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.

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.

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.

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.

Cortical processing of visceral and somatic stimulation: differentiating pain intensity from unpleasantness.

Visceral and somatic pain perception differs in several aspects: poor localization of visceral pain and the ability of visceral pain to be referred to somatic structures. The perception of pain intensity and affect in visceral and somatic pain syndromes is often different, with visceral pain reported as more unpleasant. To determine whether these behavioral differences are due to differences in the central processing of visceral and somatic pain, non-invasive imaging tools are required to examine the neural correlates of visceral and somatic events when the behavior has been isolated and matched for either unpleasantness or pain intensity. In this study we matched the unpleasantness of somatic and visceral sensations and imaged the neural representation of this perception using functional magnetic resonance imaging in 10 healthy right-handed subjects. Each subject received noxious thermal stimuli to the left foot and midline lower back and balloon distension of the rectum while being scanned. Stimuli were matched to the same unpleasantness rating, producing mild-moderate pain intensity for somatic stimuli but an intensity below the pain threshold for the visceral stimuli. Visceral stimuli induced deactivation of the perigenual cingulate bilaterally with a relatively greater activation of the right anterior insula-i.e. regions encoding affect. Somatic pain induced left dorso-lateral pre-frontal cortex and bilateral inferior parietal cortex activation i.e. regions encoding spatial orientation and assessing perceptual valence of the stimulus. We believe that the observed patterns of activation represent the differences in cortical process of interoceptive (visceral) and exteroceptive (somatic) stimuli when matched for unpleasantness.

Monosynaptic projections from the nucleus retroambiguus to motoneurons supplying the abdominal wall, axial, hindlimb, and pelvic floor muscles in the female rhesus monkey.

The nucleus retroambiguus (NRA) consists of premotor neurons in the caudal medulla. It is involved in expiration, vomiting, vocalization, and probably reproductive behavior by means of projections to distinct motoneuronal cell groups. Because no information is available about the NRA and its efferent pathways in primates, the present study examines NRA projections to the lumbosacral spinal cord in female rhesus monkeys. To identify the NRA, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected into the lumbosacral cord in three monkeys. To study the distribution of NRA axons in the lumbosacral cord, WGA-HRP injections were made into the NRA in seven monkeys. To identify motoneuronal cell groups receiving input from the NRA, the same seven monkeys also received cholera toxin subunit b (CTb) injections into different hindlimb, axial, and pelvic floor muscles. The results show that NRA neurons projecting to the lumbosacral cord are mainly located between 1 to 4 mm caudal to the obex. They send numerous axons to external oblique and pelvic floor motoneurons, whereas projections to iliopsoas and axial motoneurons are less numerous. The projections are bilateral, but show a clear contralateral predominance in the iliopsoas, axial, and pelvic floor motoneuronal cell groups. At the ultrastructural level, NRA-terminal profiles make asymmetrical contacts with labeled and unlabeled dendrites in these motoneuronal cell groups and contain large amounts of spherical and a few dense core vesicles. It is concluded that the NRA is well developed in the monkey and that there exists a direct pathway from the NRA to lumbosacral motoneurons in this species. The finding that the NRA projects to a somewhat different set of motoneuronal cell groups compared with other species fits the concept that it is not only involved in expiration-related activities but also in species specific receptive and submissive behavior.

Trigger points and acupuncture points for pain: correlations and implications.

Trigger points associated with myofascial and visceral pains often lie within the areas of referred pain but many are located at a distance from them. Furthermore, brief, intense stimulation of trigger points frequently produces prolonged relief of pain. These properties of trigger points--their widespread distribution and the pain relief produced by stimulating them--resemble those of acupuncture points for the relief of pain. The purpose of this study was to determine the correlation between trigger points and acupuncture points for pain on the basis of two criteria: spatial distribution and the associated pain pattern. A remarkably high degree (71%) of correspondence was found. This close correlation suggests that trigger points and acupuncture points for pain, though discovered independently and labeled differently, represent the same phenomenon and can be explained in terms of the same underlying neural mechanisms. The mechanisms that play a role in the genesis of trigger points and possible underlying neural processes are discussed.

Electrical stimulation of the midbrain central gray facilitates lateral vestibulospinal activation of back muscle EMG in the rat.

Electrical stimulation in the midbrain central gray in urethane-anesthetized female rats increased responses of the deep back muscles lateral longissimus and medial longissimus to stimulation of the lateral vestibular nucleus (LVN). During central gray stimulation, LVN stimuli led to larger muscle responses, recruitment of new motor units, and decreased latency of muscle response. Effective central gray sites are hypothesized to act through axons descending to medullary reticular formation. Results are consistent with participation of these neuronal groups in the activation of lordosis behavior, a vertebral dorsiflexion that requires deep back muscle contraction, but these electromyographic results could also be relevant for other behaviors that require vertebral postural adjustments.

Supraspinal and segmental input to lumbar epaxial motoneurons in the rat.

