Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending-dose study.

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol.

Opioid-induced constipation (OIC) is the most common and often a treatment-limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR-118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice-daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.

Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone.

OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and abuse potential of different formulations of oxycodone. DESIGN: The participants completed an 8-day, placebo-controlled trial with four phases: naloxone challenge, double-blind drug discrimination, double-blind abuse liability, and discontinuation. SUBJECTS: Nineteen healthy, male, recreational drug abusers participated in this study. INTERVENTIONS: The participants were administered different doses and formulations of oxycodone (40 mg immediate release [IR], 40 mg controlled release [CR], crushed 40 mg CR, and 80 mg CR) to evaluate pharmacokinetic parameters and ratings of drug liking and high. OUTCOME MEASURES: Pharmacokinetic parameters were determined over a 12-hour dosing interval. The primary pharmacodynamic endpoints were two questions from the Drug Effects Questionnaire ("Do you like the drug?" and "How high are you now?"). RESULTS: Maximal plasma concentrations and area under the curve determinations were similar for 40 mg IR, crushed 40 mg CR, and 80 mg CR, which were all greater than 40 mg CR. For drug liking and high, the maximal effect and area under the effect curve were similar for the three formulations, which were all greater than 40 mg CR. The dose required to produce comparable reports of drug liking and high was approximately twofold greater for the CR vs IR formulation. When the 40 mg CR tablet was crushed, the pharmacokinetic and pharmacodynamic profile was similar to the 40 mg IR formulation. Adverse events were consistent with opioid administration. CONCLUSIONS: Intact, orally administered oxycodone CR produced less drug liking and high than IR oxycodone, and required approximately twofold greater doses to produce subjective effects comparable to IR oxycodone.

Opioid formulations in development designed to curtail abuse: who is the target?

BACKGROUND: Opioids are increasingly prescribed for chronic cancer and noncancer pain, and misuse, abuse, and diversion have risen dramatically. Formulations are being developed with the intent to curtail abuse through physical barriers that resist alteration, inclusion of excipients that antagonize opioid effects when altered, and other technologies. OBJECTIVE: To examine various new drug formulations designed to curtail opioid abuse, their stages of development, their technologies, and the population targeted. METHODS: The discussion encompasses formulations currently undergoing clinical trials in North America. CONCLUSION: Emerging opioid formulations may prove useful to minimizing prescription opioid abuse, but the magnitude of their clinical utility and societal impact will be unknown until epidemiological studies can be conducted. Realistic expectations for what the new formulations can achieve are encouraged.

Oral tramadol for the treatment of pain of 7-30 days' duration in children.

IMPLICATIONS: This open-label, multicenter trial was designed to determine the safety profile and analgesic efficacy of tramadol for the treatment of painful conditions lasting 7-30 days in 7-16-yr-old children. We found that tramadol 1-2 mg/kg per os every 4-6 h (maximal dose = 8 mg x kg(-1). d(-1), not to exceed 400 mg/d) is a safe and effective analgesic in this patient population.

An evaluation of the efficacy and tolerability of oral tramadol hydrochloride tablets for the treatment of postsurgical pain in children.

UNLABELLED: In this double-blinded, randomized, multicenter study, we examined analgesic efficacy and tolerability of tramadol in postoperative pediatric patients. Eighty-one postsurgical ASA physical status I and II patients ages 7-16 yr received oral tramadol (approximately 1 or 2 mg/kg) for postoperative analgesia when they were ready to transition from morphine patient-controlled analgesia to oral analgesics. Rescue analgesia consisted of morphine patient-controlled analgesia or an oral equivalent dose of oxycodone. Patients rated their pain just before the administration of tramadol and at regular intervals for 8 h afterwards using the Wong-Baker Faces Pain Rating Scale. The 2-mg/kg group required approximately half as much rescue analgesia as the 1-mg/kg group (P = 0.006). Parents rated the larger dose more favorably. Adverse events were generally mild to moderate in severity (vomiting [10%], nausea [9%], pruritus [7%], rash [4%]) and similar between the two treatment groups. There were no significant changes in hemodynamic variables, respiratory rate, or SpO(2) percentages between the two treatment groups or in all patients compared with pretreatment values. IMPLICATIONS: Oral tramadol 1-2 mg/kg is well tolerated and effective in postoperative children ready to transition from morphine patient-controlled analgesia. The group receiving 2 mg/kg required less rescue analgesic compared with those receiving 1 mg/kg.