A sensitive, simple and rapid HPLC–MS/MS method for simultaneous quantification of buprenorpine and its N-dealkylated metabolite norbuprenorphine in human plasma

A sensitive, simple and rapid high performance liquid chromatography-tandem mass spectrometry （HPLC-MS/MS） method was developed and fully validated for the simultaneous quantification of buprenorphine （BUP） and its N-dealkylated metabolite norbuprenorphine （NBUP） in 200 μL human plasma. Human plasma samples were prepared using liquid-liquid extraction, and then separated on a Shiseido MG C18 （5 μm, 2.0 mm × 50 mm） via 4.1 min gradient elution. Following electrospray ionization, the analytes were quantified on a triple-quadrupole mass spectrometer in multiple-reaction-monitoring （MRM） positive ion mode. Linearity was achieved from 25.0 to 10000 pg/mL for buprenorphine, from 20.0 to 8000 pg/mL for norbupre- norphine with r2〉0.99. The method was demonstrated with acceptable accuracy, precision and specificity for the detection of buprenorphine and norbuprenorphine. Recovery was 81.8-88.8 % for buprenorphine and 77.0-84.6% for norbuprenorphine, and the matrix effect was 95.6-97.4% for buprenorphine and 94.0-96.9% for norbuprenorphine; all were not concentration dependent. With validated matrix and autosampler stability data, this method was successfully applied in a bioequivalence study to support abbreviated new drug application.

Recent advances in the treatment of opioid use disorders–focus on long-acting buprenorphine formulations

Oral methadone or sublingual buprenorphine are first-line medications for pharmacotherapy of opioid use disorders(OUDs).Three long-acting buprenorphine depot or implant formulations are currently available for the treatment of OUDs:(1)CAM 2038(Buvidal)for subcutaneous weekly and monthly application;(2)RBP-6000(Sublocade^(TM))as a monthly depot formulation;and(3)A six-month buprenorphine implant[Probuphine^(TM)].The pharmacology,clinical efficacy and prospects of these medications are discussed.

Lipid bound extended release buprenorphine(high and low doses)and sustained release buprenorphine effectively attenuate post-operative hypersensitivity in an incisional pain model in mice(Mus musculus)

Background:Extended-release buprenorphine(XR)is indicated for pain management in rodents,but little is known about its use in mice.This study aimed to investigate whether high dose XR effectively attenuates post-operative hypersensitivity better than low dose XR in a mouse model of incisional pain.Methods:Mice(n 44)were randomly assigned to 1 of 4 treatment groups:(a)saline(1 ml/kg SC,once);(b)sustained release buprenorphine(Bup-SR,1 mg/kg SC,once);(c)low dose extended-release buprenorphine(XR-lo,3.25 mg/kg SC,once);(d)high dose extended-release buprenorphine(XR-hi,6.5 mg/kg SC,once).On days1,0(4 hours),1,2,and 3,mechanical and thermal hypersensitivities were evaluated,and plasma buprenorphine concentrations were measured.Results:Mechanical(days 0-2)and thermal(days 0-1)hypersensitivities were ob-served in the saline group.Bup-SR,XR-lo,and XR-hi attenuated mechanical hyper-sensitivity on days 0,1,and 2.None of the treatment groups,except XR-Lo on day 0,attenuated thermal hypersensitivity on days 0 or 1.Plasma buprenorphine concen-tration peaked at 4 hours(day 0)in all treatment groups and remained greater than 1 ng/mL on days 0-2.No abnormal clinical observations or gross pathologic findings were seen in any groups.Conclusion:The results indicate XR-hi did not effectively attenuate post-operative hypersensitivity better than XR-lo.Thus both 3.25 and 6.5 mg/kg XR are recom-mended for attenuating post-operative hypersensitivity for at least up to 48 hours in mice.

Life after Addiction—Post-Operative Pain Management in an Obstetrical Patient on Long-Term Buprenorphine Therapy

A G6P2032 female, prior cesarean x3 with history of opioid addiction maintained on buprenorphine presented for scheduled repeat cesarean section. Pre-operatively, her maintenance dose of medication was held secondary to concerns for partial agonist effect. Post-operative pain control was suboptimal with the patient ultimately proceeding to withdrawal. Doses of hydromorphone were titrated to 10 mg every 3 hours to avoid further withdrawal. Review of expert opinion after discharge recommended against holding buprenorphine therapy in the post-operative period. Pain management options include maintenance therapy with additional doses of opioid and non-opioid pain relieving medications.

