Chronic Opiate Use Research Articles

Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice.

Despite considerable evidence that chronic opiate use selectively affects the pathophysiologic consequences of human immunodeficiency virus type 1 (HIV-1) infection in the nervous system, few studies have examined whether neuro-acquired immune deficiency syndrome (neuroAIDS) might intrinsically alter the pharmacologic responses to chronic opiate exposure. This is an important matter because HIV-1 and opiate abuse are interrelated epidemics, and HIV-1 patients are often prescribed opiates as a treatment of HIV-1-related neuropathic pain. Tolerance and physical dependence are inevitable consequences of frequent and repeated administration of morphine. In the present study, mice expressing HIV-1 Tat in a doxycycline (DOX)-inducible manner [Tat(+)], their Tat(-) controls, and control C57BL/6 mice were chronically exposed to placebo or 75-mg morphine pellets to explore the effects of Tat induction on morphine tolerance and dependence. Antinociceptive tolerance and locomotor activity tolerance were assessed using tail-flick and locomotor activity assays, respectively, and physical dependence was measured with the platform-jumping assay and recording of other withdrawal signs. We found that Tat(+) mice treated with DOX [Tat(+)/DOX] developed an increased tolerance in the tail-flick assay compared with control Tat(-)/DOX and/or C57/DOX mice. Equivalent tolerance was developed in all mice when assessed by locomotor activity. Further, Tat(+)/DOX mice expressed reduced levels of physical dependence to chronic morphine exposure after a 1-mg/kg naloxone challenge compared with control Tat(-)/DOX and/or C57/DOX mice. Assuming the results seen in Tat transgenic mice can be generalized to neuroAIDS, our findings suggest that HIV-1-infected individuals may display heightened analgesic tolerance to similar doses of opiates compared with uninfected individuals and show fewer symptoms of physical dependence.

Tu1439 African American Race and Chronic Opiate Use Are Predictors of Hospital Readmission in Patients With Cyclical Vomiting Syndrome

Tu1439 African American Race and Chronic Opiate Use Are Predictors of Hospital Readmission in Patients With Cyclical Vomiting Syndrome

HIV, opiates, and enteric neuron dysfunction.

Human immune deficient virus (HIV) is an immunosuppressive virus that targets CD4(+) T-lymphocytes. HIV infections cause increased susceptibility to opportunistic infections and cancer. HIV infection can also alter central nervous system (CNS) function causing cognitive impairment. HIV does not infect neurons but it does infect astrocytes and microglia in the CNS. HIV can also infect enteric glia initiating an intestinal inflammatory response which causes enteric neural injury and gut dysfunction. Part of the inflammatory response is HIV induced production of proteins including, Transactivator of transcription (Tat) which contribute to neuronal injury after release from HIV infected glial cells. A risk factor for HIV infection is intravenous drug use with contaminated needles and chronic opiate use can exacerbate neural injury in the nervous system. While most research focuses on the actions of Tat and other HIV related proteins and opiates on the brain, recent data indicate that Tat can cause intestinal inflammation and disruption of enteric neuron function, including alteration of Na(+) channel activity and action potential generation. A paper published in this issue of Neurogastroenterology and Motility extends these findings by identifying an interaction between Tat and morphine on enteric neuron Na(+) channels and on intestinal motility in vivo using a Tat expressing transgenic mouse model. These new data show that Tat protein can enhance the inhibitory actions of morphine on action potential generation and propulsive motility. These findings are important to our understanding of how HIV causes diarrhea in infected patients and for the use of opioid drugs to treat HIV-induced diarrhea.

Epigenetics of addiction

Chronic opiate use represses expression of Brain-derived neurotrophic factor through changes in histone modifications.

Capsule commentary on Mosher et al., Trends in prevalent and incident opioid receipt: an observational study in Veterans Health Administration 2004-2012.

