Activation of peripheral neuronal FLT3 promotes exaggerated sensorial and emotional pain-related behaviors facilitating the transition from acute to chronic pain

Background. Acute pain events have been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. However, it is unclear whether injury-induced persistent pain sensitization can promote long-term mood disorders. The receptor tyrosine kinase FLT3 is causally required for peripheral nerve injury-induced pain chronification, questioning its role in the development of pain-induced mood alterations. Methods. In a model of paw incisional pain, mice underwent single (SI) or double incision (DI) and went through behavioral and molecular phenotyping with the evaluation of both sensorial and emotional pain components. The role of FLT3 was then investigated either by inhibition using transgenic knock-out mice and functional antibodies or by activation with FLT3 ligand (FL) administrations. Results. DI mice showed significant anxiodepressive-like and spontaneous pain behaviors while SI mice did not. DI also promoted and extended mechanical pain hypersensitivity compared to SI. This emotional and sensorial pain exaggeration correlated with a potentiation of spinal microglial activation after DI versus SI. Intrathecal minocycline, a microglial inhibitor, specifically reversed DI induced-mechanical hypersensitivity. Finally, FL injections in naive animals provoked mechanical allodynia and anxiodepressive-like disorders concomitant with a significant microglial activation while FLT3 inhibition blunted the development of persistent pain and depression after DI. Conclusions. Our results show for the first time that the repetition of a peripheral lesion facilitates not only exaggerated nociceptive behaviors but also anxiodepressive disorders. The inhibition of FLT3 could become a promising therapy in the management of pain sensitization and related mood alterations.

Pain mechanisms and management in corneal cross-linking: a review

Though corneal collagen cross-linking (CXL) is an increasingly available and effective treatment for keratoconus, few reports have considered its impact on pain-related physiology in depth. This comprehensive narrative review summarises mechanisms underlying pain in CXL and clinical care possibilities, with the goal of future improvement in management of CXL-related pain. Postoperative pain associated with CXL is largely due to primary afferent nerve injury and, to a smaller extent, inflammation. Chronification of pain after CXL has not been reported, even as long-term nerve damage without regeneration following standard CXL treatment is frequently observed. The lack of pain chronification may be due to the minimally invasive nature of the procedure, with its rapidly recovering superficial corneal wound, and to the positive anti-inflammatory changes of the tear film that have been described after CXL. Different CXL approaches have been developed, with the transepithelial epithelial-on technique (epi-on) associated with less postsurgical pain than the gold standard, epithelial-off technique (epi-off). After the first few days, however, the difference in pain scores and need for analgesics between epi-on and epi-off disappear. Patients experience relatively high-intensity pain the first few days post-CXL, and many strategies for acute pain control following CXL have been studied. Currently, no method of pain management is considered superior or universally accepted. Acute pain following CXL is a recognised and clinically significant side effect, but few CXL studies have systematically investigated postoperative pain and its management. This review aims to improve patient pain outcomes following this increasingly common procedure.

The Impact of Surgery-Related Muscle Injury on Prevalence and Characteristics of Acute Postcraniotomy Headache – A Prospective Consecutive Case Series

Background and Objective The latest third edition of the International Classification of Headache Disorders delineates diagnostic criteria for acute headache attributed to craniotomy (AHAC), but data on possible predisposing factors are sparse. This prospective observational study aims to evaluate the impact of surgery-related muscle incision on the prevalence, severity, and characteristics of AHAC. Patients and Methods Sixty-four consecutive adults (mean age: 54.2 ± 15.2 years; 26 males and 38 females) undergoing cranial neurosurgery for various reasons without preoperative headache were included. After regaining consciousness, all patients reported their average daily headache on a numeric pain rating scale (NRS; range: 0–10), headache characteristics, as well as analgesic consumption from day 1 to 3 after surgery. Three distinct patient cohorts were built with respect to the surgical approach (craniotomy ± muscle incision; burr hole surgery) and group comparisons were performed. Additionally, patients with AHAC ≥ 3 NRS were reevaluated at 7.2 ± 2.3 months following treatment by means of standardized questionnaires to determine the prevalence of persistent headache attributed to craniotomy as well as headache-related disability and quality of life. Results Thirty of 64 (46.9%) patients developed moderate to severe AHAC (NRS ≥ 3) after cranial neurosurgery. There were no significant group differences with regard to age, gender, or general health condition (American Society of Anesthesiologists Physical Status Classification). Craniotomy patients with muscle incision suffered from significantly higher early postoperative mean NRS scores compared with their counterparts without procedure-related muscle injury (3.4 ± 2.3 vs. 2.3 ± 1.9) as well as patients undergoing burr hole surgery (1.2 ± 1.4; p = 0.02). Moreover, the consumption of nonopioid analgesics was almost doubled following muscle-transecting surgery as compared with muscle-preserving procedures (p = 0.03). Young patient age (odds ratio/95% confidence interval for each additional year: 0.93/0.88–0.97) and surgery-related muscle injury (5.23/1.62–19.41) were identified as major risk factors for the development of AHAC ≥ 3 NRS. There was a nonsignificant trend toward higher pain chronification rate as well as headache-related disability after craniotomy with muscle injury. Conclusion Surgery-related muscle damage may be an important predisposing factor for AHAC. Therefore, if a transmuscular approach is unavoidable, the neurosurgeon should be aware of the need for adequately adjusted intra- and postoperative analgesia in these cases.

