Effects of different intensities of treadmill exercise on cued fear extinction failure, hippocampal BDNF decline, and Bax/Bcl-2 ratio alteration in chronic-morphine treated male rats.

Chronic morphine impairs cued fear extinction, which may contribute to the high prevalence of anxiety disorders and the replase of opiate addiction. This work investigated the effects of forced exercise with different intensities on cued fear extinction impairment and alternations of hippocampal BDNF and apoptotic proteins induced by chronic morphine. Rats were injected with bi-daily doses of morphine or saline for ten days and then received a cued or contextual fear conditioning training, which was followed by fear extinction training for four consecutive days. Cued, but the not contextual fear response was impaired in morphine-treated rats. Then, different saline or morphine-treated rats underwent forced exercise for 4-weeks with light, moderate or high intensities. Subsequently, rats received a cued fear conditioning followed by four days of extinction training, and the expression of hippocampal BDNF and apoptotic proteins was determined. A relatively long time after the last injection of morphine (35 days), rats again showed cued fear extinction failure and reduced hippocampal BDNF, which recovered by light and moderate, but not high exercise. Light and moderate, but not high-intensity treadmill exercise enhanced the up-regulation of Bcl-2 and down-regulation of the Bax proteins in both saline- and morphine-treated rats, which shifted the balance between pro-apoptotic and anti-apoptotic factors in favor of cell survival. These findings highlight the impact of exercise up to moderate intensity in the recovery of cued extinction failure, more likely via BDNF in addicted individuals.

Esquema de tratamiento escalonado no opioide para reducir la adicción a la morfina: reporte de un caso / Non-opioid staircase treatment scheme to reduce morphine addiction: a case report

Los opiáceos son sustancias que se utilizan en la práctica clínica por sus propiedades analgésicas. Sin embargo, se ha visto que estos medicamentos generan adicción y dependencia, lo cual es un riesgo para los pacientes de no existir un adecuado control y seguimiento por parte del personal de salud. Reportamos el caso de una paciente mujer joven con adicción crónica a la morfina la cual acudió al establecimiento de salud por presentar mialgias, diaforesis y escalofríos. Fue estabilizada en la emergencia y diagnosticada con un Síndrome de Abstinencia secundaria a su adicción. Debido a que el establecimiento no contaba con los fármacos de elección para esta enfermedad, la paciente fue dada de alta con la siguiente terapéutica: ácido valproico, gabapentina, mirtazapina y quetiapina. Al momento de realizado este reporte, la paciente estaba cursando su cuarto mes de tratamiento con una mejoría clínica considerable. Presentamos el caso debido a la importancia de poder manejar otros esquemas de tratamiento para esta enfermedad

Opioids are substances that are commonly used in clinical practice because of their analgesic properties. However, there is evidence that these drugs generate addiction and dependence, becoming a risk for the patients in the absence of adequate control and following by health professionals. We report the case of a young female patient with a chronic addiction to morphine who arrived to the health facility due to myalgia, diaphoresis and chills. She was stabilized in the emergency service and diagnosed with Opioid Withdrawal Syndrome. Due to the fact that the establishment did not have the first line therapy, the patient was discharged from the hospital with the following medication: valproic acid, gabapentin, mirtazapine and quetiapine. At the time of this report, the patient was in her fourth month of treatment with considerable clinical improvement. We present this case due to the importance of being able to handle other therapeutic schemes for this disease

[Correlation between insufficient methadone dosage and morphine positive urine on drop out of treatment in patients with access to methadone maintenance treatment].

Objective: To estimate the incidence of drop out of treatment in patients with access to methadone maintenance treatment and explore the correlation and interaction between insufficient methadone dosage and morphine positive urine on the drop out in Guangxi Zhuang Autonomous Region. Methods: Face to face interview was conducted in 1 031 patients at 3 methadone maintenance treatment clinics in Guangxi. Results: The study included 1 031 participants, 40.6% of them (419/1 031) had stopped treatment. The drop out rates in urine morphine positive group and methadone dosage<100 mg/d group were 57.6% (99/172) and 37.4% (347/929) respectively, higher than those in urine morphine negative group and methadone dosage ≥100 mg/d group (42.3%, 363/859, and 26.5%, 27/102). Orderly logistic regression analysis results showed that after adjusted factors, such as gender, age, marital status, ethnic group, patients who received a dosage less than 100 mg/day (OR=3.05, 95%CI: 1.84-5.06) and had morphine positive urine (OR=2.25, 95%CI: 1.59-3.19) were more likely to drop out of the treatment. Interaction analysis showed that dosage less than 100 mg/d and morphine positive urine during treatment had additive interaction (RERI=256.46, AP=0.87, S= 8.05) and multiplication interaction (OR=2.45, 95%CI: 1.71-3.49). Conclusion: Insufficient dosage and morphine positive urine were significantly correlated with drop out of treatment in patients with access to methadone maintenance treatment.

