Predictors of Opioid Resistance: An Investigation in Cancer Pain.

Appropriate use of opioid analgesics according to the World Health Organization pain relief ladder has provided pain relief to many patients with cancer pain. However, a proportion of patients fail to achieve sufficient pain relief and develop opioid resistance. Individual risk factors may relate to opioid resistance. Therefore, we conducted a historical cohort study to identify risk factors for opioid resistance and to construct an index to predict it. We investigated salient factors at the time of opioid initiation in the medical records of 233 patients. The outcome was the achievement of stable pain at 14 days after opioid introduction. We identified factors contributing to opioid resistance by multivariate analysis (p < 0.05). We created a resistance score from the regression equation of the identified factors to predict opioid resistance. Forty-nine (21.0%) patients were opioid resistant without achieving the outcome. Age, neuropathic pain, and alkaline phosphatase were extracted as significant factors for opioid resistance (p < 0.05). A resistance score was created from these factors and classified into binary values, the sensitivity was 80.6% and the negative predictive value was 91.6%. The findings suggest that the resistance score could be a sensitive predictor of opioid resistance before opioid initiation.

Predictive Factors of Opioid-Induced Nausea in Cancer Patients.

Approximately 30% of patients experience nausea after initiation of opioid therapy, which can lead to poor quality of life. We aimed to identify risk factors for opioid-induced nausea at the initiation of opioid therapy by conducting a retrospective review of medical records of patients diagnosed by palliative care specialists with solid cancer and pain at the lesion site at Showa University Hospital between June 2005 and June 2011. The primary endpoint was the development of nausea grade ≥1 according to the Common Terminology Criteria for Adverse Events version 4.0 within 48 hours of initiation of opioid therapy. The median age of the 134 enrolled patients was 67.7 (range 28-95) years. Fifty-three percent were male and 44% had gastrointestinal cancer. Furthermore, 22.4% had opioid-induced nausea. Age (odds ratio (OR) 1.74; 95% confidence interval (CI), 1.13-2.69), edema (OR 5.83; 95% CI, 1.22-28.19), and gastrointestinal cancer (OR 2.61, 95% CI 1.07-6.36) were significantly associated with opioid-induced nausea. Prophylactic antiemetics were found to be ineffective.

Effects of administering different vehicles via single intratracheal instillation on responses in the lung and pleural cavity of Crl:CD(SD) rats.

Intratracheal instillation is the introduction of a substance directly into the trachea. Intratracheal instillation has been used to investigate the lung toxicity of several chemicals and requires the suspension or dissolution of test material in a vehicle for even dispersal throughout the lung. Importantly, the toxicities of vehicles used in intratracheal instillation studies are generally considered to be insignificant. Hence, evaluating the influence of different vehicles on the lung due to intratracheal instillation is crucial. We examined the toxic effects of pure water, saline, phosphate buffered saline (PBS), 0.5% Kolliphor® P188 (KP188), 0.1% Tween 20 in saline, and 1.0% BSA in PBS. These vehicles were administered to male Crl:CD(SD) rats by a single intratracheal instillation. On day 3, broncho-alveolar lavage fluid (BALF) from the right lung was collected and processed for cell counting and biochemical analysis, while the left lung was used for histopathological examination. Accumulation of alveolar macrophages was observed in all vehicle-treated groups but was minimal in the group administered saline, somewhat higher in the groups administered pure water, PBS, 0.1% Tween 20, and 1% BSA, and notably higher in the group administered 0.5% KP188. The results from BALF analysis indicated that intratracheal instillation of 0.5% KP188 also induced alveolar damage. Additionally, administering pure water did not appear to cause tissue damage. Eosinophil infiltration in the interstitial regions was histopathologically observed. Altogether, the results of this study are helpful for the selection of appropriate vehicles for use in intratracheal instillation studies.

MWCNT-7 administered to the lung by intratracheal instillation induces development of pleural mesothelioma in F344 rats.

