Intrathecal drug-infusion system for treating pain in advanced cancer: New research in patient management.

Currently, the treatment of cancer pain in China mainly follows the three-step pain relief principles formulated by the World Health Organization. As research on subarachnoid drug diffusion has intensified, intrathecal drug delivery has been gradually applied in the treatment of diseases, and improved analgesia can be achieved via the continuous infusion of small doses of morphine-derived drugs. This method can not only effectively relieve pain and enhance quality of life but also significantly reduce the incidence of nausea, vomiting, constipation, and other adverse reactions caused by the long-term intensive use of drugs in patients with cancer pain. This study summarizes the development of the intrathecal drug-infusion system for treating cancer pain in patients with advanced cancer and describes the drugs used, the advantages in pain treatment, and key nursing factors before and after device placement to provide a basis for alleviating pain in patients with cancer.

Nomogram for predicting opioid-induced nausea and vomiting for cancer pain patients.

OBJECTIVE: Opioid-induced nausea and vomiting are frequently observed as an adverse effect in the treatment of cancer-related pain. The factors that affect OINV in cancer patients remain unclear. In this study, we developed a nomogram for predicting the occurrence of OINV in this population using retrospective clinical data. METHODS: We collected data from 416 cancer pain patients, 70% of whom used the training set to analyze demographic and clinical variables. We used multivariate logistic regression to identify significant factors associated with OINV. Then, we construct a prediction nomogram. The validation set comprises the remaining 30%. The reliability of the nomogram is evaluated by bootstrap resampling. RESULTS: Using multivariate logistic regression, we identified five significant factors associated with OINV. The C-index was 0.835 (95% confidence interval [CI], 0.828-0.842) for the training set and 0.810 (95% CI, 0.793-0.826) for the validation set. The calibrated curves show a good agreement between the predicted and actual occurrence of OINV. CONCLUSION: In a retrospective study based on five saliency-found variables, we developed and proved a reliable nomogram model to predict OINV in cancer pain patients. Future prospective studies should assess the model's reliability and usefulness in clinical practice.

Prevalence of opioid-induced adverse events across opioids commonly used for analgesic treatment in Japan: a multicenter prospective longitudinal study.

PURPOSE: Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks of AEs by opioid type. This study was performed to compare the prevalence of AEs across opioids commonly used for analgesic treatment in Japan. METHODS: This study was conducted as a preplanned secondary analysis of a multicenter prospective longitudinal study of inpatients with cancer pain who received specialized palliative care for cancer pain relief. We assessed daily AEs until termination of follow-up. We rated the severity of AEs based on the Common Terminology Criteria for Adverse Events version 5.0. We computed adjusted odds ratios for each AE (constipation, nausea and vomiting, delirium, and drowsiness) with the following variables: opioid, age, sex, renal dysfunction, and primary cancer site. RESULTS: In total, 465 patients were analyzed. Based on the descriptive analysis, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs among all analyzed patients, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). The multivariate logistic analysis showed that no single opioid was identified as a statistically significant independent predictor of any AE. CONCLUSION: There was no significant difference in the prevalence of AEs among oxycodone, fentanyl, hydromorphone, and tramadol, which are commonly used for analgesic treatment in Japan.

Deficiencies with CAGE-AID questionnaire in identifying nonmedical opioid use-a report of two cases.

BACKGROUND: The CAGE-AID questionnaire (Cut-down, Annoyed, Guilty, Eye-opener scale Adapted to Include Drugs) is used to screen patients for substance use disorder and nonmedical opioid use (NMOU). Major pain guidelines encourage using such screening tools for all patients including cancer patients before initiating opioids. We present two cases where the CAGE-AID results did not accurately identify the risk for NMOU. CASE DESCRIPTION: Patient 1 is a male in his 60s with metastatic prostate cancer was admitted for uncontrolled pain. Imaging revealed extensive spinal metastasis, needing initiation of methadone and hydromorphone. The CAGE-AID score was positive, placing him at risk for NMOU. This likely biased the providers, delaying opioid titration. Subsequently, doses were adjusted, and he was discharged with adequate pain control and no evidence of NMOU. Patient 2 is a male in his 40s with metastatic cholangiocarcinoma admitted for uncontrolled abdominal pain. The patient had multiple hospitalizations at different facilities with similar symptoms. The CAGE-AID score was negative. Despite this, the patient demonstrated behaviors such as demanding intravenous opioids, dose escalation, or interventions such as nerve blocks. The workup did not identify any etiology for the increased pain. The patient left the hospital against medical advice when his demands for intravenous opioids were not met. CONCLUSIONS: The CAGE-AID questionnaire alone does not accurately identify risks for NMOU. Screening tools must always be accompanied by a thorough clinical assessment of behaviors and pain mechanism. More research is needed to better characterize CAGE-AID false positives and negatives among patients with cancer pain.

