Phase 2 Trial of Difelikefalin in Notalgia Paresthetica.

BACKGROUND: Notalgia paresthetica is a neuropathic disorder characterized by pruritus in a circumscribed region of the upper back. Difelikefalin, a selective kappa opioid receptor agonist, has shown efficacy in other chronic pruritic conditions and is being investigated for the treatment of notalgia paresthetica. METHODS: In this phase 2, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with moderate-to-severe pruritus caused by notalgia paresthetica to receive 2 mg of oral difelikefalin or placebo twice daily for 8 weeks. The primary outcome was the change from baseline at week 8 in the weekly mean score on the daily Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). The secondary clinical outcomes were itch-related quality-of-life and itch-related sleep measures. RESULTS: A total of 126 patients were enrolled; 62 patients were assigned to receive difelikefalin, and 63 were assigned to receive placebo. One patient who had been assigned to receive difelikefalin withdrew consent before the first dose and is not included in the main analyses. The mean baseline WI-NRS score was 7.6 (indicating severe itch) in each group. The change from baseline in the weekly mean WI-NRS score at week 8 was -4.0 points in the difelikefalin group and -2.4 points in the placebo group (difference in change, -1.6 points; 95% confidence interval, -2.6 to -0.6; P = 0.001). The results for the secondary outcomes generally did not support those of the primary analysis. Headache, dizziness, constipation, and increased urine output occurred more frequently in the difelikefalin group than in the placebo group. CONCLUSIONS: Among patients with notalgia paresthetica, oral treatment with difelikefalin resulted in modestly greater reductions in itch intensity scores than placebo over a period of 8 weeks but was associated with adverse events. Larger and longer trials are needed to assess the efficacy and safety of difelikefalin treatment in this disorder. (Funded by Cara Therapeutics; KOMFORT ClinicalTrials.gov number, NCT04706975.).

Do cutaneous nerves cross the midline?

Standard cutaneous innervation maps show strict midline demarcation. Although authors of these maps accept variability of peripheral nerve distribution or occasionally even the midline overlap of cutaneous nerves, this concept seems to be neglected by many other anatomists. To support the statement that such transmedian overlap exists, we performed an extensive literature search and found ample evidence for all regions (head/neck, thorax/abdomen, back, perineum, and genitalia) that peripheral nerves cross the midline or communicate across the midline. This concept has substantial clinical implications, most notably in anesthesia and perineural tumor spread. This article serves as a springboard for future anatomical, clinical, and experimental research.

Cutaneous neuropathy in Parkinson's disease: a window into brain pathology.

The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson's disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre-mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (p < 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length-dependent reduction of intraepidermal small nerve fibers (p < 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (p < 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity.

[Analysis of indications of the acupoints in the same nervous segment on back and abdomen].

OBJECTIVE: To explore the indication law of fourteen channels acupoint that is located in the same nervous segment of T1-T12 on the back and abdomen. METHODS: By retrieving indications of fourteen channels acupoint that is located in the dominating areas of T1 - T12 in LIN Zhao-geng 's New Collection of Acupuncture-moxibustion and SHEN Xue-yong's Science of meridian-collateral and acupoint, indications of fourteen channels acupoint in the same nervous segment of skin and muscle were statistically managed, respectively. RESULTS: There was an obvious nervous segmental law of acupoint in the skin and muscle. The acupoint indication of neighboring nervous segment was similar, which was closely related to corresponding internal organs. CONCLUSION: The acupoint indication is decided by the space of nervous segment which dominats their related organ. From aspect of nervous structure, this article confirms that acupoint indications focus on nervous segment to carry out the regulation effect of acupoint on internal organs function, which means it has superior regulation effect on internal organs disease that is located in the same or neighboring nervous segment of acupoint.

An investigation into the magnitude of the current window and perception of transcutaneous electrical nerve stimulation (TENS) sensation at various frequencies and body sites in healthy human participants.

