Relationship Between Patient-reported Outcome Measures and Accelerometer-measured Physical Activity and Sleep in Patients With Postherpetic Neuralgia.

OBJECTIVE: Available treatment for chronic neuropathic pain is still limited, and the positive effects are modest. Thus, clinicians aim to improve activity and quality of life despite pain. The objective monitoring of activity is attracting attention in chronic pain assessments. Therefore, we objectively evaluated daytime activity and sleep in patients with postherpetic neuralgia (PHN), using actigraphy to determine risk factors for decreased activity. METHODS: Participants with PHN wore an actigraph (a wristwatch-like accelerometer) on the nondominant hand. The actigraph measured day-time activity and sleep, which were compared with participant-reported subjective pain and sleep assessments. RESULTS: Fifty-four individuals with PHN who visited our outpatient clinic completed questionnaires and a week of actigraph monitoring. Subjective scores of pain intensity, neuropathic pain, disability in daily life, pain-catastrophizing thoughts, and insomnia were all well correlated. However, the actigraph-monitored activity levels, using 2 equations, and sleep quality were not associated with any pain or sleep-related subjective scores. CONCLUSION: The discrepancy between the subjective and objective scores in this study may be due to (1) features of PHN, an archetype of peripheral neuropathic pain affecting no motor nerves, (2) actigraph measurement limitations regarding the sedentary life of the elderly, or (3) activity misperception, a new proposition explaining the discrepancy between subjective and objective measures of activity, similar to the sleep state misperception. In patients with PHN, high pain intensity may be reported in those with highly maintained activity, in which treatment must be selected cautiously to prevent interruption of their physical abilities.

Continuous monitoring of activity and vital signs with load cells under the bed legs in advanced cancer patients: a prospective exploratory observational study-can it represent performance status?

BACKGROUND: Activity levels of patients often scaled as performance status (PS) is the most important scale in oncology populations for treatment decisions and prognosis prediction. However, it is usually subjective and open to bias. The need for more objective and reliable assessment tools is mandatory for safe and effective oncology practice. To investigate the reliability of continuous vital and activity evaluation monitored by bed sensor systems in advanced cancer patients, we conducted a cohort pilot study in hospitalized cancer patients under several PS conditions. METHODS: Adult patients, either admitted in the oncology department or palliative care unit, were enrolled in the study after written informed consent. Continuous monitoring for 48 hours from the first night of admission was performed without any restrictions on the patients. Calculated acceleration of movement [activity index (ACI)], % time on bed and number of bed leave in an 8-hour period, as well as other vital signs were monitored. Analysis focused on change of PS to 3, a standard cut-off for curative cancer treatment and PS4, vital for prognosis assessment. RESULTS: Nineteen patients' data were analyzed. In PS4 palliative care patients, ACI was significantly low and % time on bed was high from PS3 palliative care patients. Instabilities of respiratory rate, respiratory tidal weight and heart rate were significantly higher in palliative care patients (PS3, PS4) compared with oncology patients (PS1, PS2). CONCLUSIONS: This result, though in need of larger trials, shows possibilities for continuous objective monitoring of patients in bed for PS assessment in advanced cancer patients.

Effects of opioids on respiration assessed by a contact-free unconstraint respiratory monitor with load cells under the bed in patients with advanced cancer.

