Norbuprenorphine Concentrations Research Articles

Salivary Therapeutic Monitoring of Buprenorphine in Neonates After Maternal Sublingual Dosing Guided by Physiologically Based Pharmacokinetic Modeling.

Opioid use disorder (OUD) during pregnancy is associated with high mortality rates and neonatal opioid withdrawal syndrome (NOWS). Buprenorphine, an opioid, is used to treat OUD and NOWS. Buprenorphine active metabolite (norbuprenorphine) can cross the placenta and cause neonatal respiratory depression (EC 50 = 35 ng/mL) at high brain extracellular fluid (bECF) levels. Neonatal therapeutic drug monitoring using saliva decreases the likelihood of distress and infections associated with frequent blood sampling. An adult physiologically based pharmacokinetic model for buprenorphine and norbuprenorphine after intravenous and sublingual administration was constructed, vetted, and scaled to newborn and pregnant populations. The pregnancy model predicted that buprenorphine and norbuprenorphine doses would be transplacentally transferred to the newborns. The newborn physiologically based pharmacokinetic model was used to estimate the buprenorphine and norbuprenorphine levels in newborn plasma, bECF, and saliva after these doses. After maternal sublingual administration of buprenorphine (4 mg/d), the estimated plasma concentrations of buprenorphine and norbuprenorphine in newborns exceeded the toxicity thresholds for 8 and 24 hours, respectively. However, the norbuprenorphine bECF levels were lower than the respiratory depression threshold. Furthermore, the salivary buprenorphine threshold levels in newborns for buprenorphine analgesia, norbuprenorphine analgesia, and norbuprenorphine hypoventilation were observed to be 22, 2, and 162 ng/mL. Using neonatal saliva for buprenorphine therapeutic drug monitoring can facilitate newborn safety during the maternal treatment of OUD using sublingual buprenorphine. Nevertheless, the suitability of using adult values of respiratory depression EC 50 for newborns must be confirmed.

OPRD1 rs569356 polymorphism has an effect on plasma norbuprenorphine levels and dose/kg-normalized norbuprenorphine values in individuals with opioid use disorder

This study aimed to determine the effects of nine OPRM1, OPRD1 and OPRK1 polymorphisms on plasma BUP and norbuprenorphine (norBUP) concentrations and various treatment responses in a sample of 122 patients receiving BUP/naloxone. Plasma concentrations of BUP and norBUP were detected by LC–MS/MS. PCR-RFLP method was used to genotype polymorphisms. OPRD1 rs569356 GG had significantly lower plasma norBUP concentration (p = 0.018), dose- (p = 0.049) and dose/kg-normalized norBUP values (p = 0.036) compared with AA. Craving and withdrawal symptoms were significantly higher in OPRD1 rs569356 AG+GG relative to AA. There was a statistically significant difference between the OPRD1 rs678849 genotypes in the intensity of anxiety (13.5 for CT+TT and 7.5 for TT). OPRM1 rs648893 TT (18.8 ± 10.8) was significantly different to CC+CT (14.82 ± 11.3; p = 0.049) in view of the intensity of depression. This current study provides the first data on a prominent effect of the OPRD1 rs569356 variation on BUP pharmacology due to its metabolite norBUP.

Pharmacokinetics of buprenorphine and its metabolite norbuprenorphine in neutered male cats anesthetized with isoflurane

