Long-acting Opioid Antagonist Research Articles

Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone.

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.

Daily methocinnamox treatment dose-dependently attenuates fentanyl self-administration in rhesus monkeys

Opioid use disorder and opioid overdose continue to be significant public health challenges despite the availability of effective treatments. Methocinnamox (MCAM) is a novel, long-acting opioid receptor antagonist that might be an effective treatment for opioid use disorder (i.e., preventing relapse and overdose). In nonhuman primates, MCAM selectively blocks the positive reinforcing effects of mu opioid receptor agonists, including heroin, fentanyl, and its ultra-potent analogs (e.g., carfentanil) with a single administration of MCAM being effective for up to two weeks. Because treatment of opioid use disorder would involve repeated administration of a medication, MCAM was studied in rhesus monkeys (3 males and 2 females) responding under a fixed-ratio self-administration procedure for a range of doses of fentanyl (0.000032–0.1 mg/kg/infusion). The fentanyl self-administration dose-effect curve was determined before and during treatment with progressively increasing daily doses of MCAM (0.001–0.1 mg/kg) given subcutaneously 1 h before the session. MCAM dose-dependently shifted the fentanyl dose-effect curve rightward and then, at larger doses, downward. The largest treatment dose of MCAM (0.1 mg/kg/day) shifted the curve more than 120-fold rightward with monkeys receiving doses much larger than the likely lethal dose of fentanyl with no adverse effect or observable change in behavior. This study demonstrates that MCAM reliably and dose-dependently decreases fentanyl self-administration and prevents opioid overdose, with no evidence of adverse effects over a broad dose range, further supporting the potential therapeutic utility of this novel antagonist.

EOSINOPHILIC PNEUMONIA AND EXTENDED-RELEASE INJECTABLE NALTREXONE

TOPIC: Lung Pathology TYPE: Medical Student/Resident Case Reports INTRODUCTION: Extended-release injectable naltrexone is an opioid antagonist approved for the treatment of alcohol and opioid dependence. Since the release of the drug in 2006, a literature review reveals five reported cases of drug-induced eosinophilic pneumonia. Our case highlights the clinical presentation of drug-induced eosinophilic pneumonia in the setting of extended-release injectable naltrexone. CASE PRESENTATION: A 35-year-old female with a past medical history lifelong tobacco use and alcohol dependence on extended-release injectable naltrexone presented to the ED with subjective fevers, myalgias, cough, and pleuritic chest pain. She was evaluated at urgent care two days prior and sent home on a course of Levofloxacin for bronchitis. Upon ED arrival, she was noted to be hypoxic and placed on supplemental oxygen. She was afebrile and tachycardic. Exam was pertinent for tachypnea and bilateral crackles. Initial laboratory data revealed WBC 19,500 (neutrophil predominate) and lactic acid 1.4. Chest x-ray and chest CT demonstrated extensive bilateral infiltrates. Empiric antibiotics were initiated while awaiting microbiology data. Due to escalating oxygen requirements and hemodynamic instability over the next 24 hours, the patient was intubated and bedside bronchoscopy was completed. BAL studies revealed lymphocyte predominance (46%) followed by eosinophils (27%) and neutrophils (21%). Given concern for acute eosinophilic pneumonia in the setting of extended-release injectable naltrexone, corticosteroids were started. Antibiotics were discontinued given negative culture data and our patient showed marked clinical improvement with continuation of steroid therapy. DISCUSSION: Extended-release injectable naltrexone is a long-acting opioid antagonist approved for the treatment of alcohol dependence. Clinical trials showed one diagnosed case & one suspected case of naltrexone-induced eosinophilic pneumonia. A current medical literature review reveals a paucity of cases associated with naltrexone and drug-induced AEP. While the etiology & pathogenesis remain largely unknown, it is thought to be related to an acute hypersensitivity reaction to an antigen in a genetically susceptible person. Progression from mild dyspnea to overt respiratory failure is rapid. Initial diagnostics are often nonspecific, however pleural fluid analysis demonstrates striking eosinophilia (10%-50%) and BAL fluid classically shows marked eosinophilia (25%-55%). Treatment includes supportive care, withdrawal of any eliciting medications, and glucocorticoid therapy. Most patients rapidly improve within 12-48 hours of initiation of corticosteroids. The prognosis for acute eosinophilic pneumonia is excellent with the vast majority of patients enjoying complete recovery. CONCLUSIONS: This case highlights the rare but important association between drug-induced eosinophilic pneumonia and extended-release injectable naltrexone. REFERENCE #1: Korpole PR, Al-Bacha S, Hamadeh S. A Case for Biopsy: Injectable Naltrexone-Induced Acute Eosinophilic Pneumonia. Cureus. 2020;12(9):e10221. Published 2020 Sep 3. doi:10.7759/cureus.10221 REFERENCE #2: Eosinophilic pneumonia induced by injectable naltrexone. Kim H, Ali M, Buch K. http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2014.189.1_MeetingAbstracts.A2283 Am J Respir Crit Care Med. 2014;189:2283. REFERENCE #3: Saved by the BAL: a case of acute eosinophilic pneumonia after methyl-naltrexone injection. Esposito A, Lau B. Chest. 2019;156:2210. DISCLOSURES: No relevant relationships by Kari McCoy, source=Web Response No relevant relationships by Caroline Mears, source=Web Response No relevant relationships by Xian Qiao, source=Web Response