Nocturnal periodic breathing of chronic opioid users has been predominantly documented by the use of polysomnography. No previous studies have assessed the opioid effects of respiratory rhythms throughout the day without the use of physical restraint. We recently developed a contact-free unconstraint vital sign monitoring system with four load cells placed under the bed legs, which allows continuous measurements of respiratory change at the center of gravity on the bed. We aimed to reveal details of the patient's 24-h respiratory status under a monitoring system and to test the hypothesis that respiratory rhythm abnormalities are opioid dose-dependent and worsen during the night time. Continuous 48-h respiratory measurements were successfully performed in 51 patients with advanced cancer (12 opioid-free patients and 39 opioid-receiving patients). Medians of respiratory variables with minimal body movement artifacts were calculated for each 8-h split time period. Compared with opioid-free patients, opioid-receiving patients had slower respiratory rate with higher respiratory rate irregularity without changing tidal centroid shift regardless of the time period. Irregular ataxic breathing was only identified in opioid-receiving patients (33%, P = 0.023) whereas incidence rate of periodic breathing did not differ between the groups. Multivariate regression analyses revealed that opioid dose was an independent risk factor for occurrence of irregular breathing [odds ratio 1.81 (95% CI: 1.39-2.36), P < 0.001], and ataxic breathing [odds ratio 2.08 (95% CI: 1.60-2.71), P < 0.001]. Females developed the ataxic breathing at lower opioid dose compared with males. We conclude that respiratory rhythm irregularity is a predominant specific feature of opioid dose-dependent respiratory depression particularly in female patients with advanced cancer.NEW & NOTEWORTHY Through usage of a novel contact-free unconstraint vital sign monitoring system with four load cells placed under the bed legs allowing continuous measurements of respiratory changes of center of gravity on the bed, this study is the first to assess detailed respiratory characteristics throughout day and night periods without interference of daily activities in patients with advanced cancer receiving opioids. Respiratory rhythm irregularity is a predominant specific feature of opioid dose-dependent respiratory depression particularly in female patients with advanced cancer.

Low-dose of olanzapine has ameliorating effects on cancer-related anorexia.

BACKGROUND: Olanzapine (OLZ) has become well-known for its antiemetic effects on chemotherapy-induced nausea and vomiting. However, it remains unclear whether OLZ also has efficacy for treating cancer-related anorexia. This study, therefore, retrospectively examined whether or not OLZ administration affects the food intake in anorexic cancer patients who exhibit neither nausea nor vomiting. METHODS: Eighty patients prescribed OLZ were extracted from 951 inpatients who consulted with our palliative care team at Chiba University Hospital from April 2008 to March 2016. Their food intake described on a nursing record was compared before and after OLZ administration. The observation period was 3 days before and after the start of OLZ treatment, because most inpatients whose food intake increased were discharged in 3 days. RESULTS: In those 80 patients, the average dose of OLZ for 3 days was 2.28±0.87 (mean±SD) mg/day. First, the food intake in 80 patients was significantly higher after than before starting OLZ, and the relative change in food intake was 149% on average (P<0.0001, Student's paired t-test). Second, OLZ increased the food intake even in 40 out of 80 patients without nausea or vomiting, and the relative change in food intake was 143% on average (P<0.001, Student's paired t-test). Third, the average food intake increased in 13 out of 40 patients who were prescribed 1.5 mg/day of OLZ, and the relative change in food intake was 124% on average (P<0.01, Student's paired t-test). There was no significant difference in food intake between a dose of 1.5 mg/day and a dose of >1.5 mg/day of OLZ (P=0.18, Welch's unpaired t-test). CONCLUSION: We have herein reported OLZ's ameliorating efficacy in cancer-related anorexia at the low dose of 1.5 mg/day. Although our study has many limitations, low-dose OLZ can be a promising treatment for cancer-related anorexia.

Orexin-2 receptors inhibit primary afferent fiber-evoked responses of ventral roots in the neonatal rat isolated spinal cord.

Orexin-A and orexin-B are hypothalamic peptides. Orexin-A binds equally to both orexin-1 and orexin-2 receptors but orexin-B has a preferential affinity for orexin-2 receptor. In the spinal dorsal horn, orexins have been shown to be concentrated in the superficial laminae. In the present study, the authors examined the effect of spinally applied orexin-A and orexin-B on the primary afferent fiber-evoked nociceptive reflex in the isolated spinal cord of the neonatal rat. In the isolated spinal cord preparation from 0-3day old rats, single-shock stimulation of a dorsal root (L3-L5) at a strength which can activate C-fibers induced a slow depolarizing response lasting about 30s (slow ventral root potential: slow VRP) in the ipsilateral ventral root of the same segment. Bath application of orexin-A and orexin-B inhibited the slow VRP in a concentration-dependent manner. Bath application of SB-334867, a selective orexin-1 receptor antagonist, had no effect on the depressant effect of orexin-A on slow VRP. Bath application of [Ala11,d-Leu15]-orexin B, a selective orexin-2 receptor agonist, depressed the slow VRP. Both orexin-A and orexin-B depressed the level of temporal summation of synaptic activity evoked by 20 repetitive stimulations of the dorsal root. These data suggest that orexin-2 receptor, but not orexin-1 receptor, may play an inhibitory role in nociceptive transmission in the neonatal rat spinal cord.