ObjectiveTo characterize the pharmacokinetics of buprenorphine and norbuprenorphine in isoflurane-anesthetized cats. Study designProspective experimental study. AnimalsA group of six healthy adult male neutered cats. MethodsCats were anesthetized with isoflurane in oxygen. Catheters were placed in a jugular vein for blood sampling and in a medial saphenous vein for buprenorphine and lactated Ringer’s solution administration. Buprenorphine hydrochloride (40 μg kg–1 over 5 minutes) was administered intravenously. Blood samples were collected before buprenorphine administration and at various times up to 12 hours after administration. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed effect (population) modeling. ResultsA five-compartment model (three compartments for buprenorphine and two compartments for norbuprenorphine) best fitted the data. Typical value (% interindividual variability) for the three buprenorphine volumes of distribution, and the metabolic clearance to norbuprenorphine, the remaining metabolic clearance and the two distribution clearances were 157 (33), 759 (34) and 1432 (43) mL kg–1, and 5.3 (33), 16.4 (11), 58.7 (27) and 6.0 (not estimated) mL minute–1 kg–1, respectively. Typical values (% interindividual variability) for the two norbuprenorphine volumes of distribution, and the norbuprenorphine metabolic and distribution clearances were 1437 (30) and 8428 (not estimated) mL kg–1 and 48.4 (68) and 235.9 (not estimated) mL minute–1 kg–1, respectively. Conclusions and clinical relevanceThe pharmacokinetics of buprenorphine in isoflurane-anesthetized cats were characterized by a medium clearance.

Maternal-fetal biodisposition of buprenorphine and its metabolites in opioid dependent pregnant individuals

To determine the concentration of buprenorphine (BUP) and its metabolites in maternal and fetal samples and investigate the relationship between BUP concentrations and neonatal opioid withdrawal syndrome (NOWS). Matched maternal and fetal samples were collected from 12 individuals maintained on BUP for opioid use disorder during pregnancy. All delivered at term (≥37 weeks gestation) via cesarean section. Samples were collected at delivery and included maternal plasma (PL), amniotic fluid (AF), and umbilical cord blood (CB). Concentrations of BUP, its biologically active metabolite norbuprenorphine (NBUP) and its inactive metabolites glucuronide forms of buprenorphine (BUP-Gluc) and norbuprenorphine (NBUP-Gluc) were determined by liquid chromatography-mass spectrometry. The concentrations of BUP and its metabolites were compared between neonates who developed NOWS, defined as withdrawal symptoms requiring pharmacologic treatment, and those who did not. Five (42%) of neonates born to mothers in the study developed NOWS. There was no difference in gestational age, birthweight or other baseline characteristics between the two groups. All individuals in the study were receiving 16 mg daily of BUP at delivery. BUP concentrations were higher in cord blood (0.65 v 0.31ng/mL, p=0.01) and amniotic fluid (0.64 v 0.0 ng/mL, p=0.04) in neonates who developed NOWS, compared to those who did not. The concentrations of NBUP were also higher in neonates who developed NOWS (2.01 v 0.0ng/mL, p=0.03). There were no differences in maternal plasma concentrations between the two groups. Despite similar maternal dosing and plasma concentrations, NBUP concentrations in AF and BUP concentrations in AF and CB were higher for infants later diagnosed with NOWS, suggesting accumulation of the drug in the fetal compartment. Further studies are needed to determine the mechanisms and whether analysis of these specimens at delivery may help predict NOWS in buprenorphine-exposed neonates.

MATERNAL AND FETAL BUPRENORPHINE PHARMACOKINETICS IN PREGNANT SHEEP DURING TRANSDERMAL PATCH DOSING: Buprenorphine pharmacokinetics in pregnant sheep

