Efficacy and safety of naldemedine for opioid-induced constipation in older patients with cancer: a retrospective study.

BACKGROUND: Opioids are pain relievers that are often associated with opioid-induced constipation (OIC) that worsens with age. We performed a multicenter, retrospective analysis on the efficacy and safety of naldemedine, an opioid receptor antagonist, in treating OIC in patients with cancer (age >75 years). METHODS: The electronic medical records of cancer patients who received naldemedine at 10 Japanese institutions between 7 June 2017 and August 31, 2019, were retrieved. Patients aged ≥75 years who were treated with naldemedine for the first time and hospitalized for at least 7 days before and after initiating naldemedine therapy were included in this analysis. RESULTS: Sixty patients were observed for at least 7 days before and after starting naldemedine. The response rate was 68.3%, and the frequency of bowel movements increased significantly after naldemedine administration in the overall population ( P  < 0.0001) and among those who defecated <3 times/week before naldemedine administration ( P  < 0.0001). Diarrhea was the most frequent adverse event in all grades, observed in 45% of patients, of which 92.6% were Grade 1 or 2. Grade 4 or higher adverse events, including death, were not observed. CONCLUSION: Naldemedine exhibits significant efficacy and safety in OIC treatment in older patients with cancer.

Efficacy and Safety of Naldemedine Administration for Opioid-Induced Constipation in Cancer Patients with Poor Performance Status.

Background: Constipation is a concern among patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 and 4. Objectives: To assess naldemedine's efficacy and safety in cancer patients on opioids with poor PS. Design: Multicenter, retrospective study. Setting/Subjects: Japanese cancer patients with ECOG performance status 3 or 4 who received naldemedine. Measurements: Frequency of defecations before/after naldemedine use. Responders were patients whose defecation frequency increased to ≥3 times/week, from baseline ≥1 defecations/week over seven days after naldemedine administration. Results: Seventy-one patients were analyzed; 66.1% were responders (95% confidence interval: 54.5%-76.1%). Defecation frequency increased significantly after naldemedine in the overall population (6 vs. 2, p < 0.0001) and among those who defecated <3 times/week before naldemedine (4.5 vs. 1, p < 0.0001). Diarrhea (38.0%) of all grades was the most common adverse event; 23 (85.2%) events were classified as Grade 1 or 2. Conclusion: Naldemedine is effective and safe among cancer patients with poor PS.

A Retrospective Study of the Efficacy and Safety of Naldemedine for Treatment of Opioid-Induced Constipation in Patients with Hepatobiliary Pancreatic Cancer.

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

Real-World Patient Characteristics and Treatment Patterns of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Cancer: A Multicenter Retrospective Chart Review Study.

Background and Objectives: Naldemedine is a peripherally acting µ-opioid receptor antagonist that improves opioid-induced constipation. Although clinical trials have excluded patients with poor performance status (PS) and those started on naldemedine early after opioid initiation, clinical practice has used naldemedine for the same patients. Therefore, we investigated the treatment patterns of naldemedine in a real-world setting. Materials and Methods: This was a multicenter, retrospective chart review study of opioid-treated patients with cancer receiving naldemedine. Adverse events that occurred within 7 days of naldemedine initiation were evaluated in those who received one or more doses of the same. Effectiveness was assessed in patients who used naldemedine for more than 7 days. Results: A total of 296 patients satisfied the eligibility criteria, among whom 129 (43.6%) had a PS of ≥3 and 176 (59.5%) started naldemedine within 2 weeks of opioid initiation. Moreover, 203 (79.6%) patients had ≥3 bowel movements per week. Incidences of all grades of diarrhea and abdominal pain were 87 (29.4%) and 12 (4.1%), respectively. No patient had grade 4 or higher adverse events. Conclusions: Although nearly half of the patients receiving naldemedine in clinical practice belonged to populations that were not included in the clinical trials, our results suggested that naldemedine in clinical practice had the same efficacy and safety as that in clinical trials.

CT-guided nerve block: a review of the features of CT fluoroscopic guidance for nerve blocks.