INTRODUCTION: Strong nonpainful transcutaneous electrical nerve stimulation (TENS) is prerequisite to a successful analgesic outcome although the ease with which this sensation is achieved is likely to depend on the magnitude of current amplitude (mA) between sensory detection threshold (SDT) and pain threshold, that is, the current window. OBJECTIVES: To measure the current window and participant's perception of the comfort of the TENS sensation at different body sites. METHODS: A repeated measure cross-over study was conducted using 30 healthy adult volunteers. Current amplitudes (mA) of TENS [2 pulses per second (pps); 30 pps; 80 pps] at SDT, pain threshold, and strong nonpainful intensities were measured at the tibia (bone), knee joint (connective tissue), lower back [paraspinal (skeletal) muscle], volar surface of forearm (nerve) and waist (fat). The amplitude to achieve a strong nonpainful intensity was represented as a percentage of the current window. Data were analyzed using repeated measures analysis of variance. RESULTS: Effects were detected for body site and frequency for SDT (P<0.001, P=0.018, respectively), current window (P<0.001, P<0.001, respectively), and strong nonpainful TENS as a percentage of the current window (P=0.002, P<0.001, respectively). The current window was larger for the knee joint compared with tibia (difference [95% confidence interval]=12.76 mA [4.25, 21.28]; P=0.001) and forearm (10.33 mA [2.62, 18.40]; P=0.006), and for the lower back compared with tibia (12.10 mA [1.65, 22.52]; P=0.015) and forearm (9.65 mA [1.06, 18.24]; P=0.019). The current window was larger for 2 pps compared with 30 pps (P<0.001) and 80 pps (P<0.001). Participants rated strong nonpainful TENS as most comfortable at the lower back (P<0.001) and least comfortable at the tibia and forearm (P<0.001). CONCLUSIONS: TENS is most comfortable and easiest to titrate to a strong nonpainful intensity when applied over areas of muscle and soft tissue.

Cutaneous inputs from the back abolish locomotor-like activity and reduce spastic-like activity in the adult cat following complete spinal cord injury.

Spasticity is a condition that can include increased muscle tone, clonus, spasms, and hyperreflexia. In this study, we report the effect of manually stimulating the dorsal lumbosacral skin on spontaneous locomotor-like activity and on a variety of reflex responses in 5 decerebrate chronic spinal cats treated with clonidine. Cats were spinalized 1 month before the terminal experiment. Stretch reflexes were evoked by stretching the left triceps surae muscles. Crossed reflexes were elicited by electrically stimulating the right tibial or superficial peroneal nerves. Wind-up of reflex responses was evoked by electrically stimulating the left tibial or superficial peroneal nerves. We found that pinching the skin of the back abolished spontaneous locomotor-like activity. We also found that back pinch abolished the rhythmic activity observed during reflex testing without eliminating the reflex responses. Some of the rhythmic episodes of activity observed during reflex testing were consistent with clonus with an oscillation frequency greater than 3 Hz. Pinching the skin of the back effectively abolished rhythmic activity occurring spontaneously or evoked during reflex testing, irrespective of oscillation frequency. The results are consistent with the hypothesis that locomotion and clonus are produced by common central pattern-generators. Stimulating the skin of the back could prove helpful in managing undesired rhythmic activity in spinal cord-injured humans.

The existence of axillary arch in human fetus and applied importance and clinical implications in the axillary brachial plexus blocks / La existencia de arco axilar en el feto humano y la importancia aplicadae implicancias clínicas en los bloques de plexo braquial