[Cancer pain relief with drugs and neurolytic nerve blocks]. / A rosszindulatú daganatos fájdalom kezelése gyógyszerekkel és idegblokádokkal.

Drug therapy with non-opioid, opioid and adjuvant drugs is the mainstay of cancer pain relief. The three step analgesic ladder, published by WHO in 1986 Geneva, is useful for oncologists and general practitioners.
The first step is giving minor analgesics and adjuvant drugs; the second is giving minor analgesics, weak opioid and adjuvant drugs; the third step is giving minor analgesics, strong opioids and adjuvant drugs. For those patients who have severe pain it is a waste of time to prescribe the drugs of the first and second step, we suggest to start immediately with strong opioids!
Analgetic drugs should be given by the clock: the next dose is given before the effect of previous one has fully worn off. In this way it is possible to relieve pain continuously.
In selected cases the analgetic effect of nerve blockade is much better than that of the drug treatment. With successful blockades the patient can stop taking analgetic drugs for a long period of time and the blockades can be performed repeatedly. We briefly summarise the three most effective neuroblockades.

Increased quality of life in patients with breakthrough cancer pain after individualized therapy: the CAVIDIOM study.

Aim: To evaluate the quality of life (QoL) in patients with breakthrough cancer pain (BTcP) in Spanish medical oncology departments. Patients & methods: In a prospective, observational, multicenter study, we assessed QoL using the EQ-5D-5L instrument at baseline and after 15 and 30 days of individualized BTcP therapy, as well as BTcP characteristics and treatment. Results: Patients (n = 118) were mainly women, over 64 years old and with advanced cancer. QoL improved at 15 (p = 0.013) and 30 days (p = 0.011) versus baseline. Individualized BTcP therapy consisted mostly of rapid-onset opioids (transmucosal fentanyl at doses of 67-800 µg) according to the physician evaluation. BTcP improved, including statistically significant reductions in intensity, duration, number of episodes in the last 24 h and time to onset of BTcP relief. Conclusion: QoL increased after individualized pain therapy in patients with advanced cancer and BTcP in medical oncology departments.

Cancer patients can experience flares of pain, called breakthrough pain (BTcP), despite treatment with painkillers. Although BTcP can be excruciating, its intensity and other characteristics depend on several factors, including its treatment. However, even if treated, BTcP can impair quality of life for cancer patients. We assessed quality of life in 118 patients with advanced cancer and BTcP treated in 13 medical oncology departments across Spain. We treated BTcP with individualized therapy, taking into account both pain-related and patient-related factors. We also measured quality of life using a specific, widely-used questionnaire at the study visits: at onset of individualized pain therapy and after 3, 15 and 30 days' treatment. At each visit, flare-up pain therapy was adjusted or maintained as necessary. Throughout the study, quality of life and sleep quality improved for all participants. Furthermore, there was a greater reduction in intensity, duration and frequency of BTcP. The most common treatments for flare-ups were low doses of rapid-onset opioids (fentanyl given by sublingual, buccal or nasal administration), which were much better tolerated than high-dose opioids. Overall, the study showed that quality of life in patients with advanced cancer and BTcP increased after individualized pain therapy, mainly with low doses of rapid-onset opioids.

A Survey of Knowledge and Barriers of Healthcare Professionals toward Opioid Analgesics in Cancer Pain Management.

