Buprenorphine Research Articles

The safety of high-dose buprenorphine administered subcutaneously in cats.

The safety of a proprietary formulation of buprenorphine hydrochloride administered subcutaneously (SC) to young cats was investigated in a blinded, randomized study. Four cohorts of eight cats aged approximately 4 months were administered saline, 0.24, 0.72 or 1.20 mg/kg/day buprenorphine SC for nine consecutive days, representing 0×, 1×, 3× and 5× of the intended dose. Cats were monitored daily for evidence of clinical reactions, food and water intake and adverse events (AEs). Physical examinations, clinical pathology, vital signs and electrocardiograms (ECGs) were evaluated at protocol-specified time points. Complete necropsy and histopathologic examinations were performed following humane euthanasia. Four buprenorphine-treated cats experienced AEs during the study, two unrelated and two related to study drug administration. The two cats with AEs considered related to drug administration had clinical signs of hyperactivity, difficulty in handling, disorientation, agitation and dilated pupils in one 0.24 mg/kg/day cat and one 0.72 mg/kg/day cat. All of these clinical signs were observed simultaneously. There were no drug-related effects on survival, injection response, injection site inspections, body weight, food or water consumption, bleeding time, urinalysis, respiration rate, heart rate, ECGs, blood pressures, body temperatures, macroscopic examinations or organ weights. Once daily buprenorphine s.c. injections at doses of 0.24, 0.72 and 1.20 mg/kg/day for 9 consecutive days were well tolerated in young domestic cats.

Comparative analysis of post operative analgesic requirement in patient undergoing minor oral surgery using buprenorphine with lignocaine versus lignocaine-a double blind study

Aim: The aim of this study is comparative analysis of post operative analgesic requirement in patient undergoing minor oral surgery using 2% Lignocaine with 1:200000 Adrenaline and Buprenorphine versus 2% lignocaine with 1:200000 Adrenaline. Materials and Method: One hundred patients requiring minor oral surgery were included in the study. The patients were randomized by a third party and allocated to one of the two study groups. This allowed the patients and the operators to remain unaware of the group allocations. 1 ml of Buprenorphine Hydrochloride injection I.V which contains an equivalent of 0.3 mg Buprenorphine was withdrawn into a syringe and injected into a 30 ml vial of 2 % Lignocaine with Adrenaline 1:200000. Thus each ml of local anesthetic contained 0.01 mg of Buprenorphine. This solution was labelled and used for the study. Results: The duration of analgesia in Group I was found to be 13.71 ± 7.2 h and Group II was 39.58 ± the average consumption of NSAIDs was found to be 2.88 as compared to Group II mean value of 1.29 (P=0.0001). Conclusion: We concluded that addition of 0.3 mg of Buprenorphine to 30 ml Lignocaine with Adrenaline 1:200000 for minor oral surgery results in significant improvement in postoperative analgesia up to 39 h and markedly reduces the need for excessive analgesic intake. Thus reducing the adverse effects associated with excessive use of NSAIDs. Further studies needs to be done as there is less literature about Buprenorphine added to local anaesthetist. Keyword: Buprenorphine, Hydrochloride, Analgesia

Evaluation of opioid modulation in major depressive disorder.

Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a μ-opioid partial agonist, buprenorphine (BUP), and a potent μ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist–antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders.

Influence of nicotine replacement therapy on heart rate variability and relapse

Buprenorphine (BUP) is effective for treating opioid use disorder. Individuals’ heroin-use characteristics may predict their responses to BUP, which could differ during maintenance and dose-taper phases. If so, treatment providers could use pre-treatment characteristics to personalize level of individual care and possibly improve treatment outcomes.Non-treatment-seeking heroin-dependent volunteers (N = 34) initiated outpatient BUP maintenance (8-mg/day) and submitted urine samples thrice weekly tested for opioids (non-contingent result). After completing three programmatically-related inpatient behavioral pharmacology experiments (while maintained on 8-mg/day BUP), participants were discharged and underwent a double-blind BUP dose taper (4-mg/day, 2-mg/day and 0-mg/day during weeks 1–3, respectively) with an opioid-abstinence incentive ($30 per consecutive opioid-negative urine specimen, obtained thrice weekly).Participants who reported less pre-study (past-month) heroin use and shorter lifetime duration of heroin use were more likely to submit an opioid-negative urine sample during initial outpatient BUP maintenance. Participants who reported more lifetime heroin-quit attempts and provided any opioid-free urine sample during initial outpatient maintenance sustained longer continuous opioid-abstinence during the BUP dose taper. Participants who reported >3 lifetime quit attempts abstained from opioid use nearly one week longer (14 days vs. 8 days to opioid-lapse) and nearly half (46.7%) refrained from opioid use during dose taper.Number of prior heroin quit attempts may predict BUP dose taper response and provide a metric for stratifying heroin-dependent individuals by relative risk for opioid lapse. This metric may inform personalized relapse prevention care and improve treatment outcomes.

