Telehealth Utilization for Opioid Use Disorder: A Nationwide Analysis Before and After the COVID-19 Public Health Emergency Declaration.

Introduction: The COVID-19 pandemic has led to the rapid and widespread adoption of telehealth services. Telehealth may aid in bridging gaps in access to care. The specific impact of telehealth on opioid use disorder (OUD) and its treatment remains uncertain. Methods: A retrospective review of commercial insurance claim records within the United States was conducted to investigate the association between the COVID-19 pandemic and changes in the rates of(a) OUD treatments with and without telehealth support and (b) prescriptions for medications for opioid use disorder (MOUD) with and without telehealth support among individuals diagnosed with OUD. Results: In a study population of 1,340,506 individuals, OUD diagnosis rates were 5 per 1,000 in-person and 1 per 1,000 via telehealth. COVID-19 decreased in-person OUD diagnoses by 0.89 per 1,000, while telehealth diagnoses increased by 0.83 per 1,000. In-person MOUD treatment rates increased by 0.07 per 1,000 during COVID-19, while telehealth rates remained low. The onset of COVID-19 saw a 1.13 per 1,000 higher increase in telehealth-supported MOUD treatment compared to solely in-person treatment. Conclusions: A retrospective review of commercial insurance claim records within the United States was conducted to investigate the association between the COVID-19 pandemic and changes in the rates of (a) OUD treatments with and without telehealth support and (b) prescriptions for MOUD with and without telehealth support among individuals diagnosed with OUD.

Risk of Intraoperative Hyperthermia and Outcomes in Adults Undergoing Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is commonly used to treat peritoneal surface malignancies. We aimed to identify risk factors of intraoperative patient hyperthermia and the postoperative outcome of adults undergoing HIPEC PATIENTS AND METHODS: A retrospective, IRB approved, single center cohort study was conducted. Adults treated with cytoreductive surgery and HIPEC between 2006 and 2021 were included. The primary outcome was bladder hyperthermia during perfusion, stratified by severity and duration. Secondary outcomes were postoperative complications and recurrence-free (RFS) and overall (OS) survival. Multivariable logistic regression models were fit to estimate the effects of important covariates. RESULTS: Out of 214 patients, 114 had mild hyperthermia (≥ 38 °C) at any time, and in 73 of these it lasted for ≥ 30 min. Independent prognostic factors of mild hyperthermia ≥ 30 min were age (OR = 0.958, 95% CI 0.933-0.984), body mas index (BMI; OR = 0.959 95% CI 0.917-1.002), gender (OR = 0.199, 95% CI 0.092-0.431), and type of chemotherapy [cisplatin versus mitomycin (OR = 0.186, 95% CI 0.070-0.491; oxaliplatin versus mitomycin (OR = 0.430, 95% CI 0.163-1.139)]. Prognostic factors of moderate-to-severe hyperthermia (≥ 39 °C) at any time were perfusion duration (OR = 1.094, 95% CI 1.018-1.177) and blood transfusion (OR = 5.689, 95% CI 1.784-18.137). Intraoperative hyperthermia was not associated with increased postoperative complications but was associated with better RFS and OS. CONCLUSIONS: Our study demonstrates age, gender, BMI, and chemotherapy type to be associated with hyperthermia ≥ 38 °C for ≥ 30 min, whereas longer perfusion time and blood transfusion were associated with hyperthermia ≥ 39 °C. Mild hyperthermia at the end of perfusion is associated with better RFS and OS.

Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu-opioid receptor.

The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and metastasis in lung cancer cell lines. The effect of MNTX on other cell lines such as head and neck squamous cell carcinoma (HNSCC) has not been investigated. We measured the expression and activity of the receptor in different HNSCC cell lines. Then, we evaluated the impact of modulating the expression MOR and the effect of MNTX on the proliferation, clonogenic activity, invasion, and migration of two HNSCC (FaDu and MDA686Tu) cell lines expressing MOR and one cell line (UMSCC47) not expressing the receptor. We also evaluated the impact of MNTX on tumor growth and metastasis formation in vivo. Activation of the receptor with [d-Ala2,N-Me-Phe4, Gly5-ol] (DAMGO) caused a significant reduction in cyclic adenosine monophosphate levels in FaDu cells. Knockdown of MOR inhibited in vitro aggressive cell behaviors on FaDu and MDA686Tu cells and correlated with a reduction in markers of epithelial-mesenchymal transition. In vitro studies showed that MNTX strongly inhibited the proliferation, clonogenic activity, invasion, and migration of FaDu and MDA686Tu cells but has no effect on UMSCC47 cells. In vivo experiments demonstrated that MNTX suppresses tumor growth in HNSCC cell tumor-bearing mice. Our studies indicate that MOR could be considered as a therapeutic target to treat HNSCC.

The Impact of Thoracic Epidural Analgesia Versus Four Quadrant Transversus Abdominis Plane Block on Quality of Recovery After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Surgery: A Single-Center, Noninferiority, Randomized, Controlled Trial.

