OPRM1 rs2075572 has potential to affect plasma buprenorphine level in opioid users, but not OPRM1 rs562859.

OPRM1 gene encoding mu-opioid receptor (MOR) is the primary candidate gene for buprenorphine (BUP) pharmacogenetics. OPRM1 undergoes alternative splicing leading to multiple MOR subtypes. Thus, in the current study 2 SNPs (rs1799972 and rs562859) were selected due to evidence for their contribution to alternative splicing of OPRM1. The effects of 2 SNPs of OPRM1 gene on plasma buprenorphine and norbuprenorphine levels in a sample of 233 OUD patients receiving BUP/naloxone were examined. Polymorphisms were analyzed by PCR and RFLP. BUP and norbuprenorphine concentrations in plasma were measured by LC-MS/MS. OPRM1 rs2075572 GC + CC (0.12 ng/ml) had significantly higher plasma BUP level compared to GG (0.084 ng/ml) (p = 0.043). Although there was not a statistically significant difference between OPRM1 rs562859 genotypes (p = 0.46), patients with OPRM1 rs562859 CT + TT had higher plasma BUP and BUP-related values as compared to those with CC. In conclusion, the effect of OPRM1 rs2075572 on BUP levels in opioid users' plasma was shown in a Caucasian population for the first time. On the other hand, OPRM1 rs562859 seems not to influence the BUP pharmacology.

Development and validation of a rapid liquid chromatography/tandem mass spectrometry method to quantitate gabapentin and buprenorphine in human serum.

RATIONALE: Gabapentin has shown initial promise as an opioid-sparing medication in pain patients as well as a treatment for opioid withdrawal and liquid chriomatography/tandem mass spectrometry (LC/MS/MS) is often used for clinical monitoring. Despite reports of validated tandem mass spectrometric methods for the determination of gabapentin and buprenorphine, mechanisms for the collision-induced fragmentation have not been adequetely described. METHODS: A rapid analytical method has been developed to determine gabapentinoid, gabapentin, and the partial opioid agonist, buprenorphine, in 20 µL of human serum using LC/MS/MS with a chromatographic run time of 2 min. A simplified sample cleanup procedure using methanol precipitation of serum proteins/lipids followed by evaporation and reconstitution in mobile phase was demonstrated. Gabapentin and buprenorphine were detected following positive ion electrospray ionization using multiple-reaction monitoring. The internal standard approach was used for quantitation with labeled gabapentin-D10 and buprenorphine-D4 serving as internal standards. Using organic reaction principals and stable isotope labels, collision-induced fragmentation mechanisms for both gabapentin and buprenorphine are proposed. The method was validated according to the FDA Guidance for Industry - Bioanalytical Method Validation. RESULTS: Accuracy was demonstrated by error values ≤15% for buprenorphine and ≤6% for gabapentin. The inter-day precision was ≤4.88% and 15.59% for gabapentin and buprenorphine and the intra-day precision was ≤5.20% and 11.65% for gabapentin and buprenorphine. The lower limit of quantitation corresponded to 10 ng/mL for gabapentin and 1 ng/mL for buprenorphine in serum. Recoveries were 104 ± 2.55% and 85 ± 2.03% for gabapentin and buprenorphine, respectively. CONCLUSIONS: Concentrations of gabapentin and buprenorphine were determined for five authentic human serum samples to further validate the utility of the method and applicable to therapeutic drug monitoring beyond its use as a drug screening assay. Furthermore, new mechanisms for the collision-induced dissociation of gabapentin and buprenorphine have been proposed.

High-Performance Liquid Chromatography-Tandem Mass Spectrometry for Buprenorphine Evaluation in Plasma-Application to Pharmacokinetic Studies in Rabbits.

The precise and reliable determination of buprenorphine concentration is fundamental in certain medical or research applications, particularly in pharmacokinetic studies of this opioid. The main challenge is, however, the development of an analytical method that is sensitive enough, as the detected in vivo concentrations often fall in very low ranges. Thus, in this study we aimed at developing a sensitive, repeatable, cost-efficient, and easy HPLC analytical protocol for buprenorphine in rabbit plasma. In order to obtain this, the HPLC-MS2 system was used to elaborate and validate the method for samples purified with liquid-liquid extraction. Fragment ions 468.6→396.2 and 468.6→414.2 were monitored, and the method resulted in a high repeatability and reproducibility and a limit of quantification of 0.25 µg/L with a recovery of 98.7-109.0%. The method was linear in a range of 0.25-2000 µg/L. The suitability of the analytical procedure was tested in rabbits in a pilot pharmacokinetic study, and it was revealed that the method was suitable for comprehensively describing the pharmacokinetic profile after buprenorphine intravenous administration at a dose of 300 µg/kg. Thus, the method suitability for pharmacokinetic application was confirmed by both the good validation results of the method and successful in vivo tests in rabbits.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Bioavailability of subcutaneous and intramuscular administrated buprenorphine in New Zealand White rabbits.

