Pain management following major intracranial surgery in pediatric patients: a prospective cohort study in three academic children's hospitals.

INTRODUCTION: Pain management following major intracranial surgery is often limited by a presumed lack of need and a concern that opioids will adversely affect postoperative outcome and interfere with the neurologic examination. Nevertheless, evidence in adults is accumulating that these patients suffer moderate to severe pain, and this pain is often under-treated. The purpose of this prospective, clinical observational cohort study was to assess the incidence of pain, prescribed analgesics, methods of analgesic delivery, and patient/parent satisfaction in pediatric patients undergoing cranial surgery at three major university children's hospitals. METHODS: After obtaining IRB and parental consent (and when applicable, patient assent), children who underwent cranial surgery for cancer, epilepsy, vascular malformations, and craniofacial reconstruction were studied. Neither intraoperative anesthetic management nor postoperative pain management was standardized, but were based on institutional routine. Patients were evaluated daily by a study investigator and by chart review for pain scores using age appropriate, validated tools (FLACC, Faces Pain Scale-Revised, Wong-Baker Faces Scale or Self-Report on a 0-10 scale), for patient/parent satisfaction using a subset of the NRC Picker satisfaction tool and in adolescents a modified QoR-40, and for the frequency, mode of administration, and type of analgesic provided. Finally, the incidence of opioid-induced side effects, specifically nausea, vomiting, pruritus, altered level of consciousness, and need for emergency diagnostic radiologic studies for altered neurologic examination were recorded. Data are provided as mean ± SD. RESULTS: Two hundred children (98:102 M:F), averaging 7.8 ± 5.8 years old (range 2 months-18.5 years) and 32.2 ± 23.0 kg (range 4.5-111.6 kg) undergoing craniectomy (51), craniotomy (96), and craniofacial reconstruction (53) were studied. Despite considerable variation in mode and route of analgesic administration, there were no differences in average pain score, length of hospital stay, or parental satisfaction with care. Interestingly, opioid-induced side effects were not related to total daily opioid consumption, site of surgery, or method of opioid delivery. The most common side effect was vomiting. No patient developed respiratory depression or altered mental status secondary to analgesic therapy. Regardless of age or procedure, once eating, most patients were treated with oral oxycodone and/or acetaminophen. CONCLUSIONS: Despite considerable variation in modality and route of analgesic administration, there were no differences in average pain score, length of stay, or parental satisfaction with care. Pain scores were low, side effects were minimal, and parental satisfaction was high, providing equipoise for future blinded prospective randomized trials in this patient population.

IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1,2-a]pyridine binding.

A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.

IRAK-4 inhibitors. Part 1: a series of amides.

The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.

IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines.

Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.

Low molecular weight indole fragments as IMPDH inhibitors.

The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.

Novel indole inhibitors of IMPDH from fragments: synthesis and initial structure-activity relationships.

The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.

Novel 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones as IMPDH inhibitors.

The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).

Quinazolinethiones and quinazolinediones, novel inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.

The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.

8-Methoxyquinoline-5-carboxamides as PDE4 inhibitors: a potential treatment for asthma.

A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).

8-Methoxyquinolines as PDE4 inhibitors.

The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).

7-Methoxyfuro[2,3-c]pyridine-4-carboxamides as PDE4 inhibitors: a potential treatment for asthma.

The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).