Nine extensive metabolizers (EMs) and eight poor metabolizers (PMs) of sparteine took a single oral dose of 100 mg of desipramine HCI before and while taking paroxetine 20 mg per day. Before paroxetine, the median of the total desipramine clearance was 7 times higher in EMs than in PMs (102 and 15 l.h-1 respectively). This confirms that desipramine is extensively metabolized via the sparteine/debrisoquine oxidation polymorphism i.e. by CYP2D6. During paroxetine, the median clearances were 22 l.h-1 and 18 l.h-1 in EMs and PMs respectively. The 5-fold decrease in clearance in EMs when desipramine was co-administered with paroxetine confirms that paroxetine is a potent inhibitor of CYP2D6. The lack of effect on clearance in PMs shows that paroxetine is a selective inhibitor of CYP2D6, which is absent from the livers of PMs. Before paroxetine, the median of desipramine clearance via 2-hydroxylation was 40-times higher in EMs than in PMs (56 and 1.4 l.h-1 respectively), but during paroxetine, it was only 2-times higher (6 and 2.9 l.h-1 respectively). The increase in this clearance in PMs suggests that paroxetine is an inducer of the alternative, unidentified P450(s) which catalyze(s) the formation of 2-OH-desipramine in this phenotype. Before paroxetine, the median amounts of 2-OH-desipramine glucuronide recovered in urine were 69% and 68% of the total recovery of 2-OH-desipramine in urine in EMs and PMs respectively. During paroxetine, the corresponding values were 77% and 84%.(ABSTRACT TRUNCATED AT 250 WORDS)

Introduction Tonsillectomy is a frequently performed surgical procedure in children; however few multimodal analgesic strategies have been shown to improve postsurgical pain in this patient population. Systemic magnesium infusions have been shown to reliably improve postoperative pain in adults, but its effects in pediatric surgical patients remains to be determined. In the current investigation our main objective was to evaluate the use of systemic magnesium to improve postoperative pain in pediatric patients undergoing tonsillectomy. We hypothesized that children who received systemic magnesium infusions would have less post-tonsillectomy pain than the children who received saline infusions. Methods The study was a prospective, randomized, double-blinded, clinical trial. Subjects were randomized using a computer-generated table of random numbers to one of the two intervention groups: systemic magnesium infusion (initial loading dose 30 mg/kg given over 15 minutes followed by a continuous magnesium infusion 10 mg/kg/hr) or the same volume of saline. The primary outcome was pain scores in the postanesthesia care unit (PACU) measured by FLACC pain scores. Pain reduction was measured by the decrement in the area under the pain scale versus 90-minute postoperative time curve using the trapezoidal method. Secondary outcomes included opioid consumption in the PACU, emergence delirium scores (measured by the pediatric anesthesia emergence delirium scale) and parent satisfaction. Results Sixty subjects were randomized and 60 completed the study. The area under pain scores (up to 90 minutes) was not different between the study groups, median (IQR) of 30 (0 to 120) score*min and 45 (0 to 135) score*min for the magnesium and control groups, respectively, P= 0.74. Similarly, there was no clinically significant difference in the morphine consumption in the PACU between the magnesium group, median (IQR) of 2.0 (0 to 4.44) mg IV morphine compared to control, median (IQR) of 2.5 (0 to 4.99) mg IV morphine, P= 0.25. The serum level of magnesium was significantly lower in the control group compared to the treatment group at the end of the surgery (P<0.001). Discussion Despite a large number of studies demonstrating the efficacy of systemic magnesium for preventing postsurgical pain in adults, we could not find evidence for a significant clinical benefit of systemic magnesium infusion in children undergoing tonsillectomies. Our findings reiterate the importance of validating multimodal analgesic strategies in children that have been demonstrated to be effective in the adult population.

Tonsillectomy is associated with significant pain and postoperative pain control is often unsatisfactory. We discuss the various strategies that have been investigated to control pain following tonsillectomy. Codeine is a weak analgesic frequently used in children for the treatment of mild-to-moderate pain, however, due to adverse events related to its metabolism, it has been contraindicated for postoperative pain in children since 2013. Intravenous morphine is frequently used for moderate-to-severe pain in children, however, its active metabolite can lead to respiratory depressant and other undesirable side effects. Hydromorphone is a commonly used alternative that has been studied infrequently. Alternatives to narcotic pain strategies have also been studied. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective as analgesics, yet many practitioners avoid their use given the concern for postoperative bleeding. Intraoperative acetaminophen has been shown to improve postoperative pain and decrease recovery room time. Dexamethasone has been shown to improve postoperative pain, vomiting, and decrease airway swelling, and seems to be effective for use during tonsillectomy surgery. Ketamine has been shown to decrease analgesic requirements without adverse affects of hallucinations. Direct injection of local anesthetic into the tonsillar bed has been shown to be effective in improving pain control, however, there is concern that local anesthetic could be erroneously injected into the carotid artery and lead to devastating consequences. Optimal pain control regimens following pediatric tonsillectomy continue to be a challenge for both anesthesiologists and otorhinolaryngologists. Opioids are the most commonly used but are associated with significant side effects, especially postoperative respiratory depression. Adjuncts may be safely used in the perioperative period and may have narcotic sparing effects as well as improved cost effectiveness. Further research into additional analgesics strategies is necessary to improve the perioperative course.