Purpose: Pain is among the most frequent and troubling symptoms in cancer patients. Despite the availability of updated treatment guidelines and effective pharmacological therapies, undertreatment of cancer pain remains a global problem. Opioids are the mainstay analgesics to treat moderate-to-severe cancer pain. The goal of this study was to assess the knowledge and barriers towards opioid analgesics for cancer pain management among healthcare professionals in Oncology Units in Jordan. Methods: A structured questionnaire was administered to healthcare professionals (consultant doctors, resident doctors, pharmacists, and nurses) at three Oncology Units in a cross-sectional study design. Results: A total of 201 healthcare professionals completed the questionnaire. The average age was 34.8 ± 8.1 years (range 23-58) and 49.3% of respondents were nurses. The mean score for the knowledge of opioids was 12.5 ± 3.2 out of 24 points (range 2-20). An acceptable level of knowledge was observed in 50.7% of participants, while 49.3% had poor knowledge. Knowledge items mostly answered incorrectly were related to opioid administration, pharmacology, dosing, adverse events, rotation, and toxicity. Knowledge scores were significantly higher for consultant doctors compared to pharmacists and nurses (p=0.016 and p < 0.001, respectively). Healthcare professionals who handled opioid analgesics had significantly higher mean knowledge scores than those who did not (p=0.012). Linear regression analysis revealed that being a consultant physician has an independent, statistically significant association with higher knowledge scores. Among perceived barriers to using opioids, fear of addiction by patients was the most frequently reported barrier by respondents (79.6%). Other highly recognized barriers were fear of adverse effects by patients (67.2%) and lack of training programs on opioid dosing and monitoring (63.7%). Conclusions: This study revealed major gaps in the knowledge of opioids and pain management among healthcare professionals. There is an urgent need for developing innovative interventions to improve the knowledge of opioid analgesics and the understanding of pain management guidelines among healthcare professionals in Jordan.

Consensus-Based Guidance on Opioid Management in Individuals With Advanced Cancer-Related Pain and Opioid Misuse or Use Disorder.

Importance: Opioid misuse and opioid use disorder (OUD) are important comorbidities in people with advanced cancer and cancer-related pain, but there is a lack of consensus on treatment. Objective: To develop consensus among palliative care and addiction specialists on the appropriateness of various opioid management strategies in individuals with advanced cancer-related pain and opioid misuse or OUD. Design, Setting, and Participants: For this qualitative study, using ExpertLens, an online platform and methodology for conducting modified Delphi panels, between August and October 2020, we conducted 2 modified Delphi panels to understand the perspectives of palliative and addiction clinicians on 3 common clinical scenarios varying by prognosis (weeks to months vs months to years). Of the 129 invited palliative or addiction medicine specialists, 120 participated in at least 1 round. A total of 84 participated in all 3 rounds. Main Outcomes and Measures: Consensus was investigated for 3 clinical scenarios: (1) a patient with a history of an untreated opioid use disorder, (2) a patient taking more opioid than prescribed, and (3) a patient using nonprescribed benzodiazepines. Results: Participants were mostly women (47 [62%]), White (94 (78 [65%]), and held MD/DO degrees (115 [96%]). For a patient with untreated OUD, regardless of prognosis, it was deemed appropriate to begin treatment with buprenorphine/naloxone and inappropriate to refer to a methadone clinic. Beginning split-dose methadone was deemed appropriate for patients with shorter prognoses and of uncertain appropriateness for those with longer prognoses. Beginning a full opioid agonist was deemed of uncertain appropriateness for those with a short prognosis and inappropriate for those with a longer prognosis. Regardless of prognosis, for a patient with no medical history of OUD taking more opioids than prescribed, it was deemed appropriate to increase monitoring, inappropriate to taper opioids, and of uncertain appropriateness to increase the patient's opioids or transition to buprenorphine/naloxone. For a patient with a urine drug test positive for non-prescribed benzodiazepines, regardless of prognosis, it was deemed appropriate to increase monitoring, inappropriate to taper opioids and prescribe buprenorphine/naloxone. Conclusions and Relevance: The findings of this qualitative study provide urgently needed consensus-based guidance for clinicians and highlight critical research and policy gaps.

