Masako Iseki

Replacement of Gabapentin with Pregabalin in Postherpetic Neuralgia Therapy

PURPOSE Although both gabapentin and pregabalin are first-line drugs for neuropathic pain including postherpetic neuralgia (PHN), no report has directly compared the magnitude of pain relief and the incidence of side effects of both drugs. By substituting gabapentin with pregabalin in postherpetic neuralgia therapy, we can compare the two drugs. METHODS In 32 PHN patients being administered gabapentin, without changing the frequency of dosing, the drug was substituted with pregabalin at one-sixth dosage of gabapentin. After 2 weeks, an interview was conducted about the visual analog scale (VAS) pain score, changes in the time of onset of action and duration of action after the substitution of drug and side effects (such as somnolence, dizziness, and peripheral edema). In addition, the dosage was increased while paying careful attention to the side effects (titration) in 22 patients who requested a dosage increase among those whom VAS pain score of ≥25 mm remained even after the substitution. RESULTS No significant changes were observed in VAS pain scores after the substitution of gabapentin with pregabalin. Regarding the time of onset of action and the duration of action after the substitution, the highest number of patients answered that no change occurred compared with the previous drug, followed by the patients who answered that the time of onset of action became quicker, and the duration of action became longer. The incidence of somnolence and dizziness showed no significant difference before and after the substitution, but peripheral edema showed a significant increase after the substitution. The level of side effects of both drugs was mild, and continued medication was possible. In the patient group where pregabalin dosage was increased, the VAS pain score decreased significantly compared with that before and after increase the dosage (P < 0.05). On the other hand, in nine out of 22 patients in the group where the dosage was increased, side effects appeared or were exacerbated. In two out of nine patients, it was necessary to reduce the dosage to the initial volume. CONCLUSION It was suggested that the analgesic action of pregabalin in PHN was six times that of gabapentin in terms of effectiveness in dosage conversion. Regarding the side effects, although the incidence of the peripheral edema was higher with pregabalin compared with gabapentin, this finding is not conclusive because the present study was conducted in a small number of subjects. Although pain reduction can be expected to increase with pregabalin dosage, it is necessary to increase the dosage gradually and carefully because of exacerbation of side effects.

Changes in circadian rhythm for mRNA expression of melatonin 1A and 1B receptors in the hypothalamus under a neuropathic pain‐like state

Several clinical reports on neuropathic pain of various etiologies have shown that it significantly interferes with sleep. Inadequate sleep due to neuropathic pain may contribute to the stressful negative consequences of living with pain. It is generally recognized that melatonin (MT) system in the hypothalmus is crusial for circadian rhythm and sleep‐wake transition. However, little, if any, is known about whether neuropathic pain could affect the MT system associated with sleep disturbance. In this study, we investigated the possible changes in circadian rhythm for the expression of MT receptors, especially MT1A and MT1B receptors, in the hypothalamus of mice with sciatic nerve ligation. The samples for real‐time RT‐PCR assay were prepared at 8:00, 14:00, 20:00, and 2:00 on day 7 after sciatic nerve ligation or sham operation. The mRNA expression of MT1A and MT1B receptors at 2:00 in sciatic nerve‐ligated mice, which exhibited thermal hyperalgesia along with an increase in wakefulness and a decrease in nonrapid eye movement sleep, was significantly greater than those in sham‐operated mice, whereas the levels of both MT1A and MT1B receptors at 8:00 in sciatic nerve‐ligated mice were significantly lower than those in sham‐operated mice. These findings suggest that neuropathic pain‐like stimuli lead to sleep disturbance in parallel with changes in circadian rhythm for mRNA expression of MT 1A and 1B receptors in the hypothalamus of mice. Synapse 68:153–158, 2014.

Changes in the circadian rhythm of mRNA expression for µ-opioid receptors in the periaqueductal gray under a neuropathic pain-like state

Variation in the production of opioid receptors over a 24‐h period is considered to contribute to circadian alterations in neuropathic pain. In this study, we investigated the possible changes in the circadian rhythm of mRNA expression for µ‐opioid receptor (MOR), κ‐opioid receptor (KOR), and adrenaline α2a receptor (α2a) in the periaqueductal gray, frontal cortex, thalamus, and spinal cord following sciatic nerve ligation in mice. In sham‐operated mice, the latencies of hind paw‐withdrawal in response to thermal stimuli at 14:00 and 20:00 were significantly greater than that at 8:00 and the latency at 2:00 was significantly less than those at 14:00 and 20:00, indicating a “rest” period‐dominant circadian rhythm for thermal pain‐thresholds. In sciatic nerve‐ligated mice, the latencies of hind paw‐withdrawal in response to thermal stimuli at 14:00 and 20:00 were significantly less than that at 8:00, and the latency at 2:00 was significantly greater than those at 14:00 and 20:00. A correlative tendency between the time‐variation of pain latency and the time‐variation of MOR mRNA expression was observed in the periaqueductal gray of sham‐operated and sciatic nerve‐ligated mice. In contrast, neither mouse showed a strong circadian rhythm for the expressions of KOR and α2a mRNAs in any region. The present data suggest that changes in MOR mRNA expression in the periaqueductal gray may be synchronized with the circadian rhythm for the pain threshold for noxious thermal stimuli. In contrast, neuropathic pain in mice exhibited a negative circadian pattern for the expression of MOR, KOR, and α2a receptors in the frontal cortex, thalamus, and spinal cord. Synapse 67:216–223, 2013.