Effects of voluntary exercise on hippocampal long-term potentiation in morphine-dependent rats.

This study was designed to examine the effect of voluntary exercise on hippocampal long-term potentiation (LTP) in morphine-dependent rats. The rats were randomly distributed into the saline-sedentary (Sal/Sed), the dependent-sedentary, the saline-exercise (Sal/Exc), and the dependent-exercise (D/Exc) groups. The Sal/Exc and the D/Exc groups were allowed to freely exercise in a running wheel for 10 days. The Sal/Sed and the morphine-sedentary groups were kept sedentary for the same extent of time. Morphine (10 mg/kg) was injected bi-daily (12 h interval) during 10 days of voluntary exercise. On day 11, 2h after the morphine injection, the in vivo LTP in the dentate gyrus of the hippocampus was examined. The theta frequency primed bursts were delivered to the perforant path for induction of LTP. Population spike (PS) amplitude and the field excitatory post-synaptic potentials (fEPSP) slope were measured as indices of increase in synaptic efficacy. Chronic morphine increased the mean basal EPSP, and augmented PS-LTP. Exercise significantly increased the mean baseline EPSP and PS responses, and augmented PS-LTP in both saline and morphine-treated groups. Moreover, the increase of PS-LTP in the morphine-exercise group was greater (22.5%), but not statistically significant, than that of the Sal/Exc group. These results may imply an additive effect between exercise and morphine on mechanisms of synaptic plasticity. Such an interaction between exercise and chronic morphine may influence cognitive functions in opiate addicts.

Associations between heat pain perception and opioid dose among patients with chronic pain undergoing opioid tapering.

OBJECTIVE: The purpose of this study was to investigate the associations between morphine equivalent dose and heat pain (HP) perception in patients with chronic pain undergoing opioid tapering in the context of a multidisciplinary rehabilitation program. DESIGN: Prospective design. SETTING: Multidisciplinary pain rehabilitation center. PATIENTS: The cohort included 109 patients using opioids (female 52%) who met inclusion criteria, and were consecutively admitted from March 2007 to June 2008. INTERVENTION: Three-week outpatient multidisciplinary rehabilitation program that incorporates opioid tapering. OUTCOME MEASURES: Using a standardized quantitative sensory test (QST) method of levels, standardized values of HP perception were obtained one day following program admission and following completion of the opioid taper at program dismissal. RESULTS: At admission, the mean morphine equivalent dose was 192 mg/day. Univariate linear regression analysis showed that greater baseline morphine equivalent dose was associated (P = 0.040) with lower, or more hyperalgesic, values of HP 5-0.5, which is a standardized measure of HP perception. The dose dependent association retained significance (P = 0.029) after adjusting for pain severity, pain duration and pain diagnosis. Tapering of greater morphine equivalent dosages was associated (P = 0.001) with lower values of HP 5-0.5. The association retained significance (P = 0.001) after adjusting for pain severity, pain duration, pain diagnosis, opioid withdrawal symptoms, and time between completion of the taper and performance of the dismissal QST. CONCLUSION: The use of a validated QST method of levels and standardized values of HP 5-0.5 may expand the methodological approaches available for investigating the clinical effects of opioids on HP perception.

[Impact of slow-release oral morphine on drug abusing habits in Austria]. / Der Einfluss von retardiertem Morphin auf die Drogensituation in Osterreich.