A prospective, multicenter, open-label study of the clinical efficacy of tapentadol extended-release in the treatment of cancer-related pain and improvement in the quality of life of opioid-naïve or opioid-resistant patients.

PURPOSE: This study aimed to investigate the clinical efficacy of tapentadol extended-release (ER) on pain control and the quality of life (QoL) of patients with moderate to severe chronic cancer pain in clinical practice in Korea. METHODS: In this prospective, open-label, multicenter trial, patients with sustained cancer pain as well as chronic pain, who were or were not using other analgesics were enrolled. Thirteen centers recorded a total of 752 patients during the 6-month observation period, based on the tapentadol ER dose and tolerability, prior and concomitant analgesic treatment, pain intensity, type of pain, adverse effects, and clinical global impression change (CGI-C). Of those 752 patients, 688 were enrolled, and 650 completed the study for efficacy and adverse drug reactions; among them, 349 were cancer patients. RESULTS: Tapentadol ER significantly reduced the mean pain intensity including neuropathic pain during the observation period by 2.9 points (from a mean 7 ± 0.87 to 4.1 ± 2.02). Furthermore, QoL was observed to be significantly improved based on the CGI-C, an objective measure. CONCLUSION: This study showed that tapentadol ER was effective for treating patients with moderate to severe cancer pain and neuropathic pain, and therefore it significantly improved the patients' QoL.

Low-dose sublingual fentanyl improves quality of life in patients with breakthrough cancer pain in palliative care.

Aim: This subanalysis of the CAVIDIOPAL study evaluated the impact of individualized management of breakthrough cancer pain (BTcP) with fentanyl on the quality of life (QoL) of advanced cancer patients in Spanish palliative care units. Patients & methods: This was a prospective, observational, multicenter study. The European Organization for Research and Treatment of Cancer's QLQ-C30 questionnaire was used at baseline (V0) and visit 28 (V28). Results: Ninety-five patients were mainly treated with 67-133 µg fentanyl, showing a notable reduction in intensity (visual analog scale: 8.0 [V0] to 4.6 [V28]), frequency and duration of BTcP episodes shortly after the first 1-2 weeks of treatment, with significantly improved QoL (global health status: 31.1 [V0] to 53.1 [V28]). Conclusion: Low-dose sublingual fentanyl effectively reduced BTcP in advanced cancer patients in palliative care units, significantly improving QoL. Clinical trial registration: NCT02840500 (ClinicalTrials.gov).

After the CAVIDIOPAL study, we carried out an additional analysis to evaluate the impact of individualized management of breakthrough cancer pain, using the analgesic drug fentanyl, on quality of life (QoL) of advanced cancer patients receiving palliative care in Spain. We performed a prospective, observational, multicenter study, in which patients' QoL was assessed using a validated questionnaire at baseline (day 0) and after 28 days of fentanyl treatment. Of the 95 patients included in the study, the majority were treated with low doses of fentanyl and showed significant pain relief. The intensity, frequency and duration of breakthrough cancer pain episodes were notably reduced shortly after the first 1­2 weeks of treatment. Moreover, patients' QoL significantly improved during fentanyl treatment from baseline to day 28. A global impression of improvement was reported by both patients and clinicians.

Post-marketing surveillance of the safety and effectiveness of naldemedine in the management of opioid-induced constipation in patients with cancer pain in Japan.