BACKGROUND: Buprenorphine is one of the most used analgesics for postoperative pain in rabbits. The recommended dose in rabbits (0.01-0.05 mg/kg) is the same for intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration, despite lack of pharmacokinetic data. Five male and five female New Zealand White rabbits (mean ± SD body weight 3.1 ± 0.3 kg) were administered 0.05 mg/kg buprenorphine by the IV, IM and SC routes and 0.1 mg/kg by the SC route, in a cross-over design with two-week wash-out periods between treatments. Blood was collected before, and up to 8 h post buprenorphine injection, for determination of serum levels by UPHLC-MS/MS. RESULTS: The area under the time concentration curve (AUC0-t) was lower after SC (398 ± 155 ng/mL/min) than IM (696 ± 168 ng/mL/min, p < 0.001) and IV (789 ± 189 ng/mL/min, p < 0.001) administration. The maximum serum concentration was lower after SC (2.2 ± 1.4 ng/mL) than after IM (11 ± 3.2 ng/mL) administration (p < 0.001). The bioavailability was lower after SC (50 ± 19%) than after IM (95 ± 21%) administration (p = 0.006). The elimination half-life was longer after SC (260 ± 120 min) than after IM (148 ± 26 min, p = 0.002) as well as IV (139 ± 33 min) injection (p < 0.001). An increase in the SC dose from 0.05 to 0.1 mg/kg resulted in an increase in the area under the time concentration curve of 50% in female (p = 0.022) and 165% in male rabbits (p < 0.001). The bioavailability did not change in the females (36 ± 14%, p = 0.6), whereas it increased in the males (71 ± 23%, p = 0.008). CONCLUSIONS: The lower bioavailability of 0.05 mg/kg buprenorphine after SC administration could explain the lack of efficacy seen in clinical pain studies in rabbits, using this route. For immediate pain relief, IV or IM administration is therefore be recommended, whereas SC administration may be useful to sustain analgesic serum levels, once efficient pain relief has been achieved. The current data do not support an increase in dose to compensate for the lower SC bioavailability.

A Comparison of Buprenorphine, Sustained release Buprenorphine, and High concentration Buprenorphine in Male New Zealand White Rabbits.

Pain management in rabbits can be difficult because they are adept at hiding pain and can be stressed by handling and restraint for injection. The use of opioid analgesics with prolonged durations of activity could alleviate pain, but associated adverse effects including gastrointestinal ileus, inappetence, and tissue reactions have been reported. In this study, we compared gross tissue reactions at the site of injection, food consumption, and fecal production after single injections of buprenorphine HCl (Bup; n = 7), sustained-release buprenorphine (BupSR; n = 8), and high-concentration buprenorphine (BupHC; n = 7) during the first 3 d after minor survival surgery. We also measured plasma concentrations of the parent drug, buprenorphine, and 3 metabolites (buprenorphine-3-glucuronide (B3G), norbuprenorphine-3ß-glucuronide (N3G), and norbuprenorphine (NB)). Plasma levels of buprenorphine remained above the theoretical minimal analgesic concentration for 4 h for Bup and 42 h for BupHC. For BupSR, plasma levels of buprenorphine remained above the theoretical minimal analgesic concentration for approximately 77 h, starting 15 h after administration. For all 3 formulations, N3G was the most prominent metabolite in the blood. No injection site reactions were visible grossly in any rabbit. Relative to baseline measures and compared with controls (n = 8), food consumption was suppressed on days 1 through 3 in rabbits that received BupSR and on days 2 through 3 in those given BupHC. Feces production on day 3 was reduced to a greater extent in BupSR rabbits than control animals. Two rabbits in the BupHC group exhibited neurologic signs after drug administration. These adverse effects should be considered when choosing a long-lasting buprenorphine formulation to manage pain in rabbits.

Dispersive solid-phase extraction of buprenorphine from biological fluids using metal-organic frameworks and its determination by ultra-performance liquid chromatography.

