The use of buprenorphine + naloxone sublingual tablet in the treatment of neonatal opioid withdrawal syndrome: Two case reports.

INTRODUCTION: Neonatal opioid withdrawal syndrome occurs after exposure during pregnancies of mothers with an opioid use disorder. If non-pharmacological treatment is insufficient, pharmacological options are preferred, but a common treatment guideline has not yet been determined. Sublingual buprenorphine tablet is more prominent in the treatment. Since oral alternatives are not available in many clinics, as in our unit, parenteral morphine is still the drug of the first choice. In this paper, we reported that two babies with neonatal opioid withdrawal syndrome were successfully treated with a buprenorphine/naloxone combination, which was not previously shown in the literature. CASES: We followed two babies whose mothers had an opioid use disorder during their pregnancies. The modified Finnegan scoring scale was used for the assessment of the babies. Both infants developed persistent seizures with resistant withdrawal signs. An effective parenteral route could not be provided due to hemodynamic instability. Thus, IV morphine could not be used. Due to the lack of oral treatment alternatives, first, we tried phenobarbital up to 40 mg/kg orally. Afterward, we used buprenorphine/naloxone combined tablet sublingually, which has not been used in children before. Detailed written consent was obtained from the parents for the emergency use of this drug in advance. Shortly after this treatment, the seizures and withdrawal signs were controlled. There were no adverse effects and babies were discharged fully recovered. CONCLUSION: Sublingual Buprenorphine 2 mg + Naloxone 0.5 mg (4:1) tablet could be used efficiently and without side effects to treat neonatal opioid withdrawal syndrome.

Randomized clinical trial comparing buprenorphine/naloxone and methadone for the treatment of patients with failed back surgery syndrome and opioid addiction.

Opioid analgesic consumption has led to an unprecedented epidemic of overdose death and opioid addiction in the US history. The treatment of chronic pain in patients with opioid addiction who receive prescriptions for opioid medications presents a clinical dilemma. Continuing opioid medication could result in hyperalgesia rendering opioids ineffective and results in iatrogenic therapeutic damage as evidenced by the worsening of addiction. Discontinuing opioid medications could result in severe pain and cravings that often leads the patient to the illicit market. This study compared methadone and buprenorphine/naloxone in patients with failed back surgery syndrome and opioid addiction. Nineteen participants were randomly assigned to methadone or buprenorphine/naloxone and were followed for 6 months. In an intent-to-treat analysis analgesia, craving, functioning, drug use, depression, and treatment retention were assessed monthly. It was planned to enroll 66 patients with failed back surgery syndrome and opioid addiction; however, enrollment was closed early due to suspected abuse of medications. Patients in both treatment conditions exhibited significantly improved 24-hour pain severity with up to 20% reduction of pain severity at the last follow-up (p < .05). However, patients receiving methadone reported significantly reduced current pain severity, whereas patients receiving buprenorphine/naloxone did not. Patients reported significantly improved functioning, fewer cravings, less opioid use, and depression (p < .05) across the treatment conditions. When given a choice between methadone and buprenorphine/naloxone, buprenorphine/naloxone is recommended due to its superior safety profile. Treatment with either needs to be monitored closely.

Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid-dependent, human immunodeficiency virus seronegative participants.

AIMS: Regional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first-in-class attachment inhibitor that binds HIV-1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R-, S- and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered. METHODS: Study 206216 (NCT02666001) was a Phase I, open-label study, assessing the effect of FTR 600 mg (extended-release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non-HIV-infected participants on stable maintenance therapy with MET (40-120 mg; n = 16) or BUP plus naloxone (8-24 mg plus 2-6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales. RESULTS: Following coadministration with FTR, dose-normalized MET (R-, S- and total) exposures (maximum concentration in plasma, area under the plasma concentration-time curve over the dosing interval and concentration in plasma at 24 hours) increased 9-15% and BUP and norBUP exposures increased 24-39%. The 90% confidence interval ranges for MET (1.01-1.21) and BUP and norBUP (1.03-1.69) were within respective no-effect ranges (0.7-1.43 and 0.5-2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen. CONCLUSIONS: FTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.

