A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence

BACKGROUND: Buprenorphine is a partial agonist at the mu-opioid receptor that has been proposed as an alternative to traditional full agonist maintenance therapy for the treatment of opioid addiction. We report on a clinical trial in which the relative safety and efficacy of long-term fixed-dose buprenorphine maintenance was examined in comparison to low- and high-dose methadone maintenance. METHODS: Two hundred twenty-five treatment-seeking opioid addicts (46 women, 179 men) were randomly assigned to receive, in a double-blind manner, either 8 mg/d of buprenorphine, 30 mg/d of methadone, or 80 mg/d of methadone maintenance over a 1-year period. Objective and subjective measures of efficacy (urine toxicology, retention, craving, and withdrawal symptoms) were examined at the study midpoint and at termination, and safety data were tabulated over the entire 52-week study period. RESULTS: Patients assigned to high-dose methadone maintenance performed significantly better on measures of retention, opioid use, and opioid craving than either the low-dose methadone or the buprenorphine group at both 26-week and 52-week time points. Performance on these measures was virtually identical between the latter two groups. No serious adverse health effects attributable to buprenorphine were noted. CONCLUSIONS: Buprenorphine maintenance at 8 mg/d appears to be less than optimally efficacious under the conditions of the present study. Continued research is needed to reconcile these findings with the more positive results reported by other investigative groups. There are no apparent health risks associated with long-term buprenorphine maintenance at this dosage.     

Early impact of methadone induction for heroin dependence: Differential effects of two dose sequences in a randomized controlled study.

The pharmacodynamic and pharmacokinetic effects of 2 methadone (METH) induction dose sequences were evaluated in this 15-day outpatient experimental protocol. Heroin-dependent, non-treatment-seeking volunteers were randomly assigned (stratified for gender, race, and route of heroin use) to 2 groups. In 1 sequence, METH doses ascended (28, 56, then 84 mg/day; stepwise, n = 18), whereas in the other sequence doses escalated, then tapered (28-84 mg on Days 1-6 to 56 mg/day; rapid, n = 16). A contingency-management intervention was common to both groups. Drug use and heroin craving and opioid withdrawal symptoms decreased, whereas agonist symptoms and positive mood increased overall across days for both groups. Plasma concentrations and the acute reinforcing effects of METH paralleled each dose sequence. Stepwise relative to rapid METH induction significantly decreased heroin craving and opioid withdrawal symptoms and increased agonist symptoms and positive mood but did not significantly improve drug use or retention. Although these specific dosing procedures would not necessarily be used in clinical settings, they provide a procedural template that might be applied safely and effectively with a broader range of treatment-seeking individuals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

MRI of hyperpolarized 3He gas in human paranasal sinuses

Relapsed or refractory adult acute lymphoblastic leukemia (ALL) carries a grave prognosis. The most promising strategy for curing these patients is through re-induction chemotherapy followed by successful allogeneic transplant. We studied a new high-dose induction regimen in order to improve the outcome for these patients. Eighteen adult patients with relapsed/refractory ALL were treated on a phase I study of high-dose cytarabine combined with a single escalating dose of idarubicin. Five patients had primary refractory disease and 13 were treated in refractory relapse. Nine patients (50%) had Ph+ ALL. The induction regimen was cytarabine 3 g/m2/day intravenously days 1-5 and idarubicin as a single intravenous dose on day 3. G-CSF 5 microg/kg subcutaneously every 12 h was started on day 7. The initial idarubicin dose was 20 mg/m2 with dose escalations of 10 mg m2. Cohorts of three patients were treated at each idarubicin dose level. Unacceptable toxicity was encountered at 50 mg/m2 with one death from infection and one death from cardiotoxicity in a patient with significant prior anthracycline exposure. There were no instances of grade 4 non-hematologic toxicity encountered at idarubicin doses of 20 mg/m2, 30 mg/m2, or 40 mg/m2. The data suggest a dose-response relationship for increasing doses of idarubicin with 0/3 complete responses (CR) at 20 mg/m2, 1/3 CR at 30 mg/m2, and 7/12 (58%) CR at idarubicin doses > or = 40 mg/m2. We conclude that concomitant administration of cytarabine 3 g/m2/day x 5 and high-dose idarubicin at 40 mg/m2 as a single dose on day 3 can be administered safely to patients with refractory and relapsed ALL.     