Axillary arch is the most common muscle variation of axillary fossa that gains importance for regional interventional procedures, screening methods and physical examination. In order to avoid malpractice the variations must be borne in mind. This study has been planned to research the frequency and the features of the axillary arch in human fetus, to mention the potential clinical and functional significance of axillary arch while applying axillary brachial plexus block and reflect on possible complications. Axillary fossa was examined with a stereomicroscope in 20 upper extremities of ten human fetuses. The gestation ages ranged from 16 to 36 weeks. Axillary arch was determined in 2/20 specimen unilaterally. In both specimen, muscular slip detached from latissimus dorsi, passed anterior neurovascular bundle and ended posterior pectoralis major tendon and lateral border of intertubercular groove. In one specimen axillary arch was innervated with medial pectoral nerve whereas the other one did not have a particular innervating nerve branch. The possible effects of axillary arch in the axillary brachial plexus block applications are discussed. Arcus axillaris may have a potential clinical and functional significance with regard the axillary brachial plexus block applications and may have possible effects on failure rate and acute complications. Also, we think that this fetus study which the pure structure of the muscles without any usage effect can be observed will be beneficial regarding this topic.

El arco axilar es la variación muscular más común de la fosa axilar, siendo de importancia para la región en los procedimientos de intervención, los métodos de selección y el examen físico. Con el fin de evitar las negligencias se debe tener en cuenta las variaciones. El objetivo de este estudio fue determinar la frecuencia y las características del arco axilar en el feto humano. Es necesario mencionar la importancia del potencial clínico y funcional del arco axilar en la aplicación de bloqueo axilar del plexo braquial y sus posibles complicaciones. La fosa axilar fue examinada bajo microscopio estereoscópico en 20 miembros superiores de diez fetos humanos. La edad de gestación varió de 16 a 36 semanas. El arco axilar se observó unilateralmente en 2/20 especímenes. En ambos especímenes el músculo cruzó anteriormente el paquete neurovascular y terminó en el tendón del músculo pectoral mayor y en el margen lateral del surco intertubercular. En un especimen el arco axilar se encontraba inervado por el nervio pectoral medial, mientras que en el otro no existía una determinado ramo del nervio. Se discuten los posibles efectos del arco axilar en las aplicaciones de bloqueo axilar del plexo braquial. Puede tener un significado potencial clínico y funcional, en lo que se refiere a la aplicación de bloqueo axilar del plexo braquial y aademás producir efectos de complicaciones agudas.

Sensory innervation of the thoracolumbar fascia in rats and humans.

The available data on the innervation of the thoracolumbar fascia (TLF) are inconsistent and partly contradictory. Therefore, the role of the fascia as a potential source of pain in the low back is difficult to assess. In the present study, a quantitative evaluation of calcitonin gene-related peptide (CGRP) and substance P (SP)-containing free nerve endings was performed in the rat TLF. A preliminary non-quantitative evaluation was also performed in specimens of the human TLF. The data show that the TLF is a densely innervated tissue with marked differences in the distribution of the nerve endings over the fascial layers. In the rat, we distinguished three layers: (1) Outer layer (transversely oriented collagen fibers adjacent to the subcutaneous tissue), (2) middle layer (massive collagen fiber bundles oriented obliquely to the animal's long axis), and (3) inner layer (loose connective tissue covering the paraspinal muscles). The subcutaneous tissue and the outer layer showed a particularly dense innervation with sensory fibers. SP-positive free nerve endings-which are assumed to be nociceptive-were exclusively found in these layers. Because of its dense sensory innervation, including presumably nociceptive fibers, the TLF may play an important role in low back pain.

Changes in excitability of corticomotor inputs to the trunk muscles during experimentally-induced acute low back pain.