Opioid Withdrawal Precipitated by Long-Acting Antagonists.

Precipitated opioid withdrawal (POW) after opioid antagonist administration can be challenging to manage in the emergency department (ED), particularly if caused by a long-acting opioid antagonist such as naltrexone. There are no evidence-based guidelines to assist in safely and efficiently managing patients with this syndrome. To review current practice on the treatment of long-acting antagonist POW and make recommendations on the treatment of this complex disease process. A literature search of opioid withdrawal cases precipitated by naltrexone was done using PubMed. One of the authors screened all the results of this search by title and abstract, leading to a final count of 27 articles that were reviewed in full by all authors. English language cases that involved precipitated opioid withdrawal from a long-acting opioid antagonist were included. Data were extracted, including the precipitant involved and dose, severity of opioid withdrawal, treatments rendered, and response to treatment. In all cases where symptoms and signs were described, a Clinical Opiate Withdrawal Scale score was calculated based on the information available. Twenty-seven papers were included. Naltrexone alone was the primary antagonist reported in 19 of the papers, extended-release naltrexone in two, naltrexone-morphine combination in two, and nalmefene in four. Treatment most commonly included fluid replacement, benzodiazepines, antiemetics, and clonidine. Full opioid agonist treatment, although often suggested, was poorly described. Buprenorphine successfully reduced the severity and duration of withdrawal in several cases. No standardized response scale was used, and response to treatment ranged from 3 to 48h prior to resolution of clinical effects. Management of POW from long-acting antagonists is a complex problem with little formal evaluation of treatment options. There is not currently a sufficiently robust body of literature to support an evidence-based guideline. However, use of intravenous fluids, antiemetics, and benzodiazepines is commonly reported as successful and seems to be a reasonable approach until this process is better studied. A treatment strategy using partial agonists such as buprenorphine is emerging and may represent a safe and effective treatment pathway for these patients.

Perioperative management of opioid-tolerant patients

### Key points The assessment and treatment of opioid-tolerant patients in the perioperative and postoperative period can be challenging. Acute pain management can often be inadequate due to a number of factors. Compared with opioid-naive patients, opioid-tolerant patients will typically generate a greater workload for medical and nursing staff. Opioid tolerant patients express higher rest and dynamic pain scores, and two to three times greater opioid use via patient-controlled analgesia (PCA). They require more frequent consultations and prescription alterations.1 Medical and nursing staff may be unaccustomed to managing such patients and may be apprehensive in prescribing or administering large doses of opioids because of a fear of causing harm. Under-treatment of pain may result in opioid-seeking behaviour with the patient perceived as ‘manipulative’ and ‘non-cooperative’. This can have a negative impact on the doctor–patient relationship and overall patient care. Therefore the pain management plan for opioid tolerant patients requires careful consideration in the perioperative period in order to (i) prevent opioid withdrawal, (ii) provide effective analgesia, and (iii) to ensure continuity of care in the community after discharge from hospital. This review considers the various strategies that can be used in such settings. Opioids are prescribed to treat pain from a variety of causes, including chronic non-cancer pain, cancer pain, acute pain, and as substitution therapy in …

The Yin and Yang of the Opioid Growth Regulatory System: Focus on Diabetes-The Lorenz E. Zimmerman Tribute Lecture.