Hair Analysis for Long-Term Monitoring of Buprenorphine Intake in Opiate Withdrawal

Buprenorphine (BUP) is a psychoactive pharmaceutical drug largely used to treat opiate addiction. Short-term therapeutic monitoring is supported by toxicological analysis of blood and urine samples, whereas long-term monitoring by means of hair analysis is rarely used. Aim of this work was to develop and validate a highly sensitive ultrahigh-performance liquid chromatography tandem mass spectrometry method to detect BUP and norbuprenorphine (NBUP) in head hair. Interindividual correlation between oral dosage of BUP and head hair concentration was investigated. Furthermore, an intra-individual study by means of segmental analysis was performed on subjects with variable maintenance dosage. Hair samples from a population of 79 patients in treatment for opiate addiction were analyzed. The validated ultrahigh-performance liquid chromatography tandem mass spectrometry protocol allowed to obtain limits of detection and quantification at 0.6 and 2.2 pg/mg for BUP and 5.0 and 17 pg/mg for NBUP, respectively. Validation criteria were satisfied, assuring selective analyte identification, high detection capability, and precise and accurate quantification. Significant positive correlation was found between constant oral BUP dosage (1-32 mg/d) and the summed up head hair concentrations of BUP and NBUP. Nevertheless, substantial interindividual variability limits the chance to predict the oral dosage taken by each subject from the measured concentrations in head hair. In contrast, strong correlation was observed in the results of intra-individual segmental analysis, which proved reliable to detect oral dosage variations during therapy. Remarkably, all hair samples yielded BUP concentrations higher than 10 pg/mg, even when the lowest dosage was administered. Thus, these results support the selection of 10 pg/mg as a cutoff value.

Association of opioid agonist therapy with lower incidence of hepatitis C virus infection in young adult injection drug users.

Injection drug use is the primary mode of transmission for hepatitis C virus (HCV) infection. Prior studies suggest opioid agonist therapy may reduce the incidence of HCV infection among injection drug users; however, little is known about the effects of this therapy in younger users. To evaluate whether opioid agonist therapy was associated with a lower incidence of HCV infection in a cohort of young adult injection drug users. Observational cohort study conducted from January 3, 2000, through August 21, 2013, with quarterly interviews and blood sampling. We recruited young adult (younger than 30 years) injection drug users who were negative for anti-HCV antibody and/or HCV RNA. Substance use treatment within the past 3 months, including non-opioid agonist forms of treatment, opioid agonist (methadone hydrochloride or buprenorphine hydrochloride) detoxification or maintenance therapy, or no treatment. Incident HCV infection documented with a new positive result for HCV RNA and/or HCV antibodies. Cumulative incidence rates (95% CI) of HCV infection were calculated assuming a Poisson distribution. Cox proportional hazards regression models were fit adjusting for age, sex, race, years of injection drug use, homelessness, and incarceration. Baseline characteristics of the sample (n = 552) included median age of 23 (interquartile range, 20-26) years; 31.9% female; 73.1% white; 39.7% who did not graduate from high school; and 69.2% who were homeless. During the observation period of 680 person-years, 171 incident cases of HCV infection occurred (incidence rate, 25.1 [95% CI, 21.6-29.2] per 100 person-years). The rate ratio was significantly lower for participants who reported recent maintenance opioid agonist therapy (0.31 [95% CI, 0.14-0.65]; P = .001) but not for those who reported recent non-opioid agonist forms of treatment (0.63 [95% CI, 0.37-1.08]; P = .09) or opioid agonist detoxification (1.45 [95% CI, 0.80-2.69]; P = .23). After adjustment for other covariates, maintenance opioid agonist therapy was associated with lower relative hazards for acquiring HCV infection over time (adjusted hazard ratio, 0.39 [95% CI, 0.18-0.87]; P = .02). In this cohort of young adult injection drug users, recent maintenance opioid agonist therapy was associated with a lower incidence of HCV infection. Maintenance treatment with methadone or buprenorphine for opioid use disorders may be an important strategy to prevent the spread of HCV infection among young injection drug users.