In this work, various types of metal-organic frameworks were synthesized, and their affinities toward buprenorphine were evaluated using dispersive solid-phase extraction. The extracted buprenorphine was determined by ultra high performance liquid chromatography-ultraviolet detection system. The highest extraction recovery was observed by employing zeolitic imidazole framework-67. Then, a facile and fast extraction method was designed for the extraction and purification of the target drug. Optimization of the extraction method was carried out by the design of experiment approach. A linearity range of 1-1000 µg/L with the limit of detection of 0.15 µg/L and relative standard deviations (50 µg/L, n = 5) of 3.4% was obtained for standard sample analysis. Under optimized experimental and instrumental conditions, the relative recoveries were in the range of 95 to 111%. Eventually, zeolitic imidazole framework-67 was successfully employed for the extraction and determination of buprenorphine in the biological fluids with satisfactory results.

Necrotizing enterocolitis and its association with the neonatal abstinence syndrome.

OBJECTIVE: The purpose of this study was to describe an identified association between necrotizing enterocolitis (NEC) and prenatal opioid exposure with neonatal abstinence syndrome (NAS) in late preterm and full-term neonates. STUDY DESIGN: In this single-center retrospective cohort study, we analyzed inborn neonates with the diagnosis of NEC discharged from 2012 through 2017. We compared infants with NEC > 35 weeks' gestation to those with NEC<35 weeks' gestation. We compared gestational age, birth weight, age of onset of symptoms, and incidence of prenatal drug exposure between groups. Significance was determined using Mann-Whitney and Fisher's exact tests. RESULTS: Over the study period, 23 infants were identified with NEC, 9 (39%) were babies > 35 weeks at birth and 14 (61%) < 35 weeks. Those > 35 weeks had a higher birth weight, earlier onset of symptoms, and a higher percentage of prenatal exposure to opioids compared to those < 35 weeks' gestation. We further described seven infants with late gestational age onset NEC associated with prenatal opioid exposure. CONCLUSIONS: In this cohort of infants with NEC discharged over a 6 year period we found a higher than expected percentage of infants born at a later gestational age. We speculate that prenatal opioid exposure might be a risk factor for NEC in neonates born at > 35 weeks.

Fatal α-PVP and amphetamine poisoning during a sauna and autoerotic practices.

We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs' effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.

Analgesic treatment with buprenorphine should be adapted to the mouse strain.

Buprenorphine is a commonly used opioid to treat moderate to severe pain in mice. Although strain differences regarding basal pain sensitivity and the analgesic effect of other opioids have been described for mice, the data for buprenorphine is incomplete. Hence, we investigated basal pain sensitivity and the analgesic effect of buprenorphine (0.42, 4.0 mg·kg-1) in male C57BL/6J, Balb/cJ and 129S1/SvImJ mice using the incremental hot plate. Additionally, we verified single nucleotide polymorphisms in Cytochrome P450 3a (Cyp3a) genes, which encode for enzymes that are relevant for buprenorphine metabolism, and analyzed serum and brain concentrations of buprenorphine and its metabolites. Finally, in a pilot survey we determined µ-opioid receptor (MOR) protein expression in whole brain lysates. Basal pain sensitivity differed significantly between the mouse strains (Balb/cJ > C57BL/6J > 129S1/SvImJ). Additionally, buprenorphine showed a dose- and strain-dependent effect: at a higher dose it led to increased antinociception in C57BL/6J and Balb/cJ mice, whereas in 129S1/SvImJ mice this effect was diminished. Serum and brain concentrations of buprenorphine and its metabolites dose-dependently increased and differed slightly between the strains at the high dose. However, these slight strain differences did not correlate with pain behavior. Furthermore, serum buprenorphine metabolic ratio and distribution of buprenorphine and its metabolites between brain and blood showed no dose- and only some strain-dependent differences independent from nociceptive behavior. Western blot analysis revealed no strain difference in the basal MOR protein expression in brain lysates. Our results indicate that buprenorphine dosing should be determined in a pilot study for the respective mouse strain to optimize pain treatment and to avoid unwanted side effects. The present pharmacokinetic data and the coarse determination of MOR expression do not explain the strain differences in the analgesic effect of buprenorphine. However, follow-up studies focusing on more specific pharmacodynamic factors could further elucidate the reasons.

Pregnancy Alters CYP- and UGT-Mediated Metabolism of Buprenorphine.

