BUP Group Research Articles

Neonatal Abstinence Syndrome in Infants with Prenatal Exposure to Methadone versus Buprenorphine.

Neonatal abstinence syndrome (NAS) has been of increasing concern. Studies suggest that prenatal exposure to buprenorphine may be preferred to methadone in regard to neonatal withdrawal. Our aim was to determine whether the incidence and severity of NAS are different between babies prenatally exposed to methadone or buprenorphine in pregnancy. This retrospective analysis of infants ≥ 35-weeks-old exposed to methadone/buprenorphine alone or in conjunction with other substances in utero. They were divided into four groups: 1-methadone alone (Met), 2-buprenorphine alone (Bup), 3 and 4-those exposed to methadone and buprenorphine, respectively, in conjunction with other drugs (Met+ and Bup+). The frequency of NAS treatment, duration of treatment (LOT) and length of stay (LOS) were compared between groups. Of the 290 mothers, 59% were in the Met group, 18% in the Bup group, 14% in the Met or Bup and another opiate group, and 9% took methadone or buprenorphine plus various other substances. Infants born to Met/Met+ mothers had a four-times higher likelihood of developing NAS (p < 0.001). There was no difference in the LOS (p = 0.08) or LOT (p = 0.11) between groups. The buprenorphine treatment in pregnancy decreased the risk of babies developing NAS. However, once the NAS required pharmacological treatment, the type of maternal prenatal exposure did not affect the LOS or LOT.

Comparison of lidocaine alone or in combination with a local nerve block of ethanol, bupivacaine liposome suspension, or oral meloxicam to extend analgesia after scoop dehorning in Holstein calves

The American Veterinary Medical Association recommends the use of practices that reduce or eliminate pain and discomfort associated with dehorning. Identification of an effective, long-acting local anesthetic that is practical for producers to implement and reduces pain from dehorning would benefit animal welfare. Thirty-two Holstein bulls and heifers were enrolled. The objective of this study was to compare the efficacy and duration of activity of bupivacaine liposome suspension (BUP; n = 8), ethanol (ETH; n = 8), or meloxicam (LID + MEL; n = 8) co-administered with lidocaine compared with lidocaine only (LID; n = 8), and to quantify their effect on pain biomarkers and behaviors after scoop dehorning with cauterization in approximately 20-wk-old calves. Outcome variables collected included infrared thermography (IRT), mechanical nociceptive threshold (MNT), visual analog scale (VAS) scoring, and blood sampling for serum cortisol and prostaglandin E2 metabolites (PGEM). There was evidence of a sex effect for MNT, with bulls demonstrating a higher threshold (13.74 kgf) compared with heifers (12.12 kgf). There was a treatment by time interaction for cortisol concentrations (ng/mL). At 2 h, the BUP group had higher cortisol values (17.32 ng/mL) than the LID + MEL group (3.10 ng/mL). Heifers also had higher mean cortisol values (13.88 ng/mL) compared with bulls (6.96 ng/mL). There was a treatment by time interaction for PGEM concentration. Calves in the LID + MEL group had lower PGEM values at 4 and 8 h (10.23 and 9.12 pg/mL) than at −24, 0, and 0.5 h (20.38, 27.27, and 22.59 pg/mL, respectively). At 4 h, the LID + MEL group had lower PGEM concentrations (10.23 pg/mL) than the ETH group (27.08 pg/mL). At 8 h, the LID + MEL group had lower PGEM concentrations (9.12 pg/mL) than both the ETH and BUP groups (24.80 and 20.52 pg/mL). Thus, LID + MEL reduced cortisol and prostaglandin metabolite concentrations more effectively than ETH + LID or BUP + LID administered as a local infiltration and cornual block, respectively, before scoop dehorning followed by cauterization. The treatments administered in the present study did not seem to extend the duration of analgesia beyond the currently recommended multimodal approach, including local anesthesia and systemic analgesia such as lidocaine and meloxicam. Evidence from the current study suggests that sex influences pain biomarkers such as nociceptive threshold and cortisol concentration, with males having a higher nociceptive threshold and lower cortisol responses.