BackgroundBuprenorphine is used in the opioid maintenance treatment for opioid dependent patients, including pregnant women. Despite the wide use, limited data exists on buprenorphine pharmacokinetics and fetal exposure during pregnancy. The aim of our study was to determine the buprenorphine pharmacokinetics during transdermal patch dosing to pregnant sheep and, to determine the extent of transplacental transfer of buprenorphine to the fetus. MethodsPregnant sheep in late gestation (n=50) received 20, 25 or 40 µg/h of buprenorphine as a 7-day extended-release transdermal patch. Plasma samples were collected from the ewe and the fetus on days 1 – 6, and buprenorphine and norbuprenorphine concentrations were determined. During the exposure period the sheep had a surgical procedure on the second day, a recovery phase, and an experimental procedure on the sixth day. In the experiment, hypoxia was induced under anesthesia for 18 sheep to investigate if decreased fetal pH would cause ion-trapping of buprenorphine in the fetus. The fetal/maternal plasma concentration ratio was determined on the second and on the sixth exposure day at baseline and during hypoxia. Maternal pharmacokinetics were modelled with a population pharmacokinetic method using the data from this study and our previous intravenous administration study. ResultsThe transdermal patch provided an extended release of buprenorphine throughout the exposure period, but the release rate declined approximately 20 h after patch placement. The median fetal/maternal plasma concentration ratio was 13 – 27 % throughout the exposure period at baseline. A ratio over 100 % was observed for four sheep on the sixth exposure day (102 – 269 %). A minor increase was seen in the median fetal/maternal-ratios during maternal hypoxia. Norbuprenorphine was undetected in all plasma samples. ConclusionsThe low transplacental passage of less than one fourth of the ewe's exposure supports buprenorphine as an alternative to methadone in opioid maintenance therapy during pregnancy.

Buprenorphine Prevalence in DUID Cases in Southwestern Virginia: Case Studies and Observations.

Buprenorphine, a semisynthetic mixed agonist/antagonist opioid used primarily for the treatment of opioid use disorder, was reported in 194 driving under the influence of drugs (DUID) cases in Southwestern Virginia during the period from 2017 through 2019. Identifying and confirming buprenorphine in DUID cases is common in this region. Interpretation is complex due to the large range of concentrations of buprenorphine found in blood and frequent combinations with other therapeutic and abused drugs. Buprenorphine was identified by immunoassay and quantified by liquid chromatography-tandem mass spectrometry. A sensitive method was necessary as one-third of concentrations of buprenorphine and/or norbuprenorphine were <1.0 µg/L. Concentrations of buprenorphine ranged from <0.5 to 11 µg/L (mean 2.5 µg/L, median 1.8 µg/L) and concentrations of norbuprenorphine ranged from <0.5 to >20 µg/L (mean 3.3 µg/L, median 2.2 µg/L). Buprenorphine polysubstance use was common. Only 10% of the cases examined did not contain other drugs confirmed in routine DUID screening tests. The most common drug groups confirmed were benzodiazepines, amphetamines and cannabinoids. The DUID case histories presented represent examples of buprenorphine abuse, buprenorphine with no other drug groups, buprenorphine combined with other drug groups, cases consistent with impairment and cases with minimal impairment. Central nervous system depressant and narcotic analgesic symptoms were commonly observed; however, some cases contained stimulant symptoms. Buprenorphine-to-norbuprenorphine (B/NB) ratios had a mean and median ratio of 1.1 and 0.8, respectively. B/NB ratios >3.0 were found in 4.7% of the cases. The finding of a higher B/NB ratio may indicate a more recent buprenorphine administration and a greater potential for impairment. No relationship between the concentration of buprenorphine and/or norbuprenorphine in blood and the performance on drug recognition expert evaluation or standardized field sobriety tests could be determined.

Opioid Overdose Deaths with Buprenorphine Detected in Postmortem Toxicology: a Retrospective Analysis.