[Orexins and pain processing].

Orexin-A and orexin-B are hypothalamic peptides and regulate feeding behavior, energy metabolism and the sleep-wake cycle. Orexin-A binds equally to both orexin-1 and orexin-2 receptors, while orexin-B has a preferential affinity for orexin-2 receptors. Orexin-A and orexin-B are concentrated in superficial laminae of the spinal dorsal horn, and orexin-A and orexin-1 receptors are found in the dorsal root ganglion cells. Intravenous injection of orexin-A produces an anti-thermal hyperalgesic effect in the carrageenan test and this effect of orexin-A was mediated by the activation of orexin-1 receptor at the peripheral primary afferent terminal. Intrathecal and intracerebroventricular injection of orexin-A produces an analgesic effect in the formalin test and the carrageenan test and the neuropathic pain models and these effects of orexin-A are thought to be mediated by the activation of orexin-1 receptor. In the isolated spinal cord preparation from 0-to 3-day old rats, a slow depolarizing response induced by single shock stimulation of a dorsal root at C-fiber strength and wind-up phenomenon were effectively attenuated by the application of orexin-A, orexin-B and [Ala11 D-Leu15] orexin-B, a selective orexin-2 receptor agonist. This suggested that, in the neonatal rat spinal cord, orexin-2 receptor, but not orexin-1 receptor, is involved in the nociceptive transmission.

Anti-hyperalgesic effects of intrathecally administered neuropeptide W-23, and neuropeptide B, in tests of inflammatory pain in rats.

Neuropeptide W-23 (NPW23) is an endogenous ligand of both GPR7 and GPR8, and neuropeptide B (NPB) is an endogenous ligand of GPR7. GPR7 mRNA has been detected in regions of the cortex, the hippocampus, the hypothalamus, and the spinal cord in the rat, but GPR8 has not been found in rodents. GPR7 and GPR8 receptors have structural features in common with both opioid and somatostatin receptors. The effects of intrathecal (i.t.) application of NPW23 and NPB were tested in two inflammatory pain models (plantar injection of formalin or carrageenan) and two thermal nociceptive tests (52.5 degrees C and 50.5 degrees C hot plates) and one mechanical nociceptive test in the rat. I.t. injection of either NPW23 or NPB decreased the number of agitation behaviors induced by paw formalin injection and attenuated the level of mechanical allodynia, but not the level of thermal hyperalgesia, induced by paw carrageenan injection in a dose-dependent manner at a dose between 0.1 and 10 microg, significantly. The effects of either 10 microg of NPW23 or 10 microg of NPB were not antagonized by 10 microg of naloxone. I.t. injection of either NPW23 or NPB had no effect in both the 52.5 degrees C hot plate test or in the 50.5 degrees C hot plate tests at a dose between 1 and 100 microg. I.t. injection of either 10 microg of NPW23 or 10 microg of NPB had no effect in the mechanical nociceptive test. I.t. injection of either 10 microg of NPW23 or 10 microg of NPB significantly suppressed the expression of Fos-like immunoreactivity of the L4-5 spinal dorsal horn induced by paw formalin injection. These data suggest that both spinally-applied NPW23 and NPB suppressed the input of nociceptive information to the spinal dorsal horn, produced an analgesic effect in the formalin test, and attenuated the level of mechanical allodynia in the carrageenan test, and that either spinally applied NPW23 or spinally applied NPB had no effect in the physiological condition.

Activation of spinal orexin-1 receptor produces anti-allodynic effect in the rat carrageenan test.