Treatment of opioid dependence with buprenorphine/naloxone sublingual tablets: A phase 3 randomized, double-blind, placebo-controlled trial.

INTRODUCTION: The purpose of the study is to evaluate the efficacy and safety of buprenorphine/naloxone sublingual tablets for the treatment of opioid dependence in Chinese adults. METHODS: This multicenter, double-blind, placebo-controlled study included four periods: induction (3-5 days), stabilization (7-21 days), randomization/treatment (6 weeks), and postmedication follow-up (1 week). A total of 442 participants with opioid dependence were enrolled; 260 were randomized to buprenorphine/naloxone or placebo. The primary outcome was retention in treatment, defined as the time from randomization to treatment completion or treatment failure. Secondary outcomes included maximum consecutive days of abstinence from opioids, self-reported craving and opioid withdrawal symptoms, and urine drug screen results. Safety assessments included adverse event reporting, electrocardiograms, clinical laboratory tests, vital signs, and prior/concomitant medications. RESULTS: The median treatment retention time (95% confidence internal) with buprenorphine/naloxone was 32 days (26-38) versus 6 days (5-8) for placebo, with a Cox hazard ratio of 0.28 (95% confidence interval, 0.21-0.38; P < 0.0001). The median maximum consecutive days of abstinence (95% confidence interval) was: buprenorphine/naloxone, 21 days (26-38); placebo, 5 days (5-8) with a Cox hazard ratio of 0.38 (95% confidence interval, 0.25-0.60; P < 0.0001). Withdrawal and craving symptoms were significantly milder with buprenorphine/naloxone versus placebo (P < 0.001). Urine drug screen results indicated significantly lower opioid usage in the buprenorphine/naloxone group compared with placebo (P < 0.001). The most commonly reported adverse events in the buprenorphine/naloxone group during treatment were aspartate aminotransferase increased and nasopharyngitis. DISCUSSION: Efficacy and safety results from this clinical trial support a positive benefit-risk ratio for buprenorphine/naloxone sublingual tablet use in the treatment of an opioid-dependent Chinese population.

Buprenorphine/Naloxone (Zubsolv®): A Review in Opioid Dependence.

A new sublingual buprenorphine/naloxone tablet (hereafter referred to as buprenorphine/naloxone; Zubsolv®), combining a long-acting partial µ receptor agonist and an opioid antagonist, is approved for the treatment of opioid dependence in adults and adolescents aged > 15 years. This formulation has a higher bioavailability, better taste and faster sublingual dissolve time than a reference sublingual buprenorphine/naloxone tablet (Suboxone®), advantages that provide greater patient preference (potentially improving adherence) and importantly may reduce the risk of buprenorphine parenteral abuse by providing similar buprenorphine exposure at an ≈ 30% lower dosage than reference buprenorphine/naloxone. In large phase III trials of up to 28 days, buprenorphine/naloxone was associated with high treatment retention rates during the induction and stabilization phases, and also reduced opioid craving and opioid withdrawal symptoms. Although noninferiority of buprenorphine/naloxone to sublingual buprenorphine tablet during the 2-day induction phase was only shown in one of the two similarly designed trials, pooled analyses confirmed that treatment retention rates were similar in the buprenorphine/naloxone and buprenorphine groups. Where evaluated, noninferiority of buprenorphine/naloxone to sublingual buprenorphine/naloxone film (only approved in the USA) was also demonstrated at 15 days in the stabilization phase. During the 24-week extension study, buprenorphine/naloxone maintenance therapy sustained improvements in opioid craving and addiction severity scores. Buprenorphine/naloxone was generally well tolerated, displaying a tolerability profile that was generally consistent with that seen with reference buprenorphine/naloxone. In conclusion, with potentially greater patient preference and a lower potential for parenteral buprenorphine abuse than reference buprenorphine/naloxone, buprenorphine/naloxone expands the treatment options available for adults and adolescent (aged > 15 years) patients with opioid dependence.

Treatment of Kratom Dependence With Buprenorphine-Naloxone Maintenance.

