in substance use disorders(SUD).Aims This prospective cohort study aimed to assess neuroimaging biomarkers for individual response to protracted abstinence in opioid users using connectome-based predictive modelling(CPM).Methods One hundred and eight inpatients with OUD underwent structural and functional magnetic resonance imaging(fMRI)scans at baseline.The Heroin Craving Questionnaire(HCQ)was used to assess craving levels at baseline and at the 8-month follow-up of abstinence.CPM with leave-one-out cross-validation was used to identify baseline networks that could predict follow-up HCQ scores and changes in HCQ(HCQtolow V-up-HCQpa baseline).Then,the follow-up aseline predictive ability of identified networks was tested in a separate,heterogeneous sample of methamphetamine individuals who underwent MRI scanning before abstinence for SUD.Results CPM could predict craving changes induced by long-term abstinence,as shown by a significant correlation between predicted and actual HCQ fllow-up(r=0.417,p<0.001)and changes in HCQ(negative:r=0.334,p=0.002;positive:r=0.233,p=0.038).Identified craving-related prediction networks included the somato-motor network(SMN),salience network(SALN),default mode network(DMN),medial frontal network,visual network and auditory network.In addition,decreased connectivity of frontal-parietal network(FPN)-SMN,FPN-DMN and FPN-SALN and increased connectivity of subcortical network(SCN)-DMN,SCN-SALNandSCN-SMN were positively correlated with craving levels.Conclusions These findings highlight the potential applications of CPM to predict the craving level of individuals after protracted abstinence,as well as the generalisation ability;the identified brain networks might be the focus of innovative therapies in the future.

Management of Opioid Use Disorder in Sickle Cell Anaemia amidst Growing Menace in the General Population

Nigeria has a very high number of sickle cell disease (SCD) population with addition of 150,000 babies born annually with the disease. Early infant diagnosis and good care make many of these babies survive to adulthood. Severe pain requiring moderately strong or very strong analgesics is a common presentation of patients with Sickle Cell Anaemia. Paediatricians find ready usefulness of Opioids which are very useful for the painful episodes among these patients. Therefore, the chances of abuse and addiction to these medications become very high and constitute additional burden on the deficient manpower in the health sector. Opioid Use Disorder among Sickle Cell Disease patients has subtle presentation, so a high index of suspicion is required to make both the diagnosis and referral to treatment centres. In this review, the epidemiology, pain pathophysiology, behavioural and pharmacologic therapy have been re-examined.

Pain management in chronic pancreatitis incorporating safe opioid practices: Challenge accepted

Patients with chronic pancreatitis often experience severe,unrelenting abdominal pain,which can significantly impact their quality of life.Pain control,therefore,remains central to the overall management of chronic pancreatitis.Most of the strategies aimed at treating the pain of chronic pancreatitis are based on expert opinion and vary from one institution to another,as there are no uniform guidelines to direct a stepwise approach towards achieving this goal.In this editorial,we comment on best practice strategies targeted towards pain control in chronic pancreatitis,specifically highlighting the use of opioid medications in this patient population.We discuss various safe and efficacious prescription monitoring practices in this article.

Design, Synthesis of Analgesics and Anticancer of Some New Derivatives of Benzimidazole

This work, contains some new compounds from benzimidazole derivatives, which are synthesized by condensation of Orthophenylene diamine and Carbon disulfide resulting in 2-Mercapto-benzimidazole which is treated by alcoholic potassium hydroxide forming potassium salt of 2-mercaptobenzimidazole which reacts with different substances (alkyl chloroacetates, chloroacetic chloride, alkyl halides) also the ethoxy carbonyl methyl thiobenzimidazole reacts with different amines. In addition to chloromethyl benzimidazole which resulted from the reaction between orthophenylene diamine and chloroacetic acid, which reacted with different amines. The synthesized compound tested as analgesics and anticancer activity the new derivatives revealed moderate, strong and very strong analgesics and moderate and strong anticancer activity.

