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. An important consequence was that the absorption would be determined by the rate at which the drug was transferred from the stomach to the site of rapid absorption in the upper small intestine, (3) absorption also involved the process of dissolution from an orally administered solid dosage form and either the rate of transit from stomach or dissolution could be rate-limiting. Heading and colleagues [18] found that rapid gastric emptying in 14 convalescent patients was associated with the early appearance of high peak plasma paracetamol concentrations, whereas peak concentrations were low and appeared late when gastric emptying was slow.

Observed peak paracetamol concentration (C max ) and area under the plasma concentration-time curve over the 6-h dosing interval (AUC 0–6 ) were reduced in this study when oral paracetamol was co-administered with morphine, followed by an abruptly increased C max and AUC 0–6 upon the discontinuation of morphine, indicating the absorption of the accumulated paracetamol entering the small intestine after the effect of morphine dissipated. Noticeable changes were also observed for time to reach maximum drug concentration (T max ) after the 3rd and 4th doses. Variability in C max , AUC 0–6 , C 6 (paracetamol concentration before the following dosing time), as well as T max around 3rd dose was significantly higher than that of first two doses, indicating the impact of morphine on oral paracetamol absorption varies substantially among individual subjects. In contrast, intravenous paracetamol demonstrated more predictable pharmacokinetics in the setting of concomitant opioid use.

In this study, only two 0.125 mg/kg doses of morphine were given, whereas in clinical practice, patients may need more than two doses, which could have an even greater impact on gastric emptying and gut motility, resulting in greater accumulation of paracetamol following repeat oral dose administration. Once gastric function is restored upon the discontinuation of morphine, there is an abrupt release of unabsorbed paracetamol that enters the small intestine [19]. We observed a resultant approximate doubling in AUC (after the 4th dose of oral paracetamol), which may produce significant changes in paracetamol metabolism, as common pathways such as glucuronidation/sulfation get saturated and more drug is converted into the free radical metabolite N-acetyl-p-benzoquinone imine (NAPQI), which binds to and causes death of hepatocytes.

In general, the pharmacokinetic profile of paracetamol following oral administration is known to exhibit considerable inter-subject variability due to differences in normal physiologic factors such as gastrointestinal movement [18]. The plasma concentrations of paracetamol and its absorption are apparently related to the rate of gastric emptying since faster gastric emptying is associated with the rapid appearance of high peak plasma concentrations, while the peaks occur late and are lower in patients with delayed gastric emptying. Gastric emptying likely influences paracetamol absorption directly by controlling the rate at which the drug is delivered to the small intestine. Consistent with the high inter-subject variability in pharmacokinetic profiles seen in the current study in subjects who received oral paracetamol, individual variation in the rate of drug absorption may be due largely to differences in the rate of gastric emptying [18]. Furthermore, concomitant use of morphine in the current study introduced even greater variability in orally administered paracetamol exposures, plasma concentrations, and T max .

The interaction between morphine and orally administered paracetamol could be even more pronounced in postsurgical patients where factors such as concomitant medications and surgical trauma may further impair gastric function. This may result in inadequate pain control from orally administered paracetamol during opioid co-treatment and subsequent absorption of accumulated paracetamol upon cessation of opioid treatment.

The results from this study are consistent with the pharmacokinetic results of the study by Singla et al 2012 [14]. With respect to efficacy, plasma and CSF levels need to be considered, though it is difficult to correlate paracetamol CSF levels with efficacy, —i.e., paracetamol has a central effect but concentrations in CSF are not predictive of (i.e., linearly related to) efficacy [20]. This is a limitation of the study by Singla et al [14]. The “effect compartment” is unknown and could be multiple locations (e.g., brain and spinal cord) [21]. Paracetamol conversion to the active metabolite AM404 may result in active analgesia [22].

Low plasma concentrations following oral administration of paracetamol could impact efficacy relative to the intravenous route of administration. Plasma C max may be a better predictor of efficacy than AUC, in that the passive diffusion of paracetamol into the CNS is highly dependent on the concentration gradient across the blood brain barrier [14]. Post-operative intravenous paracetamol previously has been demonstrated to provide faster onset of analgesia than a similar dose given orally [23] and, more recently, that only two-thirds of patients given an oral dose of 1 g paracetamol preoperatively achieved therapeutic plasma concentrations at any point compared to 96% in those given an intravenous dose of 1 g preoperatively [24].

In the context of multimodal analgesia, when choosing medications to administer, increased efficacy, decreased adverse effects, and opioid reduction are the primary objectives [25]. Therefore, selection of non-opioids is imperative, and route of administration should be factored in, given opioid impact on gut motility, which impacts the pharmacokinetics of agents administered orally; substantial inter-subject variability could be the result of morphine’s effect, or first- pass metabolism, or both.

Results of this study suggest intravenous paracetamol is a better choice than oral paracetamol in patients receiving concomitant opioids until normal gut function can be demonstrated. A future study should evaluate the extent of the “burst effect” (i.e., the abrupt release of accumulated paracetamol at the end of morphine-mediated GI inhibition following oral administration), to evaluate both pharmacokinetics and safety (in particular, the impact on liver enzyme levels). The study should also aim to measure metabolites to determine the extent of NAPQI formation following the burst effect.