The Impact of Opioid Agonists and Clinical Protocols on the Pharmacokinetic Profile of Oral Paraceta

Opioid agonists such as morphine continue to be important analgesics in the treatment of pain in the immediate perioperative and critical care settings [1], although they are associated with numerous adverse drug events [2]. In an effort to reduce opioid exposure and thus minimize opioidrelated adverse drug events, non-opioid analgesics are being incorporated as foundational therapy into multimodal analgesia protocols for the management of postoperative pain. Numerous surgical and nonsurgical medical societies and accrediting and quality organization guidelines recommend the use of multimodal analgesia (MMA) in order to reduce exposure to opioids [3–9]. Many also recommend scheduled use of non-opioid analgesics (paracetamol [acetaminophen], non-steroidal anti-inflammatory drugs [NSAIDs]) as the first- line foundation of MMA.

A recent review [10] and the American Society of Anesthesiologists (ASA) guidelines [11] have suggested there is inadequate differentiation of intravenous and oral paracetamol to warrant the higher acquisition cost and longer time to administer the intravenous formulation. Given that opioids remain a key component of postoperative pain management, it is important to note that opioids, along with surgical stress may have a negative impact on orally administered drugs. Opioids inhibit gastrointestinal motility, including delaying gastric emptying [12] and thus the route of administration of analgesics used in multimodal regimens may be an important consideration.

Specifically, absorption of orally administered paracetamol may be compromised in patients receiving opioids, which could reduce efficacy. Furthermore, delayed absorption of orally administered paracetamol in patients receiving opioids could result in gastric accumulation of paracetamol, thereby markedly changing the pharmacokinetic profile during and after opioid administration.

This was an institutional review board (IRB)-approved, randomized, single-blind, parallel, single-site, repeat-dose study (NCT02848729) in healthy adult subjects from 18 to 55 years of age (inclusive). The study was completed with four cohorts of subjects: both males and non-pregnant females were enrolled in Cohort 1, and male subjects only in Cohorts 2–4. Subjects were randomly assigned to 1 of 2 parallel groups: 4 repeat doses of 1000 mg oral paracetamol (2 tablets, 500 mg/tablet; Mallinckrodt Inc., Hazelwood, Missouri, USA) at hours 0, 6, 12, and 18, and a dummy 15-min intravenous infusion of saline at the same time points, or 4 doses of intravenous paracetamol (1000 mg/100 mL; Ofirmev, Mallinckrodt Inc., Hazelwood, Missouri, USA) delivered as an infusion at hours 0, 6, 12, and 18, and 2 placebo tablets at the same time points.

Intravenous morphine infusions (0.125 mg/kg in 100 mL saline, approximately 15 min; morphine sulfate injection 10 mg/mL, 1 mL, West-Ward Pharmaceutical Corp., Eatontown, New Jersey, USA) occurred at hours 6 and 12 for all subjects. The total study duration for each subject was approximately 38 days. A drop-out rate of 50% was anticipated due to the required discontinuation of subjects who experienced emesis and the known association between morphine and emesis.

Bioanalytical

Method to Determine Plasma Concentration of Paracetamol Venous blood was collected by venipuncture in K2EDTAcontaining tubes, and plasma was separated and stored at -80 C. Quantification of paracetamol in plasma was performed via high-performance liquid chromatography (HPLC) with paired mass spectrometry (MS/MS). Analysis of human plasma samples began on 16 March 2016.

This study was regarded as exploratory and thus sample size was not determined by power analysis. Two populations were identified and analyzed in this study. The safety population comprised subjects enrolled in the study that received any quantity of study drug. The per-protocol population comprised subjects who received all study drug doses and provided all 33 protocol-specified blood samples within required time frames without any major protocol deviations. Pharmacokinetic simulations were performed to predict the paracetamol concentrations after the second, third, and fourth doses of paracetamol assuming no co-administration of morphine. The simulations were based on the observed pharmacokinetic values after the first dose of orally or intravenously administered paracetamol. Simulations were performed using Phoenix WinNonlin V 6.4 (Certara, Princeton, NJ).

Pharmacokinetics Mean plasma pharmacokinetic parameters of oral paracetamol administered before, during, and after morphine administration are presented in Table 1. Observed paracetamol peak concentration (Cmax) and area under the plasma concentration-time curve over the 6-h dosing interval (AUC0–6) for paracetamol following oral administration were reduced when co-administered with morphine, and increased after morphine was discontinued. The mean AUC0–6 was decreased from 31.00 lgh/ mL after the second dose (28.51 lgh/mL) and third dose (25.31 lgh/mL) of oral paracetamol, and then sharply increased following the fourth dose (52.38 lgh/mL), resulting in statistically significant increases between fourth and first dose (p.001), and fourth and third dose (p = 0.004).

The mean Cmax followed a similar trend, decreasing from 11.6 lg/mL after the first dose to 7.29 lg/ mL after the second dose and 7.25 lg/mL after the third dose of paracetamol, and then increasing significantly after the fourth dose (13.5 lg/mL, p = 0.019, when compared with the third dose). Time to peak plasma concentration (Tmax) for oral paracetamol was prolonged during and after co-administration of morphine. Significantly prolonged mean Tmax (i.e., delayed Cmax) values were also observed after the fourth (2.84 h, p = 0.031) dose of oral paracetamol when compared to the first dose (1.48 h).

Overall, this study demonstrated a substantial impact on the pharmacokinetic profile of oral paracetamol, but not intravenous paracetamol, when co-administered with morphine. Greater pharmacokinetic variability was seen following administration of paracetamol orally compared to intravenously, particularly after subjects were exposed to morphine. This variability could be attributed multiple factors: (1) much of the inter-individual inherent physiologic variability could be contributing to higher variance in absorption, (2) the uptake of paracetamol from the small intestine is much faster than from the stomach due to the greater surface area.