PURPOSE: This prospective post-marketing surveillance (PMS) was designed to collect data on the safety and effectiveness of naldemedine in routine clinical practice in patients with opioid-induced constipation (OIC) and cancer pain in Japan and explore the characteristics of patients prone to diarrhea. METHODS: The enrolled patients received naldemedine (0.2 mg, once a day) orally for up to 12 weeks. In the safety analysis, adverse drug reactions (ADRs), including diarrhea as a special interest, were assessed. Effectiveness was evaluated, especially regarding the frequency and condition of bowel movement. RESULTS: In the safety analysis set (n = 1177), 145 ADRs occurred in 133 (11.30%) patients, and diarrhea was the most frequent event (n = 107, 9.09%). Most cases of diarrhea were non-serious (98.1%). Most ADRs were non-serious (93.8%), and they resolved within 2 weeks (75.9%). No patient characteristics influenced the risk of diarrhea development or aggravation. Both the frequency (75.0% and 83.2%) and condition of bowel movement (80.0% and 88.0%) were improved at 2 and 12 weeks, respectively in the effectiveness analysis set (n = 953). Frequency and condition of bowel movement were also improved in patients excluded (e.g., Eastern Cooperative Oncology Group performance status was ≥ 3) or with very small numbers (e.g., received weak opioid) in the clinical trials. CONCLUSIONS: This PMS indicates that naldemedine is well tolerated and effective in patients of various backgrounds in routine clinical practice who have OIC and cancer pain. TRIAL REGISTRATION: UMIN000042851.

Genetic implications in quality palliative care and preventing opioid crisis in cancer-related pain management.

The prevalence of cancer-related pain is 64% among patients with metastatic, advanced, or terminal cancer, 59% among patients undergoing anticancer treatment, and 33% among patients who completed curative treatment. According to the World Health Organization cancer pain relief guidelines, opioid analgesics are the mainstay analgesic therapy in addition to conventional first-step analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen. The indications for strong opioids have recently been expanded to include mild-to-moderate pain in addition to moderate-to-severe pain. The U.S. Centers for Disease Control and Prevention guidelines emphasize that realistic expectations should be weighed against potential serious harm from opioids, rather than relying on the unrealized long-term benefits of these drugs. Therefore, treatment strategies for both cancer-related chronic or acute pain have been unfortunately deviated from opioid analgesics. The barriers hindering adequate cancer-related pain management with opioid analgesics are related to the inadequate knowledge of opioid analgesics (e.g., effective dose, adverse effects, and likelihood of addiction or tolerance). To achieve adequate opioid availability, these barriers should be overcome in a clinically suitable manner. Genetic assessments could play an important role in overcoming challenges in opioid management. To balance the improvement in opioid availability and the prevention of opioid misuse and addiction, the following two considerations concerning opioids and genetic polymorphisms warrant attention: (A) pain severity, opioid sensitivity, and opioid tolerance; and (B) vulnerability to opioid dependence and addiction.

Frequency of and Factors Associated With Nonmedical Opioid Use Behavior Among Patients With Cancer Receiving Opioids for Cancer Pain.

IMPORTANCE: One of the main aims of research on nonmedical opioid use (NMOU) is to reduce the frequency of NMOU behaviors through interventions such as universal screening, reduced opioid exposure, and more intense follow-up of patients with elevated risk. The absence of data on the frequency of NMOU behavior is the major barrier to conducting research on NMOU. OBJECTIVE: To determine the overall frequency of and the independent predictors for NMOU behavior. DESIGN, SETTING, AND PARTICIPANTS: In this prognostic study, 3615 patients with cancer were referred to the supportive care center at MD Anderson Cancer Center from March 18, 2016, to June 6, 2018. Patients were eligible for inclusion if they had cancer and were taking opioids for cancer pain for at least 1 week. Patients were excluded if they had no follow-up within 3 months of initial consultation, did not complete the appropriate questionnaire, or did not have scheduled opioid treatments. After exclusion, a total of 1554 consecutive patients were assessed for NMOU behavior using established diagnostic criteria. All patients were assessed using the Edmonton Symptom Assessment Scale, the Screener and Opioid Assessment for Patients with Pain (SOAPP), and the Cut Down, Annoyed, Guilty, Eye Opener-Adapted to Include Drugs (CAGE-AID) survey. Data were analyzed from January 6 to September 25, 2020. RESULTS: A total of 1554 patients (median [interquartile range (IQR)] age, 61 [IQR, 52-69] years; 816 women [52.5%]; 1124 White patients [72.3%]) were evaluable for the study, and 299 patients (19.2%) had 1 or more NMOU behaviors. The median (IQR) number of NMOU behaviors per patient was 1 (IQR, 1-3). A total of 576 of 745 NMOU behaviors (77%) occurred by the first 2 follow-up visits. The most frequent NMOU behavior was unscheduled clinic visits for inappropriate refills (218 of 745 [29%]). Eighty-eight of 299 patients (29.4%) scored 7 or higher on SOAPP, and 48 (16.6%) scored at least 2 out of 4 points on the CAGE-AID survey. Results from the multivariate model suggest that marital status (single, hazard ratio [HR], 1.58; 95% CI, 1.15-2.18; P = .005; divorced, HR, 1.43; 95% CI, 1.01-2.03; P = .04), SOAPP score (positive vs negative, HR, 1.35; 95% CI, 1.04-1.74; P = .02), morphine equivalent daily dose (MEDD) (HR, 1.003; 95% CI, 1.002-1.004; P < .001), and Edmonton Symptom Assessment Scale pain level (HR, 1.11; 95% CI, 1.06-1.16; P < .001) were independently associated with the presence of NMOU behavior. In recursive partition analysis, single marital status, MEDD greater than 50 mg, and SOAPP scores greater than 7 were associated with a higher risk (56%) for the presence of NMOU behavior. CONCLUSIONS AND RELEVANCE: This prognostic study of patients with cancer taking opioids for cancer pain found that 19% of patients developed NMOU behavior within a median duration of 8 weeks after initial supportive care clinic consultation. Marital status (single or divorced), SOAPP score greater than 7, higher levels of pain severity, and MEDD level were independently associated with NMOU behavior. This information will assist clinicians and investigators designing clinical and research programs in this important field.