Buprenorphine is a unique μ-opioid receptor partial agonist with avid receptor binding, nominal euphoric reward, and a ceiling effect on sedation and respiratory depression. Despite a pharmacologic profile that enhances safety, cases of fatal opioid overdose with buprenorphine on postmortem toxicology are reported, but details of these cases in the literature are limited. A retrospective review of opioid-involved drug overdose fatalities in Rhode Island (RI) from 2016 to 2018 using the RI Department of Health State Unintentional Drug Overdose Reporting System (SUDORS) database. Deaths with buprenorphine on toxicology testing versus opioid-involved overdose deaths without buprenorphine were compared to assess the type and number of co-exposures. Of 534 opioid-involved deaths, 29 (5.4%) included buprenorphine and/or norbuprenorphine on toxicology. Most frequent co-exposures are as follows: fentanyl (75.9%), norfentanyl (72.4%), cocaine (41.4%), benzoylecgonine (41.4%), cannabinoids (31.0%), ethanol (31.0%), levamisole (31.0%), and free morphine (31.0%). An average number of co-exposures for fatalities with buprenorphine were 9.24 versus 6.68 in those without buprenorphine. In one case buprenorphine was the only drug listed to cause death; all other fatalities with buprenorphine on toxicology reported additional drugs contributing to death. Decedents with buprenorphine detected on toxicology testing commonly had documented polysubstance use. Although data are limited, buprenorphine may provide some risk mitigation against full agonist opioid overdose including fentanyl. Further work should explore the use of postmortem concentrations of buprenorphine, norbuprenorphine, and other opioid metabolites to determine the role of buprenorphine in fatal overdose pharmacology.

Urinary Buprenorphine, Norbuprenorphine and Naloxone Concentrations and Ratios: Review and Potential Clinical Implications.

Treatment with medications for opioid use disorder such as buprenorphine improves patient morbidity and mortality as well as treatment adherence, an important component of patient care. Buprenorphine is combined with naloxone to reduce misuse; and, when taken sublingually, naloxone is poorly absorbed. Urine testing for buprenorphine is a common way to monitor adherence. Some patients who want to appear adherent may directly tamper with their urine by adding buprenorphine to their urine to allow for the detection without ingestion. Practitioners may rely upon the concentration of buprenorphine and the metabolite, norbuprenorphine, and utilize the ratio of metabolite to parent compound (norbuprenorphine:buprenorphine - N:B ratio) to discern possible evidence of tampering; however, there remains debate as to what specific ratio may signify this practice. Testing for naloxone may also help determine if urine tampering occurred as only low naloxone concentrations are found in the urine when taken by a sublingual route. To determine a reliable N:B ratio that may be used to identify possible urine tampering by adding parent drug directly to urine, we examined 136,605 urine samples for quantitative concentrations of buprenorphine and norbuprenorphine by LC-MS/MS performed at a commercial laboratory. After identifying abnormal ratios (<0.02), we then compared them with naloxone concentrations and specimen validity testing, other markers that may coincide with specimen tampering of this type. Correlating urinary buprenorphine and norbuprenorphine concentrations, we found 2 distinct patient populations, which could be distinguished by N:B ratios ranging from 0.01 to 0.2. In addition, while the distribution of urine naloxone concentrations itself did not demonstrate distinct populations, naloxone was able to further flag potential tampered specimens when combined with N:B ratios. Abnormal specimen validity testing was additionally found more commonly in cases with N:B ratios <0.02. This comprehensive study compared N:B ratios with naloxone concentrations and specimen validity testing. This study suggests that a N:B ratio of <0.02 in concert with high naloxone concentrations (>1000 ng/ml) can help to identify potential cases of tampered urine samples.

Pharmacokinetics and analgesic effects of intravenous, intramuscular or subcutaneous buprenorphine in dogs undergoing ovariohysterectomy: a randomized, prospective, masked, clinical trial