Nerve blocks are an attractive interventional therapy in pain medicine. Several image guidance methods are available to secure the safety, accuracy, and selectivity of the nerve block. Computed tomography (CT) guidance provides a clear view of the vital viscera and vessels that should be avoided by the needle, and accurate placement of the needle tip before neuro-destructive procedures. A recent advance in CT technology is multi-slice CT fluoroscopy, which allows for rapid and easy correction of needle tip placement during insertion. To reduce the radiation dose for both patients and staff, the lowest radiation setting, intermittent quick-check fluoroscopy, and shortening of the planning scan should be used. Preliminary CT scanning with excellent spatial resolution may facilitate the application of CT fluoroscopic guidance to various types of nerve blocks. Here we review celiac plexus and splanchnic nerve blocks, trigeminal nerve block, neurolytic sympathectomy, and spinal intervention performed under CT guidance. Additional large-scale studies are needed to optimize the use of image guidance, especially CT fluoroscopy guidance, for nerve blocks.

Location of major vessels in prone-positioned patients undergoing percutaneous lumbar sympathectomy.

INTRODUCTION: The topographic relationship between major vessels and the sympathectomy target is not identical across patients and may not be clear, especially in patients in the prone position. The aim of this study was to provide anatomic data regarding the location of the major vessels (i.e., vena cava and aorta) based on computed tomography (CT) images obtained during lumbar sympathectomy under CT fluoroscopic guidance. METHODS: Thirty-six patients with peripheral arterial occlusive disease or chronic pain syndrome were treated using fluoroscopic CT-guided percutaneous lumbar sympathectomy between April 2006 and March 2010. We analyzed the shortest distances between the sympathectomy target and the major vessels, and the relationship between the location of the major vessels and the vertebral anterior line using CT images obtained during the procedure. RESULTS: At the L3 level, the shortest distances from the right side target to the inferior vena cava were significantly shorter than the other distances (P < 0.05). In 11 of 36 patients (30.6%), the IVC was located dorsal to the vertebral anterior line at the L3 level. CONCLUSION: Needle insertion for right side sympathectomy at the L3 level may present a higher risk of major vessel puncture than sympathectomy at other sites. CT guidance is recommended for lumbar sympathectomy to reduce the risk of vascular puncture.

Regurgitant leak from the area between the stent post and the sewing ring of a stented bovine pericardial valve implanted in the aortic valve position.

Biologic valves can sometimes have a small closure or leakage backflow jet originating from the central coaptation point. This is physiologic regurgitation that usually only requires monitoring, and not treatment.Another non-central transvalvular leakage is occasionally seen in both porcine and pericardial valves and originates from the base of the stent post. Typically, it spontaneously decreases or even disappears by the end of the surgery, after administration of protamine. This leak, however, needs to be distinguished from abnormal paravalvular leakages, especially if the regurgitation is relatively large, as this may require an extra cardio-pulmonary bypass (CPB) run.In our case with stented bovine pericardial valves, detailed transesophageal echocardiography (TEE) examination immediately after CPB showed oblique and turbulent flow, which originated from the base of the stent post and flowed toward the anterior mitral leaflet. An extra CPB run, assessment of the cause of the leakage, and restoration if necessary, might have been required if the leakage did not improve or was exacerbated, because contact of the anterior mitral valve leaflet by the oblique flow is associated with the risks of infective endocarditis and hemolysis. Detailed TEE examination accurately delineated the site of the leak, which was subsequently found to originate from the site between the anterior stent post and the sewing ring. The leakage in this case was classified as non-paravalvular, non-central leakage within the sewing ring. Accurate diagnosis of the leakage by intra-operative TEE led to the decision to administer protamine and to adopt a wait-and-watch approach.

Technical communication: percutaneous radiofrequency mandibular nerve rhizotomy guided by high-speed real-time computed tomography fluoroscopy.