Inputs to medial longissimus (ML) and lateral longissimus (LL) motoneurons were studied in urethane or urethane-chloralose anesthetized rats by recording from ML and LL nerves while stimulating ipsilateral lumbosacral dorsal roots, medial medullary reticular formation (RF), vestibular nuclei (VN), dorsal midbrain (MDBR), or ventromedial hypothalamus (VMH). Stimulation of appropriate dorsal roots produced short-latency responses (1.5-3.0 ms) in nerves to medial longissimus or lateral longissimus. The connections underlying these responses, which could be monosynaptic, are weak, since generally two or more stimuli were necessary for a response to occur. Short-latency LL nerve responses required more dorsal root stimuli than did ML nerve responses and stable LL responses sometimes could not be obtained, suggesting that segmental reflexes to a back muscle (LL) could be weaker than those to a proximal tail muscle (ML). Trains of conditioning stimuli delivered to the RF, VN, and MDBR facilitated segmental responses in ML nerves or LL nerves. Temporal profiles of facilitation of ML differed for the three regions. On one extreme, the facilitation produced by RF conditioning required few stimuli (median, 3 shocks) and peak facilitation occurred at short condition-test intervals (median, 1.5 ms). On the other extreme, facilitation produced by MDBR conditioning required long trains (median, 14 stimuli) and peak facilitation occurred at longer condition-test intervals (median, 10 ms). Stimulation within the VMH never facilitated ML or LL nerve activity. These results demonstrate excitatory connections from reticular formation, vestibular nuclei and the dorsal midbrain to medial longissimus and lateral longissimus. Such connections could be involved in behaviors mediated by midbrain, and in postural regulation through brain stem control of axial musculature. Motoneuron cell bodies for LL, ML and lumbar transversospinalis (TS) muscles were localized by ejecting dye at sites where unitary antidromic responses to muscle nerve stimulation were recorded extracellularly. ML cells were found ventrolaterally in the L6-S1 ventral horn. LL and TS cells were found medially in the ventral horn of the lumbar enlargement.

[Structural and ultrastructural quantitative study of skin and nerve biopsies in the diagnosis of congenital indifference to pain]. / Contribution a l'etude quantitative structurale et ultra-structurale de biopsies cutanees et nerveuse dans le diagnostic de l'indifference congenitale a la douleur.

The muscolo-cutaneous nerve, and skin biopsies from 3rd and 5th finger-tips and the back were studied in a 8-year-old girl with congenital indifference to pain, and in a control child of the same age. The tips of the fingers, and the toes were the most damaged areas. The diameters of myelinated and unmyelinated fibers of the nerve in the sick child and the control child were compared. A loss of 54% of myelinated fibers and 33% of unmyelinated fibers was observed. In the skin, the loss of myelinated fibers was 82% in the 3rd finger-tip, 78% in the 5th, and 35% in the back, and of unmyelinated fibers, 97%, 87%, and 8%, respectively. Eighty four per cent of free endings were absent in the 3rd finger-tip and they were completely absent in the 5th. As for Meissner's corpuscles, 97% were absent in the 3rd finger, and 75% in the 5th. The absence of degenerating fibers and the unimodal distribution of unmyelinated fibers raise the problem of the nosological position of this case of congenital indifference to pain, as compared to the sensory neuropathies.

The role of magnetic stimulation in the diagnosis of multiple sclerosis.

Magnetic stimulation was used to measure motor conduction time (MCT) between head and neck, and head and lumbar region, as well as amplitude of the motor evoked potential (MEP) in normal subjects and patients with multiple sclerosis (MS). Patients with definite MS had significantly longer MCTs and smaller amplitude MEPs than normal subjects when recording from arm and leg muscles. In a comparison with visual evoked potential (VEP) recordings, head to neck MCTs were abnormal less often than VEPs, and VEPs detected more silent lesions. Recording from leg as well as arm muscles significantly increased the yield of abnormal MCT measurements. The detection of silent lesions in the patients with definite MS was improved, but there was no improvement in the non-definite cases. Amplitude measurements provided very little extra diagnostic information over MCT measurements alone and did not improve the detection of silent lesions. Interside MCT differences yielded extra abnormalities when recording from the arms but not the legs. Interside MCT abnormalities increased the detection of silent lesions in both the definite and non-definite categories. It was concluded that the majority of useful diagnostic information in patients with MS should be obtainable from bilateral MCT (head to neck) measurements, together with estimation of interside MCT differences. However, VEP recording is a better diagnostic test for MS than MEP recording as more silent lesions are detected. This may be because MCT abnormalities tend to reflect the degree of pyramidal disability.

Mapping of sensory responses to epidural stimulation of the intraspinal neural structures in man.

A database is presented of sensory responses to electrical stimulation of the dorsal neural structures at various spine levels in 106 subjects subjected to epidural spinal cord stimulation. All patients were implanted for chronic pain management and were able to perceive stimulation in the area of pain. All patients entered in this study were able to reliably report their stimulation pattern. Several patients were implanted with more than one electrode array. The electrode arrays were placed in the dorsal epidural space at levels between C-1 and L-1. The structures that were likely involved include the dorsal roots, dorsal root entry zone, dorsal horn, and dorsal columns. At the present time, exact characterization of the structure being stimulated is possible only in limited instances. Various body areas are presented with the correspondent spine levels where implanted electrodes generate paresthesias. Areas that are relatively easy targets for stimulation are the median aspect of the hand, the abdominal wall, the anterior aspect of the thigh, and the foot. Some areas are particularly difficult to cover with stimulation-induced paresthesias; these include the C-2 distribution, the neck, the low back, and the perineum.