The Opioid Growth Regulatory System consists of opioid growth factor (OGF), [Met5]-enkephalin, and its unique receptor (OGFr). OGF inhibits cell division when bound to OGFr. Conversely, blockade of the interaction of OGF and OGFr, using the potent, long-acting opioid receptor antagonist, naltrexone (NTX), results in increased DNA synthesis and cell division. The authors have demonstrated both in vitro and in vivo that the addition of exogenous OGF or an increase in available OGFr decreases corneal epithelial cell division and wound healing. Conversely, blockade of the OGF-OGFr interaction by NTX or a decrease in the production of the OGFr increases corneal epithelial cell division and facilitates corneal epithelial wound healing. The authors also have demonstrated that depressed corneal and cutaneous wound healing, dry eye, and abnormal corneal sensitivity in type 1 and type 2 diabetes in animals can be reversed by OGF-OGFr blockade by NTX. Thus, the function of the Opioid Growth Regulatory System appears to be disordered in diabetic animals, and its function can be restored with NTX treatment. These studies suggest a fundamental role for the Opioid Growth Regulatory System in the pathobiology of diabetic complications and a need for studies to elucidate this role further.

Opioid treatment at release from jail using extended-release naltrexone: a pilot proof-of-concept randomized effectiveness trial.

Relapse to addiction following incarceration is common. We estimated the feasibility and effectiveness of extended-release naltrexone (XR-NTX) as relapse prevention among opioid-dependent male adults leaving a large urban jail. Eight-week, proof-of-concept, open-label, non-blinded randomized effectiveness trial. New York City jails and Bellevue Hospital Center Adult Primary Care clinics, USA. From January 2010 to July 2013, 34 opioid-dependent adult males with no stated interest in agonist treatments (methadone, buprenorphine) received a counseling and referral intervention and were randomized to XR-NTX (n = 17) versus no medication (n = 17) within one week prior to jail release. XR-NTX (Vivitrol(®) ; Alkermes Inc.), a long-acting injectable mu opioid receptor antagonist. The primary intent-to-treat outcome was post-release opioid relapse at week 4, defined as ≥10 days of opioid misuse by self-report and urine toxicologies. Secondary outcomes were proportion of urine samples negative for opioids and rates of opioid abstinence, intravenous drug use (IVDU), cocaine use, community treatment participation, re-incarceration and overdose. Acceptance of XR-NTX was high; 15 of 17 initiated treatment. Rates of the primary outcome of week 4 opioid relapse were lower among XR-NTX participants: 38 versus 88% [P<0.004; odds ratio (OR) = 0.08, 95% confidence interval (CI) = 0.01-0.48]; more XR-NTX urine samples were negative for opioids, 59 versus 29% (P<0.009; OR = 3.5, 95% CI = 1.4-8.5). There were no significant differences in the remaining secondary outcomes, including rates of IVDU, cocaine use, re-incarceration and overdose. Extended-release naltrexone is associated with significantly lower rates of opioid relapse among men in the United States following release from jail when compared with a no medication treatment-as-usual condition.

Buprenorphine-Mediated Transition from Opioid Agonist to Antagonist Treatment: State of the Art and New Perspectives

Constant refinement of opioid dependence (OD) therapies is a condition to promote treatment access and delivery. Among other applications, the partial opioid agonist buprenorphine has been studied to improve evidence-based interventions for the transfer of patients from opioid agonist to antagonist medications. This paper summarizes PubMed-searched clinical investigations and conference papers on the transition from methadone maintenance to buprenorphine and from buprenorphine to naltrexone, discussing challenges and advances. The majority of the 26 studies we examined were uncontrolled investigations. Many small clinical trials have demonstrated the feasibility of in- or outpatient transfer to buprenorphine from low to moderate methadone doses (up to 60-70 mg). Results on the conversion from higher methadone doses, on the other hand, indicate significant withdrawal discomfort, and need for ancillary medications and inpatient treatment. Tapering high methadone doses before the transfer to buprenorphine is not without discomfort and the risk of relapse. The transition buprenorphine-naltrexone has been explored in several pilot studies, and a number of treatment methods to reduce withdrawal intensity warrant further investigation, including the co-administration of buprenorphine and naltrexone. Outpatient transfer protocols using buprenorphine, and direct comparisons with other modalities of transitioning from opioid agonist to antagonist medications are limited. Given its potential salience, the information gathered should be used in larger clinical trials on short and long-term outcomes of opioid agonist-antagonist transition treatments. Future studies should also test new pharmacological mechanisms to help reduce physical dependence, and identify individualized approaches, including the use of pharmacogenetics and long-acting opioid agonist and antagonist formulations.

