Sublingual Buprenorphine Research Articles

Perioperative management of opioid-tolerant patients

### Key points The assessment and treatment of opioid-tolerant patients in the perioperative and postoperative period can be challenging. Acute pain management can often be inadequate due to a number of factors. Compared with opioid-naive patients, opioid-tolerant patients will typically generate a greater workload for medical and nursing staff. Opioid tolerant patients express higher rest and dynamic pain scores, and two to three times greater opioid use via patient-controlled analgesia (PCA). They require more frequent consultations and prescription alterations.1 Medical and nursing staff may be unaccustomed to managing such patients and may be apprehensive in prescribing or administering large doses of opioids because of a fear of causing harm. Under-treatment of pain may result in opioid-seeking behaviour with the patient perceived as ‘manipulative’ and ‘non-cooperative’. This can have a negative impact on the doctor–patient relationship and overall patient care. Therefore the pain management plan for opioid tolerant patients requires careful consideration in the perioperative period in order to (i) prevent opioid withdrawal, (ii) provide effective analgesia, and (iii) to ensure continuity of care in the community after discharge from hospital. This review considers the various strategies that can be used in such settings. Opioids are prescribed to treat pain from a variety of causes, including chronic non-cancer pain, cancer pain, acute pain, and as substitution therapy in …

Randomised Comparison of a Novel Buprenorphine Oral Lyophilisate versus Existing Buprenorphine Sublingual Tablets in Opioid-Dependent Patients: A First-in-Patient Phase II Randomised Open Label Safety Study

Aims: To test the safety of new buprenorphine oral lyophilisate wafer (“bup-lyo”) versus standard sub-lingual buprenorphine (“bup-SL”). Design: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over. Settings: Specialised clinical trials facility and addictions treatment facility. Participants: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds). Measurements: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11). Findings: Oral lyophilised buprenorphine (“bup-lyo”) completely dissolved within 2 min for 58 vs. 5% for “bup-SL.” Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of “hold,” respiratory function. No serious adverse events (AEs), nor “severe” AEs, although more AEs and Treatment-Emergent AEs with “bup-lyo” (mostly “mild”). PK found greater bioavailability of buprenorphine with “bup-lyo” (but not norbuprenorphine). Conclusions: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with “bup-lyo” relative to “bup-SL.” In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing.

Inhibition of glucuronidation and oxidative metabolism of buprenorphine using GRAS compounds or dietary constituents/supplements: in vitro proof of concept.

The present study investigated the potential of generally recognized as safe (GRAS) compounds or dietary substances to inhibit the presystemic metabolism of buprenorphine and to increase its oral bioavailability. Using IVIVE, buprenorphine extraction ratios in intestine and liver were predicted as 96% and 71%, respectively. In addition, the relative fraction of buprenorphine metabolized by oxidation and glucuronidation in these two organs was estimated using pooled human intestinal and liver microsomes. In both organs, oxidation appeared to be the major metabolic pathway with a 6 and 4 fold higher intrinsic clearance than glucuronidation in intestine and liver, respectively. The oral bioavailability of buprenorphine was predicted to be 1.16%. Inhibition of 75% and 50% of intestinal and hepatic presystemic metabolism would result in an Foral of 49%, which is comparable to the bioavailability of sublingual buprenorphine. In human liver microsomes, chrysin, curcumin, ginger extract, hesperitin, magnolol, quercetin and silybin inhibited ≥50% glucuronidation, whereas chrysin, curcumin, ginger extract, 6-gingerol, pterostilbene, resveratrol and silybin exhibited ≥30% inhibition of oxidation. In human intestinal microsomes, curcumin, ginger extract, α-mangostin, quercetin and silybin inhibited ≥50% glucuronidation while chrysin, ginger extract, α-mangostin, pterostilbene and resveratrol exhibited ≥30% inhibition of oxidation. These results demonstrate the feasibility of our proposed approach of using GRAS or dietary compounds to inhibit the presystemic metabolism of buprenorphine and thus improve its oral bioavailability. An oral buprenorphine formulation containing these inhibitors or their combinations has promising potential to replace sublingual buprenorphine. Copyright © 2016 John Wiley & Sons, Ltd.