Buprenorphine versus methadone maintenance for opioid dependence

Buprenorphine at 2 mg and 6 mg daily was compared with methadone at 35 mg and 65 mg during 24 weeks of maintenance among 125 opioid-dependent patients. As hypothesized, 6 mg of buprenorphine were superior to 2 mg of buprenorphine in reducing illicit opioid use, but higher dosage did not improve treatment retention. Self-reported illicit opioid use declined substantially in all groups, but by the third month, significantly more heroin abuse was reported at 2 mg than at 6 mg of buprenorphine or of methadone. From an initial average of $1860/month, month 3 usage dropped to $41 (methadone 65 mg), $73 (methadone 35 mg), $118 (buprenorphine 6 mg), and $351/month (buprenorphine 2 mg). Days of use also dropped from 29 days to 1.7 (methadone 65 mg), 2.8 (methadone 35 mg), 4.0 (buprenorphine 6 mg), and 6.6 days/month (buprenorphine 2 mg). This relatively low efficacy for 2 mg of buprenorphine persisted through month 6 of the trial, with 7.2 days/month and $235/month of use for buprenorphine at 2 mg versus 1.9 days/month and $65/month for the other three groups. Increased opioid abuse also was associated with significantly greater and persistent opioid withdrawal symptoms. Our secondary hypothesis, that buprenorphine would be equivalent to methadone in efficacy, was not supported. Treatment retention was significantly better on methadone (20 vs. 16 weeks), and methadone patients had significantly more opioid-free urines (51% vs. 26%). Abstinence for at least 3 weeks was also more common on methadone than buprenorphine (65% vs. 27%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of maintenance treatment in opioid dependence

Methadone maintenance treatment (MMT) involves the daily administration of the oral opioid agonist methadone as a treatment for opioid dependence-a persistent disorder with a substantial risk of premature death. MMT improves health and reduces illicit heroin use, infectious-disease transmission, and overdose death. However, its effectiveness is compromised if low maintenance doses of methadone (<60 mg) are used and patients are pressured to become prematurely abstinent from methadone. Pregnancy and psychiatric comorbidity are not contraindications for MMT. As an alternative to MMT, other oral opioid agents (eg, naltrexone, buprenorphine) may increase patient choice and avoid some of the more unpleasant aspects of MMT. The public-health challenge for the future is to develop and continue to deliver safe and effective forms of opioid maintenance treatment to as many opioid-dependent individuals as can benefit from them.     

Chronic l-alpha acetylmethadol in rhesus monkeys: discriminative stimulus and other behavioral measures of dependence and withdrawal

This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioid l-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32-1.78 mg/kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas >90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal.     

Postoperative adhesion prevention with low-dose aspirin: effect through the selective inhibition of thromboxane production

The aim of the present study was to evaluate the efficacy of low-dose versus high-dose aspirin in the prevention of postoperative adhesion formation. Forty New Zealand White rabbits were randomized into three groups: low-dose aspirin (1.7 mg/kg per day for 5 days starting on the day of surgery), high-dose aspirin (28.0 mg/kg per day), and controls. The rabbits underwent a standardized surgical injury on the ovary, uterine horn and abdominal wall on one side at laparotomy. On postoperative day 21, a second-look laparotomy was performed for the evaluation of postoperative adhesions. In five animals in each group, peritoneal fluid samples were collected at initial surgery, then through an additional 2 cm incision performed on postoperative day 3, and at second-look laparotomy. The peritoneal concentrations of thromboxane B2 and 6-keto-prostaglandin F1alpha (the stable hydrolysis product of prostacyclin) were measured by radioimmunoassay. At second-look laparotomy, the adhesion formation rate was 46% in the low-dose aspirin group, 77% in the high-dose group, and 100% in the control group. The adhesion score in the low-dose group was significantly lower (P < 0.01) than in the high-dose and control groups. Peritoneal thromboxane decreased significantly during treatment in both low-dose and high-dose aspirin groups, whereas prostacyclin decreased only in the high-dose group. Postoperative adhesion reduction observed in this study with low-dose aspirin treatment could be due to the selective inhibition of thromboxane over prostacyclin production.     

Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence.

This study examined (1) predictors of treatment outcome for opioid-dependent participants in a single-site controlled trial comparing methadone, buprenorphine, and LAAM treatments and (2) the extent to which various subpopulations of patients may have more successful outcomes with each medication. The relationships between patient demographics, drug use history, and psychological status and outcome measures of treatment retention, opiate use, and cocaine use were assessed. We believe this study to be the first to demonstrate that predictors of treatment success appear to be largely similar in LAAM, buprenorphine, and methadone treatment for opioid dependence. We did not find any factors that would strongly guide selection of one medication over others. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation

Ninety-five patients undergoing an allogeneic bone marrow transplant (BMT) and developing acute graft-versus-host disease (aGvHD) were randomized to receive low-dose intravenous 6-methylprednisolone (6MPred; 2 mg/kg /d; n = 47) or high-dose 6MPred (10 mg/kg/d; n = 48) for 5 days, with subsequent tapering doses. On day 5 patients not responding or progressing on low-dose 6MPred could be switched to high-dose 6MPred. All patients, aged 1 to 55 years, were recipients of unmanipulated BMT from HLA identical sibling donors. Patients were stratified at randomization for age (/= 20 years), disease (acute leukemia, chronic myeloid leukemia [CML], nonneoplastic disease), disease status (early/advanced), and GvHD prophylaxis (cyclosporin/cyclosporin + methotrexate). Primary endpoints were response to treatment and evolution of aGvHD to grade III-IV. Secondary endpoints were cytomegalovirus (CMV) infections, transplant-related mortality (TRM), and relapse. The median interval between BMT and treatment was 12 days (6 to 43). Results in the two groups (2 v 10 mg/kg) were as follows: response of aGvHD 68% versus 71% (P = .9), evolution to aGvHD grade III-IV 17% versus 20% (P = . 6), CMV infections 55% versus 60% (P = .7), 3-year actuarial TRM 28% versus 32% (P = .7), relapse 17% versus 7% (P = .1). The actuarial survival at 3 years was 63% versus 62% (P = .9) with a median follow up of 580 and 778 days. On day 5 of therapy, 26 patients assigned to low-dose (2 mg/kg) 6MPred were switched to a higher dose of 6MPred because of no response or progression. Their actuarial TRM was 46%, which is significantly higher than TRM of patients who responded on 2 mg/kg and continued with tapering doses (TRM = 16%, P = .007). In conclusion, early treatment of acute GvHD with 6MPred 10 mg/kg/d does not improve the response rate as compared with 2 mg/kg/d, nor does it prevent evolution to aGvHD grade III-IV. CMV infections, TRM, and survival were also comparable. A group of patients at high risk of TRM can be identified after 5 days of treatment with 6MPred 2 mg/kg and could be eligible for alternative forms of therapy.     

Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate

BACKGROUND: A naloxone infusion is effective in reducing epidural and intrathecal opioid-related side effects. The use of naloxone infusion concomitant with intravenous morphine patient-controlled analgesia (PCA) has not been evaluated, probably because of an expected direct antagonism of the systemic opioid effect. The authors compared the incidence of morphine-related side effects and the quality of analgesia from two small doses of naloxone infusion. METHODS: Sixty patients classified as American Society of Anesthesiologists physical status 1, 2, or 3 who were scheduled for total abdominal hysterectomies were enrolled in the study. Patients received a standardized general anesthetic. In the postanesthetic care unit, patients received morphine as a PCA. They were randomized to receive either 0.25 microg x kg(-1) x h(-1) naloxone (low dose), 1 microg x kg(-1) x h(-1) (high dose), or saline (placebo) as a continuous infusion. Verbal rating scores for pain, nausea, vomiting, and pruritus; sedation scores; requests for antiemetic; and morphine use were recorded for 24 h. Blood pressure, respiratory rate, and oxyhemoglobin saturation were also monitored. RESULTS: Sixty patients completed the study. Both naloxone doses were equally effective in reducing the incidence of nausea, vomiting, and pruritus compared with placebo (P < 0.05 by the chi-squared test). There was no difference in the verbal rating scores for pain between the groups. The cumulative morphine use was the lowest in the low-dose group (42.3 +/- 24.1 mg; means +/- SD) compared with the placebo (59.1 +/- 27.4 mg) and high-dose groups (64.7 +/- 33.0 mg) at 24 h (P < 0.05 by analysis of variance). There was no incidence of respiratory depression (<8 breaths/min) and no difference in sedation scores, antiemetic use, respiratory rate, and hemodynamic parameters among the groups. CONCLUSIONS: Naloxone is effective in preventing PCA opioid-related side effects. Naloxone infusion at 0.25 microg x kg(-1) x h(-1) not only attenuates these side effects but appears to reduce postoperative (beyond 4-8 h) opioid requirements. This dosing regimen can be prepared with 400 microg naloxone in 1,000 ml crystalloid given in 24 h to a patient weighing 70 kg.     

Repeated treatment with high doses of morphine produces comparable tolerance to low- and high-dose discriminative stimulus effects of morphine.