BackgroundBuprenorphine is used for canine postoperative pain management. This study aimed to describe the pharmacokinetics and evaluate the analgesic efficacy of buprenorphine (Simbadol, 1.8 mg/mL) administered by different routes in dogs undergoing ovariohysterectomy. Twenty-four dogs were included in a randomized, prospective, masked, clinical trial. Buprenorphine (0.02 mg/kg) was administered intravenously (IV), intramuscularly (IM) or subcutaneously (SC) (n = 8/group) 0.5 h before general anesthesia with propofol-isoflurane. Carprofen (4.4 mg/kg SC) was administered after anesthetic induction and before ovariohysterectomy. Pain was scored using the short-form Glasgow composite pain scale for dogs (SF-GCPS). Dogs were administered morphine (0.25 mg/kg IV) when SF-GCPS scores were ≥ 5/20. Blood sampling was performed up to 720 min after drug administration. Plasma buprenorphine and norbuprenorphine concentrations were analyzed using liquid chromatography mass spectrometry. Pharmacokinetics of buprenorphine was described using a non-compartmental model (PK Solver 2.0). Statistical analysis was performed using linear mixed models and Fisher’s exact test (p < 0.05).ResultsPain scores were significantly higher than baseline after IV (0.5–2 h), IM (0.5–3 h) and SC (0.5–4 h) but not among groups. Prevalence of rescue analgesia was significantly higher in SC (7/8 dogs) than IV (2/8) but not different between IV and IM (3/8) or IM and SC. The frequency of rescue analgesia was not significantly different among groups (IV = 2, IM = 5 and SC = 9). Norbuprenorphine was not detected. For IV, IM and SC administration, clearance was 1.29, 1.65 and 1.40 L/hour/kg, volume of distribution was 6.8, 14.2 and 40.1 L/kg, the elimination half-life was 3.7, 5.7, 22 h, and the area under the plasma concentration-time curved extrapolated to infinity was 15.7, 12.4 and 16.4 ng/mL/hour, respectively. Bioavailability for IM and SC was 62.6 and 40%, respectively. Maximum plasma concentrations of buprenorphine were 6.2 and 1.3 ng/mL at 0.14 and 0.33 h after IM and SC administration, respectively.ConclusionsThe route of administration influences the analgesic efficacy of buprenorphine in dogs. SC administration of buprenorphine failed to provide clinical analgesia due to erratic drug absorption. At the doses administered, the IV and IM routes are preferred for postoperative analgesia.

Buprenorphine\u2013cannabis interaction in patients undergoing opioid maintenance therapy

Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug–drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring.

Urine is superior to oral fluid for detecting buprenorphine compliance in patients undergoing treatment for opioid addiction

BackgroundBuprenorphine (BUP) is commonly used in opioid agonist medication-assisted treatment (OA-MAT). Oral fluid (OF) is an attractive option for compliance monitoring during OA-MAT as collections are observed and evidence suggests that OF is less likely to be adulterated than urine (UR). However, the clinical and analytical performance of each matrix for monitoring BUP compliance has not been well studied. MethodsWe collected 260 paired OF and UR specimens. Concentrations of buprenorphine (BUP) and norbuprenorphine (NBUP) were measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) in each matrix. The glucuronide metabolites and naloxone concentrations were also measured in UR by LC–MS/MS. Medications were reviewed and UR creatinine concentrations were determined. Results147/260 specimens (57%) were positive for BUP and/or metabolites in one or both matrices. BUP and/or metabolites were more likely to be detected in UR (p < 0.001). 1 OF specimen and 12 UR specimens were considered adulterated/substituted. The majority of patients prescribed BUP were positive for BUP in UR (97%) as opposed to OF (78%). The detection of undisclosed use approximately doubled in UR. ConclusionsUR is the preferred matrix for detecting both buprenorphine compliance and undisclosed use. Clinicians should consider the ease of collection, risk of adulteration and detection of illicit drug use when deciding on an appropriate matrix. If OF testing is clinically necessary, UR should be measured in conjunction with OF at least periodically to avoid false negative BUP results.

In Utero Exposure to Norbuprenorphine, a Major Metabolite of Buprenorphine, Induces Fetal Opioid Dependence and Leads to Neonatal Opioid Withdrawal Syndrome.

