Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

Quantitative Sensory Testing Discriminates Central Sensitization Inventory Scores in Participants with Chronic Musculoskeletal Pain: An Exploratory Study.

BACKGROUND: The Central Sensitization Inventory (CSI) is often used in clinical settings to screen for the presence of central sensitization. However, various cutoff scores have been reported for this tool, and scores have not been consistently associated with widespread pain sensitivity as measured with quantitative sensory testing (QST). The purpose of this study was to compare QST profiles among asymptomatic controls and participants with chronic musculoskeletal pain (CMP), and to determine the association between self-report questionnaires and QST in participants with CMP. METHODS: Twenty asymptomatic controls and 46 participants with CMP completed the CSI, PROMIS-29, and QST assessments of mechanical and thermal pain thresholds remote to the area of pain. Receiver Operating Characteristic analysis revealed a cutoff score of 33.5 for the CSI. PROMIS-29 Quality of Life (QOL) inventory and QST measures were compared between low and high CSI groups. RESULTS: The high CSI group (n = 19) had significantly lower mechanical and thermal pain thresholds, and larger impairments in QOL measures, compared to the low CSI group (n = 27) and asymptomatic controls. Participants with CSI scores < 33.5 presented similarly to asymptomatic controls. Anxiety, pain interference, and CSI scores demonstrated the highest number of significant associations to QST measures. CONCLUSION: A cutoff score of 33.5 on the CSI may be useful for discriminating widespread pain sensitivity and quality of life impairments in participants with CMP. Future studies should consider how the presence of high or low CSI may impact differential diagnosis, prognosis, and treatment responsiveness for patients with primary or secondary CMP.

Intraoperative presentation of an undiagnosed tracheoesophageal fistula in an adult without history of abdominal or thoracic surgery.

Tracheoesophageal fistula is uncommon in adults but can cause devastating aspiration events. Herein, we report a unique case of a tracheoesophageal fistula in an adult that presented intraoperatively. The patient did not have any prior history of abdominal or thoracic surgery and was not intubated for a prolonged period of time. The diagnosis, subsequent hospital course, and recommendations for early recognition of this rare condition are discussed.

Minimally-invasive pain management techniques in palliative care.

Pain is a common source of suffering for seriously ill patients. Typical first-line treatments consist of lifestyle modifications and medication therapy, including opioids. However, medical treatments often fail or are associated with limiting systemic toxicities, and more targeted interventional approaches are necessary. Herein, we present options for minimally invasive techniques for the alleviation of pain in palliative patients from a head-to-toe approach, with a focus on emerging therapies and advanced techniques. Head and neck: image-guided interventions targeted to sympathetic ganglia of the head and neck, such as sphenopalatine ganglion (SPG) and stellate ganglion, have been shown to be effective for some forms of sympathetically-maintained and visceral pain. Interventions targeting branches of cranial nerves and upper cervical nerves, such as the glossopharyngeal nerve (GPN), are options in treating somatic head and face pain. Abdominal and pelvic: sympathetic blocks, including celiac plexus, inferior hypogastric, and ganglion impar can relieve visceral abdominal and pelvic pain. Spine and somatic pain: fascial plane blocks of the chest and abdominal wall and myofascial trigger point injections can be used for somatic pain indications. Cementoplasties, such as kyphoplasty and vertebroplasty, are used for pain related to bony metastases and compression fractures. Tumor ablative techniques can also be used for lytic lesions of the bone. Spinal cord stimulation (SCS), intrathecal drug delivery systems (IDDS), and cordotomy have also been used successfully in patients requiring advanced options, such as those with significant spinal, ischemic, or visceral pain.

Opioid prescribing practices in a pediatric burn tertiary care facility: Is it time to change?