Orexin-A and orexin-1 receptors are found in the dorsal root ganglion cells and the spinal dorsal horn and this suggests that orexin-A is involved in the spinal nociceptive transmission. The authors examined the effect of intrathecally administered orexin-A on the level of mechanical allodynia and thermal hyperalgesia induced by paw carrageenan injection in the rat. Intrathecal injection of 0.3 and 3 nmol of orexin-A suppressed the level of mechanical allodynia, but not that of thermal hyperalgesia, and the effect of orexin-A on mechanical allodynia was antagonized by the pretreatment of 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride, SB-334867, a selective orexin-1 receptor antagonist. These data suggest that the activation of spinal orexin-1 receptor modulates the mechanical information transmission, but not thermal information transmission, in the spinal cord during carrageenan test.

Anti-mechanical allodynic effect of intrathecal and intracerebroventricular injection of orexin-A in the rat neuropathic pain model.

Orexin-A has been reported to produce an analgesic effect in the hot plate test and in the inflammatory pain models. In the present study, the authors examined the effect of orexin-A on the mechanical allodynia induced by partial sciatic nerve ligation (a model of neuropathic pain) in the rat. Partial sciatic nerve ligation is created by tight ligation of one-third or one-half of the right sciatic nerve. Orexin-A was administered intrathecally or intracerebroventricularly 7 days after a partial sciatic nerve injury. Either intrathecal or intracerebroventricular injection of orexin-A attenuated the level of mechanical allodynia induced by partial sciatic nerve ligation. These data suggest that either intrathecal or intracerebroventricular injection of orexin-A is a new therapeutic approach to treating mechanical allodynia caused by nerve injury.

Analgesic effect of intrathecally administered matrix metalloproteinase 2 (MMP-2) in the rat formalin test.

Matrix metalloproteinases (MMPs) are a family of extracellular endopeptidases that selectively degrade components of the extracellular matrix. In the present study, the authors examined the effect of intrathecal injection of MMP-2 on the nociceptive transmission during the rat formalin test (a model of inflammatory pain). The paw formalin injection induces biphasic flinching (phase 1: 0-6 min; phase 2: 10-60 min) of the injected paw. Intrathecal injection of 1 microg of MMP-2 depressed the phase 1 agitation behavior, but not the phase 2 agitation behavior, and this effect of MMP-2 was antagonized by ONO-4817, an MMP inhibitor. ONO-4817 itself had no effect on the formalin test. These data suggest that exogenously applied MMP-2 to the spinal cord produces analgesic effects in the rat formalin test.

Buprenorphine activates mu and opioid receptor like-1 receptors simultaneously, but the analgesic effect is mainly mediated by mu receptor activation in the rat formalin test.

Buprenorphine is a mixed opioid receptor agonist-antagonist. Recently, buprenorphine was reported to act as an agonist to opioid receptor like-1 (ORL1) receptor. In the present study, we examined the role of spinal and supraspinal mu receptors and spinal and supraspinal ORL1 receptors in producing an analgesic effect by intrathecal (i.t.), intracerebroventricular (i.c.v.), or i.p. administration of buprenorphine in the rat formalin test. Male rats were prepared with i.t. catheters or i.c.v. injection cannulas. The paw formalin injection (50 microl of 5% formalin) induces biphasic flinching (phase 1, 0-6 min; phase 2, 10-60 min) of the injected paw. Buprenorphine, naloxone (a mu-opioid receptor antagonist), or (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J113397) (an ORL1 receptor-selective antagonist) was administered i.t., i.c.v., or i.p.. Intrathecal, i.c.v., or i.p. injection of buprenorphine produces an analgesic effect in a dose-dependent manner. The effect of i.c.v. buprenorphine was antagonized by i.c.v. naloxone or i.c.v. J113397, and the effect of i.t. buprenorphine was antagonized by i.t. naloxone or i.t. J113397. The effect of i.p. buprenorphine was antagonized by i.p. or i.t. naloxone but not by i.c.v. naloxone. The analgesic effect of i.p. buprenorphine was enhanced by i.p. J113397 or i.c.v. J113397. Intraperitoneal, but not i.t. or i.c.v., buprenorphine decreased the number of Fos-like immunoreactivity positive neurons in the L4-L5 spinal dorsal horn. These data indicated that buprenorphine affects nociceptive processing by acting at both supraspinal and spinal mu and ORL1 receptors. The analgesic effect of systemically administered buprenorphine was suppressed by the concomitant activation of supraspinal ORL1 receptor.