Acute low back pain (LBP) is associated with differential changes in motor coordination of deep and superficial trunk muscles. Whether this is related to differential changes in excitability of descending corticomotor inputs remains unclear and was investigated in nine healthy individuals. Fine-wire i.m. electrodes were inserted bilaterally into deep (transversus abdominis (TrA)) and superficial abdominal muscles (obliquus externus abdominis (OE)), and surface electrodes were placed bilaterally over obliquus internus abdominis (OI), rectus abdominis (RA) and lumbar erector spinae (LES) muscles. Corticomotor excitability was assessed as amplitude of motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) at a range of stimulator intensities, at rest and during voluntary abdominal contractions. Pain was induced by injection of hypertonic saline into interspinous ligaments of the lumbar spine. Corticomotor excitability was examined before, during and after the induction of LBP. During pain, amplitude of TrA MEPs to contralateral cortical stimulation was reduced, whereas amplitudes of OE and LES MEPs contralateral and ipsilateral to the stimulated cortex were increased. The findings highlight differential changes in excitability of corticomotor inputs to trunk muscles during acute LBP. Further work is required to reveal whether such changes involve spinal and/or supraspinal centres and their consequence for spine control.

Spinal accessory nerve monitoring in posterior fossa surgery.

The role of intraoperative monitoring of lower cranial nerves is not well established. In this study, the authors retrospectively analyzed the intraoperative monitoring data and the clinical outcome of the spinal accessory nerve (SAN) in patients who have undergone posterior fossa surgery. SAN was monitored in 19 patients. Subcutaneous needle electrodes were placed in the trapezius, and any abnormal spontaneous activity was documented for duration and amplitude. A bipolar stimulation probe was used for triggered electromyogram, with a maximum stimulation intensity of 3 mA. All patients were clinically evaluated for SAN dysfunction postoperatively 24 hours and 7 days. Neurotonic discharges, lasting between 3 and 90 minutes were seen in 84% of the patients. Continuous discharges lasting longer than 5 minutes were seen in 36% of the patients. The SAN was stimulated in 57.8% of the patients. With clinical examination, none of our patients had postoperative SAN dysfunction. Long lasting dense neurotonic discharges and high stimulation thresholds have been correlated with postoperative facial nerve injury; however, this does seem be true in the case of SAN monitoring. Neurotonic discharges are commonly false-positive and stimulation intensity up to 3 mA can be related with a good outcome. The intraoperative monitoring of SAN may not be valuable as much as facial nerve monitoring.

Can classical acupuncture points and trigger points be compared in the treatment of pain disorders? Birch's analysis revisited.

BACKGROUND: A 1977 study by Melzack et al. reported 100% anatomic and 71% clinical pain correspondences of myofascial trigger points and classical acupuncture points in the treatment of pain disorders. A reanalysis of this study's data using different acupuncture resources by Birch a quarter century later concluded that correlating trigger points to classical acupuncture points was not conceptually possible and that the only class of acupuncture points that could were the a shi points. Moreover, Birch concluded that no more than 40% of the acupuncture points examined by Melzack et al. correlated clinically for the treatment of pain (correlation was more like 18%-19%). OBJECTIVE: To examine Birch's claims that myofascial trigger points cannot conceptually be compared to classical acupuncture points and that most (at least 60%) of the classical acupuncture points examined by the study of Melzack et al. are not recommended for treating pain conditions, negating their findings of a 71% clinical pain correspondence of trigger points and acupuncture points. METHODS: Acupuncture references and literature were reviewed to examine the validity of the Birch study findings. RESULTS: Acupuncture references support the conceptual comparison of trigger points to classical acupuncture points in the treatment of pain disorders, and their clinical correspondence in this regard is likely 95% or higher. CONCLUSIONS: Although separated by 2000 years temporally, the acupuncture and myofascial pain traditions have fundamental clinical similarities in the treatment of pain disorders. Myofascial pain data and research may help elucidate the mechanisms of acupuncture's effects.

Paraspinal muscle vibration alters dynamic motion of the trunk.