Chronic pain is ubiquitous among Veterans. Over 55 % of Veterans of Afghanistan and Iraq experience chronic myalgia, thought to be due to the heavy load from body armor worn in extreme conditions.1 Mosher and colleagues report that there has been an increase in the receipt of opiates since 2004 among Veterans, from 19 % in 2004 to 33 % in 2012.2 They define receipt of opiates as “receipt of at least one opioid prescription during that year.” This would include Veterans who had surgery and other procedures that require a short course of opiates during the outpatient post-procedure period, as well as Veterans who received opiates for acute injuries. In the last couple of years, the VA has focused on chronic opiate use with a national Opiate Safety Initiative. Chronic opiate use is being monitored at national, regional and local levels. For example, in 2014, 15.5 % of Veterans received chronic opiates; at my facility, it’s 11.8 %. Opiate policy has been updated nationally,3 and each VA center is required to have an Opiate Safety person to oversee local implementation of national policy. All Veterans receiving chronic opiates are required to sign an opiate consent that details risks and patient responsibilities. Veterans on chronic opiates are required to have at least an annual urine drug screen. Providers must check state databases at least annually to make sure the Veteran is not getting opiates from other sources. The combination of benzodiazepines and opiates are discouraged, as are doses exceeding 100 mg of morphine equivalent daily. Dashboards have been created that allow providers to check what percentage of their patients are on chronic opiates, as well as what percentage of patients have had a urine drug screen, have signed an opiate consent and are on combinations of opiates and benzodiazepines. The VA electronic health record now includes clinical reminders for patients on chronic opiates to alert providers that the Veteran needs to sign an opiate agreement or is due for a urine drug screen. While the VA is no paragon of virtue, it is devoting considerable effort to increase the safety of chronic opiate use among Veterans.

Achalasia and chronic opiate use: innocent bystanders or associated conditions?

High-resolution manometry identifies three subtypes of achalasia. However, type 3 differs from classic achalasia. Although opiates affect esophageal motility, opiate use and achalasia have not been studied. Patients with a new diagnosis of achalasia at Mayo Clinic Rochester between June 1, 2012 and January 3, 2014 were identified. Clinical records were reviewed to assess symptoms, opiate use, and therapy. Fifty-six patients with achalasia were identified, 14 (25%) were on opiates. Opiate prescription was unrelated to achalasia in all cases, with chronic back and joint pain constituting the majority. Of patients on opiates, five (36%) had type 3 achalasia compared with four (10%) not on opiates (P = 0.02). No patients on opiates had type 1 achalasia. Clinical presentation did not differ with opiates, although those on opiates were more likely to report chest pain (39 vs. 14%, P = 0.05) and less likely to have esophageal dilation (62 vs. 82%, P = 0.13), none with greater than 5-cm diameter. Contractile vigor was greater with opiate use, with distal contractile integral of 7149 versus 2615.5 mmHg/cm/second (P = 0.08). Treatment response was inferior on opiates, with persistent symptoms in 22% compared with 3% without opiates (P = 0.06). Opiate use is common in type 3 achalasia, with the majority of patients on opiates. No patients on opiates were diagnosed with type 1 achalasia. Manometric findings of type 3 achalasia mimic those induced by opiates, suggesting a physiologic mechanism for opiate induced type 3 achalasia. Treatment outcome is inferior with opiates, with opiate cessation perhaps preferable. Further studies assessing opiate use and achalasia are needed.

Episodic foresight deficits in long-term opiate users.

There is considerable literature showing that opiate use is associated with a range of neurocognitive deficits, including deficits in executive control and episodic memory. However, no study to date has assessed whether these neurocognitive difficulties extend to the ability to mentally time travel into one's personal future. This is a surprising omission given that executive control and episodic memory are considered to be critical for episodic foresight. In addition, opiate-related brain changes have been identified in the neural regions that underlie the capacity for episodic foresight. In the present study, we assessed how episodic foresight is affected in the context of chronic opiate use, as well as the degree to which any deficits are related to difficulties with executive control and episodic memory. Forty-eight long-term heroin users enrolled in an opiate substitution program and 48 controls were tested. The results showed that, relative to controls, the clinical group exhibited significant impairment in episodic foresight but not episodic memory (as indexed by an adapted version of the Autobiographical Interview). For executive function, the clinical group was impaired on only one of three measures (Inhibition). These data provide important preliminary evidence that episodic foresight might be particularly susceptible to the neurocognitive effects of opiate use, as the difficulties identified were not secondary to more general executive control or episodic memory impairment. Because a number of widely used relapse prevention protocols require the ability to mentally project into the future, these data have potentially important practical implications in relation to the treatment of substance dependence disorders.

The effect of acute morphine on delay discounting in dependent and non-dependent rats.