Opioids are the mainstay therapy in burned adults. Little data in the pediatric burn population exists that elucidates opioid prescribing practices. The primary purpose of this report is to quantify opioid and non-opioid analgesic use in pediatric burn patients admitted to a tertiary referral burn center. A retrospective audit of hospital charts and discharge records for patients <18 years old from March 2016 to March 2017 was performed. Opioid amounts were converted to either oral morphine miligram equivalents (MME) or oral MME per day and subsequently adjusted for age in kilograms (kg). Of the 226 patients, 223 (98.7%) were administered an opioid during admission. The median total opioid amount administered during admission was 0.4 (IQR: 0.3-0.6) mg oral MME per kilogram per day. Anecdotally, doses above 1 mg/kg/day are considered high risk for opioid tolerance. The median total opioid amount prescribed upon discharge was high at 3.9 (IQR: 2.3, 5.6) mg of oral MME per kilogram. Hydrocodone (96.0%) was the most common opioid administered, followed by morphine (88.1%). The most commonly prescribed discharge opioid was hydrocodone (95.4%). Non-opoioid analgesia during admission was used in 112 patients (49.6%). This study provides novel insight into the opioid practices at a tertiary burn center for pediatric patients, with our analysis showcasing high usage of opioids during admission and discharge for burn analgesia. It emphasizes the need to expand beyond opioids for burn analgesia and the importance of promoting non-opioid, multimodal analgesia in the pediatric burn population.

The Efficacy of Lidocaine in Disrupting Cocaine Cue-Induced Memory Reconsolidation.

RATIONAL: Cue-induced craving memories, linked to drug-seeking behaviors, require key molecular processes for memory reconsolidation. Lidocaine, a sodium channel blocker, inhibits NMDA receptor activation and suppresses nitric oxide and ERK production. These processes are required for memory re-consolidation; inhibiting them may reduce cue-related craving memories in cocaine dependent subjects. OBJECTIVES: To assess the efficacy of lidocaine in decreasing cue-induced cocaine craving and cocaine use. METHODS: Treatment-seeking cocaine-dependent participants (n = 33, 25 men) were recruited. Personalized craving and relaxation scripts were developed. Participants were then randomly assigned in a double-blind design to either receive intravenous lidocaine immediately following a cocaine craving script (lidocaine/craving), saline following a craving script (saline/craving), or lidocaine following a relaxation script (lidocaine/relax). One week following the infusion, cue-induced craving was assessed in the same paradigm without an infusion. Cocaine use and craving were assessed for 4 weeks following infusion. RESULTS: The administration of lidocaine during craving induction (lidocaine/craving) did not decrease cue-induced craving during craving reactivation one week later or craving and cocaine use over the 4-week follow-up period compared to the saline/craving group. There were no significant differences in craving and cocaine use between the lidocaine/relax and saline/craving groups. CONCLUSION: Lidocaine administered following craving induction did not decrease subsequent cue-induced craving or cocaine use. Blocking the reconsolidation of craving-related memories with pharmacological agents remains an important area of investigation.

Lidocaine Infusion: A Promising Therapeutic Approach for Chronic Pain.

Opioid abuse is a national epidemic in the United States, where it is estimated that a prescription drug overdose death occurs every 19 minutes. While opioids are highly effective in acute and subacute pain control, their use for treatment of chronic pain is controversial. Chronic opioids use is associated with tolerance, dependency, hyperalgesia. Although there are new strategies and practice guidelines to reduce opioid dependence and opioid prescription drug overdose, there has been little focus on development of opioid-sparing therapeutic approaches. Lidocaine infusion has been shown to be successful in controlling pain where other agents have failed. The opioid sparing properties of lidocaine infusion added to its analgesic and antihyperalgesic properties make lidocaine infusion a viable option for pain control in opioid dependent patients. In this review, we provide an overview of the opioid abuse epidemic, and we outline current evidence supporting the potential use of lidocaine infusion as an adjuvant therapeutic approach for management of chronic pain.

Complex regional pain syndrome type 1 predictors - Epidemiological perspective from a national database analysis.