We present a new method of percutaneous radiofrequency mandibular nerve rhizotomy for pain relief in the mandibular region, in which needle placement is guided by high-speed real-time computed tomography (CT) fluoroscopy. Eleven patients (13 procedures) with idiopathic trigeminal neuralgia underwent the procedure. CT fluoroscopy simultaneously provided 3 slices (1-mm interval series, craniocaudally) in 1 fluoroscopic view, allowing for accurate needle placement. Trigeminal neuralgia improved in all patients without severe complications. The mean numerical rating scales of pain intensity (+ or - sd) decreased from 6.5 (+ or - 1.8, pretreatment) to 1.8 (+ or - 1.7, 1 month after treatment) and to 0.9 (+ or - 1.0, 3 months after treatment). Our limited-case series suggests potential advantages for the new CT fluoroscopy guidance, but these findings await confirmation from randomized controlled trials and large-case series.

Percutaneous radio-frequency thermocoagulation of the Gasserian ganglion guided by high-speed real-time CT fluoroscopy.

INTRODUCTION: Although Gasserian ganglion block is an established treatment for trigeminal neuralgia, the foramen ovale cannot always be clearly visualized by classical X-ray radiography. We present a new method for percutaneous radio-frequency thermocoagulation of the Gasserian ganglion, in which computed tomography (CT) fluoroscopy is used to guide needle placement. METHODS: In the present study, 15 patients with trigeminal neuralgia underwent percutaneous radio-frequency thermocoagulation of the Gasserian ganglion guided by high-speed real-time CT fluoroscopy. RESULTS: Trigeminal neuralgia was improved in all patients after treatment without any severe complications. Moderate dysesthesia occurred in only one case. CONCLUSION: CT fluoroscopy-guided percutaneous radio-frequency thermocoagulation of the Gasserian ganglion was safe, quick, and effective for patients with intractable idiopathic trigeminal neuralgia.

Anatomic analysis of computed tomography images obtained during fluoroscopic computed tomography-guided percutaneous lumbar sympathectomy.

PURPOSE: The fluoroscopic computed tomography (CT)-guidance technique increases the accuracy and safety of needle placement for percutaneous lumbar sympathectomy. The aim of the present study was to provide anatomic data from CT images and to discuss the safest route for needle insertion. METHODS: We retrospectively analyzed CT images that were obtained from 25 patients (14 men, 11 women; 37-89 years of age [mean, 68.4 years]) during fluoroscopic CT-guided percutaneous lumbar sympathectomy. The anatomy around the inserted needle was measured and the correlations between patient characteristics and the procedure-related distances were assessed. RESULTS: The distance from the midline (spinous process) to the entry point and the depth to the target site correlated with body size, especially height and weight. The maximal distance from midline to the insertion point in the range of safe needle insertion at L2 was less than 7.0 cm in approximately 20% of the patients. CONCLUSION: The present study was performed to determine the anatomic details required to guide safe percutaneous lumbar sympathectomy based on CT images. The use of CT guidance is recommended for lumbar sympathectomy, especially at the L2 spinal level.

A novel bFGF-GH injection therapy for two patients with severe ischemic limb pain.

Severe ischemic pain is difficult to treat with a single therapy. Although modern angiogenic therapies have been used in patients with peripheral arterial occlusive diseases, a regimen combining novel angiogenic therapy and classic nerve blocks, including sympathectomy, has not been discussed to date. In this case report, we present two patients with peripheral arterial occlusive disease who were first treated with medication and lumbar sympathectomy, and then with a novel gelatin hydrogel drug-delivery system loaded with basic fibroblast growth factor. The gelatin hydrogel combined with recombinant basic fibroblast growth factor was injected intramuscularly into the ischemic limbs. In the first patient, with arteriosclerosis obliterans, a foot ulcer was healed, and the original score for resting pain (visual analogue scale, 5/10) was decreased to 0/10. In the second patient, with Buerger's disease, a large toe ulcer was healed, and his resting pain (visual analogue scale, 8/10) was decreased to 1/10. Some other parameters, such as skin surface temperature, transcutaneous oxygen partial pressure, and pain-free walking distance, were also improved in both patients after the combined therapy. A multimodal approach is necessary to treat severe ischemic pain. Novel angiogenic therapy combined with nerve blocks seems to be a promising option in patients with severe pain.

Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats.