Effect of bupivacaine liposome suspension administered as a cornual nerve block on indicators of pain and distress during and after cautery dehorning in dairy calves

Dehorning is performed on a high percentage of dairies worldwide. Concern about the negative effect of dehorning on animal welfare has contributed to the development of new guidelines that require the use of pain management at the time of disbudding in the United States. However, livestock producers are limited in how to address this requirement due to a lack of (1) approved analgesic drugs, (2) analgesic options that control pain for an extended duration, and (3) analgesic formulations that are practical for producers to administer. The objective of this study was to evaluate the effectiveness of bupivacaine liposome suspension, a novel, long-acting, local anesthetic formulation administered as a nerve block at dehorning, compared with current industry standard analgesic approaches using lidocaine nerve blocks alone or in combination with the nonsteroidal anti-inflammatory drug meloxicam. Fifty male Holstein calves, 10 to 14 wk of age, were enrolled and randomly assigned to 1 of 5 treatment groups before cautery dehorning as follows: (1) bupivacaine liposome suspension block, oral placebo (BUP); (2) lidocaine block, oral placebo (LID); (3) lidocaine block, oral meloxicam (1 mg/kg of body weight; LID + MEL); (4) saline block, oral placebo (CON); and (5) saline block, oral placebo, sham dehorn (SHAM). Biomarkers were collected from 0 to 120 h postdehorning and included infrared thermography, mechanical nociceptive threshold (MNT), pressure mat gait analysis, chute defense and behavior scoring, and blood sampling for serum cortisol and prostaglandin E2 metabolites. Responses were analyzed using repeated measures with calf nested in treatment designated as a random effect, and treatment, time, and their interaction designated as fixed effects. At 2 h postdehorning, the BUP group had a higher MNT compared with the CON group. Furthermore, at 24 h postdehorning, the BUP group had a higher MNT compared with the LID group. Gait distance differed significantly between treatment groups; the CON, LID, and LID + MEL groups had an increased gait distance relative to the SHAM group. The CON group exhibited a higher chute defense behavior score during the dehorning procedure compared with all other treatments. Furthermore, the CON group exhibited more ear flicks than the BUP and LID + MEL groups postdehorning. At 4 h and 24 h after dehorning, the LID + MEL group had a lower average prostaglandin E2 metabolites concentration compared with all other treatment groups. These data showed that administration of bupivacaine liposome suspension as a cornual nerve block at the time of dehorning was as effective at controlling pain as a multimodal approach of lidocaine and meloxicam.

179 A Comparison of Local Anesthetic Effectiveness in Reducing Pain Associated with Dehorning in Dairy Calves

Abstract Dehorning is performed on a high percentage of dairies in the United States. Concern for animal welfare has led to investigating pain mitigation during dehorning. The objective was to compare the effectiveness of bupivacaine liposome suspension, lidocaine, or lidocaine + meloxicam administered at dehorning. Fifty male Holstein calves, 10–14 weeks of age were enrolled and randomly assigned to 1 of 5 treatment groups: 1) bupivacaine liposome suspension block, oral placebo, cautery dehorn (BUP); 2) lidocaine block, oral placebo, cautery dehorn (LID); 3) lidocaine block, oral meloxicam, cautery dehorn (LID + MEL); 4) saline block, oral placebo, cautery dehorn (CON); and 5) saline block, oral placebo, sham dehorn (SHAM). Biomarkers were collected from 0 to 120 hours post-dehorning and included infrared thermography (IRT), mechanical nociceptive threshold (MNT), and pressure mat gait analysis. Biomarkers were statistically analyzed using repeat measures with the calf being the repeated measure. There were no significant treatment differences for IRT measures. A treatment effect was observed for the mean difference of the right horn bud minus a control point which were -1.21 kgF, -1.41 kgF, -1.56 kgF, -1.65 kgF, and -1.68 kgF for the SHAM, CON, BUP, LID + MEL, and LID groups, respectively (P = 0.004). The BUP group did not differ from CON (P = 0.78) or SHAM (P = 0.07). A treatment effect was observed for gait distance means which were 182.05 cm, 189.69 cm, 195.77 cm, 199.54 cm, and 200.59 cm for the SHAM, BUP, LID + MEL, LID and CON groups, respectively (P = 0.04). The CON group did not differ from BUP, LID, or LID + MEL (P &amp;gt; 0.05) but did differ from SHAM (P = 0.02). These data show that administration of bupivacaine liposome suspension at the time of dehorning was not different than lidocaine or lidocaine + meloxicam.