Long-Term Buprenorphine Implants for Treatment of Opioid Dependence: Safety Outcomes from Two Open-Label Extension Trials

Objective: To assess long-term exposure to buprenorphine implants (BIs) for opioid dependence in two open-label extension clinical trials. Methods: Two six-month, open-label, multicenter extension studies of BI (Clinicaltrials.gov NCT01262261, NCT00630201) conducted with opioid-dependent adult participants who had completed 24 weeks of BI treatment in prior phase 3 trials. Subjects received four subdermal implants, each containing 80 mg buprenorphine hydrochloride. Supplemental sublingual buprenorphine or insertion of a fifth implant were available for patients meeting criteria for opioid craving or withdrawal at investigator discretion. Safety of BI was evaluated using adverse events (AEs), abnormalities in physical exams, and vital signs. Additional outcomes included plasma concentrations of buprenorphine, ratings of opioid withdrawal symptoms, and craving and treatment retention. Results: A total of 62/88 and 85/163 eligible participants continued in Study 1 and Study 2, respectively. Patient retention rates were 74.2% (46/62) and 78.8% (67/85) in Study 1 and 2, respectively. In Study 1, 47/62 participants (75.8%) experienced 329 treatment-emergent AEs; in Study 2, 57/85 participants (67.1%) experienced 172 AEs. Modifications to the implantation procedure between Study 1 and Study 2 resulted in a numerical decrease in AEs. Of these AEs, 103/329 (31.3%) in Study 1 were implant site-related; 19/57 (11.0%) in Study 2 were implant site-related. Mean concentrations of buprenorphine were stable from weeks 4 to 24, and cravings and withdrawal were well controlled.

Probuphine® (buprenorphine implant): a promising candidate in opioid dependence.

Opioid dependence leads to physical dependence and addiction which finally results in profound medical, psychological and social dysfunction. One of the useful medications for opioid dependence is buprenorphine, the partial opioid agonist, which is used alone or in combination with naloxone. However, buprenorphine is the victim of its own success due to its illicit use and accidental poisoning in children. Also, buprenorphine typically requires daily self-administration and its effectiveness heavily depends on patient adherence. So, poor treatment adherence results in ineffective treatment manifesting as craving and withdrawal symptoms. Short-term use of buprenorphine in opioid dependence is also often followed by relapse. Buprenorphine when used sublingually often results in inadequate or fluctuating blood concentrations and poorer treatment retention compared with methadone. All of these led to the development of Probuphine®, a polymeric matrix composed of ethylene vinyl acetate and buprenorphine in the form of implants, that are implanted subdermally in office practice and deliver the active drug over 6 months. Buprenorphine release from such implant is fairly consistent, avoiding plasma peaks and troughs, and the implant is also reported to be safe. In this review article, we have highlighted these aspects of treatment of opioid addiction, stressing on the pharmacology of buprenorphine and Probuphine®, and relevant clinical trials addressing the efficacy and safety of Probuphine®. This sustained-release implantable formulation of buprenorphine has the potential to be a suitable alternative to daily or alternate day sublingual buprenorphine which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations, and allowing these patients to reduce clinic or pharmacy visits.

Acute Urinary Retention Related with Sublingual Buprenorphine Administration

Acute Urinary Retention Related with Sublingual Buprenorphine Administration

Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects.

Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first‐pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four‐session paired cross‐over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6‐mg (placebo phase) or 0.8‐mg (rifampicin phase) buprenorphine sublingually on day 7. In the second part of the study, subjects received 0.4‐mg buprenorphine intravenously. Plasma concentrations of buprenorphine and urine concentrations of buprenorphine and its primary metabolite norbuprenorphine were measured over 18 h. Adverse effects were recorded. Rifampicin decreased the mean area under the dose‐corrected plasma concentration–time curve (AUC 0–18) of sublingual buprenorphine by 25% (geometric mean ratio (GMR): 0.75; 90% confidence interval (CI) of GMR: 0.60, 0.93) and tended to decrease the bioavailability of sublingual buprenorphine, from 22% to 16% (P = 0.31). Plasma concentrations of intravenously administered buprenorphine were not influenced by rifampicin. The amount of norbuprenorphine excreted in the urine was decreased by 65% (P < 0.001) and 52% (P < 0.001) after sublingual and intravenous administration, respectively, by rifampicin. Adverse effects were frequent. Rifampicin decreases the exposure to sublingual but not intravenous buprenorphine. This can be mainly explained by an enhancement of CYP3A‐mediated first‐pass metabolism, which sublingual buprenorphine only partially bypasses. Concomitant use of rifampicin and low‐dose sublingual buprenorphine may compromise the analgesic effect of buprenorphine.