Effect of buprenorphine transdermal patch combined with patient-controlled intravenous analgesia on the serum pain-related biochemical indexes in elderly patients with intertrochanteric fracture

Objective:To study the effect of buprenorphine transdermal patch combined with patient-controlled intravenous analgesia on the serum pain-related biochemical indexes in elderly patients with intertrochanteric fracture.Methods: A total of 92 elderly patients with intertrochanteric fracture who received surgical treatment in the hospital between August 2014 and January 2017 were collected and divided into control group (n=46) and observation group (n=46) according to the random number table method. The control group received patient-controlled intravenous analgesia, and the observation group received buprenorphine transdermal patch combined with patient-controlled intravenous analgesia. Differences in serum levels of inflammatory factors, oxidative stress indexes and pain mediators of two groups of patients were measured before and 24h after surgery.Results: Differences in serum levels of inflammatory factors, oxidative stress indexes and pain mediators were not statistically significant between the two groups before surgery;24 h after surgery, serum IL-1β, IL-6, IL-8, TNF-α, MDA, SP, PGE2, 5-HT, HA and NPY levels of both groups of patients increased significantly while SOD, TAC and CAT levels decreased significantly, and serum IL-1β, IL-6, IL-8, TNF-α, MDA, SP, PGE2, 5-HT, HA and NPY levels of observation group were lower than those of control group while SOD, TAC and CAT levels were higher than those of control group.Conclusion: Buprenorphine transdermal patch combined with patient-controlled intravenous analgesia can effectively inhibit the expression of pain-related indexes and relieve early postoperative pain intensity in elderly patients with intertrochanteric fracture.

BEMA Buprenorphine治疗慢性疼痛Ⅲ期临床试验获初步成功

2011年9月28日，BioDelivery公司公布了BE-MA Buprenorphine（丁丙诺啡叔丁啡）治疗中度和重度慢性疼痛的Ⅲ期临床研究结果。研究显示，BE—MA Buprenorphine与安慰剂相比在缓解所有疼痛强度上未显现明显的优势，但是其在接受过阿片类药物治疗患者中的疗效与安慰剂有显著的区别（P=0．067）。

Development of a Rapid and Simultaneous Detection Method for Buprenorphine, Norbuprenorphine and Naloxone in Human Plasma Using Ultra-high Performance Liquid Chromatography- tandem Mass Spectrometer with Solid-phase Extraction

A simultaneous method was successfully established and validated for the separation and determination of bu- prenorphine （BP）, its primary metabolite, nor-buprenorphine （NBP） and a proposed co-formulate, naloxone （NLX） in human plasma. The method used buprenorphine-d4 （BP-D4）, nor-buprenorphine-d3 （NBP-D3）, naltrexone （NTX） as internal standards （ISs）. 100 μL of plasma sample fortified with the ISs was cleaned up by solid-phase extraction （SPE）, and was then separated on a Waters AcquityTM BEH C18 column with gradient elution using methanol and water （containing 0.2% formic） at a flow rate of 0.25 mL·min^-1. The mass spectrometer was used for detection and was operated in the positive electrospray ionization with multiple reaction monitoring （MRM） mode. The three compounds were effectively separated in 5 min. The linear ranges of the compounds were 0.1--25, 0.25--25 and 0.05--25 ng·mL^-1 for BP, NBP and NLX, respectively, with r≥0.9935. The method had high sensitivity （the lim- its of detection were 0.02, 0.1 and 0.01 ng.mL-1 for BP, NBP and NLX, respectively） and high recoveries （≥97.6%）. The result was shown to be linear and satisfactorily met current acceptance criteria for validation of bio- analytical method： intra and inter assay precisions within the required limits of ≤25% RSD. The LOQs fulfilled the LOQ requirements： precision≤25% RSD, and was fully validated according to the State Food and Drug Administration （SFDA） regulations. The results demonstrated that ultra-high performance liquid chromatography- tandem mass spectrometer （UPLC-MS/MS） with SPE was a powerful detection tool and contributed to pharmaceutical analysis in biological matrices.

Fentanyl and xylazine crisis:Crafting coherent strategies for opioid overdose prevention

The United States is in the throes of a severe opioid overdose epidemic,primarily fueled by the pervasive use of fentanyl and the emerging threat of xylazine,a veterinary sedative often mixed with fentanyl.The high potency and long duration of fentanyl is compounded by the added risks from xylazine,heightening the lethal danger faced by opioid users.Measures such as enhanced surveillance,public awareness campaigns,and the distribution of fentanylxylazine test kits,and naloxone have been undertaken to mitigate this crisis.Fentanyl-related overdose deaths persist despite these efforts,partly due to inconsistent policies across states and resistance towards adopting harm reduction strategies.A multifaceted approach is imperative in effectively combating the opioid overdose epidemic.This approach should include expansion of treatment access,broadening the availability of medications for opioid use disorder,implementation of harm reduction strategies,and enaction of legislative reforms and diminishing stigma associated with opioid use disorder.