INTRODUCTION: Use of the unregulated herbal supplement kratom is on the rise in the United States. We present a case series of 2 patients who developed kratom dependence and withdrawal who were successfully transitioned to buprenorphine-naloxone maintenance. CASE SUMMARY: Two patients using kratom to self-treat chronic pain after prescription opioids were discontinued presenting to our clinic with evidence of kratom dependence and withdrawal. On examination, both patients showed signs of mild opioid withdrawal. Both patients were successfully transitioned to buprenorphine-naloxone maintenance via home initiation with control of both their opioid withdrawal and chronic pain. CONCLUSIONS: Kratom use is on the rise and with increasing evidence of developing opioid-type dependence due to chronic kratom use. This case series shows that buprenorphine can be used to treat kratom dependence and underlying chronic pain that drives it use.

Abuse liability of intravenous buprenorphine vs. buprenorphine/naloxone: Importance of absolute naloxone amount.

BACKGROUND: This study sought to determine the relative importance of a range of Bup/Nx doses compared to Bup alone in producing subjective and reinforcing effects. METHODS: Heroin-using volunteers (n=13) were transitioned onto daily oral hydromorphone (40mg). Laboratory sessions assessed the reinforcing and subjective effects of intravenous (IV) doses of Bup (1.51, 2.16, 6.15, and 8.64mg) and Bup/Nx (1.51/0.44, 2.16/0.61, 6.15/1.71, and 8.64/2.44mg). Placebo (Pbo), heroin (25mg) and Nx (0.3mg) were tested as neutral, positive, and negative controls, respectively. RESULTS: IV Bup alone was self-administered substantially less than IV heroin, though the two largest doses of Bup produced positive subjective effects, drug "Liking" (0-100mm), which were comparable to heroin (mean difference: Heroin vs Bup 6.15mg: -3.4mm, Heroin vs Bup 8.64mg: -11.3mm). All indicators of abuse potential seen with IV Bup alone were substantially decreased with the addition of Nx. All Bup/Nx combinations produced ratings of aversive effects, "Bad", which were comparable to, or greater than IV, Nx. On three of the four measures of aversive effects, the largest difference is seen with the 8.64 vs 8.64/2.44 condition. CONCLUSIONS: This study further demonstrates the ability of the Bup/Nx combination to deter IV use. Although none of the Bup/Nx combinations showed indications of abuse potential, formulations with larger absolute Nx, may be less abusable as they precipitate a greater degree of withdrawal.

Intranasal buprenorphine alone and in combination with naloxone: Abuse liability and reinforcing efficacy in physically dependent opioid abusers.

BACKGROUND: Buprenorphine can be abused by the intranasal route. This study sought to examine the relative abuse liability and reinforcing efficacy of intranasal buprenorphine compared to intranasal buprenorphine/naloxone in opioid-dependent individuals. METHODS: Eleven healthy male and female volunteers physically dependent on short-acting opioids resided as inpatients during participation in this double blind, within subject, placebo-controlled study. Participants were maintained on oxycodone (30 mg/q.i.d., p.o.) throughout the 6-week study. Eight pairs of experimental sessions were conducted at ≥48 h intervals to examine the pharmacodynamic profile (Sample) and reinforcing efficacy (Self-administration the following day) of intranasal placebo, oxycodone (60 mg), buprenorphine (2, 8 & 16 mg) and buprenorphine/naloxone (2/0.5, 8/2 & 16/4 mg). Subjective, observer-rated and physiological measures were collected to assess the magnitude of opioid agonist and antagonist effects. A progressive ratio self-administration procedure assessed choices for drug versus money. RESULTS: All active doses produced opioid agonist-like effects (e.g., increased ratings of "liking," and miosis) compared to placebo. The effects of buprenorphine and buprenorphine/naloxone were not reliably dose-dependent. Intranasal buprenorphine/naloxone elicited modest and transient opioid withdrawal-like effects in the first hour post-drug administration, while simultaneously blunting or blocking the early onset of agonist effects seen with buprenorphine alone. All active doses of buprenorphine were self-administered more than placebo, but buprenorphine/naloxone doses were not. CONCLUSIONS: These data confirm that intranasal buprenorphine/naloxone has deterrent properties related to transient withdrawal effects that likely decrease its desirability for misuse compared to buprenorphine in opioid-dependent individuals maintained on short-acting opioids.