Pain in survivors of Ewing sarcoma: Prevalence, associated factors and prediction of recurrence.

BACKGROUND: While the prognosis of patients with Ewing sarcoma (EwS) is improving, little is known about the frequency of pain and its risk factors in survivors of EwS. This study aims to analyse the prevalence and risk factors of pain and its predictive value for recurrence. PATIENTS AND METHODS: In patients with remission after treatment of EwS, frequency and characteristics of pain within the first 5 years of follow up were assessed retrospectively. RESULTS: Of 80 patients, 37 (46%) presented with at least one episode of pain. Chronic pain (>3 months) was observed in 10 patients (13%). Experience of at least one episode of pain was associated with prior combined local treatment (surgery and radiation compared to surgery alone; odds ratio [OR] 5.83, 95% confidence interval [CI] 1.43-34.9, P = .007). A total of 59 episodes of pain were observed, including 47 acute and 12 chronic episodes. Lower limb pain accounted for 46% (27/59) of all episodes of pain, and was associated with primary tumour of the pelvis or lower extremity (OR 4.29, 95% CI 1.18-18.21, P = .025), which represented 64% (51/80) of all EwS. The positive predictive value of pain for recurrence was only 12%. CONCLUSION: Pain is a common problem in survivors of EwS, which mostly affects the lower extremity, and should be regularly assessed. Interventions to reduce pain may be particularly important in patients with combined local treatment with surgery and radiation, who seem to be at considerably increased risk for pain. Patients presenting with pain should be examined for recurrence.

Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2.

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR2) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR2-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared with matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR2 in NaV1.8-positive neurons (Par2Nav1.8), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. Par2Nav1.8 and Lgmn deletion attenuated mechanical allodynia in female mice with carcinogen-induced OSCC. Lgmn caused PAR2-dependent hyperexcitability of trigeminal neurons from WT female mice. Par2 deletion, LI-1, and inhibitors of adenylyl cyclase or protein kinase A (PKA) prevented the effects of Lgmn. Under acidified conditions, Lgmn cleaved within the extracellular N terminus of PAR2 at Asn30↓Arg31, proximal to the canonical trypsin activation site. Lgmn activated PAR2 by biased mechanisms in HEK293 cells to induce Ca2+ mobilization, cAMP formation, and PKA/protein kinase D (PKD) activation, but not ß-arrestin recruitment or PAR2 endocytosis. Thus, in the acidified OSCC microenvironment, Lgmn activates PAR2 by biased mechanisms that evoke cancer pain.SIGNIFICANCE STATEMENT Oral squamous cell carcinoma (OSCC) is one of the most painful cancers. We report that legumain (Lgmn), which exhibits maximal activity in acidic environments, cleaves protease-activated receptor-2 (PAR2) on neurons to produce OSCC pain. Active Lgmn was elevated in OSCC patient tumors, compared with matched normal oral tissue. Lgmn evokes pain-like behavior through PAR2 Exposure of pain-sensing neurons to Lgmn decreased the current required to generate an action potential through PAR2 Inhibitors of adenylyl cyclase and protein kinase A (PKA) prevented the effects of Lgmn. Lgmn activated PAR2 to induce calcium mobilization, cAMP formation, and activation of protein kinase D (PKD) and PKA, but not ß-arrestin recruitment or PAR2 endocytosis. Thus, Lgmn is a biased agonist of PAR2 that evokes cancer pain.