Multi-walled carbon nanotube-7 (MWCNT-7) fibers are biopersistent and have a structure similar to asbestos. MWCNT-7 has been shown to induce malignant mesothelioma when administered by intrascrotal or intraperitoneal injection in rats and mice, and an inhalation study demonstrated that rats exposed to respirable MWCNT-7 developed lung tumors. MWCNT-N, which is similar to MWCNT-7, was shown to induce both lung tumors and malignant mesothelioma in rats when administered by trans-tracheal intrapulmonary spraying (TIPS). The present study was performed to investigate the carcinogenicity of MWCNT-7 when administered by the TIPS method. Ten-week-old male F344/Crj rats were divided into 3 groups and administered 0.5 mL vehicle, 0.250 µg/mL MWCNT-7 or 0.250 µg/mL crocidolite once a week for 12 weeks (total doses of 1.5 mg/rat) and then observed for up to 104 weeks. Rats in the MWCNT-7 group began to die from pathologies associated with the development of malignant mesothelioma 35 weeks after the final TIPS administration. Overall, the incidence of malignant mesothelioma in the MWCNT-7 group was significantly higher than in the vehicle or crocidolite groups.

Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug.

Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia.

[Trial of Micro CT Scanner SKYSCAN1176 for the Imaging of the Guinea Pig Cochlea in vivo].

The usefulness of the micro CT scanner system SKYSCAN1176 was evaluated for the study of the guinea pig cochlea. Each slice of the section was 9 µm and we were able to identify each ossicles, modiolus, upper, middle, and basal turn of the cochlea. This scanner enables us to observe inner ear structure repeatedly in vivo.

Ototoxicity of acetic acid on the guinea pig cochlea.

BACKGROUND: To evaluate the ototoxicity of acetic acid solutions. METHODS: Compound action potentials (CAPs) of the eighth nerve were measured in guinea pigs before and after the application of acetic acid in the middle ear cavity. The pH values of the acetic acid solutions were pH 3.0, 4.0, and 5.0, and the application times were 30 min, 24 h, and 1 week. RESULTS: Acetic acid solution (pH 3.0, N = 3) for 30 min caused no significant elevation in CAP threshold at 4 kHz, but a significant elevation in the threshold was noted for 8 kHz and clicks. Acetic acid solutions (pH 4.0 N = 6, 5.0 N = 5) for 30 min caused no significant elevation in CAP. Acetic acid solution (pH 4.0) for 24 h (N = 5) caused significant elevations of the CAP threshold for 8 kHz, 4 kHz, and for clicks. Acetic acid (pH 5.0) for 24 h (N = 3) caused a significant elevation of the CAP threshold for 4 kHz, but not for 8 kHz or clicks. Acetic acid (pH 5.0) for 1 week (N = 3) caused a small but significant elevation CAP the threshold for 8 kHz and 4 kHz tone bursts, but no significant change was noted for clicks. CONCLUSIONS: We found a significant toxic effect of acetic acid in guinea pigs on eighth-nerve compound action potentials when the pH was 5.0 or lower. Clearly, the stronger the acidity, and longer the exposure time, the more the CAP threshold was elevated.

Goshajinkigan reduces bortezomib-induced mechanical allodynia in rats: Possible involvement of kappa opioid receptor.

In the present study, we investigated the effect of a Kampo medicine Goshajinkigan (GJG) on the bortezomib-induced mechanical allodynia in von Frey test in rats. The single administration of tramadol (10 mg/kg), GJG (1.0 g/kg) and its component processed Aconiti tuber (0.1 g/kg) significantly reversed the reduction in withdrawal threshold by bortezomib. These effects were abolished by the intrathecal injection of nor-binaltorphimine (10 µg/body), kappa opioid receptor antagonist. These findings suggest that kappa opioid receptor is involved in the effect of GJG on the bortezomib-induced mechanical allodynia.

Behavioral and pharmacological characteristics of bortezomib-induced peripheral neuropathy in rats.

Bortezomib, an effective anticancer drug for multiple myeloma, often causes peripheral neuropathy which is mainly characterized by numbness and painful paresthesia. Nevertheless, there is no effective strategy to escape or treat bortezomib-induced peripheral neuropathy (BIPN), because we have understood few mechanism of this side effect. In this study, we evaluated behavioral and pathological characteristics of BIPN, and investigated pharmacological efficacy of various analgesic drugs and adjuvants on mechanical allodynia induced by bortezomib treatment in rats. The repeated administration of bortezomib induced mechanical and cold allodynia. There was axonal degeneration of sciatic nerve behind these neuropathic symptoms. Furthermore, the exposure to bortezomib shortened neurite length in PC12 cells. Finally, the result of evaluation of anti-allodynic potency, oral administration of tramadol (10 mg/kg), pregabalin (3 mg/kg), duloxetine (30 mg/kg) or mexiletine (100 mg/kg), but not amitriptyline or diclofenac, transiently relieved the mechanical allodynia induced by bortezomib. These results suggest that axonal degeneration of the sciatic nerve is involved in BIPN and that some analgesic drugs and adjuvants are effective in the relief of painful neuropathy.

Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined from oral morphine rescue doses in the treatment of breakthrough cancer pain.

OBJECTIVE: A randomized, crossover, double-blinded placebo-controlled and non-blinded active drug-controlled, comparative clinical trial was conducted to evaluate the efficacy and safety of sublingual fentanyl tablet. METHODS: Subjects were patients treated with strong opioids at fixed intervals for chronic cancer pain and with oral morphine as rescue medication for breakthrough pain. Sublingual fentanyl was administered at doses that were 1/25th (high dose) and 1/50th (low dose) of the dose of rescue morphine and was compared with placebo and oral morphine. The primary endpoint was pain intensity difference at 30 min after administration. (Clinical Trials Government; NCT00684632). RESULTS: Fifty-one patients were enrolled in the investigation. Their mean pain intensity in visual analog scale before rescue medication prior to the investigation was 60.96 (16.44, standard deviation) mm. Compared with placebo, the low and high doses of sublingual fentanyl showed significant analgesic effects (least squares mean difference, 4.54 and 8.49 mm; P = 0.014, P < 0.001, respectively). Adverse reactions were observed in 17.6%, the most common being constipation, nausea and somnolence. The incidence of adverse reactions during the high-dose administration period was higher than that during the low-dose and active control drug administration periods. CONCLUSIONS: Patients treated with strong opioid analgesics at fixed intervals for chronic cancer pain and with oral morphine at doses up to 20 mg as rescue medication were investigated. The doses of sublingual fentanyl to treat breakthrough pain were determined from rescue morphine doses by use of conversion ratios. In these patients, administration of sublingual fentanyl at doses determined by a conversion ratio of 1/50 was effective and safe. Further studies are needed to validate the use of this conversion method.

Ototoxicity of gentian violet on the guinea pig cochlea.

PURPOSE: Gentian violet (GV) is an antimicrobial and antifungal agent that has been used widely to treat intractable discharge in the ear. The purpose of this report is to warn clinicians about the ototoxic effect of GV in the middle ear. MATERIALS AND METHODS: GV ototoxicity was evaluated by measuring compound action potentials (CAPs) in the VIIIth nerve in adult Hartley guinea pigs. The middle ear cavities of the animals were filled with GV solution (0.5% or 0.13%), and CAPs were measured after intervals of 5 and 30 minutes and 1, 2, 6, and 24 hours. After all measurements were completed, the temporal bones were harvested for histopathologic evaluation. Celloidin-embedded specimens were cut into 20-µm slices and examined using light microscopy. The bacteriostatic activity of GV was evaluated using a disk-diffusion assay. RESULTS: A 0.5% GV solution produced a mild elevation in the CAP threshold at 30 minutes, a greater reduction at 1 hour, and complete abolishment of CAP at 24 hours. A 0.13% GV solution caused mild elevation in the CAP threshold at 2 hours and severe elevation at 6 hours. Massive new bone formation was found in the middle ear cavity at 6 weeks. GV concentrations of 0.13% and 0.06% were effective against all bacteria tested, with the exception of Pseudomonas aeruginosa. CONCLUSIONS: Although GV has marked antibacterial and antifungal activities, its use should be limited to the external ear canal. GV exerts an ototoxic effect in a concentration- and time-dependent manner, and so the use of this drug in the middle ear cavity is not recommended.

Ototoxicity of Burow solution on the guinea pig cochlea.

PURPOSE OF THE STUDY: The aim of the present study was to evaluate the ototoxicity of Burow solution. PROCEDURES: Compound action potentials (CAPs) of the eighth nerve were measured before and 30 minutes after the application of the Burow solution in the middle ear cavity. RESULTS: Use of the original Burow solution (pH 3.5) for 30 minutes caused a significant reduction of click sounds. A 2-fold diluted Burow solution (pH 4.4) for 30 minutes caused no reduction in CAP threshold. Burow solution, pH adjusted to 4.5, caused no changes in CAP threshold at 30 minutes. At 24 hours, Burow solution (pH 3.5) caused complete abolition of CAP. CONCLUSIONS: Burow solution is ototoxic in the guinea pig when applied in the middle ear cavity for 30 minutes or longer. In the clinical settings, it is advisable to avoid allowing the solution to contact the round window for extended times.