A well-established possibility to treat opiate addiction is the participation in opiate maintenance treatment programmes. For this purpose the opioids methadone and buprenorphine have been evaluated and are used nowadays in many countries. However, since 1998 also the use of slow-release oral morphine (SROM) has been legally permitted in Austria. Our data show that these morphine preparations are frequently abused and are dominating the black market in the meantime. Especially the intravenous consumption of SROM goes along with highly dangerous side effects that exceed the risks of needle sharing alone. Special galenics are supposed to ensure a 24 h effect of the otherwise quickly metabolised morphine. If dissolved and injected, insoluble contents such as talcum cause microembolisms, leading to severe damages of the inner organs. Furthermore, SROM, i.e. a drug prescribed by physicians, has been proved to be the main responsible substance in most drug related deaths since its permission and has nearly replaced heroin. Forensic physicians play a major role in the profound examination of these cases, including extensive toxicological analyses and interpretation of results. For instance, a differentiation between a recent morphine and heroin consumption is certainly possible, provided appropriate methods are used. A reliable estimation of the current situation of drug abusing habits is a premise for adequate therapeutic offers and preventive measures. Thus, well-founded and comparable data have to be collected. To facilitate data report a standardized report form has been developed that includes an obligatory statement regarding morphine or heroin consumption. This should help to enlighten the ongoing discussion on the role of SRM in drug abuse cases. Our results indicate that the prescription of SROM in opiate maintenance therapy has to be handled very strictly and should be reserved for special patients only. A slackening of the Austrian law concerning SROM is therefore objected.

Ultra-low-dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats.

RATIONALE: Ultra-low-dose opioid antagonists enhance opiate analgesia and attenuate tolerance and withdrawal. OBJECTIVES: To determine whether ultra-low-dose naltrexone (NTX) coadministration alters the rewarding effects of opiates or the aversive effects of opiate withdrawal. METHODS: We used the conditioned place preference (CPP) and conditioned place aversion (CPA) paradigms to assess whether ultra-low-dose NTX alters the acute rewarding effects of oxycodone or morphine, or the aversive aspect of withdrawal from either drug. To assess the dose response for ultra-low-dose NTX, a range of NTX doses (0.03-30 ng/kg) was tested in the oxycodone CPP experiment. In order to avoid tolerance or sensitization effects, we used single conditioning sessions and female rats, as females are more sensitive to the conditioning effects of these drugs. RESULTS: Ultra-low-dose NTX (5 ng/kg) blocked the CPP to morphine (5 mg/kg) and the CPA to withdrawal from chronic morphine (5 mg/kg, for 7 days). Coadministration of ultra-low-dose NTX (30 pg/kg) also blocked the CPA to withdrawal from chronic oxycodone administration (3 mg/kg, for 7 days). The effects of NTX on the CPP to oxycodone (3 mg/kg) revealed a biphasic dose response. The two lowest doses (0.03 and 0.3 ng/kg) blocked the CPP, the middle dose (3 ng/kg) was ineffective, and oxycodone combined with the highest dose (30 ng/kg) produced a trend toward a CPP. CONCLUSIONS: Ultra-low-dose NTX coadministration blocks the acute rewarding effects of analgesic doses of oxycodone or morphine as well as the anhedonia of withdrawal from chronic administration.

Naltrexone treatment of combined alcohol and opioid dependence: deterioration of co-morbid major depression.

Naltrexone is frequently used for the treatment of opioid or alcohol dependence. However, the reports on its potential to worsen affective disorders are contradicting. Here we report on a patient with combined alcohol and opioid dependence whose co-morbid major depression deteriorated reversibly and repeatedly under naltrexone. By exchanging buprenorphine for naltrexone, his depression and craving for alcohol and opioids disappeared. This underlines the close interaction between depression, substance dependence and the opioid system.

[Current consumer conditions among opioid addicts--implications for maintenance-treatment programmes provided by ambulatory drug treatment centers and physicians]. / Aktuelle Konsumformen bei Drogenabhängigkeit--Implikationen für Substitutionsprogramme in ambulanten Einrichtungen und bei behandelnden Arzten.

