Caffeine supplementation as part of enhanced recovery after surgery pathways: a narrative review of the evidence and knowledge gaps.

Caffeine is used daily by 85% of United States adults and caffeine withdrawal is a major cause of perioperative headache. Studies have shown that caffeine supplementation in chronic caffeinators reduces the incidence of perioperative headache. This narrative review discusses the perioperative implications of caffeine withdrawal and outlines the benefits of and strategies of caffeine supplementation in the perioperative period. It is time to "wake up and smell the coffee" on integration of caffeine into established enhanced recovery after surgery protocols as a mechanism to consistently provide perioperative caffeine replacement.

RéSUMé: La caféine est utilisée quotidiennement par 85 % des adultes aux États-Unis, et le sevrage de la caféine constitue une cause majeure de céphalées périopératoires. Des études ont montré que la supplémentation en caféine chez les grands buveurs de café réduisait l'incidence des céphalées périopératoires. Ce compte rendu narratif discute des implications périopératoires du sevrage de la caféine et décrit les avantages et les stratégies de la supplémentation en caféine en période périopératoire. Il est temps de « se réveiller à l'odeur du café ¼ quant à l'intégration de la caféine dans les protocoles de récupération rapide après la chirurgie en tant que mécanisme pour procurer de façon systématique un subsitut périopératoire à la caféine.

Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.

Preclinical toxicity evaluation of AAV for pain: evidence from human AAV studies and from the pharmacology of analgesic drugs.

Gene therapy with adeno-associated virus (AAV) has advanced in the last few years from promising results in animal models to >100 clinical trials (reported or under way). While vector availability was a substantial hurdle a decade ago, innovative new production methods now routinely match the scale of AAV doses required for clinical testing. These advances may become relevant to translational research in the chronic pain field. AAV for pain targeting the peripheral nervous system was proven to be efficacious in rodent models several years ago, but has not yet been tested in humans. The present review addresses the steps needed for translation of AAV for pain from the bench to the bedside focusing on pre-clinical toxicology. We break the potential toxicities into three conceptual categories of risk: First, risks related to the delivery procedure used to administer the vector. Second, risks related to AAV biology, i.e., effects of the vector itself that may occur independently of the transgene. Third, risks related to the effects of the therapeutic transgene. To identify potential toxicities, we consulted the existing evidence from AAV gene therapy for other nervous system disorders (animal toxicology and human studies) and from the clinical pharmacology of conventional analgesic drugs. Thereby, we identified required preclinical studies and charted a hypothetical path towards a future phase I/II clinical trial in the oncology-palliative care setting.