Loss in dynamic stability of the low back has been identified as a potential factor in the etiology of low back injuries. A number of factors are important in the ability of a person to maintain an upright trunk posture including the preparatory stiffness of the trunk and the magnitude and timing of the neuromotor response. A neuromotor response requires appropriate sensing of joint motion. In this research, the role of this sensory ability in dynamic performance of the trunk was examined using a simple pendulum model of the trunk with neuromotor feedback. An increased sensory threshold was found to lead to increased torso flexion and increased delay in neuromotor response. This was confirmed experimentally using paraspinal muscle vibration which is known to alter proprioception of the muscle spindle organs. Before, during and after exposure to bilateral, paraspinal muscle vibration for 20 minutes, the dynamic response of subjects to an unexpected torso flexion load was examined. Subjects were found to have a 19.5% slower time to peak muscle activity and a 16.1% greater torso flexion during exposure to paraspinal muscle vibration. Torso flexion remained significantly increased after vibration exposure relative to before exposure. These results suggest that the neuromotor response plays an important role in trunk dynamics. Loss in sensitivity of the sensory system can have a detrimental effect on trunk dynamics, increasing delays in neuromotor response and increasing the motion of the trunk in response to an unexpected load.

Trapezius muscle innervation from the spinal accessory nerve and branches of the cervical plexus.

The aim of this study was to demonstrate the extent of motor innervation of the trapezius muscle from the accessory nerve and branches of the cervical plexus using intraoperative electroneurography and histochemical staining. In 34 patients during radical neck dissection the accessory nerve and C2-C4 branches running to the trapezius were identified and stimulated. Potentials were registered under three conditions: intact accessory nerve, section of superior part of communication between the nerve and the cervical branches, and complete section of the nerve. Projections that did not elicit responses were analyzed for acetylcholinesterase activity. Before cutting the accessory nerve, its stimulation led to a recordable contraction in all parts of the trapezius muscle in all patients. C2 contributions were seen in 15, C3 in 21 and C4 in 20 patients. After sectioning of the upper half of the nerve, the results were similar. After the nerve was completely cut, C2 contributions were seen in only 2 patients, but C3 were seen in 20 patients and C4 in 19 patients. Histochemical staining revealed that the branches with no responses contained both motor and sensory axons. The accessory nerve provides the main motor input to the trapezius muscle, but preservation of the C2-C4 branches to the muscle during modified neck dissection should improve outcomes.

Primary somatosensory evoked magnetic fields elicited by sacral surface electrical stimulation.

To explore the brain response to sacral surface therapeutic electrical stimulation (SSTES) for the treatment of refractory urinary incontinence and frequent micturition, evoked magnetic fields were measured in six healthy males. Electrical stimuli were applied between bilateral surface electrodes over the second through fourth posterior sacral foramens with intensity just below the pain threshold. Somatosensory evoked magnetic fields (SEFs) for the bilateral median (MN) and posterior tibial nerves (PTN) were also measured for the comparison. Sources of the early SEF peaks were superimposed on individual magnetic resonance images. The first peak latency for sacral stimuli, M30, occurred at 30.2+/-0.8 ms (mean+/-standard deviation, N=6), with shorter latency than those for PTN stimulus (39.3+/-1.4 ms, N=12) and longer latency than those for MN stimulus (21.0+/-0.9 ms, N=12). The second peak latency for sacral stimuli, M50, occurred at 47.2+/-2.9 ms (N=6). Both M30 and M50 peaks showed a single dipole pattern over the vertex in the isofield maps. The equivalent current dipoles of M30 and M50 were both estimated near the medial end of the central sulcus with approximately posterior current direction. These results suggest that the sacral M30 and M50 are responses from the primary somatosensory cortex. The relatively long time lag between the onset and peak of M30 suggests that SSTES directly affects both the cauda equina and cutaneous nerve of the sacral surface.

Variation of the spinal nerve compositions of thoracodorsal nerve.