BACKGROUND: Anonymous evaluation of the current conditions of drug scene and drug consumption, entrance age, personal motives for drug consumption and satisfaction among opioid-dependent clients with treatments available within an ambulant maintenance treatment setting. METHODS: The questionnaire for the study was based on representative studies and covered 112 questions regarding drug consumption. In addition, an instrument of the "Hessische Landesstelle gegen die Suchtgefahren", which measures satisfaction of opioid clients regarding public drug-treatment centers, was used. RESULTS: A total of 158 opioid clients within an ambulant maintenance treatment setting were enrolled in the study. The mean age at first drug consumption was 15.1 (2.4) years for men and 15.2 (3.5) years for women. The Spearman correlation showed a significant positive correlation (r=0.284) between age and time of first drug consumption (p=0.019). Cannabis was the most frequent entrance drug (55.8%), followed by alcohol (33.8%), opioids (17.6%) and nicotine (11.8%). Additional consumption of benzodiazepines was observed in 44.7% of men and 39.7% of women, of cannabis in 74.5% of men and 52.4% of women, and of sustained-release morphine in 41.4% of men and 33.3% of women. Within the previous 6-12 months cocaine was consumed significantly less (p=0.024) by men (63.8%) than by women (90.5%). 93.3% of the drug users rated a follow-up assistance programme after withdrawal and 71.9% special care programmes for designer drugs very important. IMPLICATIONS: The present study supports the assumption of an earlier age of first drug consumption. In view of our findings on entrance age, and on polytoxicomanic consumption patterns and gender-specific differences, we believe that the objectives of substitution programmes can only be reached if programmes are adequately adapted to the actual conditions of the drug scene and are able to cooperate with other public drug-treatment systems.

Mianserin and trazodone significantly attenuate the intensity of opioid withdrawal symptoms in mice.

The aims of this study were to evaluate the effects of trazodone and mianserin on opioid-withdrawal symptoms in morphine-dependent mice. We used a comparative study of the effect of each drug on withdrawal symptoms in one model of acutely high-dose morphine-dependent mice, and two models (high-dose and lu-dose) of chronically morphine-dependent mice at the Tel Aviv University Sackler School of Medicine's laboratory.Trazodone, mianserin or both were given to the morphine-dependent mice together with a high dose of naloxone. Intensity of withdrawal symptoms was evaluated by tail-flick assay latencies and three behavioural measurements (rearing, jumping and grooming) in each group. Trazodone and mianserin, each separately,significantly attenuated withdrawal symptoms in all three models. However, the combined treatment of trazodone together with mianserin was not superior to each drug alone. The combination of trazodone and mianserin has no additive value to each drug alone in the control of withdrawal symptoms in opiate-dependent mice undergoing detoxification. When used in clinical settings, caution is needed in order to prevent the unknown influence of opioid-like drugs in medication-assisted detoxification programmes if complete opiate detoxification is the aim.

Time series modeling of heroin and morphine drug action.

RATIONALE: Clinical observations and recent findings suggested different acceptance of morphine and heroin by intravenous drug users in opiate maintenance programs. We postulated that this is caused by differences in the perceived effects of these drugs, especially how desired and adverse effects of both drugs interacted. OBJECTIVES: We measured the desired and adverse effects of high doses of injected morphine and heroin in patients to determine the causal interactions between both types of effects and test the hypothesis of a differential mechanism of action. METHODS: Thirty-three patients (five females, 28 males; mean duration of previous street heroin use 10.7 years, mean age 30.1 years) were randomly allocated double-blind to the substance groups. The average daily dose per participant in the heroin condition (n=17) was 491 mg, in the morphine condition (n=16) 597 mg. The observation period lasted 3 weeks; an average of 70 injections was received. After each injection of either substance, various aspects of drug effects were recorded systematically. Ratings were summarized into the factors "euphoria" and "adverse effects". Time series models were computed for each participant on the basis of the factor scores, using vector autoregression (VAR). RESULTS: A highly significant difference between the substances was found in the interaction between "euphoria" and "adverse effects". Adverse effects of heroin preceded higher euphoria, whereas adverse effects of morphine preceded subsequent lower euphoria. Additionally, the finding of a higher level of adverse effects in morphine was replicated. CONCLUSIONS: Results point to different mechanisms of action of the two opioids when the perceived drug effects are evaluated in a field setting. This may explain the better acceptance of heroin in opiate-assisted treatment of intravenous drug patients. The method used can be a valuable tool for the comparison of substance groups other than opioids.

[Central nervous system activation in opioid dependent patients, evaluation with Fourier analysis of pupillary oscillations]. / Zentralnervöse Aktiviertheit bei opioidabhängigen Patienten, evaluiert durch Fourieranalyse der Pupillenoszillationen.