Long-Acting Opioid Antagonist OK'd for Relapse Prevention

Long-Acting Opioid Antagonist OK'd for Relapse Prevention

Severe Uncontrolled Pain in Buttock in a Patient on Naltrexone: A Diagnostic Challenge

A 26-year-old woman with a history of intravenous drug use was admitted to hospital with worsening pain in the right buttock radiating to the lateral part of the thigh and to the calf with no suspicion of cauda equina compression. Eventually, a diagnosis of sacroiliitis was made and appropriate antibiotics were administered. Provision of analgesia for this patient was difficult. On admission her medications included naltrexone, venlafaxine and tramadol. Initially naltrexone was continued and analgesia provided by epidural local anaesthetic and clonidine, intravenous ketamine and oral agents. After several days, naltrexone was ceased and opioids were used in addition to the other analgesics. The epidural analgesia was only partially effective, perhaps because of inadequate blockade of the L4-S1 nerve roots, which carry sensation from the sacroiliac joint. Naltrexone is a long-acting opioid antagonist. If opioid analgesia is planned, it is necessary to cease naltrexone for 24 to 72 hours. In an emergency, if non-opioid techniques prove ineffective, short-acting opioids can be titrated to effect in a monitored environment.

Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone

Repeated intermittent exposure to psychostimulants was found to produce behavioral sensitization. The present study was designed to establish a mouse model and by which to investigate whether opioidergic system plays a role in methamphetamine-induced behavioral sensitization. Mice injected with 2.5 mg/kg of methamphetamine once a day for 7 consecutive days showed behavioral sensitization after challenge with 0.3125 mg/kg of the drug on day 11, whereas mice injected with a lower daily dose (1.25 mg/kg) did not. Mice received daily injections with either 1.25 or 2.5 mg/kg of methamphetamine showed behavioral sensitization after challenge with 1.25 mg/kg of the drug on days 11, 21, and 28. To investigate the role of opioidergic system in the induction and expression of behavioral sensitization, long-acting but non-selective opioid antagonist naltrexone was administrated prior to the daily injections of and challenge with methamphetamine, respectively. Our results show that the expressions of behavioral sensitization were attenuated by pretreatment with 10 or 20 mg/kg of naltrexone either during the induction period or before methamphetamine challenge when they were tested on days 11 and 21. These results indicate that repeated injection with methamphetamine dose-dependently induced behavioral sensitization in mice, and suggest the involvement of opioid receptors in the induction and expression of methamphetamine-induced behavioral sensitization.

Opioid growth factor (OGF) inhibits anchorage-independent growth in human cancer cells.

Opioid growth factor (OGF) is a native endogenous opioid peptide ([Met5]-enkephalin) that interacts with the OGF receptor (OGFr), and serves as a tonically active negative growth factor in neoplasia. To inquire whether OGF modulates anchorage-independent growth, HT-29 human colon cancer cells were grown in soft agar and subjected to this peptide. In contrast to controls, HT-29 cells exposed to OGF had 57% fewer colonies, and these colonies were reduced in area by 75%. The changes induced by OGF were abolished by concomitant treatment with naloxone, indicating a receptor-mediated mechanism for peptide activity. Continuous blockade of opioid-receptor interactions with the potent and long-acting opioid antagonist, naltrexone (NTX), revealed an increase of 81 and 49% in the number and area, respectively, of colonies compared to control levels. These data suggest that OGF is tonically active in neoplastic cells growing in soft agar medium. HT-29 cells studied under anchorage-independent conditions were not influenced in growth by a variety of natural and synthetic opioids, including those selective for micro, delta, and kappa opioid receptors. Similar effects on anchorage-independent growth by OGF and NTX observed for HT-29 cells were recorded in pancreatic adenocarcinoma cells (Mia PaCa-2, Panc-1) and squamous cell carcinoma of the head and neck (CAL-27). These results using anchorage-independent conditions are consistent with previous data showing that OGF can markedly influence tumor growth in xenografts, and suggest that clonogenic assays can be utilized as indicators of tumorigenicity when tumor transplantation experiments are restricted.