Pain at home during childhood cancer treatment: Severity, prevalence, analgesic use, and interference with daily life.

BACKGROUND: Pain is a common symptom in childhood cancer. Since children spend more time at home, families are increasingly responsible for pain management. This study aimed at assessing pain at home. PROCEDURE: In this longitudinal observational study (April 2016-January 2017), pain severity and prevalence, analgesic use, and pain interference with daily life (Brief Pain Inventory Short Form) were assessed for 4 consecutive days around the time of multiple chemotherapy appointments. Descriptive statistics (frequencies and percentages) were used to report pain severity (with clinically significant pain defined as: score ≥ 4 on "worst pain" or "average pain in the last 24 h"), pain prevalence, and analgesic use. Mixed models were estimated to assess whether patient characteristics were associated with pain severity, and whether pain severity was associated with interference with daily life. RESULTS: Seventy-three children (50.7% male) participated (1-18 years). A majority (N = 57, 78%) experienced clinically significant pain at least once, and 30% reported clinically significant pain at least half the time. In 33.6% of scores ≥ 4, no medication was used. We found an association between pain severity and interference with daily life: the higher the pain, the bigger the interference (estimated regression coefficient = 1.01 [95% CI 0.98-1.13]). CONCLUSIONS: The majority of children experienced clinically significant pain at home, and families frequently indicated no medication use. A stronger focus on education and coaching of families seems essential, as well as routine screening for pain in the home setting.

Ketamine mouthwash versus placebo in the treatment of severe oral mucositis pain in children with cancer: A randomized double-blind placebo-controlled trial.

BACKGROUND AND AIMS: Oral mucositis (OM) is a common and distressing toxicity in children on chemotherapy. There are a limited number of safe and effective therapeutic options available for OM. Ketamine oral rinse has shown promising results in a few studies in adults. This randomized, double-blind placebo-controlled trial aimed to test the efficacy of ketamine mouthwash in reducing chemotherapy-induced severe OM pain in children. METHODS: Children aged 8-18 years with severe OM were randomized to a single dose of ketamine mouthwash (4 mg/mL solution; dose 1 mg/kg) or a placebo. A sample size of 44 patients was determined. Pain score (6-point faces scale) was noted at baseline and 15, 30, 45, 60, 120, 180, and 240 min. The outcome variables were a reduction in pain score, need for rescue medications, and adverse events. RESULTS: The baseline characteristics were comparable in the two groups. The mean OM pain at 60 min decreased by 1.64 points (CI 1.13-2.14) in the ketamine group and 1.32 points (CI 0.76-1.87) in the placebo group (P = 0.425), with a group difference of 0.32 points. Rescue pain medication (at 60 min) was required in 13.6% in the ketamine group and 18.2% in the placebo group (P = 1.000). No significant adverse events were observed. CONCLUSIONS: Among children on cancer chemotherapy with severe OM, ketamine mouthwash at a dose of 1 mg/kg did not significantly reduce OM pain. It did not decrease the need for rescue pain medications. Further research is warranted to test higher doses of ketamine for a clinically significant effect.

Health-related Quality of Life and Pain in a Real-world Castration-resistant Prostate Cancer Population: Results From the PRO-CAPRI Study in the Netherlands.