Buprenorphine is the preferred treatment of opioid use disorder during pregnancy but can cause fetal opioid dependence and neonatal opioid withdrawal syndrome (NOWS). Notably, withdrawal severity is independent of maternal buprenorphine dose, suggesting that interindividual variance in pharmacokinetics may influence risk and severity of NOWS. Using a rat model of NOWS, we tested the hypothesis that clinically relevant doses of the active metabolite norbuprenorphine (NorBUP) can induce in utero opioid dependence, manifested as naltrexone-precipitated withdrawal signs in the neonate. Pregnant Long-Evans rats were implanted with 14-day osmotic minipumps containing vehicle, morphine (positive control), or NorBUP (0.3-10 mg/kg per day) on gestation day 9. By 12 hours post-delivery, an intraperitoneal injection of the opioid antagonist naltrexone (1 or 10 mg/kg) or saline was administered to pups. Precipitated withdrawal signs were graded by raters blinded to treatment conditions. In a separate group, NorBUP concentrations in maternal and fetal blood and brain on gestation day 20 were determined by liquid chromatography-tandem mass spectrometry. Steady-state maternal blood concentrations of NorBUP in dams infused with 1 or 3 mg/kg per day were comparable to values reported in pregnant humans treated with buprenorphine (1.0 and 9.6 ng/ml, respectively), suggesting a clinically relevant dosing regimen. At these doses, NorBUP increased withdrawal severity in the neonate as shown by an evaluation of 10 withdrawal indicators. These findings support the possibility that NorBUP contributes to fetal opioid dependence and NOWS following maternal buprenorphine treatment during pregnancy.

Voriconazole greatly increases the exposure to oral buprenorphine.

Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine. Twelve healthy volunteers were given either placebo or voriconazole (orally, 400mg twice on day 1 and 200mg twice on days 2-5) for 5days in a randomized, cross-over study. On day 5, they ingested 0.2mg (3.6mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0mg. Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC0-18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0-18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases. Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.

2421 Development and validation of a translational rat model of neonatal abstinence syndrome

OBJECTIVES/SPECIFIC AIMS: Rodent models can be used to study neonatal abstinence syndrome (NAS), but the applicability of findings from the models to NAS in humans is not well understood. The objective of this study was to develop a rat model of norbuprenorphine-induced NAS and validate its translational value by comparing blood concentrations in the norbuprenorphine-treated pregnant rat to those previously reported in pregnant women undergoing buprenorphine treatment. METHODS/STUDY POPULATION: Pregnant Long-Evans rats were implanted with 14-day osmotic minipumps containing vehicle, morphine (positive control), or norbuprenorphine (0.3–3 mg/kg/d) on gestation day 9. Within 12 hours of delivery, pups were tested for spontaneous or precipitated opioid withdrawal by injecting them with saline (10 mL/kg, i.p.) or naltrexone (1 or 10 mg/kg, i.p), respectively, and observing them for well-validated neonatal withdrawal signs. Blood was sampled via indwelling jugular catheters from a subset of norbuprenorphine-treated dams on gestation day 8, 10, 13, 17, and 20. Norbuprenorphine concentrations in whole blood samples were quantified using LC/MS/MS. RESULTS/ANTICIPATED RESULTS: Blood concentrations of norbuprenorphine in rats exposed to 1–3 mg/kg/d of norbuprenorphine were similar to levels previously reported in pregnant women undergoing buprenorphine treatment. Pups born to dams treated with these doses exhibited robust withdrawal signs. Blood concentrations of norbuprenorphine decreased across gestation, which is similar to previous reports in humans. DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that dosing dams with 1–3 mg/kg/day norbuprenorphine produces maternal blood concentrations and withdrawal severity similar to those previously reported in humans. This provides evidence that, at these doses, this model is useful for testing hypotheses about norbuprenorphine that are applicable to NAS in humans.

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats.