Thoracodorsal nerve distributes to the latissimus dorsi muscle. The aim of this study was to investigate the anatomic variation of the spinal nerve compositions of thoracodorsal nerve and to confirm which spinal nerve is a main component in participating amount. The most frequent type was consisted of C7 and C8 in 60%. Next frequent type was C6, C7, and C8 in 25%. Third type was C6 and C7 in 10% and fourth type was C7 alone in 5%. The diameter of each spinal nerve comprising thoracodorsal nerve was 1.20 +/- 0.23 (mean +/- SD) mm at C7, 0.43 +/- 0.15 mm at C8, and 0.33 +/- 0.09 mm at C6. These results show that the C7 nerve was the main component of thoracodorsal nerve and the anatomic variation appeared at the spinal nerve that participate by small amounts, as be excepted (C6 and C8).

Localization of motoneurons that extend axons through the ventral rami of cervical nerves to innervate the trapezius muscle: a study using fluorescent dyes and 3D reconstruction method.

It has been suggested that in addition to motor axons, which extend directly into the spinal accessory nerve (SAN), ventral rami-associated motor fibers of cervical nerves also innervate the trapezius muscle. Using fluorescent dye labeling and 3D reconstruction in adult rats, this study clarifies the localization of motoneurons, which extend axons either directly through the SAN or through the ventral rami of cervical nerves to innervate the trapezius. DiI or DiI and DiO were used to label the ventral rami of cervical nerves entering the SAN, as well as branches of the SAN. We show that motoneurons whose axons pass through the ventral rami of cervical nerves and then enter the SAN, and those extending axons directly through the SAN are distributed within the same area. The neurons that extend axons through the SAN had a greater diameter than those axons that pass through the cervical nerves en route to the trapezius muscle. In addition, the axons that ultimately extend through the SAN exit the spinal cord dorsolaterally, while those that pass through the cervical nerves extend out the spinal cord through the ventral roots. We presume that the neurons that extend axons through the SAN are mainly alpha-motoneurons and that those projecting axons through the cervical nerves to the trapezius are mainly gamma-motoneurons. Taken together, these results could explain why patients in whom the SAN was used to treat brachial plexus injury retain some control of the trapezius muscle.

Temporal analysis of cortical mechanisms for pain relief by tactile stimuli in humans.

The mechanisms by which vibrotactile stimuli relieve pain are not well understood, especially in humans. We recorded cortical magnetic responses to paired noxious (intra-epidermal electrical stimulation, IES) and innocuous (transcutaneous electrical stimulation, TS) stimuli applied to the back at a conditioning-test interval (CTI) of -500 to 500 ms. Results showed that IES-induced responses were remarkably attenuated when TS was applied 20-60 ms later and 0-500 ms earlier than IES (CTI = -60 to 500 ms). Since the signals evoked by IES reached the spinal cord (CTI = -60 to -20 ms conditions) and the cortex (-60 and -40 ms condition) earlier than those evoked by TS, the present results indicate that cortical responses to noxious stimuli can be inhibited by innocuous tactile stimuli at the cortical level, with minimal contribution at the spinal level.

The course of the greater occipital nerve in the suboccipital region: a proposal for setting landmarks for local anesthesia in patients with occipital neuralgia.

The anatomical relationships of the greater occipital nerve (GON) to the semispinalis capitis muscle (SCM) and the trapezius muscle aponeurosis (TMA) were examined to identify topographic landmarks for use in anesthetic blockade of the GON in occipital neuralgia. The course and the diameter of the GON were studied in 40 cadavers (29 females, 11 males), and the points where it pierced the SCM and the TMA were identified. The course of the GON did not differ between males and females. A left-right difference was detected in the site of the GON in the TMA region but not in the SCM region. The nerve became wider towards the periphery. This may be relevant to entrapment of the nerve in the development of occipital neuralgia. In three cases, the GON split into two branches before piercing the TMA and reunited after having passed the TMA, and it pierced the obliquus capitis inferior muscle in another three cases. The GON and the lesser occipital nerve reunited at the level of the occiput in 80% of the specimens. The occiput and the nuchal midline are useful topographic landmarks to guide anesthetic blockade of the GON for diagnosis and therapy of occipital neuralgia. The infiltration is probably best aimed at the site where the SCM is pierced by the GON.