636 Prenatal methadone exposure is associated with smaller fetal and neonatal cranial measurements compared to buprenorphine

Limited information about differential effects of methadone (mthdn) vs. buprenorphine (bup) on fetal and neonatal outcomes exists. Objectives of this study were to compare fetal measurements, including unique ultrasound measures of fetal brain, and neonatal outcomes in women who receive mthdn or bup in pregnancy. Data were obtained from the ENRICH prospective cohort study; 60 women receiving mthdn and 86 receiving bup. Ultrasound measurements were obtained for 127 women in the 2nd trimester (18-22 weeks) and 132 in the 3rd trimester (28-32 weeks). Fetal measurements included standard biometric parameters as well as frontal lobe width and length, fronto-thalamic distance, and caval-calvarial distance (CCD). Neonatal measurements included birth weight, length, and head circumference (HC). Group comparisons used Wilcoxon rank sum, Fisher’s exact, or Chi-square tests as appropriate. Ultrasound measures were compared using analysis of variance models (non-percentile measures adjusted for gestational age). Least-square means±standard error are reported. Methadone-exposure was associated with smaller cranial measurements beginning in the 2nd trimester and persisting to birth compared to buprenorphine-exposure. Second trimester ultrasound demonstrated significantly lower HC percentile (29.2±2.7 vs. 38.6±2.3), CCD (21.8±0.3 vs. 23.1±0.3mm), and occipitofrontal diameter (OFD) (63.4±0.3 vs. 65.0±0.3mm) in the mthdn compared to bup group (all p’s<0.05). These differences persisted in the 3rd trimester (HC percentile 27.3±4.2 vs. 42.1±3.6; OFD 95.3±1.5 vs. 101.3±1.3mm). Differences were also observed at birth between mthdn and bup treated groups (HC percentile: 28.3±2.9 vs. 49.5±3.5; p<0.01; length percentile: 34.0±3.5 vs. 45.6±3.4; p=0.04). Buprenorphine-exposed infants had shorter hospital stays (14.5±5.2 vs 18.6±1.8 days; p<0.01) and were less likely to require withdrawal treatment (31.4% vs 58.3%; p<0.01). Prenatal methadone exposure was associated with smaller head circumference and body length measurements and longer neonatal hospital stays due to withdrawal treatment.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Bupropion promotes alterations in the spermatogenesis of mice and congenital malformations in the offspring.

Bupropion hydrochloride (BUP) has been associated with male sexual dysfunction. The aim of this study was to evaluate the effects of BUP on the reproductive function of male mice and to evaluate offspring development. The mice were distributed into BUP group (40mgkg-1) and control group (saline). On Day 35 of treatment the males were placed to mate with females and then killed on Day 46 for evaluation of reproductive function. On Day 18 of pregnancy, pregnant females were killed for evaluation of congenital malformations in the offspring. The BUP group showed a decrease in the Johnsen score (Control, 9.354±0.092; BUP, 7.615±0.147), Sertoli (Control, 5.623±0.184; BUP, 4.215±0.097) and Leydig (Control, 11.430±0.817; BUP, 7.531±0.213) cell counts, testosterone levels (Control, 783.5±154.2ngdL-1; BUP, 201.4±54.8ngdL-1) and sperm production (Control, 2.852±0.211; BUP, 1.988±0.116) and increased morphological alterations of the sperm head (Control, 8.134%; BUP, 10.423%) and tail (Control, 4.96%; BUP, 16.211%). The congenital malformations observed in BUP-derived offspring were: kyphosis (Control, 0.00%; BUP, 5.26%), retroverted rear legs (Control, 14.43%; BUP, 53.68%), incomplete ossification of the supraoccipital and exoccipital (Control, 21.82%; BUP, 86.00%) and sternum (Control, 25.45%; BUP, 82.00%). BUP had toxic effects on testicular function and teratogenic potential.

Diphenyleneiodonium Mitigates Bupivacaine-Induced Sciatic Nerve Damage in a Diabetic Neuropathy Rat Model by Attenuating Oxidative Stress.