Chronic opiate use is associated with increased impulsivity in both humans and animals, and previous studies suggest that acute morphine can increase impulsivity in non-dependent rats. However, the extent to which chronic opiate usage modulates the effect of acute morphine is unknown. Rats were trained to delay discount 20% sucrose solution and then randomly assigned to either a dependent group that received a nightly 30mg/kg subcutaneous dose of morphine or a non-dependent group that received a nightly saline injection. Once dependence was established, rats were then assigned to one of four acute morphine doses (0, 1.25, 2.5, 5mg/kg). For 5 days, delay discounting curves were determined 22.5h after maintenance doses and 1h after their prescribed acute injections. In non-dependent rats, 2.5 and 5mg/kg doses of morphine caused decreased preference for the large reward at all delays. Acute morphine had no effect on discounting curves in dependent rats. Morphine dependence can cause tolerance to the effects of acute morphine on delay discounting.

Effects of an oxycodone conjugate vaccine on oxycodone self-administration and oxycodone-induced brain gene expression in rats.

Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination.

Association between initial morphine intake and body weight change, acoustic startle reflex and drug seeking in rats.

Although chronic use of opiates can induce physical dependence and addiction, individual differences contributing to these symptoms are largely unknown. Using intravenous morphine self-administration (MSA), we investigated whether individual differences in drug intake are associated with weight change, acoustic startle reflex (ASR), pre-pulse inhibition (PPI), and drug seeking during spontaneous withdrawal. Male Sprague-Dawley rats self-administered morphine (0.5 mg/kg/infusion) or saline for 3 weeks (4-6 h/day, 5 days/week) and drug intake and body weight were monitored daily. The ASR and the PPI (baseline, 1 day and 1 week) and drug seeking (1 week) were measured during spontaneous withdrawal. Morphine animals did not gain weight (101 % ± 0.69), while the control animals did (115 % ± 1.06) after 3 weeks of self-administration. The ASR and the PPI were not significantly different between morphine and saline animals in 1-day or 1-week withdrawal. However, individual differences in initial (first 10 min), but not total (4-6 h), morphine intake of the daily sessions were positively correlated with weight change (r = 0.437, p = 0.037) and drug seeking (r = 0.424, p = 0.035) while inversely correlated with the ASR (r = -0.544, p = 0.005) in 1-week withdrawal from chronic morphine. A subgroup of animals that self-administered a larger amount of morphine at the beginning of the daily sessions exhibited subsequent weight gain, reduced ASR, and enhanced drug seeking in morphine withdrawal. Thus, individual differences in initial morphine intake may reveal a novel behavioral phenotype in opioid addiction.

Chronic opiate use in pregnancy and newborn head circumference.

The aim of the study is to evaluate whether chronic opiate use in pregnancy affects newborn head circumference (HC). All newborns from January 1, 2010, to June 30, 2012, admitted to the neonatal intensive care unit for treatment of neonatal abstinence syndrome were prospectively collected. The demographic, obstetrical, neonatal, and perinatal ultrasound data were retrospectively obtained. A gestational age-matched control was used for comparison purposes. Of 332 neonates admitted for the treatment of neonatal abstinence syndrome, 98 (29.5%) had a HC ≤ 10th percentile for gestational age that was significantly increased when compared with controls (p < 0.001). Of these 98, 25 had a HC ≤ 3rd percentile. Of the case population, 141 had an ultrasound in the perinatal unit within 10 days of birth. A HC < 5th percentile was found in 38.3% of cases of which 74% were ≤ 10th percentile postdelivery. The ultrasound femur and humerus length measurements were also < 5th percentile in 36.2 and 28.9%, respectively. Chronic opiate use in pregnancy appears to increase the risk for a HC ≤ 10th percentile and ≤ 3rd percentile when compared with controls. From ultrasound findings, femur and humerus lengths also appear to be shortened suggesting a possible effect on bone growth.

An Under-Recognized and Under-Reported Cause of Adrenal Insufficiency

We report a unique case of potentially life-threatening secondary adrenal insufficiency in a 58year-old female who was maintained on a high dose fentanyl patch and hydrocodone for many years for chronic back pain. She presented to the emergency room (ER) with severe hypotension, weight loss and fatigue. We suspected hypothalamic-pituitary-adrenal (HPA) axis suppression induced by chronic use of opioids. Subsequently, after appropriate laboratory investigations, she was diagnosed with secondary adrenal insufficiency attributed to chronic opiate use. We discontinued the hydrocodone, decreased the dose of her fentanyl patch and began oral prednisone. The patient responded to treatment and her symptoms were resolved as seen on an outpatient follow up visit three months later. Currently, she is off prednisone and is doing well without demonstrating any symptoms or signs of adrenal insufficiency. Physicians must be aware of this potentially life- threatening side effect of opioid medications and should discourage long term opiate use. To the best of our knowledge, this is the first case report in the United States showing opioid-induced secondary adrenal insufficiency.