Effects of mirtazapine on sleep disturbance under neuropathic pain-like state

Sleep disturbance has been reported to be one of the most frequent symptoms in patients suffered from severe pain. Benzodiazepines are effective and reduce anxiety in the hours after use, but the induced sleep tends to be less than ideal in quality, with increased Stages I–II and reduces Stages III–IV sleep. In the present study, we investigated sleep disturbance under a neuropathic pain‐like state in mice using electroencephalogram (EEG)/electromyogram (EMG). In a model of neuropathic pain, sciatic nerve ligation caused a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under this condition, sciatic nerve‐ligated animals showed a statistically significant increase in wakefulness and a decrease in non‐rapid eye movement (NREM) sleep during the light phase. Mirtazapine (MTZ) is an antidepressant, which is considered to enhance noradrenergic and serotonergic neurotransmission via antagonistic action at central α2‐adrenergic autoreceptors and heteroreceptors. In the present binding study, MTZ showed higher affinity for histamine H1 and serotonin 5‐HT2A/2C receptors than other receptors, including α2‐adrenergic receptor, in the mouse brain tissue. The thermal hyperalgesia and sleep disturbance following nerve ligation were almost completely alleviated by MTZ. These findings suggest that MTZ may improve the quality of sleep as well as control pain in patients with neuropathic pain mainly through histamine H1‐ and serotonin 5‐HT2‐receptor antagonistic actions. Synapse, 2012.

Enhancement of glutamatergic transmission in the cingulate cortex in response to mild noxious stimuli under a neuropathic pain-like state.

Pain is evoked by noxious body stimulation or through negative emotional events and memories. There are several caveats to the simple proposition that pain and emotion are linked in the cingulate cortex (CG). In this study, we investigated whether mild noxious heat stimuli could affect the neuronal activity in the CG of rats with sciatic nerve ligation. We produced a partial sciatic nerve injury by tying a tight ligature in rats. Seven days after sciatic nerve ligation, rats received mild noxious heat stimuli. Mild noxious heat stimuli produced flinching behaviors in sciatic nerve‐ligated rats, but not sham‐operated rats. In addition, the mild noxious heat stimuli caused a significant increase in the release of glutamate in the CG of nerve‐ligated rats compared with that of sham‐operated rats. Furthermore, phosphorylated‐NR1‐positive cells in this area significantly increased after mild noxious heat stimuli under a neuropathic pain. Under this condition, there were no significant changes in the levels of immediate‐early genes such as c‐fos, c‐jun, JunB, and Fra1 in the CG between nerve‐ligated and sham‐operated rats. However, mild noxious heat stimuli under a neuropathic pain‐like state produced a marked increase in the phosphorylated‐c‐jun (p‐c‐jun) immunoreactivity, which is commonly used to map neurons in the brain that can be activated after N‐methyl‐D‐aspartate receptor activation. These findings raise the possibility that mild noxious heat stimuli under a peripheral nerve injury may increase the release of glutamate and promote its related postneuronal activity in the CG. Synapse, 2010.

Changes in the expression of IL-6-Mediated MicroRNAs in the dorsal root ganglion under neuropathic pain in mice

A multiplex analysis for profiling the expression of candidate microRNAs (miRNAs), which are small noncoding RNAs that function as key post‐transcriptional regulators, may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we performed a miRNA array analysis using tissues of the dorsal root ganglion (DRG), a primary site for pain processing, obtained from mice with partial sciatic nerve ligation. Among 1135 total miRNAs, 26 miRNAs showed up‐regulation (more than 2‐fold change) and only 4 miRNAs showed down‐regulation (less than 0.5‐fold change) in the DRG of nerve‐ligated mice. In a RT‐qPCR assay, the levels of miR‐21, miR‐431, and miR‐511‐3p were significantly increased on the ipsilateral side of the DRG from 3 to 7 days after sciatic nerve ligation. These elevations were almost absent in IL‐6 knockout mice. Furthermore, the expression level of miR‐21, but not those of miR‐431 or miR511‐3p, was significantly increased in exosomes extracted from blood of nerve‐ligated mice. These findings suggest that the increased expression of IL‐6‐regulated miR‐21, miR‐431, and miR‐511‐3p in the DRG and increased exosomal miR‐21 extracted from blood after sciatic nerve ligation may play at least a partial role in neuropathic pain. Synapse 70:317–324, 2016.