Increased oxidative stress has been linked to local anesthetic-induced nerve injury in a diabetic neuropathy (DN) rat model. The current study explores the effects of diphenyleneiodonium (DPI) chloride, an NADPH oxidase (NOX) inhibitor, on bupivacaine-induced sciatic nerve injury in DN rats. A rat DN model was established through high-fat diet feeding and streptozotocin injection. The model was confirmed via testing (i) blood glucose, (ii) hindpaw allodynia responses to von Frey (VF) monofilaments, (iii) paw withdrawal thermal latency (PWTL), and (iv) nerve conduction velocity (NCV). Bupivacaine (Bup, 0.2 mL, 5 mg/mL) was used to block the right sciatic nerve. DPI (1 mg/kg) was injected subcutaneously 24 hours and 30 minutes before the sciatic block. At 24 hours after the block, NCV, various reactive oxygen species, and Caspase-3 were evaluated to determine the extent of sciatic nerve injury. The DN rat model was successfully established. Compared with the DN control group, the postblock values of VF responses (DN-Con, 16.5 ± 1.3 g; DN + Bup, 19.1 ± 1.5 g, P < .001) and PWTL significantly increased (DN-Con, 13.3 ± 1.1 seconds; DN + Bup, 14.6 ± 1.1 seconds, P = .028); the NCV of sciatic nerve was significantly reduced (DN-Con, 38.8 ± 2.4 m/s, DN + Bup, 30.5 ± 2.0 m/s, P = .003), and sciatic nerve injury (as indicated by axonal area) was more severe in the bupivacaine-treated DN group (DN-Con, 11.6 ± 0.3 μm, DN + Bup, 7.5 ± 0.3 μm, P < .001). In addition, DPI treatment significantly improved nerve function (VF responses, 17.3 ± 1.3 g; PWTL, 13.4 ± 1.1 seconds; NCV, 35.6 ± 3.1 m/s) and mitigated loss of axonal area (9.6 ± 0.3 μm). Compared to the DN + Bup group (without DPI), the levels of lipid peroxides and hydroperoxides, as well as the protein expression of NOX2, NOX4, and Caspase-3, were significantly reduced in the DN + Bup + DPI group (P < .05). Subcutaneous injection of DPI appears to protect against the functional and neurohistological damage of bupivacaine-blocked sciatic nerves in a high-fat diet/streptozotocin-induced DN model.

Intraspinal administration of morphine hydrochloride combined with low doses of bupivacaine in hemorrhoidectomy: a clinical randomized trial.

Intrathecal local anesthetics, associated or not to opioids, is commonplace in anorectal surgery, but it is unknown which is the option with the best risk-benefit ratio. The main aim was to assess whether the combination of morphine (50 mcg) with low-dose bupivacaine (3 mg) in an intradural solution has a better analgesic short-term effect than bupivacaine alone at standard doses (5 mg) in hemorrhoidectomy. Sixty-six patients of any sex were randomly assigned to two alternative treatments and 63 patients were considered valid for analysis. Hyperbaric bupivacaine 3 mg combined with 50 mcg of intradural morphine hydrochloride (BUP-MOR group) was compared with 5 mg hyperbaric bupivacaine (BUP group). The primary outcome was pain evaluated through a visual analog scale (from 0 to 100 mm) at 24 hours post-surgery. The proportion of patients requiring rescue analgesia, and those presenting with motor blockade and other adverse events was also compared between the two groups. BUP-MOR group showed a higher efficacy than BUP group in the visual analog scale at 24 hours postsurgery (15±12 vs. 33±22 mm; P<0.001). Also, BUP-MOR group presented a lower percentage of patients who needed rescue analgesia at resuscitation room (6.7% vs. 24.2%; P=0.08) and a lower proportion of patients who had motor blockade (23.3% vs. 51.5%; P=0.02), while they presented a non-significant increased incidence of urinary retention (23.3% vs. 9.0%; P=0.17). The addition of intradural morphine allows a reduction in the dosage of local anesthetic improves short-term postoperative analgesia and is associated with less motor blockade.