BACKGROUND: In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug Administration, has been increasingly used in pregnant women for the treatment of opioid use disorder. Pregnancy is associated with various anatomic and physiological changes, which may result in altered drug pharmacokinetics (PKs). Previously, we reported that dose-adjusted plasma concentrations of BUP are lower during pregnancy than after pregnancy. The mechanism(s) responsible for this difference has not yet been defined. Our study aimed to evaluate alterations in cytochromes P450 (CYP)- and uridine diphosphate glucunosyltransferases (UGT)-mediated metabolism of BUP during pregnancy to determine the mechanism(s) responsible for this observation. METHODS: Data from 2 clinical studies were included in the current analysis. Study 1 was a prospective, open-labeled, nonrandomized longitudinal BUP PK study in pregnant women with a singleton gestation, stabilized on twice-daily sublingual BUP opioid substitution therapy. Each subject participated in up to 3 studies during and after pregnancy (the second, third trimester, and postpartum). The design of study 2 was similar to study 1, with patients evaluated at different time points during the pregnancy (first, second-half of pregnancy), as well as during the postpartum period. In addition, the dosing frequency of BUP study 2 participants was not restricted to twice-daily dosing. At each study visit, blood samples were collected before a BUP dose, followed by multiple collection times (10-12) after the dose, for up to 12 hours or till the end of the dosing interval. Plasma concentrations of BUP and 3 metabolites were quantified using validated ultraperformance liquid chromatography-tandem mass spectrometric assays. RESULTS: In total, 19, 18, and 14 subjects completed the PK study during 1/2 trimester, third trimester, and postpartum, respectively. The AUC ratios of norbuprenorphine and norbuprenorphine glucuronide to buprenorphine, a measure of CYP3A mediated N-demethylation, were 1.89, 1.84, and 1.33 during the first and second, third trimesters, and postpartum, respectively. The AUC ratios of buprenorphine glucuronide to BUP, indicative of UGT activity, were 0.71, 2.07, and 0.3 at first/second trimesters, third trimester, and postpartum, respectively. Linear mixed-effect modeling analysis indicated that the AUC ratios of CYP- and UGT-mediated metabolism of BUP were significantly higher during pregnancy compared with postpartum. CONCLUSIONS: The CYP and UGT activities were significantly increased as determined by the metabolic ratios of BUP during pregnancy compared with the postpartum period. The increased UGT activity appeared to account for a substantial part of the observed change in metabolic activity during pregnancy. This is in agreement with the need for BUP dose increment in pregnant women to reach similar BUP exposure and therapeutic effect as in nonpregnant subjects.

Determination of buprenorphine, naloxone and phase I and phase II metabolites in rat whole blood by LC-MS/MS.

Buprenorphine and buprenorphine/naloxone combination are maintenance treatments used worldwide. However, since their marketing, despite ceiling respiratory effects, poisonings and fatalities have been attributed to buprenorphine misuse and overdose. Therefore, to better understand the mechanisms of buprenorphine-related toxicity in vivo, experimental investigations have been conducted, mainly in the rat. We developed a liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method with electrospray ionization for the simultaneous quantification of buprenorphine, naloxone and their metabolites (norbuprenorphine, buprenorphine glucuronide, norbuprenorphine glucuronide and naloxone glucuronide) in rat whole blood. Compounds were extracted from whole blood by protein precipitation and chromatographically separated using gradient elution of aqueous ammonium formate and methanol in a Raptor Biphenyl core-shell column (100 mm x 3,0 mm x 2,7 µm). Following electrospray ionization, quantification was carried out in the multiple reaction monitoring (MRM) mode by the tandem mass spectrometer API 3200 system. The LC-MS/MS method was validated according to the currently accepted criteria for bioanalytical method validation. The method required small sample volumes (50 µL) and was sensitive with limits of quantification of 6.9, 6.2, 3.6, 3.3, 1.3 and 57.7 ng/mL for buprenorphine, norbuprenorphine, buprenorphine glucuronide, norbuprenorphine glucuronide, naloxone and naloxone glucuronide respectively. The upper limit of quantification was 4000 ng/ml for all the studied compounds. Trueness (88-115 %), repeatability and intermediate precision (both <15%) were in accordance with the international recommendations. The procedure was successfully used to quantify these compounds in the whole blood sample from one rat 24 h after the intravenous administration of buprenorphine/naloxone (30.0/7.5 mg/kg).

Bupenorphine in Wisconsin Drivers: Concerns for Impairment?