Modulation of somatosensory abilities and the feeling of ear fullness in patients with acute sensorineural hearing loss.

OBJECTIVE: Patients with acute sensorineural hearing loss (ASNHL) often complain of a feeling of ear fullness (FEF) that is similar to the sensation experienced during barometric pressure changes. This suggests that modulation of somatosensory abilities may relate to the manifestation of FEF, whereas it cannot simply be assumed that somatosensory abilities would be directly affected by ASNHL. To examine this possible relationship, we estimated somatosensory abilities of the tympanic membrane, and investigated the relationship between them and the manifestation of FEF. METHODS: To estimate somatosensory abilities of the tympanic membrane, 83 new patients demonstrating unilateral sudden deafness were studied. The air pressure was loaded through an exclusive device on the external auditory canals in order to measure the minimum change in air pressure sensed by the subjects. The minimum pressure was defined as the minimum sensory threshold for air pressure loading (MSTAP; daPa). We estimated patient's somatosensory abilities and inquired about their experiences with FEF at the first medical examination (point 1) and at the time a steady audiogram was obtained (point 2). We also estimated MSTAP in 65 volunteers (130 ears) with no history of ear diseases and compared their MSTAP with that of sudden deafness patients. RESULTS: MSTAP values (-64.0±32.2daPa, 60.5±26.0daPa) on the affected side with both negative pressure and positive pressure measured at point 1 were significantly higher than those (-40.7±15.0daPa, 40.0±12.7daPa) obtained at point 2 in all sudden deafness patients (p=0.0001, p=0.0001). There was no difference between MSTAP values (-39.6±10.7daPa, 39.9±11.4daPa) in normal subjects and those obtained at point 2 in all sudden deafness patients. On the other hand, significant differences of MSTAP with negative pressures between the affected and unaffected sides at point 1 were seen in 32 patients, and manifestation of FEF showed an insignificant association in these 32 patients (p<0.05). CONCLUSION: Modulation of somatosensory abilities in ASNHL seemed to be the best possible explanation for results, suggesting that a rise in MSTAP may somehow be associated with FEF. Although it cannot be verified by result of the current study, consideration of the previous literature suggests that the phenomenon may be caused by cross-modality of hearing and somatosensory abilities.

Multiple evaluation of a hospital-based palliative care consultation team in a university hospital: activities, patient outcome, and referring staff's view.

OBJECTIVE: Although the number of hospital-based palliative care consultation teams (PCCTs) is rapidly increasing in Japan, there is limited information available concerning the activities and usefulness of PCCT in the country. The aim of this study is to clarify the activities, patient outcome, and referring staff's view of an established PCCT in Japan. METHOD: This was a prospective study to follow patients referred to a PCCT for 28 days over a 1-year period. Patients were assessed by the Support Team Assessment Schedule-Japanese version (STAS-J) and EORTC QLQ C-30 at the time of referral and on days 7, 14, and 28. A staff survey was implemented using a questionnaire after each observation period. RESULTS: Of 180 patients referred, 53 patients were eligible for the study. Although the median of the number of the reasons for referral was 1, the PCCT provided several kinds of support: pain management, 94%; emotional support for the patient, 49%; and emotional support for the family, 36%. On day 7 after referral, of the items of STAS-J and the EORTC QLQ C-30 subscales, only insomnia improved significant whereas "other physical symptoms" and constipation were significantly exacerbated. In the staff survey, of the 98 respondents, more than 90% considered the effect of the PCCT as "excellent" or "good" and were satisfied with the support provided. SIGNIFICANCE OF RESULTS: This study showed that the PCCT performed comprehensive assessments on referred patients and provided extra support. No patient's QOL 1 week after referral was improved with the exception of insomnia. Referring staff highly evaluated the activities of the PCCT. In the evaluation of PCCTs, further research about the variation of clinical activities of PCCTs, their applicability, and benefit is needed.

Treatment efficacy of neural blockade in specialized palliative care services in Japan: a multicenter audit survey.