Opioid antagonist treatment modulates the brain responses to baby schema in opioid-dependent patients

Vivitrol®) for reducing cocaineuse inparticipantswhometDSMIV criteria for cocaine dependence and past or current opioid dependence or abuse. Methods: This multi-centered, double-blind, placebocontrolled study provided XR-NTX to 302 participants before random assignment to 1 of 3 daily sublingual BUP conditions: 4mg BUP (BUP4, n=100), 16mg BUP (BUP16, n=100), and 0mg BUP (PLB, n=102). Participants received pharmacotherapy for 8 weeks, with thrice-weekly clinic visits for observed dosing, provision of takehome medication, urine drug screening (UDS), and assessments. Cognitive Behavioral Therapy was provided weekly. Follow-up assessments occurred at 1 and 3 months post-intervention. Results: Planned primary analyses of self-reported cocaine use corrected by UDS found no difference in cocaine use during the last 4 weeks of medication (weeks 4–8) between placebo and each BUP group (BUP4 vs PLB, p=0.143, BUP16 vs PLB, p=0.165). Secondary longitudinal analysis of UDS found a significant difference between BUP16 and PLB (p=0.030), but no difference betweenBUP4 and PLB (p=0.529). No differences across groupswere found for adherence, retention, or adverse events. Conclusions: Although the primary outcome analysis did not find a treatment effect, other analyses suggest that treatment with buprenorphine/naloxone, used in combination with naltrexone, may be beneficial in reducing cocaine use for some individuals. Future studies to evaluate this medication combination pharmacotherapy for cocaine use disorder appear warranted. Financial support: DA13045.

Aripiprazole and risperidone in treatment of methamphetamine associated psychosis in China: A pilot randomized study

Vivitrol®) for reducing cocaineuse inparticipantswhometDSMIV criteria for cocaine dependence and past or current opioid dependence or abuse. Methods: This multi-centered, double-blind, placebocontrolled study provided XR-NTX to 302 participants before random assignment to 1 of 3 daily sublingual BUP conditions: 4mg BUP (BUP4, n=100), 16mg BUP (BUP16, n=100), and 0mg BUP (PLB, n=102). Participants received pharmacotherapy for 8 weeks, with thrice-weekly clinic visits for observed dosing, provision of takehome medication, urine drug screening (UDS), and assessments. Cognitive Behavioral Therapy was provided weekly. Follow-up assessments occurred at 1 and 3 months post-intervention. Results: Planned primary analyses of self-reported cocaine use corrected by UDS found no difference in cocaine use during the last 4 weeks of medication (weeks 4–8) between placebo and each BUP group (BUP4 vs PLB, p=0.143, BUP16 vs PLB, p=0.165). Secondary longitudinal analysis of UDS found a significant difference between BUP16 and PLB (p=0.030), but no difference betweenBUP4 and PLB (p=0.529). No differences across groupswere found for adherence, retention, or adverse events. Conclusions: Although the primary outcome analysis did not find a treatment effect, other analyses suggest that treatment with buprenorphine/naloxone, used in combination with naltrexone, may be beneficial in reducing cocaine use for some individuals. Future studies to evaluate this medication combination pharmacotherapy for cocaine use disorder appear warranted. Financial support: DA13045.

Transdermal opioids for cancer pain control in patients with renal impairment

As guidelines for opioid use in renal-impaired patients with cancer are limited, the authors sought to assess the efficacy, safety, and tolerability, of transdermal buprenorphine for moderate/severe cancer pain in renal-impaired outpatients. In a prospective parallel-group active-controlled study, n = 42 consecutively recruited outpatients with or without renal impairment (serum creatinine ≥1.3 or ≤1.2 mg/dL, respectively) were treated with transdermal buprenorphine (group BUP) or fentanyl (group FEN), respectively. Patients were followed up, at home, by the nonprofit ANT-Italia-foundation physicians in Bologna, Italy. Measurements at 10 (T1), 30 (T2), and 90 (T3) days after enrollment (T0) were pain intensity (Numerical Rating Scale [NRS]), Karnofski score, opioid dose (μg/h), rescue-dose consumption, and occurrence of adverse effects. Patients recorded subjective measurements in a personal diary. Upon data analysis, investigators were blinded to the patient group. At T0, in groups BUP and FEN, median NRS score was 8.0 (CI, 7.4-8.4); its reduction over time (T3; NRS = 3.0; CI, 2.1-3.8 and 2.0-4.0, respectively) was significant and constant in both groups (t-test; T0-T1, T1-T2, and T2-T3; p < 0.0001, p < 0.001, and p < 0.05, respectively). At all times, there were no significant differences in pain scores between the groups. In all evaluations, adverse effects were reported n = 73/126 times (60.8 percent) and showed no significant association (X(2), p > 0.05) with the study groups. Transdermal buprenorphine, in outpatients with cancer and renal impairment, is as effective, safe, and tolerable as fentanyl in patients without such impairment. These results add further evidence to the notion that buprenorphine, with its peculiar pharmacokinetics, may be an appropriate choice for opioid treatment in patients with renal impairment.