Direct Evidence for the Ongoing Brain Activation by Enhanced Dynorphinergic System in the Spinal Cord under Inflammatory Noxious Stimuli

Background:Dynorphin A in the spinal cord is considered to contribute to nociceptive stimuli. However, it has not yet been determined whether activation of the spinal dynorphinergic system under nociceptive stimuli plays a role in direct acceleration of the ascending nociceptive pathway. In this study, the authors investigated the role of spinal dynorphinergic transmission in ongoing brain activation under noxious stimuli in mice. Methods:The changes in prodynorphin messenger RNA expression and dynorphin A (1–17)-like immunoreactivity in the mouse spinal cord were determined after the intraplantar injection of complete Freunds adjuvant in mice. The signal intensity in different brain regions after the intraplantar injection of complete Freunds adjuvant or intrathecal injection of dynorphin A (1–17) was measured by a pharmacological functional magnetic resonance imaging analysis. Results:Complete Freunds adjuvant injection produced pain-associated behaviors and induced a dramatic increase in signal intensity in the mouse cingulate cortex, somatosensory cortex, insular cortex, and thalamic nuclei. These effects were not seen in prodynorphin knockout mice. Prodynorphin messenger RNA expression and dynorphin A (1–17)-like immunoreactivity on the ipsilateral side of the spinal cord were markedly increased in complete Freunds adjuvant-injected mice. Furthermore, intrathecal injection of dynorphin A (1–17) at relatively high doses caused pain-associated behaviors and a remarkable increase in the activities of the cingulate cortex, somatosensory cortex, insular cortex, and medial and lateral thalamic nuclei in mice. Conclusions:These findings indicate that spinally released dynorphin A (1–17) by noxious stimuli leads to the direct activation of ascending pain transmission.

Methicillin-resistant Staphylococcus aureus sepsis resulting from infection in paravertebral muscle after continuous epidural infusion for pain control in a patient with herpes zoster

I n many cases of epidural infection, neurological symptoms caused by cord compression due to abscess formation are the major concern. Such neurological symptoms are classified as phase I (spinal ache), phase II (root pain), phase III (weakness of voluntary muscles and sphincters and/or loss of sensation), and phase IV (paralysis), which serve as guidelines for selecting appropriate therapeutic methodologies (1). There have been reports of epidural abscess formation arising from epidural catheterization (2-4). The possibility of developing epidural abscess is, however, low compared with the probability of finding microorganisms on catheter tips during catheterization (4,5), and the microorganisms discovered are usually Staph~ZOCOCCUS aureus (4 6). We present a patient who, after continuous epidural infusion for the treatment of pain associated with herpes zoster, first developed a methicillin-resistant StaphyZococcus aureus (MRSA) infection with neurological symptoms in phase I, which later progressed to sepsis.

Possible involvement of activated locus coeruleus–noradrenergic neurons in pain-related sleep disorders

The locus coeruleus (LC) is a noradrenergic brainstem structure that is considered to play a role in promoting arousal. To further clarify the role of LC noradrenergic neurons, we performed an optogenetic assay by injecting AAV-channelrhodopsin-2 (ChR2) into the LC of cre-tyrosine hydrolase (TH) mice. We found here that the specific activation of LC noradrenergic neurons produced a significant increase in wakefulness and a significant decrease in non-rapid eye movement (NREM) sleep during photostimulation. On the other hand, neuropathic pain is believed to significantly interfere with sleep, and inadequate sleep may contribute to the stressful negative consequences of living with pain. In the present study, sciatic nerve ligation, which produced significant thermal hyperalgesia, significantly increased the levels of noradrenaline released in the prefrontal cortex (PFC) by the weak electrical stimulation of neurons in the LC. Under these conditions, the systemic administration of adrenaline α and β inhibitor cocktail at 7 days after sciatic nerve ligation restored the increased wakefulness and decreased NREM sleep to normal levels. These results suggest that neuropathic pain may accelerate neurons in the LC, and its overactivation may be, at least in part, associated with sleep disturbance under neuropathic pain.

The Effect of Guidance regarding Home Exercise and ADL on Adolescent Females Suffering from Adverse Effects after HPV Vaccination in Japanese Multidisciplinary Pain Centers

Background. Two prophylactic papillomavirus (HPV) vaccines have been available for primary prevention of cervical cancer. Although serious adverse effects (AE) were rare, more than 230 women have been suffering from severe AEs such as persistent pain and headache in Japan. Our research group started to treat adolescent females suffering from the AEs. Objective. To survey the characteristics of and the effects of cognitive behavioral therapy on adolescent female suffering from the AEs in Japanese multidisciplinary pain centers. Methods. One hundred and forty-five patients suffering from the AEs were reviewed retrospectively and 105 patients of them were provided guidance on home exercise and activities of daily living based partially on a cognitive-behavioral approach. The intensity of pain was rated by the patients using a numerical rating scale (NRS). Furthermore, the Hospital Anxiety and Depression Scale (HADS) and the Pain Catastrophizing Scale (PCS) were used. Results. Eighty out of the 105 patients who received the guidance were followed up, 10 displayed a marked improvement, and 43 showed some improvement. Conclusions. Guidance on home exercise and activities of daily living based on a cognitive-behavioral approach alleviated the AEs that women suffered from after HPV vaccination in Japan.