What’s New in the Management of Pain in Children

What’s New in the Management of Pain in Children

Nalmefene for elective reversal of procedural sedation in children

Nalmefene is a newer, long-acting opioid antagonist. Its use in children for the elective reversal of emergency department procedures has not been investigated. The objective was to evaluate the safety of nalmefene in children. An open-label pediatric clinical trial was performed. The study was conducted at the emergency department of an urban, university-affiliated children's hospital and consisted of children aged 6 months to 12 years who required procedural sedation where an opioid agent was administered. Patients were excluded if there was altered mental status, history of head trauma, history of opioid allergy, or the anticipated need for opioid agents for pain relief after the procedure. At the completion of the procedure, nalmefene was administered in a dose of 0.25 microg/kg increments (max 10 microg) until sedation was resolved, or to a maximum of 1.0 microg/kg (max 40 microg). Serial ECGs, vital signs, and oxygen saturation were recorded. Sedation was assessed using the Clinical Global Impression Scale (CGIS) at baseline, 2, 4, 6, 8, and 10 minutes after the initial nalmefene dose. The observer's assessment of alertness and sedation (OAA/S) was measured at baseline, 10, 30, 60, 90, and 120 minutes after the first dose of nalmefene. Episodes of resedation were recorded. All patients received follow-up by telephone at 4 and 24 hours after the initial dose of nalmefene to identify any potential late adverse effects. Over the study interval 15 patients were enrolled. Mean age was 59.1 +/- 41.5 months. Procedures involved fracture reduction (n=8), laceration repair (n = 4), abscess drainage (n = 2), and arthrocentesis (n = 1). All patients received IV fentanyl and midazolam. The mean dosage of fentanyl and midazolam was 3.21 +/- 1.03 microg/kg and 0.07 +/- 0.03 mg/kg, respectively. The mean dose of nalmefene at the time of complete response (CGIS = 1 or 2) was 0.55 +/- 0.29 microg/kg. The median number of nalmefene doses was 2. All but one patient (93%) had a complete response based on CGIS at 10 minutes after the initial dose of nalmefene was given. Nalmefene resulted in a significant improvement in CGIS (1.60 +/- 0.82 v 3.26 +/- 0.88, P =.001) and OAA/S (median score 5 v 4) when compared at baseline with 10 minutes after the initial dose of nalmefene. Nalmefene also resulted in increased diastolic blood pressure (62.6 +/- 10.5 v 55.8 +/- 10.7, P =.04) as well as improved oxygen saturation when compared at 120 minutes to baseline (99.5 +/- 0.74% v 98.5 +/- 0.4%, P =.03). There were no significant changes in pulse, systolic blood pressure, respiratory rate, and ECG. None of the patients became resedated after nalmefene was given. One patient developed nausea and vomiting within the first 2 hours after nalmefene; this resolved without intervention before discharge. No adverse events occurred in any of the patients at 4 and 24 hours postadministration. The results of this study showed that nalmefene is effective and safe for reversal of procedural sedation by opioids in children.

