Ohmefentanyl stereoisomers induce changes of CREB phosphorylation in hippocampus of mice in conditioned place preference paradigm

The present study was designed to determine the changes of phosphorylation of cAMP- response ele-ment binding protein (CREB) in hippocampus induced by ohmefentanyl stereoisomers (F9202 and F9204)in conditioned place preference (CPP) paradigm. The results showed that mice receiving F9202 and F9204displayed obvious CPP. They could all significantly stimulate CREB phosphorylation and maintained for along time without affecting total CREB protein levels. The effect of F9204 was similar to morphine whicheffect was more potent and longer than F9202. We also examined the effects of ketamine, a noncompetitiveN-mthyl-D-aspartate receptor (NR) antagonist, on morphine-, F9202- and F9204- induced CPP and phos-phorylation of CREB in hippocampus. Ketamine could suppress not only the place preference but also thephosphorylation of CREB produced by morphine, F9202 and F9204. These findings suggest that alterationsin the phosphorylation of CREB be relevant to opiates signaling and the development of opiates dependence.NR antagonists may interfere with opiates dependence and may have potential therapeutic implications.

Opiate exposure increases arterial stiffness, advances vascular age and is an independent cardiovascular risk factor in females: A cross-sectional clinical study

Background: Whilst several studies have demonstrated poor cardiovascular health in opiate dependence, its role as a cardiovascular risk factor has not been considered. Methods: Pulse wave analysis was undertaken by radial arterial tonometry (SphygmoCor) in female control and opiate-dependent patients and compared to lifetime opiate use. Results: 222 opiate dependent women were compared to 175 controls. Opiate dependent patients were receiving treatment with buprenorphine (83.3%), methadone (13.5%), or naltrexone (3.2%). Non log transformed chronologic age (CA) for the two groups was 33.58 ± 0.57 (opiate) vs. 32.62 ± 0.96 (controls) years (mean ± S.E.M.;P = 0.39). Vascular Reference Age (RA) 39.30 ± 1.28, vs. 35.03 ± 1.41 the RA-CA difference (5.73 ± 1.02 vs. 2.41 ± 0.91) and the RA/CA ratio (1.16 ± 0.03 vs. 1.07 ± 0.02;all P < 0.02), and all measurements of central arterial stiffness (P < 0.02) were significantly worse for opiates compared to controls. When adjusted for CA, RA and central augmentation pressure and index were all worse by themselves and in interaction with CA (all P < 0.005). At 60 years the modelled RA’s were 83.79 and 67.52 years respectively. The opiate dose-duration interaction showed a dose-response effect with RA (P = 0.0033). After full adjustment for established cardiovascular risk factors, the dose-duration interaction remained significant (P = 10-6), was included in 10 other terms, and dose or duration was included in 15 other interactions. Conclusion: These data show that lifetime opiate use is significantly associated with increased arterial stiffness and vascular age and suggest a dose-response relationship. This relationship is robust and persists after full multivariate adjustment. These findings carry far-reaching implications for opiate-induced generalized acceleration of organismal ageing.

Heroin-Induced Toxic Leukoencephalopathy

Toxic leukoencephalopathy is an important complication of heroin abuse and has mostly been described after inhaling heroin vapor, known as “chasing the dragon syndrome” or heroin inhalation leukoencephalopathy (HIL). We present a 51 year-old male patient with toxic leukoencephalopathy following intranasal administration of heroin.

Sickle Cell Patient and Addiction to Tramadol: Case Management in Senegal

Introduction: Tramadol* is a synthetic opioid agonist used as an analgesic. Despite its minor potential of addiction, it created recently a lot of concern. Its misuse may be motivated by a need to control the pain or by looking for her euphoric character. The aim of our study was to proceed a psychopathological reading of a case of addiction to Tramadol in a sickle cell patient with histrionic personality traits. Methods: We report the case’s management of a patient with addiction to Tramadol in a sickle cell patient with histrionic personality traits. The diagnosis was based on the DSM IV criteria. The review was done in the model of semi-structured interviews. Observation: Miss DP is 23 years old, sickle cell patient (AS profile). It is addressed to us for the management of an excessive consumption of Tramadol* started 4 years ago. Because of the difficulties of care in outpatient, we conducted hospitalization. The interviews highlight the histrionic personality traits and disruption of family dynamics. Discussion: Painful chronic diseases require a long analgesic treatment. It is a factor of dependence specially when the patient has a personality disorder. Multidisciplinary treatment between psychiatrist and addiction specialist and medical doctor is a guarantee of success.

Life after Addiction—Post-Operative Pain Management in an Obstetrical Patient on Long-Term Buprenorphine Therapy

A G6P2032 female, prior cesarean x3 with history of opioid addiction maintained on buprenorphine presented for scheduled repeat cesarean section. Pre-operatively, her maintenance dose of medication was held secondary to concerns for partial agonist effect. Post-operative pain control was suboptimal with the patient ultimately proceeding to withdrawal. Doses of hydromorphone were titrated to 10 mg every 3 hours to avoid further withdrawal. Review of expert opinion after discharge recommended against holding buprenorphine therapy in the post-operative period. Pain management options include maintenance therapy with additional doses of opioid and non-opioid pain relieving medications.