OBJECTIVE: Complex regional pain syndrome type 1 is a disabling pain disorder with unclear etiology. It is usually triggered by an injury to a limb with or without specific nerve injury. The objective of this study is to explore the risk factors and predictors for this disease utilizing a large national database. DESIGN: Retrospective analysis of the Nationwide Inpatient Sample database from 2007 to 2011 in the United States. SETTING AND PATIENTS: Adult inpatients diagnosed with complex regional pain syndrome type 1. STATISTICAL ANALYSIS: Chi-square, simple and multivariate logistic regression analyses were conducted. The regression model was adjusted to the patient's demographics and comorbidities. MAIN RESULTS: There were 22,533 patients with the discharge diagnosis of complex regional pain syndrome type 1 of an inpatient sample of 33,406,123. It peaks between age 45 and 55. Female gender, Caucasian race, higher median household income, headache, depression, drug abuse and private insurance patients (vs Medicaid patients) were associated with higher rate of complex regional pain syndrome type 1. On the other hand, diabetes, obesity, hypothyroidism, and anemia were associated with a lower rate. CONCLUSIONS: Utilizing a large database, our study added more information to the risk profile of the complex regional pain syndrome type 1 in an inpatient population. Such information should be useful for physician for early recognition, diagnosis of patients at risk.

Anesthetic management for laser excision of recurrent respiratory papillomatosis in a third trimester parturient.

Recurrent respiratory papillomatosis (RRP) is characterized by the development of laryngeal papillomas, which can produce partial to complete upper airway obstruction. Patients with RRP often require intermittent surgical excision to treat symptoms such as hoarseness and stridor, and to control progression of the lesions. The anesthetic management of such patients is challenging, and it requires carefully coordinated care between an anesthesiologist and otolaryngologist. We present 2 cases of general anesthesia administration during surgical excision of laryngeal papillomas, both occurring during the third trimester of separate pregnancies in the same parturient. The complexity of management was amplified in these cases because of the physiological and anatomical changes associated with pregnancy, along with the need to monitor fetal well-being. Possible complications included complete airway obstruction, pulmonary aspiration of gastric contents, hypoxemia, fetal distress, and preterm labor. Because pregnancy may lead to activation of human papillomavirus, the causative organism of RRP, management guidelines are provided for anesthesiologists who may care for patients with RRP during pregnancy.

Outcomes of a preoperative "bridging" strategy with glycoprotein IIb/IIIa inhibitors to prevent perioperative stent thrombosis in patients with drug-eluting stents who undergo surgery necessitating interruption of thienopyridine administration.

AIMS: Surgery after drug-eluting stent (DES) implantation may be associated with increased risk for perioperative stent thrombosis (ST). METHODS AND RESULTS: We evaluated the outcomes of 67 patients who underwent non-cardiac (n=51) or cardiac (n=16) surgery after DES implantation at our institution between 2008 and 2010 and who underwent preoperative "bridging" with a glycoprotein IIb/IIIa inhibitor. Surgery occurred after a mean time of 13.9 ± 1.7 and 8.7 ± 2 months post stenting for non-cardiac (NCS) and cardiac surgery, respectively. Glycoprotein IIb/IIIa inhibitors were administered preoperatively for a mean of 7.1 ± 0.4 and 7.8 ± 0.7 days, respectively, then discontinued four to six hours before surgery. Most patients received aspirin through the perioperative period (33 NCS patients and 15 cardiac surgery patients). Clopidogrel was restarted as early as possible in the postoperative period. In the non-cardiac surgery group, two patients (3.9%, 95% confidence intervals 0.5% to 13.5%) suffered acute ST in the immediate postoperative period and four patients suffered major bleeding by the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria. One cardiac surgery patient had probable ST one hour postoperatively. CONCLUSIONS: In spite of preoperative "bridging" with a glycoprotein IIb/IIIa inhibitor, postoperative stent thrombosis can still occur in patients with prior DES undergoing surgery requiring antiplatelet medication interruption.