The aim of the present investigation was to determine whether Fourier analysis of pupillary oscillations permits detection of differences in the activation of the central nervous system of opioid-addicted patients. We analysed pupillary oscillations during the recording period of static pupillometry, which lasted 25.6 s. Using Fourier analysis, the spectrum was divided into five frequency bands (0.0-0.20, 0.21-0.40, 0.41-0.60, 0.61-0.80, 0.81-1.0 Hz); the total spectrum (0-1 Hz) was also assessed. Three groups of patients were selected: the group addicted to heroin (consuming exclusively heroin) consisted of 26 patients with a mean age of 25.0 +/- 6.3 years, the methadone substitution group of 20 patients with a mean age of 30.9 +/- 8.2 years, and the morphine substitution group of 20 patients with a mean age of 33.2 +/- 4.6 years. The 3 patient groups were compared with normal controls of similar age (25.1 +/- 4.6 years). In the frequency band of 0.0-0.20 Hz the morphine group showed significantly lower amplitudes than the heroin group. Also in the frequency band of 0.41-0.60 Hz the morphine group differed significantly from the other groups concerning lower amplitudes, reflecting deactivation. In the total spectrum of 0 to 1 Hz the differences between these two groups were significant. Comparison with normal controls also showed significant differences. The groups were further divided according to dose (high/low): Patients of the heroin group as well as those of the methadone and morphine groups who had consumed higher doses showed greater activation of the central nervous system. In conclusion the morphine group was more deactivated than the methadone and heroin group and patients who received higher doses of the substances showed greater central nervous activation. Thus, the measurement of central nervous activation by means of Fourier analysis of pupillary oscillations might be useful in monitoring substitution therapy.

Nervous regulation of breathing in opiate dependent patient. Part II. Respiratory system efficiency and breathing regulation of persons classified to the methadone maintenance treatment.

The measurements of respiratory pattern parameters, occlusion pressure and respiratory tract resistance had never been performed in opiate dependent persons administered by the methadone maintenance treatment. The aim of this study was assessment of ventilatory efficiency and nervous regulation of 35 depended on opiates before starting the treatment. The presently examined opiate addicts classified to the methadone programme had intensified changes in nervous breathing regulation compared to the group of opiate dependent patients treated at the Department of Clinical Toxicology CMUJ in the first stage of controlled abstinence and to the control group. They had the higher values of minute ventilation, occlusion pressure and higher value of tidal volume to the inspiratory flow (VT/TIN) index which is the driving component of the breathing cycle and reflects the activity of the respiratory centres in the spinal cord and pons. A monitoring of respiratory patterns parameters, occlusion pressure and respiratory resistance, which are not disturbed or biased by lack of patient's cooperation, will allow to determinate the direction of changes in ventilatory efficiency in the course of methadone maintenance treatment programme.

Effect of fusidic acid on the hepatic cytochrome P450 enzyme system.

OBJECTIVE: To investigate the effects of fusidic acid therapy on the hepatic cytochrome P450 (CYP450) enzyme system. METHODS: Thirty HIV-seropositive L-methadone-substituted i.v. drug abusers (stage CDC/WHO B2 - 3 with CD4+-counts ranging from 65 to 293/microl) were randomized into 3 groups (A - C). Ten patients were treated with fusidic acid 500 mg/day over a period of 14 (group A) or 28 days (group B), respectively. Patients in group C served as a control group and did not receive any medication apart from L-methadone. In order to investigate the hepatic monooxygenase system, pharmacokinetics were determined in all patients before initiation and 14 and 28 days after starting therapy with fusidic acid. The concentration of antipyrine and its 3 main metabolites (norantipyrine (NORA), 4-hydroxyantipyrine (OHA), 3-hydroxymethylantipyrine (HMA)) in plasma and urine were measured by high-performance liquid chromatography (HPLC). RESULTS: No effects on antipyrine pharmacokinetics and pharmacokinetics of antipyrine metabolites were found in group A after 14 days of fusidic acid intake and in the control group without therapy. However, in contrast an activation of the CYP450 enzyme system was observed in group B after 28 days of fusidic acid therapy with an increase of total antipyrine clearance (43.0 +/- 7.62 ml/min to 51.0 +/- 9.03 ml/min) as well as clearances to all metabolites (NORA 7.11 +/- 1.75 to 8.60 +/-2.10 ml/min, OHA 11.5 +/- 2.89 to 14.0 +/- 3.97 ml/min, HMA 4.05 +/- 0.99 to 4.94 +/- 1.27 ml/min). Antipyrine half-life was significantly reduced (12.3 +/- 2.8 h to 9.4 +/- 2.2 h) and some patients developed clinical signs of L-methadone underdosage. CONCLUSIONS: Our results suggest that fusidic acid has a time-dependent activating effect on the CYP450 enzyme system. Especially in treatment of patients who are frequently under multidrug regimens such as HIV-positive patients drug interactions should be taken into consideration.