(483) Transdermal pain creams attenuate pain in military (TRICARE) chronic pain sufferers

Studies are showing that chronic pain development following severe trauma is increased with the use of opiates compared to other treatment options. The pain is significantly higher with poorer psychological outcomes with chronic opiate use. This is attributed, in part, to Opiate Induced Hyperalgesia (OIH), which magnifies and increases pain upon discontinuation of the therapy and disruption of the Hypothalamic Pituitary Gonadal (HPG) axis and the Hypothalamic Pituitary Adrenal (HPA) axis. These effects can cause downstream disruption of physiologic functions and contribute to comorbidities not normally recognized as a complication of opiate use.

Estado actual del tratamiento de la artrosis

Osteoarthritis is the most frequent cause of joint pain and it is estimated that it is the most common cause of incapacity and adults. The objectives of the treatment are relief of symptoms, maintain or improve joint mobility, limit physical dysfunction and improve quality of life. The patient's should receive a personalized treatment plan that includes education, plan of approach for exercise and joint rest, control of obesity, reduction of adverse mechanical factors (for example, the use of appropriate shoes) and to consider aids for walking and other technical aids. The self-care programs and other psychosocial interventions, manual therapies, thermal agents, TENS or tai-chi may be useful in some patients. The pharmacological treatment is based on the combined use of analgesics, NSAIDs, local infiltrations or topical medication. Paracetamol with or without tramadol is the first step of the treatment although the NSAIDs are more effective. In some cases, the chronic use of opiates may be justified. Symptomatic slow-acting drugs for osteoarthritis (SYSADOA) have limited efficacy. If these measures fail, performing an arthroscopy, osteotomy or prosthetic replacement of the joint may be necessary.

Chronic Use of Opioid Medications Before and After Bariatric Surgery

Obesity is associated with chronic noncancer pain. It is not known if opioid use for chronic pain in obese individuals undergoing bariatric surgery is reduced. To determine opioid use following bariatric surgery in patients using opioids chronically for pain control prior to their surgery and to determine the effect of preoperative depression, chronic pain, or postoperative changes in body mass index (BMI) on changes in postoperative chronic opioid use. Retrospective cohort study in a distributed health network (10 demographically and geographically varied US health care systems) of 11,719 individuals aged 21 years and older, who had undergone bariatric surgery between 2005 and 2009, and were assessed 1 year before and after surgery, with latest follow-up by December 31, 2010. Opioid use, measured as morphine equivalents 1 year before and 1 year after surgery, excluding the first 30 postoperative days. Chronic opioid use is defined as 10 or more opioid dispensings over 90 or more days or as dispensings of at least a 120-day supply of opioids during the year prior to surgery. Before surgery, 8% (95% CI, 7%-8%; n = 933) of bariatric patients were chronic opioid users. Of these individuals, 77% (95% CI, 75%-80%; n = 723) continued chronic opioid use in the year following surgery. Mean daily morphine equivalents for the 933 bariatric patients who were chronic opioid users before surgery were 45.0 mg (95% CI, 40.0-50.1) preoperatively and 51.9 mg (95% CI, 46.0-57.8) postoperatively (P < .001). For this group with chronic opiate use prior to surgery, change in morphine equivalents before vs after surgery did not differ between individuals with loss of more than 50% excess BMI vs those with 50% or less (>50% BMI loss: adjusted incidence rate ratio [adjusted IRR, 1.17; 95% CI, 1.07-1.28] vs ≤50% BMI loss [adjusted IRR, 1.03; 95% CI, 0.93-1.14] model interaction, P = .06). In other subgroup analyses of preoperative chronic opioid users, changes in morphine equivalents before vs after surgery did not differ between those with or without preoperative diagnosis of depression or chronic pain (depression only [n = 75; IRR, 1.08; 95% CI, 0.90-1.30]; chronic pain only [n = 440; IRR, 1.17; 95% CI, 1.08-1.27]; both depression and chronic pain [n = 226; IRR, 1.11; 95% CI, 0.96-1.28]; neither depression nor chronic pain [n = 192; IRR, 1.22; 95% CI, 0.98-1.51); and P values for model interactions when compared with neither were P = .42 for depression, P = .76 for pain, and P = .48 for both. In this cohort of patients who underwent bariatric surgery, 77% of patients who were chronic opioid users before surgery continued chronic opioid use in the year following surgery, and the amount of chronic opioid use was greater postoperatively than preoperatively. These findings suggest the need for better pain management in these patients following surgery.

