Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study.

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.

Efficacy of treatments for pain and numbness in cancer survivors: a systematic review and meta-analysis.

BACKGROUND: Pain and numbness in cancer survivors frequently have negative impacts on quality of life (QoL). This meta-analysis aimed to identify the current treatment options for pain and numbness in cancer survivors and to evaluate their effects. METHODS: Cancer survivors were defined as patients diagnosed with cancer who had completed active cancer treatment, whose conditions were stable, and who had no evidence of recurrent or progressive disease. A systematic search through the PubMed, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, PsycInfo, and CINAHL databases was conducted, which targeted randomized controlled trials (RCTs) published until April 2022 that evaluated any type of treatment for pain or numbness in cancer survivors. A meta-analysis was conducted using the random-effects model to obtain the effect sizes of 7 types of treatments: opioid therapy, nonopioid pharmacotherapy, interventional therapy, acupuncture, education/cognitive behavioral therapy (CBT), physical exercise, and alternative medicine. RESULTS: A total of 36 studies involving 2,870 cancer survivors were included. Among them, 35 (n=2,813) were included in the meta-analysis for pain. The analysis suggested that physical exercise [n=761; 13 studies; standardized mean difference (SMD) -0.84; 95% confidence interval (CI): -1.14 to -0.55], acupuncture (n=409; 3 studies; SMD -0.80; 95% CI: -1.04 to -0.56), and alternative medicine (n=206; 6 studies; SMD -0.44; 95% CI: -0.71 to -0.16) could significantly reduce pain. Nonopioid pharmacotherapy and education/CBT did not demonstrate significant effects. No studies were identified that investigated the effects of opioid therapy or interventional therapy on pain. Regarding numbness, 5 studies (n=566) were included in the meta-analysis. Acupuncture (n=99; 2 studies) did not demonstrate significant effects on numbness, and the effects of nonopioid pharmacotherapy, education/CBT, and physical exercise could not be determined due to the small number of included studies. No studies were identified that investigated the effects of opioid therapy, interventional therapy, or alternative medicine on numbness. CONCLUSIONS: This meta-analysis suggested that physical exercise, acupuncture, and alternative medicine may reduce pain in cancer survivors, with a very small to moderate amount of evidence. The effect of treatments for numbness could not be determined due to the limited number of included studies. Further studies are needed, particularly on widely used pharmacotherapy.

Different Profiles of the Triad of Lysophosphatidylcholine, Lysophosphatidic Acid, and Autotaxin in Patients with Neuropathic Pain Diseases: a Preliminary Observational Study.

The mechanisms underlying neuropathic pain remain unclear. Lysophosphatidic acid (LPA) is a bioactive phospholipid derived mainly from lysophosphatidylcholine (LPC) by extracellular autotaxin (ATX), and has attracted attention as a candidate biomarker of neuropathic pain. We aimed to investigate the levels of LPA, LPC, and ATX in patients with lumbar spinal canal stenosis (LSCS) or other neuropathic pain diseases, and to distinguish the underlying mechanism of LSCS from other neuropathic pain conditions. Furthermore, the levels of phosphorylated neurofilament heavy chain (pNF-H), an objective surrogate marker of axonal damage, were also measured. Cerebrospinal fluid (CSF) samples were obtained from 56 patients with LSCS (n = 31) and various etiologies other than LSCS (n = 25). Patients with LSCS complained of pain intensity comparable to that of patients without LSCS. The LPA levels were significantly higher in patients with LSCS than in non-LSCS patients, while the ATX levels were significantly lower. However, the differences in LPC and pNF-H levels between the two patient groups were not significant. The LPA/LPC ratio was significantly higher in the LSCS group. Notably, the difference in LPA between the two groups diminished in the analysis of covariance (ANCOVA) with ATX as a covariate. Thus, it helped to reveal that LPA synthesis in patients with LSCS depends more efficiently on ATX than in non-LSCS neuropathic pain patients with other etiologies. Our findings further suggest that the triad of LPA, LPC, and ATX in LSCS may contribute to the development and maintenance of neuropathic pain in a manner different from non-LSCS neuropathic conditions.

Imaging features inferring symptom onset due to spinal metastasis progression: a preliminary study.