Cirrhosis-induced morphological changes in the retina:possible role of endogenous opioid

·AIM: To investigate the impact of cirrhosis on retinal morphology and to evaluate the role of endogenous opioids as a mediator in cirrhosis induced retinal change.·METHODS: Thirty-six male rats were divided into 3main groups; the common bile duct ligated(BDL) group,the sham-operated(Sham) group and the unoperated(Unop) group. Then each of these three main groups was divided into two subgroups; the first subgroup received daily injection of naltrexone hydrochloride(NTX) and the second group was injected with normal saline(Saline)daily. After 28 d, rats were anesthetized and their right eyes were enucleated and assessed for histological changes. The thickness of the rod and cons layer, outer nuclear layer, outer plexiform layer, inner nuclear layer,inner plexiform layer and ganglion cell layer for each eye were measured in micrometers by light microscope.· RESULTS: Ganglion cell layer showed significant increase in thickness in the BDL group(P 【0.05). This increase was eliminated in the group where BDL rats received daily intraperitoneal injection of naltrexone hydrochloride(20 mg/kg). No other histological changes were detected in the other 5 layers we measured·CONCLUSION: The morphological change we detected in the retina of cirrhotic rats is probably due to opioids increased tone in cirrhosis since the increase in thickness in the ganglion cell layer was almost eliminated when naltrexone hydrochloride was injected.These results suggest a possible role for endogenous opioids in the morphological retinal changes detected in cirrhotic rats.

Corelation Between Single Nucleotide Polymorphisms in Mu Opioid Receptor Exon 2 and Stereotypic Behaviour in Sows

Three breeds of sows were observed to investigate the relationship between Single Nucleotide Polymorphisms（SNPs） in Mu Opioid Receptor（MOR）and stereotypic behaviour,such as,sham-chewing,bar biting and standing still in order to better understand the mechanism of stereotypic development of the animals in restrained conditions.MOR exon 2 partial sequences were amplified to analyze single nucleotide polymorphisms by PCR-SSCP.One SNP,a silence mutant was found.A significant difference （P〈0.01）was found in the frequency of genotypes in these 3 breeds where only the BB genotype,which was identical to that published in GenBank,was found in the Duroc breed,while no AA genotype was found in Landrace,3 genotypes AA,BB and AB were found in Yorkshire.The result also indicated that the individuals with AA and AB genotypes tended to be more active in sham-chewing than those with the BB genotype（P〈0.05）.The overall results of this study suggested that sham-chewing of sows may be subjected to both genetic control and environmental conditions,but activity level was more likely to be affected by their environment.We can putatively draw the conclusion that MOR gene has effect on the sham-chewing behavioral traits of sow.

Research Progresses in Effects of Analgesics and Sedatives on Intracranial Pressure of Neurointensive Care Patients

At present, there are some concerns and problems to treat neurointensive care patients by using analgesics and sedatives. Conditions of neurointensive care patients change quickly. For neurointensive care patients who cannot have auxiliary examination timely, clinicians judge intracranial conditions mainly through relevant monitoring devices and consciousness and pupil changes of patients. The use of analgesics and sedatives is limited due to worry about influences on consciousness evaluation and judgment and different degrees of inhibition on cardiovascular system and respiratory system. Common sedatives (e.g. benzodiazepines) and common analgesics (e.g. morphine, fentanyl and sufentanil) both may inhibit respiration. The specification often provides taboos for the use of drugs by patients with increase intracranial pressure (ICP) and craniocerebral injuries. Through literature review, the author analyzed influences of analgesics and sedatives on ICP of neurointensive care patients comprehensively.

Emergency medicine providers＇ opioid prescribing practices stratified by gender, age, and years in practice

BACKGROUND: Emergency medicine providers(EMPs) prescribe about 25% of opioids, but the effect of EMP risk perception on decisions to prescribe opioids is unknown. This study was undertaken to identify factors that infl uence EMP risk and opioid prescribing practices.METHODS: We distributed an anonymous questionnaire to EMPs at a military trauma and referral center. Response frequencies and distributions were assessed for independence using the Chi-square test.RESULTS: Eighty-nine EMPs completed the questionnaire(100% response). Respondents were primarily younger male physicians(80%) in practice under fi ve years(55%). Male EMPs were more likely to prescribe more opioid tablets than female ones both when and when not concerned for opioid misuse(P<0.001, P<0.007, respectively). Of the providers, 70% stated that patient age would inf luence their prescribing decisions. Hydrocodone and oxycodone were the opioids prescribed most frequently. About 60% of the providers reported changing their prescribing behavior would not prevent opioid misuse. Additionally, 40% of the providers believed at least 10% of patients seen at this military ED misused opioids.CONCLUSION: Female EM providers reported prescribing fewer opioid tablets. Patient age infl uenced prescribing behavior, but the effect is unknown. Finally, EM providers reported that altering their prescribing behavior would not prevent prescription opioid misuse.