Intracerebroventricular opiate infusion for refractory head and facial pain

AIM: To study the risks and benefits of intracerebroventricular(ICV) opiate pumps for the management of benign head and face pain.METHODS: SSix patients with refractory trigeminal neuralgia and/or cluster headaches were evaluated for implantation of an ICV opiate infusion pump using either ICV injections through an Ommaya reservoir or external ventricular drain. Four patients received morphine ICV pumps and two patient S received a hydromorphone pump. Of the Four patients with morphine ICV pumps, one patient had the medication changed to hydromorphone. Preoperative and post-operative visual analog scores(VAS) were obtained. Patients were evaluated post-operatively for a minimum of 3 mo and the pump dosage was adjusted at each outpatient clinic visit according to the patient's pain level.RESULTS: All 6 patients had an intracerebroventricular opiate injection trial period, using either an Ommaya reservoir or an external ventricular drain. There was an average VAS improvement of 75.8%. During the trial period, no complications were observed. Pump implantation was performed an average of 3.7 wk(range 1-7) after the trial injections. After implantation, an average of 20.7 ± 8.3 dose adjustments were made over 3-56 mo after surgery to achieve maximal pain relief. At the most recent follow-up(26.2 mo, range 3-56), VAS scores significantly improved from an average of 7.8 ± 0.5(range 6-10) to 2.8 ± 0.7(range 0-5) at the final dose(mean improvement 5.0 ± 1.0, P < 0.001). All patients required a stepwise increase in opiate infusion rates to achieve maximal benefit. The most common complications were nausea and drowsiness, both of which resolved with pump adjustments. On average, infusion pumps were replaced every 4-5 years.CONCLUSION: These results suggest that ICV delivery of opiates may potentially be a viable treatment option for patients with intractable pain from trigeminal neuralgia or cluster headache.

Incidental biliary dilation in the era of the opiate epidemic:High prevalence of biliary dilation in opiate users evaluated in the Emergency Department

BACKGROUND Biliary dilation is frequently related to obstruction;however,non-obstructive factors such as age and previous cholecystectomy have also been reported.In the past two decades there has been a dramatic increase in opiate use/dependence and utilization of cross-sectional abdominal imaging,with increased detection of biliary dilation,particularly in patients who use opiates.AIM To evaluate associations between opiate use,age,cholecystectomy status,ethnicity,gender,and body mass index utilizing our institution’s integrated informatics platform.METHODS One thousand six hundred and eighty-five patients(20%sample)presenting to our Emergency Department for all causes over a 5-year period(2011-2016)who had undergone cross-sectional abdominal imaging and had normal total bilirubin were included and analyzed.RESULTS Common bile duct(CBD)diameter was significantly higher in opiate users compared to non-opiate users(8.67 mm vs 7.24 mm,P<0.001)and in patients with a history of cholecystectomy compared to those with an intact gallbladder(8.98 vs 6.72,P<0.001).For patients with an intact gallbladder who did not use opiates(n=432),increasing age did not predict CBD diameter(r^2=0.159,P=0.873).Height weakly predicted CBD diameter(r^2=0.561,P=0.018),but weight,body mass index,ethnicity and gender did not.CONCLUSION Opiate use and a history of cholecystectomy are associated with CBD dilation in the absence of an obstructive process.Age alone is not associated with increased CBD diameter.These findings suggest that factors such as opiate use and history of cholecystectomy may underlie the previously-reported association of advancing age with increased CBD diameter.Further prospective study is warranted.

Serotonin Influences the Endogenous Opiate Peptides in the Rat Spinal Cord to Participates in Pain Modulation

Spinal cord is a necessary pathway that transfers the body nociceptive inputs to the brain. Endogenous opiate peptides have been proven to participate in the nociceptive process at spinal level. It has reported that serotonin (5-HT, 5-hydroxytryptamine) in spinal cord plays a role in pan modulation, which can be blocked by opiate receptor antagonists. The present study was designed to investigate the interaction between 5-HT and endogenous opiate peptides at rat spinal level effecting on pain modulation. The results showed that 1) pain stimulation increased not only leucine-enkephalin (L-Ek), β-endorphin (β-Ep) and dynorphin A1-13 (DynA1-13) concentrations but also 5-HT and 5-hydorxyindoleace acid (5-HIAA, the 5-HT main metabolic product) concentrations in spinal cord significantly;2) 5-HT could increase L-Ek, β-Ep and DynA1-13 concentrations in spinal cord in a dose-dependent manner, whereas cypotolamine (a 5-HT receptor antagonist) decreased L-Ek, β-Ep and DynA1-13 concentrations in spinal cord. The data suggested that 5-HT antinociceptive role might be involved in the endogenous opiate peptide system through 5-HT receptors at spinal level.