BACKGROUND: Spinal metastases can cause intractable pain and neurological deficits, which can markedly worsen both patients' activities of daily living (ADL) and their health-related quality of life (QOL). Early intervention is essential to prevent irreversible neurological deficits and pain associated with spinal metastases. We investigated the imaging features of spinal metastases that led to neurological deficits. METHODS: We analyzed axial cross-sectional computed tomography (CT) images of cervical and thoracic spinal metastases in patients with and without lower limb motor paralysis, neuropathic pain, and local nociceptive pain. We distinguished regions of the spine associated with these respective symptoms, and explored their inferable performance using images obtained before symptom onset. In addition, we analyzed the imaging features and type of bone metastasis (osteolytic and osteoblastic). RESULTS: Spinal lesions occupied the area in and around the spinal canal and around the pedicle in patients with motor paralysis. Lesions around the pedicle and in the most posterior vertebral body part before symptom onset were inferable. In patients with neuropathic pain, spinal metastases spread along the pedicle before symptom onset, and had surrounded the spinal canal circumferentially at symptom onset. Local nociceptive pain was more common near the center of the vertebral body either at or before symptom onset. There was no difference in the imaging features according to the type of bone metastasis. CONCLUSIONS: Lesions in certain regions in the asymptomatic metastatic spine can indicate the onset of spinal metastasis-related symptoms in the next few months. Early therapeutic intervention might be applied to prevent neurological disorder.

Capecitabine-induced hand-foot syndrome does not emerge in the complex regional pain syndrome-affected limb: A case report.

Hand-foot syndrome (HFS) is a frequent adverse effect of various anti-tumour drugs, such as capecitabine, that affects their dose-limiting toxicity. The mechanism of HFS remains unknown and there are currently no effective strategies to treat HFS, except for cessation. The current study presented a female case where one hand, affected by brachial plexus infiltration due to the subclavian lymph node metastasis of breast cancer, exhibited not only pain and partial motor paralysis but also anhidrosis, oedema and skin colour changes. The patient met the diagnostic criteria for complex regional pain syndrome (CRPS). After treatment with capecitabine, their anhidrosis hand completely prevented HFS. The other hand and both feet demonstrated typical symptoms of HFS, which improved consequent to capecitabine cessation. The CRPS-affected hand remained normal. Considering the limited presentation of HFS concomitant with anhidrosis, the exocrine release of condensed capecitabine through sweat glands might be a promising mechanism of HFS induction.

Prefectural Adequacy of Opioid Availability for Cancer Pain and Its Determinants in Japan: A Preliminary Study.

INTRODUCTION: Opioid analgesics are the mainstay of cancer pain management. The annual opioid consumption globally indicates adequate opioid availability and the quality of palliative care. We investigated the current situation regarding the adequacy of opioid availability in individual prefectures in Japan and explored the determinants of adequacy. METHODS: We analyzed nationwide databases open to public inspection depicting the current Japanese healthcare situation. Opioid consumption for cancer pain was estimated from oxycodone and morphine data in the nationwide database. On the basis of the World Health Organization recommendations, we calculated adequacy based on the annual cancer deaths in each prefecture in 2013 and 2015. We investigated the associations between adequacy and either outpatient medical expenditure for hypertension and diabetes as a proxy of primary care practice or ratios of these risk holders in community. Outpatient medical expenditures for musculoskeletal disorders and neoplasms were also investigated. RESULTS: The nationwide adequacy of opioid availability was approximately 75%. The largest gaps in adequacy between prefectures were more than 65%. The adequacy correlated with expenditure but not local volumes of hypertension and diabetes in both years. The other two expenditures did not relate to opioid availability. CONCLUSIONS: Although precise data are required, our preliminary findings indicate that primary care practice is the key regulator of adequate opioid availability. Opioid adequacy in Japan is thus delayed in matching the global standard, and gaps in opioid adequacy among prefectures should be bridged rapidly to expand universal access to effective palliative care and cancer pain relief.

Use of three-dimensional printing of a lumbar skeletal model for intrathecal administration of nusinersen: a brief technical report.

Spinal muscular atrophy (SMA) is an autosomal recessive hereditary neurodegenerative disease causing progressive muscle atrophy, weakness and kyphoscoliosis. Nusinersen is a therapeutic agent for SMA that should be administered intrathecally. However, due to severe kyphoscoliosis, lumbar puncture can be challenging. Here, we present our experience of intrathecal administration of nusinersen in an SMA patient with severe kyphoscoliosis using a life-size three-dimensional printing (3D) skeletal model created with 3D printer. With this strategy, we were able to rapidly and safely perform the lumbar puncture.

Clopidogrel, an ADP-P2Y12 Receptor Antagonist, Can Prevent Severe Postoperative Pain: A Retrospective Chart Review.