Melanocortin-4 Receptor Expression in the Cuneiform Nucleus Is Involved in Modulation of Opioidergic Signaling

Substantial evidence has suggested that deep brain stimulation of the cuneiform nucleus has become a remarkable treatment option for intractable pain,but the possible mechanism is poorly understood. Using a melanocortin-4 receptor（MC4R）-green fluorescent protein（GFP） reporter knockin mouse,we showed that a large number of MC4R-GFP-positive neurons were expressed in the cuneiform nucleus. Immunofluorescence revealed that approximately 40%–50% of MC4R-GFP-positive neurons expressed mu opioid receptors,indicating that they were opioidergic signaling. Our findings support the hypothesis that MC4 R expression in the cuneiform nucleus is involved in the modulation of opioidergic signaling.

Treatment with analgesics after mouse sciatic nerve injury does not alter expression of wound healingassociated genes

Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion（DRG） sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model.

Genetics of adult attachment and the endogenous opioid system

Since the pioneering work by Panksepp et al,the neurobiological bases of attachment behavior have been closely linked with opioid neurotransmission.Candidate gene studies of adult individuals have shown that variation in the muopioid receptor gene(OPRM1)influences attachment behavior.Early maternal care and the A/A genotype of the A118G polymorphism interact in modulating levels of fearful attachment.Compared to their counterparts carrying the A/A genotype,individuals expressing the minor 118G allele show lower levels of avoidant attachment and experience more pleasure in social situations.Brain imaging research has strengthened the biological plausibility of candidate gene studies.The avoidance dimension of attachment correlates negatively with muopioid receptor availability in the thalamus and anterior cingulate cortex,as well as the frontal cortex,amygdala,and insula.Overall,findings from human studies combined with those from animal models suggest that research on the genetic bases of attachment should include the endogenous opioid system among the investigated variables.

Gender Differences in Usage of Over-the-Counter Analgesics among Norwegian Adolescents

Introduction: Usage of over-the-counter (OTC) analgesic has increased among Norwegian adolescents since 2001. It has been noted that females tend to have a higher usage compared to males. In this paper we explore this gender difference. Data: Our dataset consists of 284,674 from Norwegian adolescents attending junior high school and high school between 2014 and 2017. Methods: The econometric approach consists of applying ordered logistic regressions with usage of OTC analgesics as the dependent variable and a dichotomous gender variable as the independent variable. Control variables include variables such as frequency of physical and mental health problems and other sociodemographic variables. Results: Gender, physical and mental health problems and various sociodemographic variables are found to have a significant effect on usage of OTC analgesics. Females are predicted to use significantly more analgesics. A large proportion of the gender difference evaporates when controlling for various other determinants. Conclusion: A considerable part of the observed gender difference in OTC analgesic usage can be traced back to differences in frequency and severity of physical and mental health problems. Part of the gender difference in usage, however remains unexplained.

Clinical Research on Nourishing Yin and Unblocking Meridians Recipe Combined with Opioid Analgesics in Cancer Pain Management

Objective： To investigate the analgesic effects of Nourishing yin and Unblocking meridians Receipe （NUR） combined with opioid analgesics in managing cancer pain. Methods： All the patients enrolled were differentiated as of yin deficiency and meridian blocked syndrome type of TCM. Forty-one of them in the treated group were treated with NUR combined with opioid analgesics, while 43 of them in the control group were given opioid analgesics alone with successive 14 days as one treatment course for both groups. Results： The indexes of the treated group were superior to those in the control group as to the degree of pain-relieving, the therapeutic effect of analgesia, the occurrence frequency of cancer pain every day and its duration each time, the analgesic initial time, and the quality of life. Conclusion： NUR combined with opioid analgesics in cancer pain management was more effective than opioid analgesics alone. KEY WORDS