Acetylcholine participates in pain modulation by influencing endogenous opiate peptides in rat spinal cord

The spinal cord is a necessary pathway that transfers the body nociceptive inputs to the brain, and endo-genous opiate peptides (EOP) play an important role in pain modulation. Our previous work has proven that arginine vasopressin (AVP) antinociception in the caudate nucleus (CdN) relates with the acetylcholine (Ach) system mainly. The communication was de-signed to investigate the interrelations between Ach system and EOP system at the spinal level during pain process. The results showed that: 1) pain stimulation increased L-enkephalin (L-Ek), β-endorphin (β-Ep), dynorphin A1-13(DynA1-13), Ach and choline (Ch, an Ach metabolic product) concentrations in the spinal cord;2) Ach increased L-Ek, β-Ep and DynA1-13 concentrations in the spinal cord;and 3) Atropine (M-receptor inhibitor) or hexahydric gallamine (N-receptor inhibitor) decreased L-Ek, β-Ep and DynA1-13 concentrations in the spinal cord. The data suggested that Ach antinociception was involved in the EOP system at the spinal level.

Acupuncture's Role in Solving the Opioid Epidemic: Evidence, Cost-Effectiveness, and Care Availability for Acupuncture as a Primary, Non-Pharmacologic Method for Pain Relief and Management-White Paper 2017

The United States （U.S.） is facing a national opioid epidemic, and medical systems are in need of non- pharmacologic strategies that can be employed to decrease the public＇s opioid dependence. Acupuncture has emerged as a powerful, evidence-based, safe, cost-effective, and available treatment modality suitable to meeting this need. Acupuncture has been shown to be effective for the management of numerous types of pain conditions, and mechanisms of action for acupuncture have been described and are understandable from biomedical, physiologic perspectives. Further, acupuncture＇s cost-effectiveness can dramatically decrease health care expenditures, both from the standpoint of treating acute pain and through avoiding addiction to opioids that requires costly care, destroys quality of life, and can lead to fatal overdose. Numerous federal regulatory agencies have advised or mandated that healthcare systems and providers offer non-pharmacologic treatment options for pain. Acupuncture stands out as the most evidence-based, immediately available choice to fulfil these calls. Acupuncture can safely, easily, and cost-effectively be incorporated into hospital settings as diverse as the emergency department, labor and delivery suites, andneonatal intensive care units to treat a variety of commonly seen pain conditions. Acupuncture is already being successfully and meaningfully utilized by the Veterans Administration and various branches of the U.S. Military, in some studies demonstrably decreasing the volume of opioids prescribed when included in care.

PHARMACOLOGICAL STUDY OF AN IRREVERSIBLE PARTIAL AGONIST OF OPIATE RECEPTORS, A-α-CAO

A-α-CAO induces weak analgesia with very short duration in mice and is able to antagonize the analgesic effect of morphine (Mor) up to 3—4 days after a single injection. No tendency of dependence has been observed. It acts as a partial agonist on MVD with Ke value of 9×10^(-9) mol/L. Its antagonist effect remains after several washes and its agonist effect cannot be reversed by naloxone (Nx), provided the incubation time or the concentration of the agent is sufficient. On isolated GPI, A-α-CAO is a pure agonist with IC_(50) of 5.7×10^(-10) mol/L; this agonist effect cannot be removed by washing but can be reversed by Nx. On RVD and RbVD, it has antagonist effect against β-endorphine (β-end) and US0488H, which cannot be washed out easily, and the pA_2are 7.5 and 7.6 respectively. A-α-CAO also inhibits the specific binding of ~3H-etorphine (~3H-Etor) to the P_2 fraction of the mouse brain membrane with an IC_(30) of 3.2×10^(-9) mol/L. The inhibition on the high affinity binding sites of ~3H-Etor remains 95％ even after 6 washes.

GroupⅢmetabotropic glutamate receptors and drug addiction

Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction.Accumulating data have demonstrated roles of ionotropic glutamate receptors and groupⅠandⅡmetabotropic glutamate receptors(mGluRs)in this event.Emerging evidence also identifies Gαi/o-coupled groupⅢmGluRs(mGluR4/7/8 subtypes enriched in the limbic system)as direct substrates of drugs of abuse and active regulators of drug action.Auto-and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways,respectively.These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis.In response to operant administration of common addictive drugs,such as psychostimulants(cocaine and amphetamine),alcohol and opiates,limbic groupⅢmGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior.As a result,a loss-of-function mutation(knockout)of individual groupⅢreceptor subtypes often promotes drug seeking.This review summarizes the data from recent studies on three groupⅢreceptor subtypes(mGluR4/7/8)expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs(psychostimulants,alcohol,and opiates).