Dose-adjusted plasma concentrations of sublingual buprenorphine are lower during than after pregnancy

Buprenorphine is a Food and Drug Administration-approved maintenance therapy for opioid use disorders and is increasingly being used in pregnant women with opioid use disorders as an alternative to methadone. Dosing of buprenorphine in pregnant women is based on the regimen recommended for nonpregnant females and males. Limited data are available defining the pharmacokinetic properties of sublingual buprenorphine administered during pregnancy. This study evaluated the impact of physiological changes associated with pregnancy on the pharmacokinetics of sublingual buprenorphine during and after pregnancy. Pregnant women (n= 13), between 180/7 and 376/7 weeks' singleton gestation, receiving sublingual buprenorphine twice daily for opioid use disorders were studied. Pharmacokinetic-2 studies were performed between 18 and 25 weeks (n= 7), pharmacokinetic-3 studies were performed between 31 and 37 weeks (n= 11), and pharmacokinetic-P was performed 4-18 weeks postpartum (n= 10). On the day of the study, blood was withdrawn prior to the daily morning dose of buprenorphine and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours after the dose. Buprenorphine plasma concentrations were analyzed by liquid chromatography tandem mass spectrometric detection. All pharmacokinetic parameters were observed or estimated using Microsoft Excel. Statistical analyses were performed to identify significant changes in study participants' buprenorphine pharmacokinetic parameter estimates over the duration of the study. Univariate linear and generalized linear mixed models were used to investigate changes in these measures over time, some of which were log transformed for normality. Dose-normalized (plasma concentration per dose) buprenorphine plasma concentrations were significantly lower during pregnancy (pharmacokinetic-2 plus pharmacokinetic-3) than during the postpartum period (pharmacokinetic-P). Specific pharmacokinetic parameters (and level of significance) were as follows: the area under the buprenorphine plasma concentration-time curves (P < .003), maximum buprenorphine concentrations (P < .018), buprenorphine concentrations at 0 hour (P < .002), and buprenorphine concentrations at 12 hours (P < .001). None of these parameters differed significantly during pregnancy (ie, pharmacokinetic-2 vs pharmacokinetic-3). The time to maximum buprenorphine concentrations did not differ significantly between groups. The dose-normalized plasma concentrations during a dosing interval and the overall exposure of buprenorphine (area under the buprenorphine plasma concentration-time curves) are lower throughout pregnancy compared with the postpartum period. This indicates an increase in apparent clearance of buprenorphine during pregnancy. These data suggest that pregnant women may need a higher dose of sublingual buprenorphine compared with postpartum individuals. The dose of buprenorphine should be assessed after delivery to maintain similar buprenorphine exposure during the postpartum period.

Puffy hand syndrome

A 45-year-old man presented to the rheumatology outpatient unit with bilateral swelling of the hands from the proximal segments of the fi ngers to the wrist that developed gradually over the past 3 years (fi gure). The oedema was non-pitting and was not aff ected by raising the hands. Function of the hands and fi ngers was not impaired. He had no generalised or pretibial oedema. The patient reported drinking 1–1·5 L of wine per day; medical history was otherwise unremarkable. Blood tests and an ultrasound scan confi rmed hepatitis (alanine aminotransferase [ALT] 175 IU/L, aspartate amino transferase [AST] 170 IU/L, albumin 4·68 mg/dL) with a positive antibody test for hepatitis C virus; hepatitis B virus and HIV tests were negative. Rheumatoid factor was 29 IU/mL (normal <14 IU/mL); anti-nuclear antibodies, anticitrullinated peptide antibodies, complement, protein electrophoresis, and total bilirubin were normal. On further questioning he admitted that he had been injecting high-dose sublingual buprenorphine for more than 5 years, preferentially in the wrist either into or around the veins, three to four times a day. Puff y hand syndrome is a complication of intravenous drug misuse. Users themselves are often aware of the risk, particularly from hand injections, but most physicians, including addiction specialists and general practitioners, rarely encounter this presentation and might not be familiar with it. The frequency of puff y hand syndrome is unknown. The pathogenesis of the oedema probably includes venous and lymphatic insuffi ciency, and the direct toxicity of injected drugs. Biopsy samples of skin and subcutaneous tissue and lymphangiograms can show destruction of the lymphatics that leads to fi brosis of the subcutaneous tissue, probably due to soluble compounds of the drugs that damage lymphatic vessels. Treatment with lowstretch bandaging and the wearing of elastic garments help to decrease the volume in puff y hand syndrome.