PURPOSE: Systemic ketamine suppresses several types of chronic pain. Although ketamine is used as a general anesthetic agent, the analgesic effect of systemic ketamine for early-stage postoperative pain is not clear. We investigated the efficacy and mechanism of systemic ketamine in a rat model of postoperative pain. METHODS: An incision was made in the plantar aspect of the left hind paw in male Wistar rats. Mechanical hypersensitivity was measured using calibrated von Frey filaments. The anti-hypersensitivity effect of systemic or intrathecal administration of ketamine was determined every hour after making the incision. We examined the effects of intrathecal pretreatment with yohimbine, an alpha2-adrenoceptor antagonist, and methysergide, a serotonergic receptor antagonist, on the anti-hypersensitivity effect of ketamine. We also examined the effect of systemic ketamine on the c-fos immunoreactivity in the spinal cord. RESULTS: Systemic administration of ketamine at doses from 3 to 30 mg.kg(-1) produced anti-hypersensitivity effects in a dose-dependent manner. Intrathecal administration of ketamine had no effect. There was no significant difference between effects of pre- and post-incisional administration. Intrathecal pretreatment with yohimbine (10 microg) or methysergide (15 microg) completely reversed the anti-hypersensitivity effects of systemic ketamine. Systemic ketamine reduced fos expression in laminae I-II in the dorsal horn of the lumbar spinal cord ipsilateral to the paw incision. CONCLUSIONS: The results suggest that systemic administration of ketamine perioperatively suppresses early-stage postoperative pain via monoaminergic descending inhibitory pathways.

Percutaneous radiofrequency lumbar facet rhizotomy guided by computed tomography fluoroscopy.

X-ray fluoroscopy-guided percutaneous radiofrequency facet rhizotomy is used to treat chronic low back pain. The traditional fluoroscopic approach to the medial branch of the posterior rami, however, is associated with a small incidence of complications. We describe a new method for radiofrequency lumbar facet rhizotomy in which computed tomography (CT) fluoroscopy is used to guide needle placement. Three patients with chronic intractable low back pain underwent CT fluoroscopy-guided percutaneous facet rhizotomy. After the safest and shortest route to the target site was determined on the CT image, the needle was advanced along the predetermined route under real-time CT fluoroscopy. When the needle tip was located at the target site, electrical stimulation was applied to verify proper electrode placement. After confirming the clinical effect and lack of complications under test block with a local anesthetic, denervation was performed using radiofrequency current. Pain scores of all patients were reduced after the procedure without any complications such as paralysis or neuritic pain. None of the patients complained of severe discomfort during the procedure. CT fluoroscopy-guided percutaneous lumbar facet rhizotomy appears to be safe, fast, and effective for patients with lumbar facet pain.

Thermogangliolysis of the Gasserian ganglion under computed tomography fluoroscopy.

Gasserian ganglion block is an established treatment for trigeminal neuralgia. A landmark approach assisted by X-ray fluoroscopy is the most common method; however, visualization of the foramen ovale is difficult in some cases. Here we report two cases in which a novel technique using modern computed tomography (CT) fluoroscopy was employed. A 63-year-old woman suffering pain in the maxillary nerve area was treated by thermogangliolysis under CT fluoroscopy. The patient was positioned on a CT stage with the head in an overhanging position. The CT gantry was set at an oblique angle to obtain a coronal view of the foramen ovale. The safest and shortest route to the foramen was designed using the CT image and a 22-gauge insulated needle was advanced following the designed route under CT fluoroscopy. The effect of the nerve block was estimated by injection of a test dose of mepivacaine, after which the ganglion was thermally coagulated at 90 degrees C. Satisfactory analgesia was obtained in this case without any complications. Another patient (65 years old) was also treated by the same technique, and satisfactory pain relief was obtained. In conclusion, CT fluoroscopy-guided Gasserian ganglion thermolysis is considered a safe, quick, and effective treatment for trigeminal neuralgia.

The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.