The purinergic P2Y12 receptor regulates microglial activation, resulting in persistence and aggravation of pain in neuropathic and nociceptive pain models. We conducted a retrospective chart review to explore the analgesic potency of the P2Y12 receptor-specific antagonist, clopidogrel, for clinical management of postoperative pain in patients who underwent abdominal surgery. Twenty-seven patients with cardiovascular comorbidities, who underwent laparoscopic abdominal surgery and had ceased aspirin (ASP, n = 17) or clopidogrel (CLP, n = 10) for 14 days pre-operatively, were enrolled retrospectively. In both groups, the number of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) consumed for managing postoperative pain was compared using the chi-square test and Mann-Whitney test. Our results showed that from postoperative day (POD) 0 to POD 3, the average numerical rating reflecting the postoperative pain was comparable between the two groups (CLP: 4.0 ± 1.4 vs. ASP: 3.7 ± 0.8, P-value = 0.56). However, at POD 7, opioid consumption in the CLP-treated group (fentanyl-equivalent dose: 0.49 ± 0.56 mg) was significantly lower than that in the ASP-treated group (1.48 ± 1.35 mg, P-value = 0.037). After reaching a stable state by repeated systemic administration, clopidogrel sustained the analgesic efficacy for a certain period. In conclusion, microglial P2Y12 receptors may mediate signal transduction of postoperative nociceptive pain and enhance clinical opioid analgesia.

Adiponectin receptor 1 gene is potentially associated with severity of postoperative pain but not cancer pain.

Adiponectin is an adipose tissue-derived cytokine that exerts its antiinflammatory effects by binding to 2 adiponectin receptors, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2). However, the role of these adiponectin receptors on inflammatory pain remains unclear. We investigated the association between single nucleotide polymorphisms (SNPs) of these genes and inflammatory pain, such as postoperative pain and cancer pain.We analyzed 17 SNPs of the ADIPOR1 gene and 27 SNPs of the ADIPOR2 gene in 56 adult patients with postlaparotomy pain. We compared these genotypes with pain intensity and opioid consumption, adjusting for multiple testing. We analyzed the genotypes of 88 patients with cancer pain and examined the association of the relevant SNP(s) with pain intensity and opioid consumption.One variant of the ADIPOR1 gene (rs12045862) showed significant association with postoperative pain intensity; patients with minor allele homozygote (n = 7) demonstrated significantly worse pain intensity than that of combined patient group exhibiting major allele homozygote or the heterozygote (n = 49; Mann-Whitney test, P < .00002), although their opioid consumptions were comparable. Cancer pain intensity between minor allele homozygote patients (n = 7) and other 2 genotype patients (n = 81) were comparable.The rs12045862 SNP of the ADIPOR1 gene was associated with postoperative pain but not cancer pain. This might result from functional alteration of the ADIPOR1 signalling pathways, which influence the inflammatory process. ADIPOR1 may be a novel potential target for developing analgesics of postoperative pain.

A Novel Technique Using Magnetic Resonance Imaging in the Supine and Prone Positions for Diagnosing Lumbar Adhesive Arachnoiditis: A Preliminary Study.

BACKGROUND: Lumbar adhesive arachnoiditis is a debilitating neuropathic condition and is difficult to diagnose owing to lack of definitive diagnostic criteria. By focusing on the intrathecal mobility of nerve roots, we assessed whether useful diagnostic criteria could be established using MRI. METHODS: Seventeen patients with a high risk for lumbar adhesive arachnoiditis and 18 no-risk patients with chronic low back pain and/or leg pain participated in this study. The patients underwent MRI in both the supine and prone positions. Eleven axial T2-weighted images between the L2 and L5/S levels were obtained, and the proportion of the low-intensity area in the dorsal half to the total low-intensity area in the dural sac was calculated for each axial view. RESULTS: At some lumbar levels, the low-intensity area in the dorsal half of the dural sac was relatively larger in patients with a high risk for lumbar adhesive arachnoiditis than in the no-risk patients. In the no-risk group, the proportion of the low-intensity area in the dorsal half in the supine position was significantly higher than that in the prone position at all lumbar levels. However, in the high-risk group, at some levels, the proportions were not significantly different in the dorsal half of the dural sac between the supine and prone positions. CONCLUSION: In patients with a known risk for lumbar adhesive arachnoiditis, nerve roots lose their potential to migrate in the dural sac in the gravitational force direction on MRI.

Characteristics of Locomotive Syndrome in Japanese Patients with Chronic Pain and Results of a Path Analysis Confirming the Relevance of a Vicious Cycle Involving Locomotive Syndrome, Musculoskeletal Pain, and Its Psychological Factors.