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.

Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine

The effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion. To determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence. Outpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study conducted at 21 US sites from June 26, 2014, through May 18, 2015. Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician. Participants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks). The primary end point was between-group difference in proportion of responders (≥4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). The noninferiority established for the lower bound of the 95% confidence interval was greater than -0.20 (P < .025). Secondary end points included cumulative percentage of negative opioid urine results, abstinence, and time to first illicit opioid use. Safety was assessed by adverse event reporting. Of 177 participants (mean age, 39 years; 40.9% female), 90 were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ∞; P < .001 for noninferiority). Over 6 months, 72 of 84 (85.7%) receiving buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95% CI, 0.018-0.258; P = .03). Non-implant-related and implant-related adverse events occurred in 48.3% and 23% of the buprenorphine implant group and in 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively. Among adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine, the use of buprenorphine implants compared with continued sublingual buprenorphine did not result in an inferior likelihood of remaining a responder. However, the study population had an exceptionally high response rate in the control group, and further studies are needed in broader populations to assess the efficacy in other settings. clinicaltrials.gov Identifier: NCT02180659.

Observational Evidence for Buprenorphine's Impact on Posttraumatic Stress Symptoms in Veterans With Chronic Pain and Opioid Use Disorder.

Posttraumatic stress disorder (PTSD), chronic pain, and substance use disorders are prevalent co-occurring conditions that are challenging to treat individually, and there is no evidence-based treatment for all 3. Buprenorphine, used to treat opioid use disorder and chronic pain, is a partial nociceptin opioid receptor agonist. In preclinical studies, a nociceptin opioid receptor agonist was shown to mitigate PTSD symptoms in acute trauma. We compared buprenorphine to other opioid medications in its impact on PTSD symptoms in patients with chronic pain and opioid and/or other substance use disorders. We assembled a retrospective cohort of 382 Iraq and Afghanistan veterans in US Department of Veterans Affairs health care from October 1, 2007, to July 29, 2013, with ICD-9-CM diagnoses of PTSD, chronic pain, and substance use disorders. We used time-varying general estimating equation models to assess the primary outcome, which was change in PTSD symptoms (measured using the PTSD Checklist and the Primary Care PTSD Screen) among veterans initiated on sublingual buprenorphine versus those maintained on moderately high-dose opioid therapy. Twice as many veterans in the buprenorphine group (23.7%) compared to those in the opioid therapy group (11.7%) experienced improvement in PTSD symptoms (P = .001). Compared to veterans in the opioid therapy group, veterans receiving buprenorphine showed significant improvement in PTSD symptoms after 8 months, with increasing improvement up to 24 months (incidence rate ratio = 1.79; 95% CI, 1.16-2.77; P = .009). There were no differences in the longitudinal course of pain ratings between groups. This observational study is the first to report an incidental effect of buprenorphine compared to opioid therapy in improving PTSD symptoms in veterans.

Injection of Pharmaceuticals Designed for Oral Use: Harms Experienced and Effective Harm Reduction Through Filtration.