Opinions vary on whether buprenorphine can cause impairment in drivers. Relatively little information on the observed effects of buprenorphine, outside a laboratory or a controlled driving course, exist in the literature. The Wisconsin State Laboratory of Hygiene monitored the detection of buprenorphine and its pharmacologically active metabolite, norbuprenorphine (NBUP), in Wisconsin drivers over a 2-year period. A total of 204 individuals (78 females and 126 males) were driving under the influence of buprenorphine and/or NBUP. Concentrations in whole blood (ng/mL) ranged (mean) from 0.6 to 14 (2.0) and 0.5 to 20 (2.1) for buprenorphine and NBUP, respectively. Poly-substance use is extremely prevalent in Wisconsin operating while intoxicated casework, so prevalent that only four of the previously described cases had buprenorphine and/or NBUP as the only drug(s) detected. This paper summarizes and highlights the case histories and observed impairments of those four cases. Law enforcement (LE) made contact with three of the four subjects due to either a crash or poor/reckless driving. Police reports and observations made by LE, including drug recognition expert (DRE) evaluations, were collected. Physical and behavioral observations made by LE varied and included a combination of narcotic analgesic, central nervous system depressant- and stimulant-like effects. Impaired balance and lack of coordination during the administration of the Standardized Field Sobriety Tests were documented by the arresting officers and/or the DRE. While the number of buprenorphine-only cases reported here is limited, the results demonstrate the complex paradigm associated with forensic interpretation of buprenorphine in driving under the influence of drugs casework and the frequency of poly-substance administration in Wisconsin drivers.

Ascorbic Acid Improves the Stability of Buprenorphine in Frozen Whole Blood Samples.

Buprenorphine (BUP) was not long-term stable in whole blood samples preserved with fluoride citrate (FC) and fluoride oxalate (FX) mixtures when stored at -20°C. On average, only half of the initial concentrations of BUP was recovered after 12 weeks of storage at -20°C when interrupted by 3-4 thaw/freeze cycles. Norbuprenorphine (NBUP) was less unstable; approximately 90% was recovered after 12 weeks of storage at -20°C. The instability was less at 5°C, but the formation of BUP and NBUP from their glucuronides was observed at that temperature, especially in FC-preserved blood. The substances were stable for at least 5 months when stored uninterrupted at -80°C. The instability of BUP and NBUP in FC- and FX-preserved whole blood stored at -20°C was eliminated when the samples were modified with 30 mM ascorbic acid (ASC) prior to storage. The mean recoveries were greater than 95% after a 5-month interrupted storage period at -20°C when modified with ASC.

In situ synthesis of rhodium nanoparticles - Mesoporous carbon hybrid via a novel and facile nanocasting method for simultaneous determination of morphine and buprenorphine.

An in situ and facile nanocasting procedure has been developed to embed Rhodium nanoparticles (RhNPs) in mesoporous carbon (MC) matrix via carbonizing ß-Cyclodextrin capped RhNPs (ß-CDs@RhNPs) as a source of both carbon and metal, in the presence of SBA-15 as hard template. Firstly, ß-CDs was used to coat and stabilize the RhNPs, and then coated RhNPs was applied as carbon source during the carbonization step. In this way, biocompatible materials are used as much as possible. The transmission electron microscopy, field emission scanning electron microscopy, Fourier transform infrared, BET surface area and X-ray diffraction devices were used to characterize the nanomaterials. The nanocomposite (RhNPs-MC) was casted on the glassy carbon electrode (GCE) to fabricate an electrochemical sensor (RhNPs-MC/GCE). This sensor shows high efficiency toward simultaneous determination of Morphine (Mp) and Buprenorphine (Bp), electrochemically, what other modified electrodes cannot do. For Mp, the linear range and limit of detection were obtained 0.1-20 µM and 40 nM, respectively, and these data were obtained about 0.1-14 µM and 45 nM for Bp determination. Less steps of synthesis, biocompatibility and facility are the major advantages of the process, and some benefits of the sensor are its separate signals, fast response time, sensitivity, and simple use without need for pretreatment.

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals.

Buprenorphine is absorbed following sublingual administration, which would be a low-stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3-period, 5-sequence, 3-treatment crossover prospective study. Foals received 0.01-0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half-life (t1/2ß 1.95 ± 0.7 hr), large volume of distribution (6.46 ± 1.54 L/kg), and a high total clearance (55.83 ± 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 ± 0.11 ng/ml and bioavailability was 25.1% ± 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur.

The pharmacokinetics and analgesic effects of extended-release buprenorphine administered subcutaneously in healthy dogs.