Cyclic Vomiting Syndrome (CVS): is there a difference based on onset of symptoms - pediatric versus adult?

BackgroundCyclic Vomiting Syndrome (CVS) is a well-recognized functional gastrointestinal disorder in children but its presentation is poorly understood in adults. Genetic differences in pediatric-onset (presentation before age 18) and adult-onset CVS have been reported recently but their clinical features and possible differences in response to therapy have not been well studied.MethodsThis was a retrospective review of 101 CVS patients seen at the Medical College of Wisconsin between 2006 and 2008. Rome III criteria were utilized to make the diagnosis of CVS.ResultsOur study population comprised of 29(29%) pediatric-onset and 72 (71%) adult-onset CVS patients. Pediatric-onset CVS patients were more likely to be female (86% vs. 57%, p = 0.005) and had a higher prevalence of CVS plus (CVS + neurocognitive disorders) as compared to adult-onset CVS patients (14% vs. 3%, p = 0.05). There was a longer delay in diagnosis (10 ± 7 years) in the pediatric-onset group when compared to (5 ± 7 years) adult-onset CVS group (p = 0.001). Chronic opiate use was less frequent in the pediatric-onset group compared to adult-onset patients (0% vs. 23%, p = 0.004). Aside from these differences, the two groups were similar with regards to their clinical features and the time of onset of symptoms did not predict response to standard treatment. The majority of patients (86%) responded to treatment with tricyclic antidepressants, anticonvulsants (topiramate), coenzyme Q-10, and L-carnitine. Non-response to therapy was associated with coalescence of symptoms, chronic opiate use and more severe disease as characterized by longer episodes, greater number of emergency department visits in the year prior to presentation, presence of disability and non-compliance on univariate analysis. On multivariate analysis, only compliance to therapy was associated with a response. (88% vs. 38%, Odds Ratio, OR 9.6; 95% Confidence Interval [CI], 1.18-77.05).ConclusionDespite reported genetic differences, the clinical features and response to standard therapy in pediatric- and adult-onset CVS were mostly similar. Most patients (86%) responded to therapy and compliance was the only factor associated with a response.

Opioid receptor heteromers in analgesia

Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.

577 Per Oral Pancreatoscopy With Intraductal Holmium Laser Lithotripsy for Treatment of Main Pancreatic Duct Calculi: A Multi-Center U.S. Experience

Per Oral Pancreatoscopy With Intraductal Holmium Laser Lithotripsy for Treatment of Main Pancreatic Duct Calculi: A Multi-Center U.S. Experience Raj J. Shah*, Augustin R. Attwell, Isaac Raijman, Michel Kahaleh, Sandeep Patel University of Colorado Hospital, Aurora, CO; Weill Cornell University, New York, NY; University of Texas, San Antonio, San Antonio, TX; Digestive Associates of Houston, Houston, TX Background: Theoretical advantages of per oral pancreatoscopy (POP)-guided laser (LL) vs. electrohydraulic (EHL) lithotripsy of pancreatic duct (PD) stones is treating firmer calculi and reusing fibers; however, more precision is required. An advantage over ESWL is fragmenting and removing stones during the same procedure. We evaluated the technical success of LL for PD stones. Methods: Patients undergoing POP-LL at four U.S. centers were retrospectively identified. Opiate use, hospitalizations, pain scores, duct clearance, ESWL, and complications were recorded. Study definitions: Technical Success: complete or partial stone clearance. Clinical Success: greater than 50% reduction in opiate use, pain scores, or hospitalizations. Stone fragments were retrieved using baskets and balloons and strictures were dilated and stented. Follow-up was obtained by chart review and patient contact. Categorical variables are reported as medians. Results: Between October 2008 and November 2011, 28 patients [26M, 12F, age 51(17-74) years] underwent POP for PD stones with attempted LL using Spyglass. CP etiology: alcohol (N 14, 50%), idiopathic (N 7, 28%), other (N 7, 28%). Baseline parameters: pain requiring hospitalization (N 19, 68%), chronic opiate use (N 14, 50%), weight loss (N 11, 39%). Interventions preceding index POP-LL: ERCP [(22/28 (79%) had 1 (1-5)]; ESWL [9/28 (32%) had 2 (1-3)]; POP /EHL with failed or incomplete stone fragmentation [7/28 (25%) had 1 (1-3)]. At index POP, a median of 1 (1-5) stone 15mm (4-32mm)in size was located in the head (N 9, 25%) neck (N 3, 11%), body (N 9, 36%), tail (N 1, 4%%) or multiple sites (N 6, 21%). LL settings: 1-10J/5-10W using 200365nm probes and range of 2850-7763 pulses. Stricture dilation was performed in 21/28 (75%)patients and all were stented. Mild complications in 7/28 (25%) index POP-LL procedures. 100% follow-up for 11 (1-25) months. Additional interventions: 38 ERCPs [median 1 (1-6) per patient] and 11 POP (1-3 per pt) were performed to achieve 97% Technical Success with complete (24/28; 86%) and partial (3/28; 11%) clearance. Six patients are ongoing endotherapy for strictures (N 4), stones (N 1), or both (N 1). Clinical Success in 27/28 (96%) by improvement in pain (N 26), reduction in narcotics (N 25) or hospitalizations (N 19). No stone recurrence or surgery was observed. Conclusions: 1) When POP reaches the target stone, LL performed at expert centers results in a high rate of complete stone clearance and clinical improvement at nearly one year of follow-up. 2) POP-LL appears to have utility in cases where fragmentation with EHL is ineffective or incomplete. 3) Although ESWL was adjunctive in 1 of 3 patients with obstructing stones, ERCP-POP may be a preferred primary modality due to the ability to stent strictures and extract stone fragments at the same procedural session.