Several pharmaceutical products are liable to 'abuse' or use outside their prescription, which frequently involves their injection. Examples are slow-release forms of morphine and oxycodone, and sublingual buprenorphine. During injection preparation, the drug is extracted into water, after crushing and heating the tablet if considered necessary. Since these products are designed for oral administration, they can contain excipients (ingredients other than the drug) which are poorly soluble, resulting in suspension of particles in the injection solution. Injected particles are able to produce medical complications such as the blockage of small blood vessels leading to ischaemia (inadequate blood flow) and tissue damage. Filtration can be used to remove particles from the suspension; including bacteria if the porosity is small enough (0.2μm). However, filters are liable to blockage when overloaded, especially if the pore size is small. This problem can be minimised by using a larger pore size (e.g. 5-10μm), but the resulting filtrate will contain many residual small particles. The use of two filters, coarse and fine, either sequentially or in a double membrane device, enables removal of the majority of particles as well as bacteria, although not quite meeting pharmaceutical standards for safe injection. Although not yet evaluated by a clinical trial, this highly effective filtration process would be expected to greatly reduce the risk of vascular and related complications, as well as non-viral infections. Careful technique ensures that drug is not lost by filtration, a priority for most drug consumers. Practical issues that affect acceptability of filtration by injecting drug users, including ease of use and cost, will need to be considered. However, given the laboratory evidence demonstrating the effectiveness of filters it is time to consider these tools as essential for safe injection as sterile needles/syringes for the world's approximately 16 million people who inject drugs.

Acute Urinary Retention Related with Sublingual Buprenorphine Administration

Acute Urinary Retention Related with Sublingual Buprenorphine Administration

A Single Dose of 55 mg of Buprenorphine for the Treatment of Heroin Dependence: A New Result

Background: Heroin abuse is a growing problem. Objective: To assess the efficacy of a single dose of 55 mg of sublingual buprenorphine in the treatment of heroin dependence. Result: Administration of 55 mg of buprenorphine as a single dose is very helpful in the treatment of heroin dependence. Discussion: The present study clarifies that one dosage of 55 mg of buprenorphine is outstanding for the treatment of heroin dependence. This is a fascinating finding. Conclusion: We concluded that a single dose of sufficient buprenorphine could treat heroin withdrawal symptoms. This finding is a substantial addition to the literature.

Quick Opium Detoxification With 100 mg of Buprenorphine

Background: Dependency to opium is a worldwide problem. Objective: To merit the competency of a single high dose of buprenorphine in opium detoxification. Results: Administration of 100 mg of buprenorphine as a single dose is very effective in the opium detoxification. Discussion: Our study suggests that administration of 100 mg of sublingual buprenorphine as a high single dose is quite practical in opium detoxification. Hence, this experience could be a factual addition to the literature. Conclusions: We infer that a single high dose of buprenorphine efficaciously treats opium withdrawal symptoms.

Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial.

Suicidal ideation and behavior currently have no quick-acting pharmacological treatments that are suitable for independent outpatient use. Suicidality is linked to mental pain, which is modulated by the separation distress system through endogenous opioids. The authors tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation. This was a multisite randomized double-blind placebo-controlled trial of ultra-low-dose sublingual buprenorphine as an adjunctive treatment. Severely suicidal patients without substance abuse were randomly assigned to receive either buprenorphine or placebo (in a 2:1 ratio), in addition to their ongoing individual treatments. The primary outcome measure was change in suicidal ideation, as assessed by the Beck Suicide Ideation Scale at the end of each of 4 weeks of treatment. Patients who received ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; N=40) had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference -4.3, 95% CI=-8.5, -0.2) and after 4 weeks (mean difference=-7.1, 95% CI=-12.0, -2.3). Concurrent use of antidepressants and a diagnosis of borderline personality disorder did not affect the response to buprenorphine. No withdrawal symptoms were reported after treatment discontinuation at the end of the trial. The time-limited, short-term use of very low dosages of sublingual buprenorphine was associated with decreased suicidal ideation in severely suicidal patients without substance abuse. Further research is needed to establish the efficacy, safety, dosing, and appropriate patient populations for this experimental treatment.