BACKGROUND: Recovery after CRS-HIPEC influenced by several factors, including pain and opioid consumption. We hypothesized that 4Q-TAP blocks provide not inferior quality of recovery compared with TEA after CRS-HIPEC. We conducted a randomized, controlled trial to determine whether 4-quadrant transversus abdominis plane (4Q-TAP) block analgesia was noninferior to thoracic epidural (TEA) among patients who underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS HIPEC). METHODS: Patients 18 years or older who underwent a CRS-HIPEC surgery were randomly assigned to have either TEA or 4Q-TAP blocks. The primary outcome of this study was the change in quality of recovery 2 days after surgery. Secondary outcomes included quality of recovery on Days 1, 3, 5, 7, 10, and 30 postoperatively, opioid consumption, pain intensity, length of stay, and postoperative complications. Analyses were performed on a per-protocol basis. RESULTS: Sixty-eight patients were included in the analysis. The difference between 4Q-TAP and TEA in the mean QoR-15 change from surgery at postoperative Days 1, 2, and 3 was 0.80 (P = 0.004), -4.5 (P = 0.134), and 3.4 (P = 0.003), respectively. All differences through postoperative day 30 were significantly within the noninferiority boundary of -10 except at postoperative Day 2 (P = 0.134). Length of stay, opioid-related adverse events, and frequency and grade of complications were not significantly different between TEA and 4Q-TAP patients. CONCLUSIONS: Despite the significantly higher use of opioids after CRS-HIPEC in patients with 4Q-TAP blocks, their short-term quality of recovery was not inferior to those treated with TEA. Patients undergoing CRS-HIPEC can be effectively managed with 4Q-TAP blocks.

MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain.

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activity (SA), none of these have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we show that inhibition of mitogen activated protein kinase interacting kinase (MNK) with eFT508 (25 nM) reverses SA in human sensory neurons associated with painful dermatomes. MNK inhibition in spontaneously active nociceptors decreased action potential amplitude and produced alterations in the magnitude of afterhyperpolarizing currents suggesting modification of Na+ and K+ channel activity downstream of MNK inhibition. The effects of MNK inhibition on SA took minutes to emerge and were reversible over time with eFT508 washout. MNK inhibition with eFT508 led to a profound loss of eIF4E Serine 209 phosphorylation, a specific target of the kinase, within 2 min of drug treatment, consistent with the rapid action of the drug on SA in electrophysiology experiments. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.

Fadu head and neck squamous cell carcinoma induces hyperexcitability of primary sensory neurons in an in vitro coculture model.

Introduction: Currently, cancer pain is viewed as a process orchestrated by the release of pronociceptive molecules and the invasion of neural structures, referred to as perineural invasion (PNI). Cancer pain resulting from PNI is well-documented, but the mechanisms leading to peripheral sensitization because of tumor growth are not fully known. Methods: A retrospective study was used to examine how the use of anti-inflammatory medications affected preoperative pain in patients with oral squamous cell carcinoma cancer. We then used an in vitro coculture model in which dorsal root ganglion (DRG) neurons were incubated together with Fadu human head and neck squamous cell carcinoma cancer cells to explore how cancer cells affect the electrical membrane properties of sensory neurons. Results: We found that inflammation contributes to preoperative pain in patients with oral squamous cell carcinoma. After coculture with Fadu human head and neck squamous cell carcinoma cancer cells, we identified markers of inflammation in coculture media and found evidence of neuronal sensitization, including spontaneous activity, reduced current thresholds, depolarized resting membrane potential, and enhanced responses to current stimulation in human and rat DRG neurons. In rats, these effects were influenced by sex and age: neurons from young adult female rats were resistant to changes in neuronal activity, in contrast to neurons from older adult female rats or male rats of either age group. Conclusions: Pro-inflammatory substances released in cancer cell-DRG coculture promoted neuronal hyperexcitability and may contribute to cancer pain after PNI, and these effects may differ across age groups and sexes.

Impact of Ketamine on Opioid Use and Persistent Pain After Cytoreductive Surgery with Hyperthermic Chemotherapy.

BACKGROUND: Persistent pain and opioid use can be devastating after cytoreductive surgery (CRS) and hyperthermic intraoperative chemotherapy (HIPEC). METHODS: We conducted a retrospective study to investigate the impact of ketamine use on postoperative complications and persistent and chronic pain after CRS-HIPEC. RESULTS: Ketamine reduced perioperative opioid use before and after implementation of recovery after surgery programs. Ketamine did not impact the formation of persistent and chronic pain formation and long-term opioid use. Postoperative complications and postoperative re-operations were independent predictors of persistent pain. Interestingly, the risk of having a complication was increased by 1% for every doubling in opioids used intraoperatively. CONCLUSION: Ketamine use reduces perioperative opioid consumption in patients undergoing CRS-HIPEC, but it is not associated with improvements in long-term opioid use and chronic pain.

Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma.