Opioid growth factor modulates angiogenesis

Objective: Induced angiogenesis has recently been attempted as a therapeutic modality in patients with occlusive arterial atherosclerotic disease. We investigated the possible role of endogenous opioids in the modulation of angiogenesis. Methods: Chick chorioallantoic membrane was used as an in vivo model to study angiogenesis. Fertilized chick eggs were incubated for 3 days, explanted, and incubated for an additional 2 days. Three-millimeter methylcellulose disks were placed on the surface of the chorioallantoic membrane; each disk contained opioid growth factor ([Met5]-enkephalin; 5 μg), the short-acting opioid receptor antagonist naloxone (5 μg), opioid growth factor and naloxone together (5 μg of each), the long-acting opioid antagonist naltrexone (5 μg), or distilled water (control). A second series of experiments was performed with distilled water, the angiogenic inhibitor retinoic acid (1 μg), and vascular endothelial growth factor (1 μg) to further evaluate our model. The developing vasculature was imaged 2 days later with a digital camera and exported to a computer for image analysis. Total number of blood vessels, total vessel length, and mean vessel length were measured within a 100-mm2 region surrounding each applied disk. Immunocytochemical analysis was performed with antibodies directed against opioid growth factor and its receptor (OGFr). Results: Opioid growth factor had a significant inhibitory effect on angiogenesis, both the number of blood vessels and the total vessel length being decreased (by 35% and 20%, respectively) in comparison with control levels (P <.005). The simultaneous addition of naloxone and opioid growth factor had no effect on blood vessel growth, nor did naloxone alone. Chorioallantoic membranes exposed to naltrexone displayed increases of 51% and 24% in blood vessel number and length, respectively, in comparison with control specimens (P <.005). These results indicate that the opioid growth factor effects are receptor mediated and tonically active. Immunocytochemistry demonstrated the presence of both opioid growth factor and OGFr within the endothelial cells and mesenchymal cells of the developing chorioallantoic membrane vessel wall. Retinoic acid significantly reduced the number and the total length of blood vessels, whereas vascular endothelial growth factor increased both the number and the length of blood vessels in comparison with the controls (P <.0001). The magnitude of opioid growth factor's effects were comparable to those seen with retinoic acid, whereas inhibition of opioid growth factor with naltrexone induced an increase in total vessel length comparable to that for vascular endothelial growth factor. Conclusions: These results demonstrate for the first time that endogenous opioids modulate in vivo angiogenesis. Opioid growth factor is a tonically active peptide that has a receptor-mediated action in regulating angiogenesis in developing endothelial and mesenchymal vascular cells. (J Vasc Surg 2000;32:364-73.)

Acute Effects of Nalmefene on LH, Prolactin, and Testosterone in Male Rhesus Monkeys

The effects of the long-acting opioid antagonist, nalmefene [17-N-cyclopropylmethyl-3,14-β-dihydroxy-4,5-α-epoxy-6-methylene morphinan hydrochloride] on LH, T, and prolactin release in rhesus monkeys are unknown. The acute effects of nalmefene (0.01 and 0.10 mg/kg, IV) or placebo on LH, PRL, and T were studied, and samples were collected at 10-min intervals for 360 min to permit cluster analysis of pulsatile release patterns. LH increased significantly within 30 min after nalmefene, and remained significantly above baseline levels for 50 to 60 min ( p < 0.05). Testosterone increased significantly within 70 to 80 min after nalmefene, and remained significantly above baseline for 60 min ( p < 0.05). Although nalmefene antagonizes opioid agonists for 6–8 h, inhibitory feedback by testosterone appeared to limit the duration of its antagonism of endogenous opioid inhibition of LHRH and stimulation of LH. Nalmefene did not change LH or PRL pulse frequency or amplitude significantly in comparison to placebo administration.

Nalmefene: A Long-Acting Opioid Antagonist. Clinical Applications In Emergency Medicine

The use of the opioid antagonist naloxone is well known to the experienced health care provider. The availability of the longer acting opioid antagonist nalmefene has several potential benefits in clinical practice. Nalmefene has a plasma half-life of almost 11 h, compared to 60–90 min for naloxone. Nalmefene has been shown to reverse opioid intoxication for as long as 8 h, reducing the need for continuous monitoring of intoxicated patients and repeated dosing of naloxone. Single dose administration has also been used effectively in the reversal of opiate-assisted conscious sedation. In addition, this agent has been used in the treatment of diseases as diverse as interstitial cystitis and chronic alcohol dependence. However, the long duration of action enables extended withdrawal reactions in the chronically opioid-dependent patient. The prolonged opioid antagonism of nalmefene has several applications in the clinical practice of emergency medicine, and is a useful addition in certain situations to the pharmacologic armamentarium of the practicing emergency physician.

Changing pattern of oxytocin-induced excitation of neurons in the bed nuclei of the stria terminalis and ventrolateral septum in the peripartum period

