Opioid use in treated and untreated obstructive sleep apnoea: remifentanil pharmacokinetics and pharmacodynamics in adult volunteers.

Abstract

Background: Patients with obstructive sleep apnoea (OSA) are considered more sensitive to opioids and at increased risk of opioid-induced respiratory depression. Nonetheless, whether OSA treatment (continuous positive airway pressure, CPAP; or bilevel positive airway pressure, BIPAP) modifies this risk remains unknown. Greater opioid sensitivity can arise from altered pharmacokinetics or pharmacodynamics. This preplanned analysis of a previous cohort study of remifentanil clinical effects in OSA tested the null hypothesis that the pharmacokinetics, pharmacodynamics, or both of remifentanil, a representative μ-opioid agonist, are not altered in adults with treated or untreated OSA.

Methods: A single-centre, prospective, open-label, cohort study administered a stepped-dose, target-controlled remifentanil infusion (target effect-site concentrations 0.5, 1, 2, 3, 4 ng ml^-1) to awake adult volunteers (median age 52 yr, range 23-70) without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). Type III (in-home) polysomnography verified OSA. Remifentanil plasma concentrations, end-expired CO₂, thermal heat tolerance, and pupil diameter (miosis) were assessed. Population pharmacokinetic (clearance, volume of distribution) and pharmacodynamic (miosis, thermal heat tolerance, end-expired CO₂) models were developed.

Results: Remifentanil clearance (median) was 147, 143, and 155 L h^-1 (P=0.472), and volume of distribution was 19.6, 15.5, and 17.7 L (P=0.473) for subjects without OSA, untreated OSA, or treated OSA, respectively. Total body weight was an influential covariate on both remifentanil clearance and central volume of distribution. There were no statistically or clinically significant differences between the three groups in miosis EC₅₀ or Emax, or the slopes of thermal heat tolerance or end-expired CO₂vs remifentanil concentration. At a plasma remifentanil concentration of 4 ng ml^-1, in participants without OSA, with untreated OSA, or with treated OSA, respectively, model-estimated pupil area (12%, 13%, and 17% of baseline, P=0.086), thermal heat tolerance (50°C, 51°C, and 51°C, P=0.218), and end-expired CO₂ (6.3 kPa, 6.4 kPa, and 6.7 kPa, P=0.257) were not statistically different between groups.

Conclusions: OSA (untreated or treated) did not influence remifentanil pharmacokinetics or pharmacodynamics (miosis, analgesia, respiratory depression). Results support the null hypothesis that neither pharmacokinetics nor pharmacodynamics of remifentanil, a representative μ-opioid, are altered in adults with treated or untreated OSA. These findings provide a mechanistic explanation for the lack of influence of OSA or OSA treatment on the clinical miotic, sedative, analgesic, or respiratory depressant response to remifentanil in awake adults. The conventional notion that OSA alters sensitivity to the effects of opioids in awake adults is not supported by our findings, such that opioid dosing might not need adjustment for pharmacokinetic or pharmacodynamic considerations.

Clinical trial registration: ClinicalTrials.gov, NCT02898792, https://clinicaltrials.gov/ct2/show/NCT02898792. First Posted: September 13, 2016.