Forced opiate withdrawal under anaesthesia augments and prolongs the occurrence of withdrawal signs in rats.

A newly developed treatment for rapid detoxification of opiate addicts is the use of continuous naloxone/naltrexone administration under general anaesthesia. This method is now introduced in several European countries despite the fact that there is only spare evidence for its effectiveness. Here we report on the assessment of withdrawal symptoms in morphine-dependent rats which received continuous naloxone administration combined with barbiturate anaesthesia. Morphine-dependent rats were implanted with osmotic minipumps filled with either saline or naloxone (delivering 0.5 mg/kg per hour) under barbiturate anaesthesia (lasting for 8 h). Animals were tested daily for the occurrence of withdrawal signs for the subsequent 7 days. All signs of withdrawal which are frequently observed in rats undergoing morphine withdrawal such as body weight loss, diarrhea, writhing, teeth chattering and wet dog shakes were significantly augmented and observed over longer time periods in morphine-dependent animals treated continuously with naloxone versus rats receiving saline. The present study demonstrates that continuous naloxone treatment under anaesthesia worsen and prolongs the detoxification phase in rats. This conflicts with reported clinical observations, and strongly suggests a need for controlled clinical studies before this method enters the everyday clinical routine.

The relationship of methadone dose and other variables to outcomes of methadone maintenance.

The authors evaluated the relationship of methadone dose to retention in treatment and to urine tests for morphine and cocaine in a cohort of 610 opioid users admitted to methadone maintenance and followed for 1 year. Methadone dosing was flexible, with patient participation in dose decisions. The maximum dose during treatment ranged from 10 mg to 110 mg, with a mean of 52 mg. Higher doses were associated with increased retention through the dose range of 60 mg-69 mg. Dose was not related to the likelihood of a positive morphine test but was related to the likelihood of a positive cocaine test. In this study, with flexible dosing and patient participation in dose decisions, patients were retained on methadone about as well as was reported in a previous study with patients on a fixed dose of 80 mg.

Cyclazocine revisited.

Recently synthesized compounds which have long-term mu antagonist activity and short-term kappa agonist effects prevent self-administration of cocaine and morphine in rats. Cyclazocine, a compound synthesized in 1962 and studied in animals and man in the 1960's and in the early 1970's is a mu antagonist in rats and man and is a potent kappa agonist in both species. It also prevents self-administration of cocaine and morphine in rats. Although it produces unpleasant side effects in man, subjects become tolerant to these side effects but not to the antagonistic actions of the drug after prolonged administration.

Subcutaneous injection of an analog of neuropeptide FF prevents naloxone-precipitated morphine abstinence syndrome.

There is evidence that neuropeptide FF (NPFF) has antiopiate activity and may play a role in opiate dependence and subsequent abstinence syndrome. A fragment of NPFF was modified at the C-terminal in an effort to convert it to an NPFF antagonist. It was also dansylated at the N-terminal in an effort to render it more lipophilic and increase its penetration of the blood-brain barrier. Third ventricle administration of the resulting compound, dansyl-PQRamide (0.75 microgram and 1 microgram), dose-dependently antagonized the quasi-morphine abstinence activity of NPFF (10 micrograms) in opiate-naive rats. Subcutaneous injection of dansyl-PQRamide (13 mg/kg) in chronically morphine-infused rats attenuated opiate dependence as indicated by prevention of naloxone-precipitated abstinence syndrome. Dansyl-PQRamide displaced radiolabelled ligand from NPFF receptors in a concentration-dependent manner with a Ki of 13 microM, and had a half-life over 300 times longer than NPFF under aminopeptidase digestion.