Morphine tolerance was studied in 9 pigeons (Columba livia, N?=?9) trained to discriminate among a low dose of morphine (1.8 mg/kg), a high dose of morphine (10 mg/kg), and saline. Doses of morphine required for low-dose or high-dose stimulus effects were determined before, during, and after a 4-week treatment period, during which training was suspended. Treatment with 56 mg/kg, but not 10 mg/kg, morphine, b.i.d., increased the doses required for either low-dose or high-dose stimulus effects by approximately 10-fold. Both treatments increased doses required for rate suppression. Sensitivity recovered after a week of saline treatment. Acute treatment with 56 mg/kg morphine did not change sensitivity. These results suggest that chronic morphine treatment can produce surmountable, reversible tolerance to morphine acting as a discriminative stimulus, without disrupting a discrimination between low-dose and high-dose stimulus effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of insulin-like growth factor-1 on cyclic change of tendon cell

BACKGROUND: Myoclonus is a possible side effect of opioid therapy, and have been described following systemic as well as spinal application. CASE REPORT: We report the case of a patient with metastatic carcinoma of the rectum who developed myoclonus following administration of high-dose epidural combined with iv morphine. This complication occurred with maximum daily doses of 300 mg epidurally and 80 mg intravenously and disappeared completely after dose reduction. Treatment trials are presented, the pathophysiology of the myoclonus is discussed. CONCLUSION: For treatment of opioid-induced myoclonus a dose reduction or a change of the opioid should be considered as well as symptomatic treatment with benzodiazepines or baclofen.     

Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators

BACKGROUND: Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates. METHODS AND RESULTS: Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg x kg(-1) x h(-1) for 12 hours then 0.125 mg x kg(-1) x h(-1)), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg x kg(-1) x h(-1) for 12 hours then 0.25 mg x kg(-1) x h(-1)). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P=.023; heparin versus high-dose hirulog, P=.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients (P=NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) (P=NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P<.01). CONCLUSIONS: Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.     

The competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist LY293558 attenuates and reverses analgesic tolerance to morphine but not to delta or kappa opioids

Antagonists of the NMDA type of excitatory amino acid (EAA) receptor attenuate or reverse the development of tolerance to the analgesic effects of the mu opioid agonist morphine, the delta-1 opioid agonist DPDPE but not the kappa-1 agonist U50,488H or the kappa-3 agonist naloxone benzoylhydrazone. The role of the AMPA subtype of EAA receptor in analgesic tolerance was examined using LY293558, a selective competitive antagonist that is active after systemic administration. Administration of morphine, DPDPE, or U50,488H three times daily for 3 days according to an escalating dosing schedule resulted in analgesic tolerance as indicated by an increase in analgesic ED50 values using the tail-flick test in mice. Analgesic tolerance was attenuated when mice received a continuous subcutaneous infusion of LY293558 at doses of 30, 45 or 60 mg/kg/24 hr via an osmotic pump concurrent with the morphine treatment. Continuous subcutaneous infusion of LY293558 (45 mg/kg/24 hr) also reversed established morphine tolerance. In contrast, continuous subcutaneous infusion of the highest dose of LY293558 (60 mg/kg/24 hr) was ineffective in preventing the development of analgesic tolerance to DPDPE or U50,488H. Continuous subcutaneous infusion of LY293558 (60 mg/kg/24 hr) for 3 days protected mice from generalized convulsions produced by the selective AMPA agonist ATPA, indicating that the dosage of LY293558 that attenuated morphine tolerance was effective as an antagonist at AMPA receptors. These results demonstrate that AMPA receptors may play a role in the development and maintenance of morphine, but not DPDPE or U50,488H, analgesic tolerance.     

Differences in narrow-band ultraviolet B and broad-spectrum ultraviolet photocarcinogenesis in lightly pigmented hairless mice

The carcinogenic effect of 4 ultraviolet (UV) sources was studied in lightly pigmented hairless mice. Two narrow-band UV sources, Philips TL01 and Philips TL12 with a Tempax filter, and two broad-spectrum UV sources, Philips TL12 and Bellarium S, were used. Exposure doses were calculated from the CIE erythema action spectrum. Four groups of mice (n = 20) were exposed to a nonerythemogenic dose (low dose), and 4 groups were exposed to an erythemogenic dose (high dose) of each of the 4 UV sources. One group (control) was not irradiated. The mice in the 4 low-dose groups were all exposed to 0.6 basic minimal erythema doses (B-MED) 5 days/week, and all the mice in the high-dose groups to 1.2 B-MED 5 days/week. After 16 weeks of acclimatization, the doses were doubled. Bellarium S and Philips TL12 were equally carcinogenic in the low-dose regimen and the high-dose regimen. Mice exposed to Philips TL12 with a Tempax filter developed tumors significantly earlier compared with Bellarium and Philips TL12. Philips TL01 was more carcinogenic than any of the other UV sources. Equally erythemogenic doses calculated from the CIE erythema action spectrum seem to be more carcinogenic when derived from narrow-band UVB sources than from broad-band UV sources.     

Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.     

Opioid agonist effects on mouse writhing after irreversible mu receptor blockade with clocinnamox.

The antinociceptive effects of the mu opioid agonists morphine, fentanyl, etonitazene, and the high-potency fentanyl analog NIH 10741 were assessed before and after administration of the irreversible mu opioid antagonist clocinnamox (CCAM) in a mouse acetic acid-induced writhing procedure. CCAM caused hyperalgesia and shifted the dose-response curves of all 4 tested agonists to the right in a dose-dependent manner without, however, preventing the complete suppression of writhes by agonist doses >100–20,000 times their respective ED?? values. In the case of etonitazene and NIH 10741, 10 mg/kg CCAM produced biphasic agonist dose-response curves. Further experiments with naltrexone, naltrindole, and nor-binaltorphimine suggested that in the presence of 10 mg/kg CCAM, low- to intermediate-agonist doses produced mu opioid-mediated antinociception, whereas very high agonist doses (530–2,800-fold higher than their ED?? value under control conditions) suppressed writhing by nonopioid mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

D-cycloserine--naloxone interactions in opioid-dependent humans under a novel-response naloxone discrimination procedure.

Six participants currently in opioid maintenance treatment were trained to distinguish between naloxone (0.15 mg/70 kg, intramuscularly [i.mj) and placebo under an instructed novel-response drug-discrimination procedure. Doses of the partial glycine agonist D-cyclostrine (0-500 mg/70 kg, per os [P.O.]) alone and combined with naloxone (0.15 mg/70 kg) were then tested. D-cycloserine alone produced minimal drug-appropriate responding, no significant changes in self-reported effects, and increases only in systolic blood pressure. When combined with the naloxone, D-cycloserine partially attenuated naloxone-appropriate responding. D-cycloserine attenuated naloxone-induced increases in visual analog scale ratings of "like naloxone" and scores on the Lysergic Acid Diethyl Amide subscale of the Addiction Research Center Inventory (D. R. Jasinski, 1977; W. R. Martin, J. W. Sloan, J. D. Sapiro, & D. R. Jasinski, 1971). Naloxone attenuated D-cycloserine-induced increases in systolic blood pressure. These results suggest that D-cycloserine at doses up to 500 mg/70 kg may have some limited usefulness in relieving symptoms of opioid withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of marijuana on divergent and convergent production cognitive tests.

In a study of the effects of cannabis on cognitive functioning, several cognitive and psychomotor tests were administered to 4 groups of male college Ss (84 Ss): (a) a high-dose group [equivalent to 6 mg of Δ–9-tetrahydrocannabinol (THC)], (b) a low-dose group (equivalent to 3 mg of THC), (c) a placebo group, and (d) a control group. Cannabis was smoked in the form of marihuana. Even Ss who received the low dose showed impairment on the WAIS Block Design test and the Memory-for-Designs Test. High-dose Ss gave an impaired performance on several other cognitive tests; however, on some cognitive tests, mainly those measuring divergent production and oral fluency, low-dose Ss performed the best and high-dose Ss performed the worst. Consequently, there is a possibility, requiring further exploration, that cannabis at low dose levels can act as a stimulant and can improve performance on certain tests. (69 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules

BACKGROUND: Little information is available about the safety of high doses of mesalazine during pregnancy. AIM: To study the fate of pregnancy and foetal outcome in women taking 1-4 g/day of mesalazine microgranules for inflammatory bowel disease. PATIENTS AND METHODS: Case reports were collected from the Pharmacovigilance Department of Ferring SA, France, from a survey conducted in three gastroenterology units, and from a teratology information service. The evolution of pregnancy and foetal outcome were assessed by questionnaire. RESULTS: The study covered a total of 123 pregnancies (126 foetuses). Ninety-six women took mesalazine during the first trimester, 85 during the second and 83 during the third. The mean daily dose was 2.1+/-0.8 g; 86 women received <3 g/day (low-dose group), 37 women received > or =3 g/day (high-dose group). The following abnormalities were observed in the low-dose and high-dose groups, respectively: ectopic pregnancy (1/0), spontaneous abortions (1/1), foetal death (0/1), premature deliveries (3/5, P < 0.05), congenital malformations (3/1) and one case of lethal oxalosis. Abnormalities were not considered to be related to mesalazine. CONCLUSIONS: The use of oral mesalazine microgranules during pregnancy is safe at doses < or =2 g/day, and probably also at a dose of 3 g/day.