Tenderness at motor points. A diagnostic and prognostic aid for low-back injury.

In patients with low-back injury the motor points of some muscles may be tender. Of fifty patients with low-back "strain", twenty-six had tender motor points and twenty-four did not, while forty-nine of fifty patients with radicular signs and symptoms suggesting disc involvement had tender motor points, and the one without such tender points had a hamstring contusion which limited straight leg raising. Of fifty controls with no back disability, only seven had mild tender points after strenuous activity, while forty-six of another fifty controls with occasional back discomfort had mild motor-point tenderness. In all instances the tender motor points were located in the myotomes corresponding to the probable segmental levels of spinal injury and of root involvement, when present. Patients with low-back strain and no tender motor points were disabled for an average of 6.9 weeks, while those with the same diagnosis but tender motor points were disabled for an average of 19.7 weeks, or almost as long as the patients with signs of radicular involvement, who were disabled for an average of 25.7 weeks. Tender motor points may therefore be of diagnostic and prognostic value, serving as sensitive localizers of radicular involvement and differentiating a simple mechanical low-back strain from one with neural involvement.

Trigger point--acupuncture point correlations revisited.

UNLABELLED: In 1977, Melzack and colleagues examined the possible correspondence of acupuncture points and trigger points for the treatment of pain. They claimed a 71% correspondence between these two classes of points. Their findings have influenced many researchers and practitioners but have not been examined since 1977. The current study explores the claim of a 71% correspondence between these two classes of points through a more extensive examination of the acupuncture literature. OBJECTIVES: To investigate the claim of a 71% correspondence of acupuncture points and trigger points for the treatment of pain. METHODS: The study involved a review of acupuncture texts published since 1977, focusing on five textbooks for the in-depth analyses and a broader range of texts for the more general analyses. RESULTS: If trigger points correspond to any class of acupuncture points it would have to be to the a shi points rather than the "channel" or "extra" points with which the 1977 study attempted to find correlation. Approximately 35% of recommended acupuncture points in the treatment of pain are distant from the site of the pain, making assumptions about the infrequency of use of distant acupuncture points for pain suspect. Sixty-one percent (61%) of the acupuncture points that the 1977 study examined for the treatment of pain are not recommended at all for the treatment of pain, and 44% are not recommended in the treatment of any problem, while only 19% of the acupuncture points are frequently recommended for pain and 20% for all conditions. For the acupuncture points that corresponded in the 1977 study, the equivalent numbers are: 60% not recommended at all for pain, 47% not recommended for anything, 18% commonly recommended for pain, and 16% commonly recommended for anything. CONCLUSION: The claimed 71% correspondence of trigger points to acupuncture points is conceptually not possible. Furthermore, even putting this conceptual problem aside, no more than 40% of the acupuncture points that the 1977 study examined could correlate for the treatment of pain, and more likely, only approximately 18%-19% correlate rather than the 71% that was claimed. However, this study found a probable correspondence of trigger points to a different class of acupuncture points, the a shi points, which appears to be an important finding. Researchers and clinicians who have assumed the conclusions of the 1977 study to be correct will need to reexamine the impact of the current findings on any claims that are dependent on the conclusions of that study.

[A case of painful involuntary contraction of the left latissimus dorsi muscle, successfully treated with left thoracodorsal nerve resection].

A 66-year-old Japanese man underwent the resection of the upper lobe of the left lung for primary lung cancer. One year later, his back muscles neighboring the operation scar gradually began to twitch upwards intermittently. The involuntary muscle twitch was accompanied with severe local pain, and intensity of the pain and contraction slowly increased. The abnormal muscle contractions were confined to the left latissimus dorsi muscle on needle EMG. The pain and movement ceased by blocking of either thoracodorsal nerve or brachial plexus, and disappeared finally by resection of the nerve. The impulses causing involuntary, painful contractions were thought to originate in the damaged thoracodorsal nerve, transmitted to CNS and re-transmitted to the thoracodorsal nerve.

[A case of thoracic spondylosis presented with an attack of abnormal sensation and hyperhydrosis on the upper back].

A 23-year-old man presented an attack of abnormal sensation and hyperhydrosis on his upper back when he was tense or took a bath. This presentation continued for a month after commencement of Judo practise. Neurological examination found hyperactivity of bilateral deep tendon reflex alone. Magnetic resonance image demonstrated that the anterior thoracic spinal cord at the Th 4/5, 5/6 and 7/8 level were compressed by a bony spur. In our case, limitation of exercise, and prescription of adenosine triphosphate disodium and vitamin B led to a favourable outcome. Thoracic spondylosis in a young person is rare and there have been no standard protocols for the treatment. Thus, further clinical investigations are warranted.

[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.