Evaluation of drug-drug interaction between daclatasvir and methadone or buprenorphine/naloxone.

IntroductionDaclatasvir (DCV) is a potent hepatitis C virus (HCV) NS5A replication complex inhibitor with pangenotypic (1–6) activity in vitro. Methadone (MET) and buprenorphine (BUP) are opioid medications used to treat opioid addiction; patients on HCV therapy may require MET or BUP treatment. The effect of DCV on the pharmacokinetics (PK) of MET or BUP/naloxone (NLX) was assessed in subjects on stable MET or BUP.Materials and MethodsAn open-label, two-part study assessed the effect of steady-state oral administration of DCV on the PK of MET (Part 1, P1) or BUP/NAL (Part 2, P2). Safety/tolerability and pharmacodynamics (PD, opioid withdrawal scales/overdose assessment) were also assessed. Subjects (P1, N=14; P2, N=11) received daily single-dose oral MET (40–120mg) or BUP/NLX (8/2–24/6mg) based on their prescribed stable dose throughout, in addition to DCV (60mg QD) on Days 2–9. Serial PK sampling occurred predose and postdose till 24 hours on Day 1 (MET/BUP) and Day 10 (MET/BUP/DCV). Noncompartmental PK were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for MET/BUP/norBUP Cmax and AUCTAU were derived from linear mixed effects models.ResultsSubjects were aged 19–39 years, mostly white (P1, 93%; P2, 100%) and male (P1, 71%; P2, 91%). All subjects completed the study. No clinically meaningful effect was demonstrated as the GMR and 90% CIs fell within the prespecified interval (P1, 0.7–1.4; P2, 0.5–2.0: see Table 1). DCV coadministration was well-tolerated: overall, six (43%) subjects had adverse events (AEs) (all mild and resolved without treatment). DCV had no clinically significant effect on the PD of MET or BUP/NLX.ConclusionsSteady-state administration of DCV 60mg QD had no clinically meaningful effect on the PK of MET or BUP/NLX and was generally well-tolerated, suggesting that no dose adjustments will be required.

Antidepressant-like effects of buprenorphine in rats are strain dependent

The prevalence of major depressive disorder and the limited efficacy of conventional drug treatments provide significant impetus to develop novel and more rapidly acting antidepressants for individuals with treatment resistant forms of depression. The primary goal of these studies was to ascertain whether buprenorphine (BPN), a medically available drug with mixed effects at opioid receptors, was effective in behavioral tests using the Wistar Kyoto (WKY) rat strain, a rodent model of exaggerated depressive and anxiety behaviors that demonstrates resistance to certain antidepressants. As WKY rats are maintained by different sources, we assessed the behavioral effects of BPN using the modified rat forced swim test (FST) and the emergence test in WKY rat colonies obtained from different vendors. BPN dose-dependently reduced immobility and increased swimming behavior in the FST and reduced emergence latencies in two WKY lines (Charles River (WKY/NCrl) and Harlan laboratories (WKY/NHsd)) that also showed high baseline immobility in the FST. WKY rats from Taconic (WKY/NTac) did not show high baseline immobility in the FST or anxiety as had been previously reported, suggesting a drift in the phenotype of rats from this supplier. Furthermore, BPN did not reduce immobility in the FST or reduce latencies in the emergence test in WKY rats from Taconic. BPN also failed to produce antidepressant-like effects in Wistar and Sprague-Dawley rats. These results indicate a striking strain-selectivity for the effects of BPN, producing antidepressant and anxiolytic-like responses in WKY/NCrl and WKY/NHsd lines but not in the normosensitive control Wistar and Sprague-Dawley strains.