Buprenorphine is a partial µ agonist opioid used for analgesia in dogs. An extended-release formulation (ER-buprenorphine) has been shown to provide effective analgesia for 72 hr in rats and mice. Six healthy mongrel dogs were enrolled in a randomized, blinded crossover design to describe and compare the pharmacokinetics and pharmacodynamics of ER-buprenorphine administered subcutaneous at 0.2 mg/kg (ER-B) and commercially available buprenorphine for injection intravenously at 0.02 mg/kg (IV-B). After drug administration, serial blood samples were collected to measure plasma buprenorphine concentrations using liquid chromatography/mass spectrometry detection. Heart rate, respiratory rate, body temperature, sedation score, and thermal threshold latency were recorded throughout the study. Median (range) terminal half-life, time to maximum concentration, and maximum plasma concentration of ER-buprenorphine were 12.74 hr (10.43-18.84 hr), 8 hr (4-36 hr), and 5.00 ng/ml (4.29-10.98 ng/ml), respectively. Mild bradycardia, hypothermia, and inappetence were noted in both groups. Thermal threshold latency was significantly prolonged compared to baseline up to 12 hr and up to 72 hr in IV-B and ER-B, respectively. These results showed that ER-buprenorphine administered at a dose of 0.2 mg/kg resulted in prolonged and sustained plasma concentrations and antinociceptive effects up to 72 hr after drug administration.

The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome.

Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety. The time to NAS stabilization was found to decrease with increasing buprenorphine exposure. This pharmacokinetic-pharmacodynamic (PK-PD) relationship was able to be quantified and adequately described with a mathematical model. The findings confirm a previous PK model of buprenorphine and extend the model to describe the PK of norbuprenorphine and to identify a novel PK-PD relationship of buprenorphine in NAS. This model will allow optimization of dosing strategies in future clinical trials.

Norbuprenorphine and respiratory depression: Exploratory analyses with new lyophilized buprenorphine and sublingual buprenorphine
.

OBJECTIVES: To investigate plasma levels of buprenorphine and norbuprenorphine and their relationship to respiratory depression. MATERIALS AND METHODS: Opioid-dependent subjects were randomized 2 : 1 to novel lyophilized rapid-disintegrating tablet ("bup-lyo") or standard sublingual buprenorphine tablet ("bup-SL"). Measurements included oximetry scores and linked plasma buprenorphine and norbuprenorphine levels. RESULTS: Respiratory depression (cumulative duration of SpO2 < 90% over 30-minute periods) increased with corresponding exposure levels (AUC30 min) of buprenorphine and particularly with norbuprenorphine. A lower buprenorphine/norbuprenorphine ratio was predictive of respiratory depression. The mean (SD) observed ratio was significantly higher for "bup-lyo" (3.4 (2.8)) compared to "bup-SL" (1.7 (0.77)), p < 0.0001. CONCLUSION: Exploratory investigation found respiratory depression more strongly associated with norbuprenorphine than with buprenorphine. This accords with animal studies.
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Converting from Transdermal to Buccal Formulations of Buprenorphine: A Pharmacokinetic Meta-Model Simulation in Healthy Volunteers.

Objective: To develop a model to predict buprenorphine plasma concentrations during transition from transdermal to buccal administration. Design: Population pharmacokinetic model-based meta-analysis of published data. Methods: A model-based meta-analysis of available buprenorphine pharmacokinetic data in healthy adults, extracted as aggregate (mean) data from published literature, was performed to explore potential conversion from transdermal to buccal buprenorphine. The time course of mean buprenorphine plasma concentrations following application of transdermal patch or buccal film was digitized from available literature, and a meta-model was developed using specific pharmacokinetic parameters (e.g., absorption rate, apparent clearance, and volumes of distribution) derived from analysis of pharmacokinetic data for intravenously, transdermally, and buccally administered buprenorphine. Results: Data from six studies were included in this analysis. The final transdermal absorption model employed a zero-order input rate that was scaled to reflect a nominal patch delivery rate and time after patch application (with decline in rate over time). The transdermal absorption rate constant became zero following patch removal. Buccal absorption was a first-order process with a time lag and bioavailability term. Simulations of conversion from transdermal 20 mcg/h and 10 mcg/h to buccal administration suggest that transition can be made rapidly (beginning 12 hours after patch removal) using the recommended buccal formulation titration increments (75-150 mcg) and schedule (every four days) described in the product labeling. Conclusions: Computer modeling and simulations using a meta-model built from data extracted from publications suggest that rapid and straightforward conversion from transdermal to buccal buprenorphine is feasible.