BackgroundThe aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats.MethodsSix healthy cats (4.9 ± 0.7 kg) were included in a prospective, randomized, blinded, crossover study. Simbadol™ (1.8 mg mL-1) was administered by the subcutaneous (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) route of administration and thermal thresholds (TT) were compared with a saline group (SAL). Thermal threshold testing and blood sampling were performed at predetermined time points up to 72 hours including a placebo group. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography mass spectrometry. A bespoke bicompartmental pharmacokinetic model simultaneously fitted data from two analytes/three routes of administration. Temporal changes in TT were analyzed using one-way ANOVA followed by Dunnett’s test and treatment comparisons using two-way ANOVA with Bonferroni’s correction (P < 0.05).ResultsThermal thresholds were significantly increased after SC, IV and OTM from 1–24 hours (except 2 hours), 0.5–8 hours (except 6 hours), and 1–8 hours (except 6 hours), respectively, when compared with baseline. Thermal thresholds were significantly increased after SC (1–30 hours), IV (1–8 hours) and OTM (1–12 hours) when compared with SAL, but not different among buprenorphine-treated cats. The absolute buprenorphine clearance was 0.98 L kg-1 hour-1, volume of distribution at steady state was 7.9 L kg-1 and the elimination-half-life was 12.3 hours. Bioavailability for SC and OTM was 94% and 24%, respectively. Subcutaneous absorption was biphasic. An initial peak (0.08 hours) was followed by a slow (half-life 11.2 hours) and progressive (peak acceleration at 2.8 hours) uptake.ConclusionThe SC administration of Simbadol™ was characterized by prolonged absorption half-life and sustained plasma concentrations yielding long-lasting antinociception (≥ 24 hours) when compared with the IV and OTM routes.

Pharmacokinetics of buprenorphine following constant rate infusion for postoperative analgesia in dogs undergoing ovariectomy

ObjectiveTo investigate the pharmacokinetics of buprenorphine and its main active metabolite, norbuprenorphine, after administration of an intravenous loading dose followed by constant rate infusion (CRI) in dogs. Study designProspective, clinical study. AnimalsA total of seven healthy dogs undergoing elective ovariectomy. MethodsBuprenorphine was administered as a loading dose (intravenous bolus of 15 μg kg−1) followed by CRI (2.5 μg kg−1 hour−1 for 6 hours). Moreover, intraoperative analgesia was supplemented by an intramuscular carprofen (4 mg kg−1) injection, administered prior to surgery, and by lidocaine, administrated through subcutaneous infiltration and through a splash on the ovarian vascular pedicle during surgery. Pain and sedation were scored for all animals throughout the 24-hour study period and rescue analgesia was administered when a visual analogue scale score was > 40 mm. Blood samples were collected from a jugular catheter at regular intervals, and plasma concentrations of buprenorphine and norbuprenorphine were determined by a validated liquid chromatography–tandem mass spectrometry method. ResultsBuprenorphine showed a two-compartment kinetic profile. Maximum concentration was 23.92 ± 8.64 ng mL−1 at 1 minute (maximum time); elimination half-life was 41.87 ± 17.35 minutes; area under the curve was 486.68 ± 125.66 minutes ng−1 mL−1; clearance was 33.61 ± 13.01 mL minute−1 kg−1, and volume of distribution at steady state was 1.77 ± 0.50 L kg−1. In no case was rescue analgesia required. Norbuprenorphine resulted below the lower limit of quantification in almost all samples. Conclusions and clinical relevanceThe results suggest that a buprenorphine CRI can be a useful tool for providing analgesia in postoperative patients, considering its minor side effects and the advantages of a CRI compared to frequent boluses. The negligible contribution of norbuprenorphine to the therapeutic effect was confirmed.

Maternal Buprenorphine Maintenance and Lactation.