Simultaneous determination of buprenorphine, norbuprenorphine and naloxone in human plasma by liquid chromatography/tandem mass spectrometry

A simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC–ESI-MS/MS) method was developed and validated for simultaneous quantification of naloxone, buprenorphine and its metabolite norbuprenorphine in human plasma. Human plasma samples were extracted using a single step liquid–liquid extraction, and then separated on an Imtakt Unison UK-C18 column (2.1×50mm, 3μm) using alkaline mobile phases with gradient elution. All of the analytes were detected in positive ion mode using multiple reaction monitoring (MRM). The method was validated and the specificity, linearity, lower limit of quantitation, precision, accuracy, recoveries and stability were determined. The linear range was 20–10000pg/mL for buprenorphine and norbuprenorphine; and 1–500pg/mL for naloxone. The correlation coefficient (R2) values for all three analytes were ≥0.995. The precision and accuracy for intra-day and inter-day were <11.0%. The recoveries were >63% and matrix effects were tracked by the deuterated internal standards (IS) with the IS-normalized matrix factor ranging from 0.96 to 1.33 for all three analytes. The validated method was successfully applied in a clinical pharmacokinetic study with low dose administration of sublingual buprenorphine and naloxone.

A Cohort Comparison of Buprenorphine versus Methadone Treatment for Neonatal Abstinence Syndrome

To compare the duration of opioid treatment and length of stay among infants treated for neonatal abstinence syndrome (NAS) by using a pilot buprenorphine vs conventional methadone treatment protocol. This retrospective cohort analysis evaluated infants who received pharmacotherapy for NAS at 6 hospitals in Southwest Ohio from January 2012 through August 2014. A single neonatology provider group used a standardized methadone protocol across all 6 hospitals. However, at one of the sites, infants were managed with a buprenorphine protocol unless they had experienced chronic in utero exposure to methadone. Linear mixed models were used to calculate adjusted mean duration of opioid treatment and length of inpatient hospitalization with 95% CIs in infants treated with oral methadone compared with sublingual buprenorphine. The use of adjunct therapy was examined as a secondary outcome. A total of 201 infants with NAS were treated with either buprenorphine (n = 38) or methadone (n = 163) after intrauterine exposure to short-acting opioids or buprenorphine. Buprenorphine therapy was associated with a shorter course of opioid treatment of 9.4 (CI 7.1-11.7) vs 14.0 (12.6-15.4) days (P < .001) and decreased hospital stay of 16.3 (13.7-18.9) vs 20.7 (19.1-22.2) days (P < .001) compared with methadone therapy. No difference was detected in the use of adjunct therapy (23.7% vs 25.8%, P = .79) between treatment groups. The choice of pharmacotherapeutic agent is an important determinant of hospital outcomes in infants with NAS. Sublingual buprenorphine may be superior to methadone for management of NAS in infants with select intrauterine opioid exposures.

Comparison of Intravenous Morphine with Sublingual Buprenorphine in Management of Postoperative Pain after Closed Reduction Orthopedic Surgery.

Postoperative pain is a common side effect following surgery that can significantly reduce surgical quality and patient's satisfaction. Treatment options are morphine and buprenorphine. We aimed to compare the efficacy of a single dose of intravenous morphine with sublingual buprenorphine in postoperative pain control following closed reduction surgery. This triple blind clinical trial was conducted on 90 patients referred for closed reduction orthopedic surgery. They were older than 18 years and in classes I and II of the American Society of Anesthesiologists (ASA) with an operation time of 30-90 minutes. Patients were divided into two groups of buprenorphine (4.5µg/kg sublingually) and morphine (0.2mg/kg intravenously). Baseline characteristics, vital signs, pain score, level of sedation and pharmacological side effects were recorded in the recovery room (at 0 and 30 minutes), and in the ward (at 3, 6 and 12 hours). SPSS version 19 software was used for data analysis and the significance level was set at P<0.05. Ninety patients were studied, 60 males and 30 females with a mean age of 37.7±16.2 years. There was no significant difference between the two groups in terms of baseline characteristics. Pain score in the morphine group was significantly higher than the buprenorphine group with an average score of 2.5 (P<0.001). Postoperative mean heart rate in the buprenorphine group was four beats lower than the morphine group (P<0.001). Also, in the buprenorphine 48.6% and in the morphine group 86.7% of cases were conscious in recovery (P=0.001) with a higher rate of pruritus in the latter group (P=0.001). Sublingual buprenorphine administration before anesthesia induction in closed reduction surgery can lead to better postoperative pain control in comparison to intravenous morphine. Due to simple usage and longer postoperative sedation, sublingual buprenorphine is recommended as a suitable drug in closed reduction surgery.