Development of an Electrochemical Sensor Based on Reduced Graphene Oxide Modified Screen‐Printed Carbon Electrode for the Determination of Buprenorphine

AbstractIn this research, we have developed an electrochemical buprenorphine (BN) sensor based on reduced graphene oxide (r‐GO) as an electrode modifier on the screen printed carbon electrode (SPCE) surface. BN oxidation pathway was proposed using voltammetric studies and with the aid of Density Functional Theory (DFT). The effects of various parameters including pH, modifier amount, accumulation time, and accumulation potential on the oxidation peak current of BN were optimized. Under the optimized conditions, the linear response range and the limit of detection were obtained as 0.50–100 µM and 0.16 µM (S/N=3) using differential pulse voltammetry (DPV), respectively. The selectivity of the modified electrode in the presence of potential interferences was also studied, and finally the electrode was successfully employed for the determination of BN in spiked urine samples.

Comparative prices of diverted buprenorphine/naloxone and buprenorphine in a UK prison setting: A cross-sectional survey of drug using prisoners

BackgroundThere is evidence regarding the abuse potential of buprenorphine in prison settings. There is also emerging evidence from community settings that buprenorphine/naloxone is less amenable to abuse than the single preparation buprenorphine hydrochloride as evidenced by cost-differentials of diverted medication. This study sought to explore cost-differentials within a prison setting of diverted buprenorphine/naloxone medication relative to either single preparation buprenorphine hydrochloride or methadone. MethodsCross-sectional survey in one remand prison. ResultsA total of 85 prisoners participated in the survey. Prisoners estimated buprenorphine to have a significantly (p<0.001) higher cost than buprenorphine/naloxone both inside and outside of prison. This finding was supported when the analysis was restricted to both the prisoners with a longer-term experience of taking opioid substitution drugs during their current prison stay and those with a longer-term experience prior to reception. ConclusionsConsideration should be given to the recommendation that buprenorphine/naloxone medication is the prescribed buprenorphine preparation of choice for clinicians offering opiate substitution therapy to prisoners, pending developments of buprenorphine preparations that have less abuse potential than sublingual preparations.

Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice.

Buprenorphine (BPN) has been shown to rapidly improve mood in treatment-resistant depressed patients in small clinical studies. However, BPN's effects in preclinical tests for mood and antidepressant efficacy are largely unexplored. The current study examined the effects of BPN in the forced swim test (FST) and novelty-induced hypophagia (NIH) test as measures of antidepressant and anxiolytic-like effects in C57BL/6J mice. Microdialysis was used to measure whether BPN engaged kappa-opioid receptor (KORs) in the nucleus accumbens shell (NAcSh) at a behaviorally active dose (0.25mg/kg). BPN was tested in the FST at both 30min and 24h post-administration. Also measured in the FST at 24h post-administration were the KOR antagonist norbinaltorphimine (nor-BNI), the MOR agonist morphine and the reference antidepressant desipramine. The anxiolytic effects of BPN were examined in the NIH test 24h after treatment. The effects of acute injection of BPN and the KOR agonist U50,488 were measured on extracellular dopamine (DA) levels in the NAcSh. BPN produced significant reductions in FST immobility without changing locomotor activity and reduced approach latencies in the novel environment of the NIH test when tested 24h after treatment. Repeated daily BPN injections for 6days did not produce tolerance to these behavioral effects. nor-BNI produced a similar antidepressant-like response in the FST 24h post-injection but morphine and desipramine were ineffective. BPN (0.25mg/kg) did not alter DA levels when given alone but prevented the KOR agonist U50,488 from reducing DA levels. Acute and subchronic treatment with BPN produced antidepressant and anxiolytic-like responses in mice at doses that engage KORs. These studies support the clinical evidence that BPN may be a novel rapid-acting antidepressant medication and provides rodent models for investigating associated neurochemical mechanisms.

Buprenorphine for cancer pain: is it ready for prime time?

Buprenorphine (BUP) is a semisynthetic derivative of the opium alkaloid thebaine found in the poppy Papaver somniferum. Its chemical structure contains the morphine structure but differs by having a cyclopropylmethyl group. Buprenorphine is a potent µ opioid agonist. Buprenorphine undergoes extensive first-pass metabolism in the liver and gut. The development of a transdermal BUP formulation in 2001 led to its evaluation in cancer pain. This article provides the practitioner with an update on the current role of BUP in cancer care. It highlights data suggesting effectiveness in various types of cancer pain. The article reviews pharmacology, routes of administration, adverse effects, drug interactions, and cost considerations.

Evaluation of thermal antinociceptive effects after intramuscular administration of buprenorphine hydrochloride to American kestrels (Falco sparverius).