Concordance between self-report and urine drug screen data in adolescent opioid dependent clinical trial participants

Objective measures of drug use are very important in treatment outcome studies of persons with substance use disorders, but obtaining and interpreting them can be challenging and not always practical. Thus, it is important to determine if, and when, drug-use self-reports are valid. To this end we explored the relationships between urine drug screen results and self-reported substance use among adolescents and young adults with opioid dependence participating in a clinical trial of buprenorphine–naloxone. In this study, 152 individuals seeking treatment for opioid dependence were randomized to a 2-week detoxification with buprenorphine–naloxone (DETOX) or 12weeks of buprenorphine–naloxone (BUP), each with weekly individual and group drug counseling. Urine drug screens and self-reported frequency of drug use were obtained weekly, and patients were paid $5 for completing weekly assessments. At weeks 4, 8, and 12, more extensive assessments were done, and participants were reimbursed $75. Self-report data were dichotomized (positive vs. negative), and for each major drug class we computed the kappa statistic and the sensitivity, specificity, positive predictive value, and negative predictive value of self-report using urine drug screens as the “gold standard”. Generalized linear mixed models were used to explore the effect of treatment group assignment, compensation amounts, and participant characteristics on self-report. In general, findings supported the validity of self-reported drug use. However, those in the BUP group were more likely to under-report cocaine and opioid use. Therefore, if used alone, self-report would have magnified the treatment effect of the BUP condition.

Predictors of attrition with buprenorphine/naloxone treatment in opioid dependent youth

BackgroundIn opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment. MethodsOpioid dependent adolescents and young adults (n=152), aged 15–21, were randomized to 12weeks (BUP, n=74) or 2weeks of detoxification (DETOX, n=78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression. ResultsIn the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition. ConclusionsPrompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2weeks of treatment, may improve treatment retention. Extended Bup/Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics.

The effects of adding epinephrine or xylazine to lidocaine solution for lumbosacral epidural analgesia in fat-tailed sheep

This blinded, randomised experimental study was designed to compare the analgesic effects of lumbosacral epidural administration of lidocaine-epinephrine or lidocaine-xylazine combinations in fat-tailed sheep. Nine healthy fat-tailed male lambs (mean ± s.d. age, 4.6 ± 0.4 months; weight, 24.6 kg ± 2.5 kg) were randomly allocated into four groups of six sheep: lidocaine 2% (LID), lidocaine-epinephrine 5 µg/mL (LIDEP), lidocaine-xylazine 0.05 mg/kg (LIDXY) or bupivacaine 0.5% (BUP). The onset and duration of flank, perineum and hindlimb anaesthesia and the onset and duration of hindlimb paralysis were recorded. Epidural administration of LID, LIDEP, LIDXY or BUP produced anaesthesia within 6.6 min, 7.6 min, 3.4 min and 8.4 min, respectively. The mean onset of anaesthesia in the LIDXY group was significantly shorter compared with the BUP group (p = 0.02). The mean duration of anaesthesia was 107.9 min, 190.4 min, 147.6 min and 169.7 min for LID, LIDEP, LIDXY and BUP, respectively. The onset of hindlimb paralysis was faster in the LIDXY group than in the BUP group; however, the duration of hindlimb paralysis was shorter in LIDXY compared with LIDEP. Epidural administration of LIDEP or LIDXY provides a comparable duration of local anaesthesia without any adverse effects in fat-tailed sheep. Epidural LIDXY did not appear to be advantageous over epidural LIDEP.

Control study of buprenorphine sublingual tablets and methadone for heroin addicts on out patients treatment during recovery period

Objective To observe the effect of buprenorphine sublingual tablets (Bup) and methadone for heroin addicts on out patients treatment during recovery period. Methods Heroin addicts who completed acute drug detoxification treatment were assigned in the order of cross to the observation group and control group. The observation group and the control group were treated with Bup and methadone, respectively for six months. Both groups were observed on the time of keeping heroin abstinence during the treatment and were assessed with Anxiety Scale before and after Bup or methadone treatment. Results Bup group kept abstinence from heroin longer than methadone group ( P ＜0.01 ) ,and had lower anxiety scores( P ＜0.05). Conclusion Bupernorphine sublingual tablets used for out patients at recovery period could better alleviate heroin addicts' anxiety and prolong their abstinence time. Key words: Buprenorphine sublingual tablets; Methadone; Heroin addicts

Smoking cessation in primary care - a randomized controlled trial of bupropione, nicotine replacements, CBT and a minimal intervention.