BACKGROUND: The purpose of this study was to determine generic, cancer-specific, and prostate cancer-specific health-related quality of life (HRQoL), pain and changes over time in patients with metastatic castration-resistant prostate cancer (mCRPC) in daily practice. PATIENTS AND METHODS: PRO-CAPRI is an observational, prospective study in 10 hospitals in the Netherlands. Patients with mCRPC completed the EQ-5D, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Brief Pain Inventory-Short Form (BPI-SF) every 3 months and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Cancer Module (EORTC QLQ-PR25) every 6 months for a maximum of 2 years. Subgroups were identified based on chemotherapy pretreatment. Outcomes were generic, cancer-specific, and prostate cancer-specific HRQoL and self-reported pain. Descriptive statistics were performed including changes over time and minimal important differences (MID) between subgroups. RESULTS: In total, 151 included patients answered 873 questionnaires. The median follow-up from the start of the study was 19.5 months, and 84% were treated with at least 1 life-prolonging agent. Overall, patients were in good clinical condition (Eatern Cooperative Oncology Group performance status 0-1 in 78%) with normal baseline hemoglobin, lactate dehydrogenase, and alkaline phosphatase. At inclusion, generic HRQoL was high with a mean EQ visual analog score of 73.2 out of 100. The lowest scores were reported on role and physical functioning (mean scores of 69 and 76 of 100, respectively), and fatigue, pain, and insomnia were the most impaired domains. These domains deteriorated in > 50% of patients. CONCLUSION: Although most patients were treated with new treatments during follow-up, mCRPC has a negative impact on HRQoL with deterioration in all domains over time, especially role and physical functioning. These domains need specific attention during follow-up to maintain HRQoL as long as possible by timely start of adequate supportive care management.

The Effect of Therapeutic Exercises on Balance, Quality of Life, and Pain in Patients Who Were Receiving Neurotoxic Chemotherapy.

OBJECTIVE: The aim of the study was to evaluate the effect of lower limb strengthening and balance exercises on balance, quality of life and neuropathic pain of the cancer patients receiving neurotoxic chemotherapy. DESIGN: Patients who were planning to receive neurotoxic chemotherapy agents were included in the first group. They were trained before the neurotoxic chemotherapy sessions with the 10-wk home-based exercise program including lower limb strengthening and balance exercises. The second group of patients who had received the third cycle of neurotoxic chemotherapy had no exercise program. Both groups were evaluated after the third cycle. Neurocom Balance Master and Berg Balance Scale were used to evaluate balance. The neuropathic pain was questioned by PainDETECT questionnaire and the quality of life was assessed with the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire. RESULTS: Sixty patients were admitted to this study. Twenty-four patients were in the exercise group (F = 14, M = 10) and 36 patients were in the control group (F = 17, M = 19). Sociodemographic and clinical data of both groups were similar. Berg Balance Scale (P = 0.005), European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire global quality of life, physical function, and emotional status were higher, and symptom scores and PainDETECT questionnaire score were lower in the exercise group (P < 0.05). Balance tests were different between the groups. CONCLUSIONS: Strengthening and balance exercises have a valuable effect on balance, quality of life, and neuropathic pain in patients receiving neurotoxic chemotherapy.

Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting.

Despite remaining one of the most widely abused drugs worldwide, Cannabis sativa exhibits remarkable medicinal properties. The phytocannabinoids, cannabidiol and Δ-9-tetrahydrocannabinol, reduce nausea and vomiting, particularly during chemotherapy. This is attributed to their ability to reduce the release of serotonin from enterochromaffin cells in the small intestine, which would otherwise orchestrate the vomiting reflex. Although there are many preclinical and clinical studies on the effects of Δ-9-tetrahydrocannabinol during nausea and vomiting, little is known about the role that cannabidiol plays in this scenario. Since cannabidiol does not induce psychotropic effects, in contrast to other cannabinoids, its use as an anti-emetic is of great interest. This review aims to summarize the available literature on cannabinoid use, with a specific focus on the nonpsychotropic drug cannabidiol, as well as the roles that cannabinoids play in preventing several other adverse side effects of chemotherapy including organ toxicity, pain and loss of appetite.