To evaluate the thermal antinociceptive effects and duration of action of buprenorphine hydrochloride after IM administration to American kestrels (Falco sparverius). 12 healthy 3-year-old American kestrels. Buprenorphine hydrochloride (0.1, 0.3, and 0.6 mg/kg) and a control treatment (saline [0.9% NaCl] solution) were administered IM in a randomized crossover experimental design. Foot withdrawal response to a thermal stimulus was determined 1 hour before (baseline) and 1.5, 3, and 6 hours after treatment administration. Agitation-sedation scores were determined 3 to 5 minutes before each thermal stimulus. Adverse effects were monitored for 6 hours after treatment administration. Buprenorphine hydrochloride at 0.1, 0.3, and 0.6 mg/kg, IM, increased thermal threshold for 6 hours, compared with the response for the control treatment. There were no significant differences among buprenorphine treatments. A mild sedative effect was detected at a dose of 0.6 mg of buprenorphine/kg. At the doses tested, buprenorphine hydrochloride resulted in thermal antinociception in American kestrels for at least 6 hours, which suggested that buprenorphine has analgesic effects in this species. Further studies with longer evaluation periods and additional forms of noxious stimuli, formulations, dosages, and routes of administration are needed to fully evaluate the analgesic effects of buprenorphine in American kestrels.

Club-based drug use and its associated risk factors among HIV-positive methadone maintenance treatment clients

To describe club-based drug use and to explore the determinants on those HIV-positive methadone maintenance treatment (MMT) clients. This study was conducted in 5 MMT clinics in Yunnan province and 612 MMT clients who met the survey criteria were recruited for the study. Urine sample was tested as a biological marker to identify if heroin, methamphetamine, methylene-dioxy-methyl-amphetamine, buprenorphine or benzodiazepine had been used. The average age among the 612 clients was 38.9 ± 6.3 years. Among these, 78.9% were males, with the average years of education as 8.0 ± 3.4 years. There were 60.5% clients who had good relationship with their families. 153 (25.0%) clients reported having used club-related drugs in the last 12 months. Results from the urine test showed that the positive rate on morphine was 14.4%, while the positive rate for club-related drugs was 26.6%. Factors as residential area, casual sexual partners, retention on MMT and occasionally use of heroin were associated with urine results on club-related drugs and the prevalence of self-reported club drug use (P < 0.05). Club-related drug use was common among HIV-positive MMT clients. Inspection and supervision for club-related drugs and the education and intervention programs on related high risk behaviors should be strengthened.

Pharmacokinetics of buprenorphine hydrochloride following intramuscular and intravenous administration to American kestrels (Falco sparverius).

To determine the pharmacokinetics of buprenorphine hydrochloride after IM and IV administration to American kestrels (Falco sparverius). 13 healthy 3-year-old captive-bred American kestrels. Buprenorphine hydrochloride (0.6 mg/kg) was administered IM to all birds. Blood samples were collected at 9 times, ranging from 5 minutes to 9 hours after drug administration. Plasma buprenorphine concentrations were measured by use of tandem liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by use of least squares linear regression and noncompartmental analysis of naïve pooled data. After a washout period of 2 weeks, the same dose of buprenorphine was administered IV to all birds and blood samples were collected at the same times after drug administration. Maximum plasma buprenorphine concentration was achieved within 5 minutes after IM administration. For IM administration, bioavailability was 94.8% and elimination half-life was 92.1 minutes. For IV administration, steady-state volume of distribution was 4,023.8 mL/kg, plasma clearance was 49.2 mL/min/kg, and elimination half-life was 105.5 minutes. Buprenorphine was rapidly absorbed, and bioavailability was good after IM administration to American kestrels. Plasma buprenorphine concentrations were > 1 ng/mL for 9 hours after both IM and IV administration. These results, in combination with those of a pharmacodynamic study, suggested that the analgesic effects of buprenorphine could last at least 6 to 9 hours in this species. Further investigations of the duration of analgesic effects, multiple-dose protocols, and potential adverse effects of buprenorphine are warranted in American kestrels and other raptors.

Evaluation of an improved sustained-release buprenorphine formulation for use in mice.