In addition to the well-known benefits of human milk and breastfeeding for the mother and infant, breastfeeding may mitigate neonatal abstinence syndrome severity in prenatally opioid-exposed infants. However, lack of conclusive data regarding the extent of the presence of buprenorphine and active metabolites in human milk makes the recommendation of breastfeeding for buprenorphine-maintained women difficult for many providers. This study seeks to determine the concentrations of buprenorphine and its active metabolites (norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide) in human milk, maternal plasma, and infant plasma of buprenorphine-maintained women and their infants. Up to 10 buprenorphine-maintained women provided paired breast milk and plasma samples at 2, 3, 4, 14, and 30 days postdelivery, and 9 infants provided plasma samples on day 14 of life. All samples were analyzed via liquid chromatography tandem mass spectrometry to determine concentrations of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide by a fully validated method. Concentrations of buprenorphine and metabolites are low in human milk and maternal plasma. Breastfed infant plasma concentrations of buprenorphine were low or undetectable and metabolite concentrations undetectable at 14 days of infant age. There were significant correlations between maternal buprenorphine dose and maternal plasma and human milk buprenorphine concentrations. These data find low concentrations of buprenorphine and metabolites in human milk and lend support to the recommendation for lactation among stable buprenorphine-maintained women. However, the correlation between maternal dose and maternal plasma and human milk buprenorphine concentrations bears further study.

Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction.

This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4mg (0.6mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400mg twice daily on the first day and 200mg twice daily thereafter or (iii) posaconazole 400mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18h and pharmacological effects were measured. Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC0-∞) of buprenorphine 1.80-fold (90% confidence interval 1.45-2.24; P<0.001), its peak concentration (Cmax) 1.37-fold (P<0.013) and half-life (t ½ ) 1.37-fold (P<0.001). Posaconazole increased the AUC00-∞ of buprenorphine 1.25-fold (P<0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90% confidence interval 1.18-2.12; P<0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases. Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.

Opioid-induced constipation: rationale for the role of norbuprenorphine in buprenorphine-treated individuals

Buprenorphine and buprenorphine–naloxone fixed combinations are effective for managing patients with opioid dependence, but constipation is one of the most common side effects. Evidence indicates that the rate of constipation is lower when patients are switched from sublingual buprenorphine–naloxone tablets or films to a bilayered bioerodible mucoadhesive buccal film formulation, and while the bilayered buccal film promotes unidirectional drug flow across the buccal mucosa, the mechanism for the reduced constipation is unclear. Pharmacokinetic simulations indicate that chronic dosing of sublingually administered buprenorphine may expose patients to higher concentrations of norbuprenorphine than buprenorphine, while chronic dosing of the buccal formulation results in higher buprenorphine concentrations than norbuprenorphine. Because norbuprenorphine is a potent full agonist at mu-opioid receptors, the differences in norbuprenorphine exposure may explain the observed differences in treatment-emergent constipation between the sublingual formulation and the buccal film formulation of buprenorphine–naloxone. To facilitate the understanding and management of opioid-dependent patients at risk of developing opioid-induced constipation, the clinical profiles of these formulations of buprenorphine and buprenorphine-naloxone are summarized, and the incidence of treatment-emergent constipation in clinical trials is reviewed. These data are used to propose a potential role for exposure to norbuprenorphine, an active metabolite of buprenorphine, in the pathophysiology of opioid-induced constipation.

Use of an Acetyl Derivative to Improve GC-MS Determination of Norbuprenorphine in the Presence of High Concentrations of Buprenorphine in Urine.

Certain patients being treated with Suboxone™ or Subutex™ can exhibit very high buprenorphine and low norbuprenorphine concentrations in urine. Very high buprenorphine can interfere with buprenorphine-D4 used as an internal standard, causing errors in norbuprenorphine determination by gas chromatography-mass spectrometry (GC-MS). We used a modified method of Wu et al. to introduce norbuprenorphine-D3 as a separate internal standard for norbuprenorphine. This allowed us to accurately measure norbuprenorphine in neat urine specimens when buprenorphine is present in extremely high concentrations. Laboratories measuring buprenorphine and metabolite by GC-MS may face this problem if their clientele includes patients being treated with other medications that interfere with the cytochrome p450 CYP 3A4-mediated conversion of buprenorphine to norbuprenorphine.