INTRODUCTION: The current aging population has a major impact on public health. Locomotive syndrome (LS) is a condition that carries a high risk for developing systemic musculoskeletal disability. METHODS: Participants were patients with chronic pain (n = 415) who were examined at the Japanese multidisciplinary pain centers of the research consortium. They completed the 25-question geriatric locomotive function scale (GLFS-25; LS screening tool), an 11-point numerical rating scale (NRS) of pain intensity and its psychological distresses, health-related quality of life (HRQOL) questionnaire, and a survey of exercise habits. A multifaceted analysis of the relevance of the pain, psychological distresses, and LS were conducted using SPSS and AMOS software. RESULTS: 337 patients (81.2%) were found to have LS. The final model of a multifaceted analysis demonstrated good fitness for the "vicious cycle" model among the results of LS, pain intensity, impairment of self-efficacy, and depression; these parameters independently impaired HRQOL. Anxiety related to falling (GLFS-25) and exercise habits affected the model. CONCLUSIONS: These findings indicate LS, LS-related pain, and psychological distress create a vicious cycle, resulting in the impairment of HRQOL. Treatment strategies for LS should inclusively focus on musculoskeletal disorders, pain, and pain-related psychological factors.

Lysophosphatidic acid is associated with neuropathic pain intensity in humans: An exploratory study.

The underlying mechanisms of neuropathic pain remain to be elucidated. Basic animal research has suggested that lysophosphatidic acids, which are bioactive lipids produced by autotaxin from lysophosphatidylcholine, may play key roles in the initiation and maintenance of neuropathic pain. Here, we investigated the clinical relevance of lysophosphatidic acids signaling on neuropathic pain in humans. Eighteen patients who had been diagnosed with neuropathic pain with varied etiologies participated in the study. Cerebrospinal fluid samples were obtained by lumbar puncture and the concentrations of 12 species of lysophosphatidic acids and lysophosphatidylcholine, autotaxin, and the phosphorylated neurofilament heavy subunit were measured. Pain symptoms were assessed using an 11-point numeric rating scale and the Neuropathic Pain Symptom Inventory regarding intensity and descriptive dimensions of neuropathic pain. The total lysophosphatidic acids were significantly associated with both pain intensity and symptoms. 18:1 and 20:4 lysophosphatidic acids in particular demonstrated the most correlations with dimensions of pain symptoms. Autotaxin and the phosphorylated neurofilament heavy subunit showed no association with pain symptoms. In conclusions, lysophosphatidic acids were significantly associated with pain symptoms in neuropathic pain patients. These results suggest that lysophosphatidic acids signaling might be a potential therapeutic target for neuropathic pain.

Gamma-aminobutyric acid transaminase genetic polymorphism is a candidate locus for responsiveness to opioid analgesics in patients with cancer pain: An exploratory study.

AIM: Cancer pain impairs not only physical functions but also social functions and roles. Consequently, the overall health-related quality of life of patients with cancer pain deteriorates. Opioid analgesics are recommended for treating moderate to strong cancer pain. Advances in human genome research have fueled a growing interest to understand individual differences in responsiveness to opioid analgesics. This study aimed to explore and identify novel loci for genes predisposing an individual to opioid analgesic responsiveness. METHODS: A total of 71 cancer patients rated their pain on an 11-point numerical rating scale twice before and after increasing opioid analgesics. A genomewide association study focusing on single nucleotide polymorphisms (SNPs) was conducted to associate pain decrease with increased dosage of opioid analgesics based on weight (ie, responsiveness to opioid analgesics). A genomewide significance (P < 5E-8) was set for multiplicity of analyses to control for false positives. RESULTS: Two SNPs passed the genomewide threshold for significance. One exonic SNP (rs1641025) was located in the ABAT [4-aminobutyrate aminotransaminase (GABA transaminase)] gene on chromosome 16. The other SNP (rs12494691) was located on chromosome 3, which was not associated with any known genes. These SNPs were not associated with opioid-related adverse effects. CONCLUSIONS: Our results preliminarily suggest that both SNPs might be potential candidate loci for responsiveness to opioid analgesics, and GABA transaminase might be a possible target for developing adjuvant pharmacotherapy with opioid analgesics in adjuvant pharmacotherapy. Our results should be validated in a large-scale study with a larger sample size.

Aortic intramural hematoma associated with metastatic carcinoma.

We present a case of aortic intramural hematoma, a variant of aortic dissection, with metastatic carcinoma invasion within the aortic wall and pseudolumen. An elderly male patient with a history of controlled hypertension initially experienced chest pain. A computed tomographic scan revealed aortic intramural hematoma; thus, conservative therapy was performed. One and a half months later, tumors in both adrenal glands and the lumbar vertebra were discovered. The primary site was not identified, and the patient died following septic shock 1 month later. An autopsy revealed intramural hematoma throughout the aorta, as well as systemic metastases of adrenocortical carcinoma with invasion into the aortic wall and formation of a pseudolumen accompanied by disruption of the vasa vasorum. As far as we know, this is the second case of aortic dissection associated with metastatic carcinoma. The highly aggressive nature of the tumor cells was demonstrated by high mitotic ratio and Ki-67 labeling index. The tumor was also positive for matrix metalloproteinase-12, thus suggesting disruption of the aortic media.