To evaluate analgesic effects of an improved sustained-release buprenorphine (BUP-SR) formulation administered to mice. 36 male Swiss-Webster mice. Mice were assigned to each of 3 treatment groups (n = 12 mice/group). Treatments were administered SC (vehicle [control treatment], 1.5 mg of buprenorphine hydrochloride [BUP-HCl]/kg, and 1.5 mg of BUP-SR/kg). Mice were evaluated (total activity, gastrointestinal tract motility, respiratory rate, cataleptic behavior, and tall-flick and hot plate nociception tests) to determine behavioral and physiologic responses at 4, 24, and 48 hours after treatment administration. Body weight and respiratory rate were measured before and at each time point after treatment administration. SC administration of BUP-SR resulted in significant antinociception effects for 48 hours for the hot plate and tall-flick nociception tests without substantial adverse effects. Gastrointestinal tract motility and total activity were higher at 4 hours for mice receiving BUP-SR than for mice receiving the vehicle, but values were the same between these groups at 24 and 48 hours. The BUP-SR group had a lower respiratory rate than did the control group at all times after treatment administration. Mice treated with BUP-SR had no significant changes in body weight during the study, whereas mice treated with BUP-HCl had a significant decrease in body weight at 24 and 48 hours. BUP-SR administration resulted in antinociception effects for 48 hours. Results of this study indicated that the improved BUP-SR formulation could be safely administered SC and conferred superior analgesia, compared with that for BUP-HCl, in mice.

Determination of buprenorphine by differential pulse voltammetry on carbon paste electrode using SDS as an enhancement factor

In the present study, a facile electrochemical approach is proposed for the determination of buprenorphine (BPR) in the presence of sodium dodecyl sulfate (SDS). SDS was applied for amplification of oxidation signal. Carbon paste electrode (CPE) used as working electrode and cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) were carried out in phosphate buffer solution (pH3.0). Under optimal experimental conditions, the oxidation current increased with the addition of BPR in the sample and two dynamic ranges obtained from 4.00nM to 0.126μM and from 0.126 to 0.317μM by DPV and exhibited a low detection limit (LOD) of 1.33nM (S/N=3). This offered method has been used for the determination of BPR in the real samples and has validated with the recovery test for BPR spiked urine samples. The result demonstrated that this method is a simple, sensitive, rapid, low-cost, and stable method for BPR detection.

P39: Predictive value of meconium concentrations of buprenorphine and methadone in neonatal abstinence syndrome (NAS)

Introduction Buprenorphine (BPN) and methadone (MTD) are two drugs authorized during pregnancy for opioid-dependence treatment. Substitution by MTD or BPN reduce fetal heroin exposure, obstetric complications, and neonatal morbidity and mortality (OFDT, 2003; Lejeune, 2004). Few days after birth newborns exposed in utero to MTD or BPN may suffered of neonatal abstinence syndrome (NAS), consisting in hyperirritability, gastrointestinal dysfunction, respiratory distress, and neurovegetative dysregulations and sometimes convulsions. NAS is treated with morphine, depending of the intensity of the symptoms (measured with Lipsitz scale). Previous studies show that maternal buprenorphine or methadone dose does not predict the severity or duration of NAS. Aim Meconium, the first neonatal feces, could represent the cumulative exposure to drugs in utero all along the gestation. A cohort of 80 opioid-dependent women and their newborn was enrolled for an inter-regional clinical assay managed by Caen university hospital. We assayed in meconium MTD and BPN concentrations, their metabolites and other drugs, and try to correlate them as prognostic factors of time, severity and duration of NAS. Methods 10 women treated with buprenorphine, 12 with methadone, and their newborns were currently included. NAS was followed by repeated Lipsitz scores (positive when >4). Meconium sample preparation included deproteinization followed by solidphase extraction (SPE) with Strata XC ® column. BPN, MTD with their main metabolites norbuprenorphine and EDDP, and morphine were quantified by a liquid chromatography - tandem mass spectrometry (LC-MS/MS) method, developed and validated for this study. Separation was done with a Macherey-Nagel Nucleodur Polartec ® (150 mm x 2,1 mm, 5 μm) column using 10mM ammonium formiate, 0,2 % formic acid and acetonitrile, 0,1 % formic acid as mobile phases at a flow rate of 0,35 mL/min in a gradient mode. The analytes were identified and quantified by LC-MS/MS on an ABSciex ® QTRAP3200 instrument with a TurboIon-Spray source operating in positive mode. Total time for each chromatograph was 15 min. Correlations were determined between meconium concentrations and 3 parameters: NAS onset, peak NAS score, and total amount of morphine used for NAS treatment. Other illicit substances and drugs which may have an impact on NAS are screened in maternal and newborn urines. Results For MTD mean meconium concentrations were 4200 ng/g, for EDDP 11700 ng/g (with a mean ratio MTD/EDDP = 0.42). EDDP meconium concentration and methadone/EDDP ratio were correlated with the peak NAS score (p=0.034 and p=0.029 respectively), and with the total amount of morphine used for NAS treatment (p=0.020 and p=0.013). There was no correlation with MTD meconium concentrations. Results are unavailable for buprenorphine at this time. Urine drug screens revealed frequently tobacco, opiates, cannabis, cocaine, hydroxyzine and benzodiazepines, confirming drugs of abuse are commonly used in opioid-dependent pregnant women. Conclusion These results show that measurement of meconium concentrations of EDDP and methadone/EDDP ratio may help clinicians to predict the severity of NAS, and so adapt earlier treatment with morphine. These preliminary results must be confirmed on large cohorts, higher than 30 newborns per group, including buprenorphine results.