Oxytocin acts within the limbic system (bed nuclei of the stria terminalis and ventrolateral septum) to induce maternal behaviour and to facilitate neuroendocrine activity at specific times during the peripartum period. Studies were undertaken to determine whether the timing of these effects arises from modulation of the oxytocin-induced excitation of limbic neurons. Extracellular activity of single units was recorded on urethane-anaesthetized rats and neurons were tested for responses to intracerebroventricular injection of 1.1 ng oxytocin. In the first part, animals were recorded on days 19 and 22 of pregnancy and on days 3 and 5 of lactation. No significant differences in the basal firing rates or in the proportion of oxytocin-responsive neurons were detected, but responses by neurons on day 22 of pregnancy occurred after a significant delay (10.7±2.0 min), resulting in a smaller overall response compared to the other groups. These differences in the pattern of response were not due to changes in density of oxytocin binding in the limbic areas studied, since autoradiographic detection of oxytocin binding sites using the iodinated antagonist [ 125I]d(CH 2) 5[Tyr(Me) 2,Thr 4,Orn 8,Tyr-NH 2 9]-vasotocin showed no differences between the pregnant and postpartum animals. In the second part, parturient animals (day 22 of pregnancy) received intravenous injection of the long-acting opioid antagonist naltrexone, or unilateral knife-cut lesions to the stria terminalis, a source of inhibitory inputs (including enkephalinergic) to the bed nuclei of the stria terminalis and ventrolateral septum. Both treatments abolished the characteristic delay of oxytocin-induced excitation in non-treated animals on day 22 of pregnancy, and increased the overall excitatory response. Thus, during the peripartum period, a population of limbic neurons sensitive to oxytocin display a dynamically changing pattern of excitatory responses, apparently modulated by an endogenous opioid tone and independent of changes in oxytocin receptor expression. The attenuated neuronal response to central oxytocin seen on the day of parturition could account for the absence of a facilitatory effect of oxytocin on neuroendocrine activity at this time.

Kappa opioid receptors participate in nerve growth factor-induced hyperalgesia

It has recently been observed that nerve growth factors induces the rapid onset of thermal hyperalgesia, and the more delayed onset of mechanical hyperalgesia when administered to mature rats. Though several mechanisms have been proposed to explain this phenomenon, it is still not well understood. Previous studies have shown that nerve growth factor can directly excite nociceptive sensory ganglion neurons in culture via activation of kappa excitatory opioid receptors. The possible involvement of these excitatory opioid receptors in mediating the hyperalgesia was investigated. Nerve growth factor-induced thermal hyperalgesia in rodents was prevented by co-administration of the non-selective opiate antagonist naloxone, as well as by the kappa-selective antagonist nor-binaltorphimine. Addition of the long-acting opioid antagonist, naltrexone, partially prevented mechanical hyperalgesia. Administration of low dose dynorphin to mice (a selective kappa-receptor agonist) mimicked the hyperalgesia effects of nerve growth factor. Opiate antagonists and anti-nerve growth factor antibody both interfered with Freund's adjuvant-induced inflammatory hyperalgesia. Altogether, these observations suggest that activation of excitatory opioid receptors plays a role in mediating nerve growth factor-induced hyperalgesia and that, in turn, nerve growth factor contributes to the hyperalgesia associated with inflammatory states. Since opioid receptor antagonists are well tolerated clinically, they may be useful for patients receiving nerve growth factor as part of ongoing trials of the factor in peripheral neuropathy.

Opioid Peptide Modulation of Stress-Induced Plasma Steroid Changes in the Frog Rana esculenta

The present paper aims to evaluate whether a neuroendocrine system including opioids accounts for the effects of stress in the frog, Rana esculenta. Using an acute-stress paradigm, the involvement of hypothalamic opioid peptides was investigated biochemically as well as by in vivo studies. HPLC and RIA investigations confirm the presence of β-endorphin-like peptides in the brain of this frog. Several immunoreactive peaks are present, two of them coeluting with β-endorphin and acetyl β-endorphin reference peptides. Quantitative evaluation revealed that the β-EP content of 24-hr captured animals was higher than that in fresh captured ones. The stress paradigm, applied here was consistent with the measurement of plasma androgens and corticosterone levels in females after short-captivity confinement. In comparison with fresh-captured animals, a sharp decrease of these levels was found within 10-24 hr after capture. These effects were reversed by naltrexone, a long-acting opioid antagonist, after 24 hr of treatment. In fact, in the captive animals injected with 100 ng of naltrexone, the plasma androgen titers remained low at the 10th hour postcapture, but rose to the control levels within 24 hr. A similar effect was found for the plasma corticosterone levels. These data demonstrate that, in this anuran, endogenous opioids could mediate the stress-induced inhibition of gonadal function, and perhaps the inhibition of the hypothalamus-pituitary-adrenal axis.