Traditional Chinese Medicine-facilitated switch from methadone to buprenorphine-naloxone for treatment of heroin dependence: a case report

The switch from methadone to buprenorphine-naloxone for individuals with heroin dependence is associated with several obstacles and challenges.Such patients may experience discomfort from discontinuing methadone, precipitated withdrawal symptoms induced by buprenorphine-naloxone,and poor psychosocial adjustments such as anticipatory anxiety regarding severe opioid withdrawal.We herein describe a 46-year-old man with a history of heroin dependence who underwent Traditional Chinese Medicine(TCM)-facilitated switching from methadone to buprenorphine-naloxone. No precipitated withdrawal was induced by buprenorphine-naloxone. The drug-switching process was successful and smooth. He maintained abstinence from heroin for the following year. In this case, we applied TCM for enhancement of methadone metabolism and detoxification, analgesic effects, and anxiolytic and hypnotic effects during the drug switch. We observed that TCM effectively facilitated the switch from methadone to buprenorphine-naloxone in our case. Further studies regarding TCM-facilitated treatment for heroin dependence should be conducted.

Effect of thienorphine on intestinal transit and isolated guinea-pig ileum contraction

AIM: To evaluate the effect of thienorphine on small intestinal transit in vivo and on guinea-pig ileum (GPI) contraction in vitro . METHODS: The effects of thienorphine on intestinal transit were examined in mice and in isolated GPI. Buprenorphine and morphine served as controls. The distance traveled by the head of the charchol and the total length of the intestine were measured in vivo . Gastrointestinal transit was expressed as a percentage of the distance traveled by the head of the marker relative to the total length of the small intestine. The isolated GPI preparations were connected to an isotonic force transducer and equilibrated for at least 1 h before exposure to drugs. Acetylcholine was used for muscle stimulation. RESULTS: Thienorphine (0.005-1.0 mg/kg, ig ) or bu-prenorphine (0.005-1.0 mg/kg, sc ) dose-dependently significantly inhibited gut transit compared with saline. Thienorphine inhibited gut transit less than buprenorphine. The maximum inhibition by thienorphine on the intestinal transit was 50%-60%, whereas the maximum inhibition by morphine on gut transit was about 100%. Thienorphine also exhibited less inhibition on acetylcholine-induced contraction of GPI, with a maximum inhibition of 65%, compared with 93% inhibition by buprenorphine and 100% inhibition by morphine. Thienorphine induced a concentration-dependent decrease in the basal tonus of spontaneous movement of the GPI, the effect of which was weaker than that with buprenorphine. The duration of the effect of thienorphine on the GPI was longer than that with buprenorphine. CONCLUSION: Thienorphine had less influence, but a longer duration of action on GPI contraction and moderately inhibited intestinal transit.

Pharmacokinetic-Pharmacodynamic modeling of the analgesic effect of bupredermTM, in mice

Purpose: BupredermTM-Buprenorphine transdermal delivery system (BTDS) was developed for the treatment of post-operative and chronic pains. This study examined the relationship between the plasma concentration of buprenorphine and its analgesic effect (tail flick test) in order to assess the usefulness of pharmacokinetic-pharmacodynamic (PK-PD) modeling in describing this relationship. Methods: After patch application, plasma concentrations of bu- prenorphine in mice were measured for 72 hours with a validated LC/MS/MS system, and the analgesic effects were assessed by tail flick test for the period of 24 hours. A modified two- compartment open model was used to explain the PK properties of BTDS, and the PD model was characterized by slow receptor binding. Results: The peak buprenorphine level in plasma was achieved at 1-24 h and the effective therapeutic drug concentration was maintained for 72 hours. BupredermTM induced prolongation of tail-flick latency in a dose and time dependent manner. Maximum analgesic effect was attained at 3-6 h and was maintained for 24 h after patch application. Counter-clockwise hysteresis between the plasma concentration and the analgesic efficacy of BTDS was observed after BupredermTM application, indicating there was a delay between plasma concentrations and the effect observed. From the developed PK-PD model, Kd values (0.69-0.82 nM) that were derived from the pharmacodynamic parameters (Kon and Koff) are similar to the reported values (Kd = 0.76 ± 0.14 nM). Good agreement between the predicted and observed values was noted for the rate of change in analgesic effect data (R2 = 0.822, 0.852 and 0.774 for 0.24, 0.8 and 2.4 mg/patch, respectively). Conclusions: The established PK- PD model successfully described the relationship between plasma concentration of buprenorphine and its analgesic efficacy measured by the tail flick test. Our model might be useful in estimation and prediction of onset, magnitude and time course of concentration and pharmacological effects of BTDS and will be useful to simulate PK-PD profiles with clinical regimens.