Buprenorphine and nor-buprenorphine levels in head hair samples from former heroin users under Suboxone® treatment.

In the current study, buprenorphine (BUP) and its major metabolite, nor-buprenorphine (NBUP), were determined in hair samples from former heroin users following Suboxone® treatment. Hair samples from 36 subjects were analyzed. The drugs of interest were isolated from hair by solid-liquid extraction with methanol and were determined by liquid chromatography-mass spectrometry, using an electrospray ionization interface. The analytical parameters of the method (such as linearity, limits of quantification, recovery, accuracy, and precision) were determined. The inter-quartile range of BUP levels was from 11.4 to 37.4 pg/mg (mean value 56.6 pg/mg) for the proximal hair segment, from 5.8 to 43.3 pg/mg for the middle hair segment (mean value 25.3 pg/mg), while a range from 4.3 to 33.9 pg/mg (mean value 105.2 pg/mg) for the distant to the root hair segment was determined. For NBUP the corresponding inter-quartile range was from 27.0 to 147.6 for the proximal segment (mean value 95.4 pg/mg), from 21.5 to 164.7 pg/mg for the middle segment (mean value 102.0 pg/mg) and from 20.4 to 103.6 pg/mg for the distant segment (mean value 156.8 pg/mg). The mean BUP/NBUP concentration ratio was 0.5. The daily dose of Suboxone® correlated significantly with BUP and NBUP levels in hair (p = 0.001 and p = 0.023) as well as with the BUP/NBUP ratio (p = 0.010). No significant correlation was found between the levels of BUP and NBUP and the duration of Suboxone® administration. The developed and validated method was successfully used for the determination of BUP and NBUP in hair samples collected from former heroin users under Suboxone® treatment.

Improved buprenorphine immunoassay performance after urine treatment with β-glucuronidase.

Buprenorphine (BUP), a semi-synthetic opioid analgesic, is increasingly prescribed for the treatment of chronic pain and opioid dependence. Urine immunoassay screening methods are available for monitoring BUP compliance and misuse; however, these screens may have poor sensitivity or specificity. We evaluated whether the pretreatment of urine with β-glucuronidase (BG) improves the sensitivity and overall accuracy of three BUP enzyme immunoassays when compared with liquid chromatography-tandem mass spectrometry (LC-MS-MS). Urine samples sent to our laboratories for BUP testing (n = 114) were analyzed before and after BG pretreatment by cloned enzyme donor immunoassay (CEDIA), enzyme immunoassay (EIA) and homogenous EIA (HEIA) immunoassays using a common 5 ng/mL cutoff. Total BUP and norbuprenorphine (NBUP) concentrations were measured by LC-MS-MS as the reference method. Urine BG pretreatment improved EIA, HEIA and CEDIA sensitivities from 70, 82 and 94%, respectively, to 97% for each of the three methods, when compared with LC-MS-MS. While the specificity of the EIA and HEIA remained 100% after BG pretreatment, the specificity of the CEDIA decreased from 74 to 67%. Urine pretreatment with BG is recommended to improve sensitivity of the EIA and HEIA BUP screening methods.