Smoking cessation has been shown to be effective in randomized controlled trials. It is unclear though, whether interventions also work in routine primary care. In 167 primary care settings we conducted a randomized four-armed smoking cessation trial to examine the efficacy of a minimal intervention (MI; n = 81), cognitive-behavioral therapy (CBT; n = 175), bupropion (BUP; n = 108) and nicotine replacements (NRT; n = 103). Overall, 467 current smokers were enrolled. Abstinence rates at the end of treatment (12 weeks) were 32.8% for MI patients, 34.8% for CBT, 35.3% for NRT, and 46.5% for BUP patients (ITT, intention to treat) (no differential effects). Retention rates were highest in the BUP group (59.3%) and lowest in the NRT group (50.5%). Completer findings were: MI, 56.4%; CBT, 64%; BUP, 79.3%; NRT, 69.2% (LOCF, lost to follow-up). No serious adverse events occurred during or after the medication phase. At 12-month follow-up continuous abstinence rates were: BUP, 29.0%; CBT, 20.9%; NRT, 29.6%; MI, 29.6%. Our findings suggest that established smoking cessation treatments are effective when applied by non-specialist primary care physicians. Our data supports a structured, multimodal treatment structure as core ingredient of successful smoking cessation in primary care.

Effect of dexamethasone on toxicity of bupivacaine in murine neurons

Objective To investigate the effect of dexamethasone on the toxicity of bupivacaine in murine neurons.Methods Murine neuroblastoma cell line N2a was obtained from ATCC cell bank (USA). The cells were cultured in 10% fetal cow serum/MEM culture medium and divided into 4 groups voup I control (Con); group II bupivacaine ( Bup); group Ⅲ dexamethasone (Dex) and group IV Dex + Bup. The culture medium contained bupivacaine 900 μmol/L in group Bup and dexamethasone 1 μmol/L in group Dex respectively. In group Dex + Bup ( IV ) Bup was added to the culture medium with a final concentration of 900 μmol/L at 12 h after pretreatment with Dex 1 μmol/L. The cells were inoculated in 24 well plates (0.5 ml in each well, 24 wells in each group) and 10 cm culture dishes (7 ml in each dish, 4 dishes in each group). The release rate of LDH was calculated and the morphology of the cells and nucleus condensation (by Hoechst 3334224 fluorescent staining) was detected at 9 h of incubation in 24 well plates. The mitochondrial transmembrane potential (by JC-1 assay) and phosphorylation of Akt and ERKs (by Western blot) were measured at 5 h of incubation in 24 well plates and in culture dishes respectively. ResultsBupivacaine caused severe damage to the N2a cells as evidenced by increase in LDH release and nucleus condensation (apoptosis), dephosphorylation of Akt and ERKs, decrease in mitochondrial transmembrane potential and severe morphological changes. Dexamethasone pretreatment significantly attenuated bupivacaine-induced neurotoxicity. Conclusion Dexamethasone can protect N2a cells from bupivacaine-induced neurotoxicity through stabilization of mitochondrial transmembrane potential and inhibition of dephosphorylation of Akt and ERKs. Key words: Dexamethasone; Bupivacaine; Neurons; Toxic actions

Retention rate and substance use in methadone and buprenorphine maintenance therapy and predictors of outcome: results from a randomized study