An Emerging New Paradigm in Opioid Withdrawal: A Critical Role for Glia-Neuron Signaling in the Periaqueductal Gray

The chronic use of opiates (i.e., narcotics such as the natural derivatives of opium including morphine or codeine) or opioids (i.e., semisynthetic derivatives of opium and other molecules that activate opioid receptors) induces dependence, which is associated with various specific behavioral and somatic signs after their withdrawal or after the administration of an opioid antagonist. Among the brain regions implicated in opiate dependence and withdrawal, the periaqueductal gray area (PAG) appears to be critical in regulating the complex signs and symptoms of opioid withdrawal. Numerous neurochemical mechanisms in the PAG have been identified that may contribute to the opioid withdrawal syndrome. Accumulating evidence suggests that glial activation leading to the release of proinflammatory molecules acting on neurons is important in the complex syndrome of opioid dependence and withdrawal. This paper focuses on the recent advances in our understanding of the vital role that glia-neuron interactions play in opioid dependence and withdrawal within the PAG. We summarize those neurochemical mechanisms associated with opioid withdrawal including the recently defined importance of TNFα release from activated glial cells that communicate with TNF receptors on PAG neurons.

Inhibition of Morphine-Induced cAMP Overshoot: A Cell-Based Assay Model in a High-Throughput Format

Opiates are not only potent analgesics but also drugs of abuse mainly because they produce euphoria. Chronic use of opiates results in the development of tolerance and dependence. Dr Marshall Nirenberg's group at the National Institutes of Health (NIH) was the first to use a cellular model system of Neuroblastoma × Glioma hybrid cells (NG108-15) to study morphine addiction. They showed that opiates affect adenylyl cyclase (AC) by two opposing mechanisms mediated by the opiate receptor. Although the cellular mechanisms that cause addiction are not yet completely understood, the most observed correlative biochemical adaptation is the upregulation of AC. This model also provides the opportunity to look for compounds which could dissociate the acute effect of opiates from the delayed response, upregulation of AC, and thus lead to the discovery of non-addictive drugs. To identify small molecule compounds that can inhibit morphine-induced cAMP overshoot, we have validated and optimized a cell-based assay in a high throughput format that measures cellular cAMP production after morphine withdrawal. The assay performed well in the 1536-well plate format. The LOPAC library of 1,280 compounds was screened in this assay on a quantitative high-throughput screening (qHTS) platform. A group of compounds that can inhibit morphine-induced cAMP overshoot were identified. The most potent compounds are eight naloxone-related compounds, including levallorphan tartrate, naloxonazine dihydrochloride, naloxone hydrochloride, naltrexone hydrochloride, and naltriben methanesulfonate. The qHTS approach we used in this study will be useful in identifying novel inhibitors of morphine induced addiction from a larger scale screening.