AIMS: In vitro and in vivo studies suggest that the mu-opioid receptor (MOR) is involved in tumorigenesis, and metastasis in cancer. In humans, the use of MOR agonists (opioids) is associated with head and neck squamous cell carcinoma (HNSCC) progression. In the present study, we aimed to examine the role of MOR activation in MOR (+) HNSCC. MAIN METHODS: FaDu, MDA686Tu and UMSCC47 cell lines were used in in vitro and in vivo experiments. Cells and animals were treated with a highly selective MOR agonist DAMGO, [D-Ala (2), Me Phe (4), Glycol (5)]-enkephalin] or saline 0.9%. KEY FINDINGS: MOR activation significantly increased the proliferation, colony formation, invasion, and migration of FaDu and MDA6868Tu cells and promoted tumor growth in vivo. SIGNIFICANCE: These findings suggest that MOR is implicated in tumorigenesis of HNSCC. Overall, our findings identify that MOR could be used as a potential therapeutic target in patients with MOR (+) HNSCC.

Chemotherapy-induced peripheral neuropathy in a dish: dorsal root ganglion cells treated in vitro with paclitaxel show biochemical and physiological responses parallel to that seen in vivo.

The mechanisms underlying chemotherapy-induced peripheral neuropathy have yet to be fully elucidated, but primary afferent neurons have emerged as an especially vulnerable initiating pathophysiological target. An important recent study has also shown that the initial toxicity produced by paclitaxel in patients was highly predictive of long-term outcome. In this study, we therefore focused on defining the mechanisms of acute toxicity produced by paclitaxel treatment on primary sensory neurons under in vitro conditions. In primary rat dorsal root ganglion (DRG) culture with paclitaxel, an increase of pERK and pp38 was observed at 2 hours, and this was accompanied by an increase in expression and release of C-C chemokine ligand 2 (CCL2). There was no change in pJNK. The increase in pERK was sustained at 48 hours of exposure when the expression of TLR4, MyD88, and IL-6 was also increased. IL-6 and CCL2 were colocalized to TLR4-positive cells, and all these responses were prevented by coincubation with a TLR4 antagonist (LPS-RS). Whole-cell patch-clamp recordings revealed that DRG neurons developed spontaneous depolarizing fluctuations (DSFs) in membrane potential and hyperexcitability to current injection but no ectopic action potential activity at 24 and 48 hours of paclitaxel incubation. However, CCL2 applied to cultured neurons not only induced DSFs but also evoked action potentials. Evidence of oxidative stress and mitotoxicity was observed at 48 hours of exposure. These results closely parallel the responses measured in the DRG with paclitaxel exposure in vivo and so indicate that acute toxicity of paclitaxel on the DRG can be modelled using an in vitro approach.

International multicentre observational study to evaluate the association between perioperative red blood cell transfusions and 1-year mortality after major cancer surgery (ARCA-1): study design, statistical analysis plan and study protocol.

INTRODUCTION: Blood transfusion is still common in patients undergoing major cancer surgery. Blood transfusion can be associated with poor prognosis in patients with cancer. Perioperative Care in the Cancer Patient -1 (ARCA-1) aims to assess in a large cohort of patients the current incidence, pattern of practice and associations between perioperative blood transfusions and 1-year survival in patients undergoing major cancer surgery. METHODS AND ANALYSIS: ARCA-1 is a prospective international multicentre observational study that will include adult patients scheduled to have major cancer surgical procedures with the intention to cure, and an overnight planned hospital admission. The study will be opened for 1 year for enrolment (7 January 2020-7 February 2021). Each centre will enrol patients for 30 days. The primary endpoint of this study is all-cause mortality 1 year after major cancer surgery. Secondary endpoints are rate of perioperative blood product use, cancer-specific mortality at 1 year and PFSs and 30-day morbidity and mortality. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board at The University of Texas-MD Anderson Cancer Center. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT04491409.

Postoperative acute pain challenges in patients with cancer.

It is expected that the number of surgical procedures to diagnose, treat, and palliate cancers will increase in the near future. While many of those interventions can be performed with minimally invasive techniques, others require surgical large incisions and in some instances, they involve multiple areas of the body (i.e., tumor resections with flap reconstructions). Pain after major oncological procedures can be severe and many times difficult to treat as patients can present to the operating room with several conditions including preoperative pain (i.e., rapidly growing tumors and painful neuropathies), opioid tolerance, and contraindications to nonopioid analgesics or regional anesthesia. Inadequately treated postoperative pain is associated with activation of the sympathetic system, postoperative complications, large perioperative opioid use, and an increased risk of developing postoperative persistent pain. Furthermore, it has been theorized that poorly treated pain is associated with cancer recurrence and a reduced survival. Lastly, recent research questions the oncological safety of robotic surgery in gynecological procedures and indicates the need of open surgeries, which will be associated with an increased risk in moderate-to-severe postoperative pain. In conclusion, the management of acute postoperative pain in patients with cancer can be challenging.