Antidepressants are often used to treat neuropathic pain. In the present study, we determined the antiallodynic effects of selective monoamine reuptake inhibitors in the spinal cord in a rat model of neuropathic pain. Mechanical allodynia was produced by tight ligation of the left L5 and L6 spinal nerves and determined by applying von Frey filaments to the left hindpaw. A serotonin noradrenaline reuptake inhibitor, milnacipran, a selective serotonin reuptake inhibitor, paroxetine, or a selective noradrenaline reuptake inhibitor, maprotiline, was administered intrathecally via a chronically implanted catheter. Milnacipran produced dose-dependent antiallodynic effects at doses between 3 microg and 100 microg. The effect lasted for 7 h after injection of 100 microg (P < 0.05). The antiallodynic effect of 30 microg of milnacipran was attenuated by intrathecal coadministration of 30 microg of yohimbine, an alpha(2)-adrenoceptor antagonist, 30 microg of methysergide, a serotonin receptor antagonist, or 30 microg of atropine, a muscarinic receptor antagonist (P < 0.01, respectively). Intraperitoneal administration of milnacipran had no antiallodynic effects at doses of 3 to 30 mg/kg. Antiallodynic effects were not produced by intrathecal administration of paroxetine (10 to 100 microg) or maprotiline (10 to 100 microg). These findings suggest that simultaneous inhibition of serotonin and noradrenaline reuptake in the spinal cord is essential to mediate antiallodynic effects. Milnacipran might be effective for suppression of neuropathic pain.

[Postoperative laryngeal edema presumably due to hypoalbuminemia causing acute airway obstruction after extubation in a patient after nephrectomy].

We report here a case of upper airway obstruction occurring after extubation in a 55-yr-old 60 kg man after elective nephrectomy. Anesthesia was maintained with O2 (33%), N2O, sevoflurane (1.5-2%), and propofol infusion (2 mg x kg(-1) x hr(-1)). Blood loss was 1,965 ml, part of which was substituted by blood transfusion and albumin infusion. After surgery, the patient recovered uneventfully and could be extubated shortly. Twenty minutes after extubation, he developed dyspnea progressively with stridor and became cyanotic despite the use of oxygen mask and assisted ventilation. Oxygen saturation decreased gradually, and bradycardia (<30 beats x min(-1)) and severe hypotension were also observed. Cardiopulmonary resuscitation using epinephrine was immediately started. Re-intubation of the trachea was difficult due to severe edema, but eventually performed using a tube of a smaller size (internal diameter 7.0 mm). Subsequent investigations using a fiberscope confirmed extensive soft tissue swelling, maximal at the level of the vocal cord and extending up- and down-wards to the trachea, indicating that the obstruction is caused by severe laryngeal edema. We believe that edema may have been caused by hypoalbuminemia (1.3 g x dl(-1)) at the end of operation. Therefore, it should be noted that hypoalbuminemia may cause laryngeal edema leading to acute airway obstruction.

Oral etodolac, a COX-2 inhibitor, reduces postoperative pain immediately after fast-track cardiac surgery.

PURPOSE: The present study was designed to evaluate the efficacy of a cyclooxygenase (COX)-2 inhibitor, etodolac, on postoperative pain after fast-track cardiac surgery, and to examine the changes in plasma etodolac concentration after oral administration. METHODS: Thirty patients scheduled for elective coronary artery bypass grafting (CABG) surgery were randomly assigned preoperatively in a double-blind fashion to receive either vehicle ( n = 15) or etodolac 400 mg ( n = 15) via a gastric tube at the end of the surgery. Standardized fast-track cardiac anesthesia was used. In both groups, postoperative pain was treated with buprenorphine suppository. Visual analogue pain scores (VASs) were recorded immediately after extubation and at 24 h after surgery. Plasma etodolac concentration was measured at 1, 2, and 6 h after administration ( n = 8). RESULTS: No difference was detected in time to extubation between the etodolac group (209 +/- 85 min, mean +/- SD) and the vehicle group (207 +/- 98 min). VASs were significantly lower in the etodolac (2.3 +/- 2.1) vs the vehicle group (5.8 +/- 2.0) immediately after extubation ( P = 0.009), but no difference was detected in pain scores at 24 h after surgery, or in the amount of buprenorphine administered in the intensive care unit (ICU), or in the incidence of side effects. Plasma etodolac concentration was within the pharmaceutically recommended range at 1 h, 2 h, and 6 h after administration. CONCLUSION: The oral use of etodolac with rectal buprenorphine reduces pain scores immediately after cardiac surgery without an increase in side effects.