More than 85% of cancer-related pain is pharmacologically controllable, but some patients require interventional treatments. Although audit assessment of these interventions is of importance to clarify the types of patients likely to receive benefits, there have been no multicenter studies in Japan. The primary aims of this study were (1) to clarify the frequency of neural blockade in certified palliative care units and palliative care teams, (2) determine the efficacy of interventions, and (3) explore the predictors of successful or unsuccessful intervention. All patients who received neural blockade were consecutively recruited from seven certified palliative care units and five hospital palliative care teams in Japan. Primary responsible physicians reported pain intensity on the Support Team Assessment Schedule, performance status, communication levels on the Communication Capacity Scale, presence or absence of delirium, opioid consumption, and adverse effects before and one week after the procedure on the basis of retrospective chart review. A total of 162 interventions in 136 patients were obtained, comprising 3.8% of all patients receiving specialized palliative care services during the study period. Common procedures were epidural nerve block with local anesthetic and/or opioids (n = 84), neurolytic sympathetic plexus block (n = 24), and intrathecal nerve block with phenol (n = 21). There were significant differences in the frequency of neural blockade between palliative care units and palliative care teams (3.1% vs. 4.6%, respectively, P = 0.018), and between institutions whose leading physicians are anesthesiologists or have other specialties (4.8% vs. 1.5%, respectively, P < 0.001). Pain intensity measured on the Support Team Assessment Schedule (2.9 +/- 0.8 to 1.7 +/- 0.9, P < 0.001), performance status (2.7 +/- 1.0 to 2.4 +/- 1.0, P < 0.001), and opioid consumption (248 +/- 348 to 186 +/- 288 mg morphine equivalent/day, P < 0.001) were significantly improved after interventions. There was a tendency toward improvement in the communication level measured on the Communication Capacity Scale. There was no significant improvement in the prevalence of delirium, but six patients (32%) recovered from delirium after interventions. Adverse effects occurred in 9.2%, but all were predictable or transient. No fatal complications were reported. Pain intensity was significantly more improved in patients who survived 28 days or longer than others (P = 0.002). There were no significant correlations of changes in pain intensity with the performance status or previous opioid consumption. In conclusion, neural blockade was performed in 3.8% of cancer patients who received specialized palliative care services in Japan. Neural blockade could contribute to the improvement of pain intensity, performance service status, and opioid consumption without unpredictable serious side effects.

[The development of methicillin-resistant Staphylococcus aureus sepsis in a patient with herpes zoster during treatment with continuous epidural infusion].

A 79-year-old man with herpes zoster was referred to our hospital for pain control. He was a survivor of the atomic bombing of Hiroshima, and had a history of cerebral infarction and hypertension. A cervical epidural catheter was placed for continuous analgesic infusion. After 20 days of catheterization, he gradually developed a high fever and confusion, and complained of nausea and headaches. An urgent blood examination revealed a white blood cell count of 15,200 mm-3 and a C-reactive protein of 32.4 mg.dl-1. The catheter was removed and antibiotic therapy was started. Repeated magnetic resonance imaging could not confirm epidural abscess formation. The bacterial culture of the cerebrospinal fluid was negative, but the cultures of the blood, the catheter tip, and the nasal cavity swab were positive for methicillin-resistant Staphylococcus aureus. Although intravenous vancomycin was administered, systemic inflammation persisted. The patient consecutively suffered varied disorders such as acute renal failure, disseminated intravascular coagulation, and gastrointestinal bleeding. Although symptomatic treatment had been prolonging his life, 58 days after the catheter removal, the patient suddenly developed cerebellopontine infarction, which made mechanical ventilation necessary. He remained unconscious until his death 117 days after the catheter removal. We discussed the possible pathogenetic mechanisms of the present case.

[Severe low back pain and muscular weakness in the thigh following urological surgery in the hyperlordotic position].

A 57-year-old male with prostatic cancer was scheduled for a radical prostatectomy under general anesthesia combined with epidural anesthesia. An epidural catheter was introduced at the L 1-2 interspace without problem. The patient was placed in a hyperlordotic supine position with a bolster under his lower back for the seven and a half hour operation. Upon emergence from anesthesia, he complained of severe low back pain in addition to incisional pain. On the second postoperative day, the epidural catheter was removed. After residural analgesic effects had fully disappeared, he experienced muscular weakness in the left thigh and could not walk. Regional sensory loss and edema were also observed where pressure had been applied by the bolster, although spinal cord magnetic resonance imaging studies were almost normal. It took him seven weeks to walk without the support of a brace after surgery. Hyperextension of the lumbar spine could increase the pressure on the inferior vena cava which is transmitted to the intraspinal vein, and could lead to the disci intervertebrales compression and the stress on the facet joint. We believe that the primary cause of the presented symptoms was related to this position. Prolonged and/or excessive hyperlordosis during surgery should be avoided.