This was a 6-month, randomized, flexible-dose study comparing the effects of methadone (Meth) and buprenorphine (Bup) on retention rate and substance use in a sample of 140 opioid-dependent, primarily heroin-addicted, patients who had been without opioid substitution therapy in the 4 weeks prior to the study. The major aims were to compare the efficacy of Bup and Meth in a flexible dosing regimen and to identify possible predictors of outcome. There were no major inhomogeneities between treatment groups. All patients also received standardized psychosocial interventions. Mean daily dosages after the induction phase were 44-50 mg for Meth and 9-12 mg for Bup. Results from this study indicate a favourable outcome, with an overall retention rate of 52.1% and no significant differences between treatment groups (55.3% vs. 48.4%). Substance use decreased significantly over time in both groups and was non-significantly lower in the Bup group. Predictors of outcome were length of continuous opioid use and age at onset of opioid use, although these were only significant in the Bup group. Mean dosage and other parameters were not significant predictors of outcome. Overall, the results of this study give further evidence that substitution treatment is a safe and effective treatment for drug dependence. Meth and Bup are equally effective. Duration of continuous opioid use and age at onset were found to have predictive value for negative outcome. The intensity of withdrawal symptoms showed the strongest correlation with drop-out. Future studies are warranted to further address patient profiles and outcome under different substitution regimens.

Mood and Neuroendocrine Response to a Chemical Stressor, Metyrapone, in Buprenorphine-Maintained Heroin Dependence

Heroin dependence is associated with a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, proposed as a biological correlate of craving. Maintenance treatment with methadone normalizes HPA axis activity. Here, we examined HPA axis activity under maintenance treatment with the increasingly utilized partial opiate agonist buprenorphine. Responses to a metyrapone challenge were compared in 20 buprenorphine-maintained heroin addicts and 20 healthy volunteers (10 received a single 50 mg naltrexone dose [NTX+] and 10 received no naltrexone [NTX-]). Patients were 16 male subjects and 4 female subjects, aged 30 to 38 years, heroin-dependent and relapse-free under buprenorphine maintenance (BUP) for a minimum of 6 months. Healthy volunteers were 9 male subjects and 11 female subjects, aged 36 to 49 years, with no history of dependence. Serial measures were obtained of plasma adrenocorticotropic hormone (ACTH) and cortisol and Profile of Mood States (POMS) ratings over time. Subjects were genotyped for the OPRM1 118A/G polymorphism. Buprenorphine maintenance showed a dampened HPA axis response to metyrapone, with OPRM1 118G carriers showing a significantly attenuated response compared with 118A carriers. The response of the NTX+ group was markedly increased. In contrast, negative affect was elevated in the BUP group but did not differ between NTX- and NTX+. Buprenorphine maintenance and NTX- groups did not differ in positive affect, whereas the NTX+ group was lower. In contrast to exaggerated HPA axis responsiveness reported in untreated heroin dependence, response to metyrapone was subnormal in heroin addicts maintained on buprenorphine. Despite this, increased measures of negative affect were seen in this group. This implies a dissociation of HPA axis responsiveness and affect in heroin dependence.

Clonidine as an Analgesic Adjuvant to Continuous Paravertebral Bupivacaine for Post-thoracotomy Pain

We prospectively evaluated the effect of clonidine as an adjuvant to bupivacaine for continuous paravertebral intercostal nerve block, measuring pain and sedation scores and pulmonary function tests. Thirty patients scheduled to undergo thoracotomy were randomized to receive either a bolus of 0.125% bupivacaine 2 mg/kg (group BUP) or 0.125% bupivacaine 2 mg/kg with clonidine 2 microg/kg (group BUP+CLO), followed by an infusion of 0.125% bupivacaine at 0.5 mg/kg/h, or 0.125% bupivacaine at 0.5 mg/kg/h with clonidine at 2 microg/kg/h, in respective groups, through a paravertebral intercostal catheter. Haemodynamic parameters, pain and sedation scores and pulmonary function tests were recorded at 6, 12, 24 and 48 hours after arrival in postoperative care unit. There were significantly lower pain scores at rest and on coughing in group BUP+CLO compared with group BUP (P <0.01). Multiple comparisons revealed a significant reduction in pain score at each time point (P<0.01), except at 12h to 24h, in group BUP+CLO. Sedation scores were significantly higher in group BUP+CLO compared with group BUP at each time point (all P<0.01). There was a linear effect of time on sedation score in group BUP whereas in group BUP+CLO, the effect was quadratic. Patients in the clonidine group had a higher incidence of hypotension (P < 0.01). There was no significant difference in pulmonary function between the groups. We conclude that using clonidine as an adjunct to bupivacaine for continuous paravertebral intercostal nerve block improves pain relief after thoracotomy, but hypotension and sedation are adverse effects interfering with its clinical application.