Neonatal opioid exposure:public health crisis and novel neuroinflammatory disease

Substance use,specifically the use of prescription and non-prescription opioids among pregnant women,is a major public health issue and chief contributor to the opioid crisis.The prevalence of Neonatal Opioid Withdrawal Syndrome has risen 5-fold in the past decade,and is a well-recognized consequence of perinatal opioid exposure.By contrast,the long-term damage to the developing brain from opioid medications is just beginning to be recognized as a serious concern.Published data suggest that opioid exposure commencing in utero negatively affects the maturation of the neural-immune system,and trajectory of central nervous system development.Methadone induces peripheral immune hyper-reactivity,lasting structural and microstructural brain injury,and significant deficits in executive function and cognitive control in adult animals following in utero exposure.Thus,to address the cascading public health crisis stemming from the multitude of infants with in utero opioid exposure who will grow up with altered neurodevelopmental trajectories,rigorous preclinical,mechanistic studies are required.Such studies will define the long-term sequelae of prenatal opioid exposure in an effort to develop appropriate and targeted interventions.Specifically,the development of novel fluid,neuroimaging and biobehavioral biomarkers will be the most useful to aid in early identification and treatment of opioid exposed infants with the greatest risk of poor clinical outcomes.These studies will be essential to understand how in utero insults determine brain structure and function in adulthood,and what targeted interventions will be required to improve longterm outcomes in the countless children being born exposed to opioids each year.

Substance use disorders among older adults: A review of randomized controlled pharmacotherapy trials

Substance use disorders(SUDs)are a growing problem among older adults.Acamprosate,disulfiram,and naltrexone are United States Food and Drug Administration(referred to as FDA)approved for the treatment of alcohol use disorder,and buprenorphine is approved for the treatment of opiate use disorder among adults.However,the data on the use of these medications for the treatment of SUDs among older adults are unclear from randomized controlled trials(referred to as RCTs).A review of the literature indicates that there are only two RCTs that evaluated the use of pharmacologic agents for SUDs among older adults(≥50 years).One trial evaluated the use of naltrexone when compared to placebo for the treatment of alcohol use disorder among individuals,50-70 years in age.The other trial evaluated the use of naltrexone or placebo as adjuncts with sertraline in the treatment of alcohol use disorder among individuals older than 55 years in age.Both trials indicated that the use of naltrexone reduced the rates of relapse among older adults with alcohol use disorder.However,we did not identify any RCTs that studied the use of buprenorphine,acamprosate,or disulfiram for SUDs among older adults.Based on available evidence,it would be safe to conclude that limited data indicate some efficacy for naltrexone in the treatment of alcohol use disorder among older adults.However,data from controlled trials on the use of other medications that are FDA approved for the treatment of SUDs among younger adults are nonexistent among older adults with SUDs.

Advancing Service Integration in Opioid Treatment Progams for the Care and Treatment of Hepatitis C Infection

It is estimated that approximately 200 million people globally are infected with the hepatitis C virus and that roughly half of these people live in Asia. Without treatment, it is estimated that roughly twenty percent of those infected with hepatitis C virus progress to chronic liver disease, then subsequently, end-stage liver disease. Thus, access to hepatitis C testing and subsequent care and treatment of chronic hepatitis C infection are essential to address the global burden of disease. In the United States, the Center for Disease Control and Prevention estimates that 60% of new cases of hepatitis infection are due to injection drug use. Opioid Treatment Programs (OTP’s) dispense methadone and buprenorphine under specific federal regulations to injection drug users diagnosed with opioid dependence. OTPs are developing comprehensive care and treatment model programs that integrate general medical and infectious disease-related medical care with substance abuse and mental health services. Integrating hepatitis care services and treatment in the substance abuse treatment settings foster access to care for patients with hepatitis C infection, many who otherwise would not receive needed care and treatment. This may serve as a national model for highly cost-efficient healthcare that has a measurable outcome of improved public health with reduced hepatitis C prevalence.

Long-Term Suboxone Maintenance Therapy for Opioid Use Disorder: 2 Case Reports

The medical profession is divided in its approach to treating patients with addiction issues, particularly in regards to the treatment of opioid use disorder with Suboxone (buprenorphine/naloxone). Here we present two cases of patients who have achieved over 11 years of sobriety with long-term Suboxone maintenance therapy. Their stories help to demonstrate that Suboxone is a viable long-term treatment option for severe opioid addiction. While life-long Suboxone use can lead to physical dependence on the drug, this is far from simply replacing one addiction with another. Some providers may feel that physical dependence on a medication does not represent appropriate or adequate treatment of opioid use disorder;however, when compared with the grave potential consequences of severe opioid use disorder, the potential benefits of achieving sobriety with Suboxone maintenance far outweigh the risks.

Treatment with analgesics after mouse sciatic nerve injury does not alter expression of wound healingassociated genes

Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion（DRG） sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model.