Sensory characteristics according to chronic diseases and chronic pain in adults: cross-sectional study

Aim: To investigate somatosensory, gustative and olfactory characteristics of subjects according to their chronic diseases and the presence of chronic pain complaints. Materials & methods: A total of 254 chronic pain patients and 52 healthy subjects were evaluated with a clinical and sensory systematized evaluation. Statistical analysis consisted of Fisher’s exact, Student’s t-tests, Pearson’s co-efficient and multivariate nonlinear/logistic regressions. Results: Patients had more chronic diseases (p < 0.001) than healthy subjects. Chronic pain was associated with vibratory hypoesthesia (p = 0.047) and sour hypergeusia (p = 0.001) and several chronic diseases correlated with sensory features. Hyposmia was strongly associated with chronic pain symptoms, chronic diseases and cardiovascular disease. Conclusion: The sensory findings observed suggest the need for further investigation about the overlap between the olfactory function, pain chronification, chronic diseases and cognitive impairment in these patients.

Vitamin D, Chronic Migraine, and Extracranial Pain: Is There a Link? Data From an Observational Study

Several studies focused on the role of vitamin D (vitD) in pain chronification. This study focused on vitD level and pain chronification and extension in headache disorders. Eighty patients with primary headache underwent neurological examination, laboratory exams, including serum calcifediol 25(OH)D, and headache features assessment along with three questionnaires investigating depression, anxiety, and allodynia. The 86.8% of the population had migraine (48% episodic and 52% chronic). The 44.1% of patients had extracranial pain, and 47.6% suffered from allodynia. A vitD deficit, namely a serum 25(OH)D level &lt;20 ng/ml, was detectable in 46.1% of the patients, and it occurred more frequently (p = 0.009) in patients suffering from chronic migraine (CM)–medication overuse migraine (MOH) (62.9%) than in episodic migraine (EM, 25.7%) or tension-type headache (TTH, 11.4%). The occurrence of extracranial pain and allodynia was higher in the CM-MOH than in the EM and in the TTH groups but was not related to the co-occurrence of vitD deficiency (Fisher's exact test p = 0.11 and p = 0.32, respectively). Our findings show that 25(OH)D deficit is also related to chronic headache, probably because of vitD anti-inflammatory and tolerogenic properties, reinforcing the idea of a neuroinflammatory mechanism underpinning migraine chronification.

Pain and the field of affordances: an enactive approach to acute and chronic pain

In recent years, the societal and personal impacts of pain, and the fact that we still lack an effective method of treatment, has motivated researchers from diverse disciplines to try to think in new ways about pain and its management. In this paper, we aim to develop an enactive approach to pain and the transition to chronicity. Two aspects are central to this project. First, the paper conceptualizes differences between acute and chronic pain, as well as the dynamic process of pain chronification, in terms of changes in the field of affordances. This is, in terms of the possibilities for action perceived by subjects in pain. As such, we aim to do justice to the lived experience of patients as well as the dynamic role of behavioral learning, neural reorganization, and socio-cultural practices in the generation and maintenance of pain. Second, we aim to show in which manners such an enactive approach may contribute to a comprehensive understanding of pain that avoids conceptual and methodological issues of reductionist and fragmented approaches. It proves particularly beneficial as a heuristic in pain therapy addressing the heterogenous yet dynamically intertwined aspects that may contribute to pain and its chronification.

Pain chronification and the important role of non-disease-specific symptoms in patients with systemic sclerosis

Background Pain is a frequent, yet inadequately explored challenge in patients with systemic sclerosis (SSc). This study aimed to conduct an extensive pain assessment, examining pain chronification and its association with disease manifestations. Methods Consecutive SSc patients attending their annual assessment were included. SSc-specific features were addressed as defined by the European Scleroderma Trials and Research (EUSTAR) guidelines. Pain analysis included intensity, localization, treatment, chronification grade according to the Mainz Pain Staging System (MPSS), general well-being using the Marburg questionnaire on habitual health findings (MFHW) and symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS). Results One hundred forty-seven SSc patients completed a pain questionnaire, and 118/147 patients reporting pain were included in the analysis. Median pain intensity was 4/10 on a numeric rating scale (NRS). The most frequent major pain localizations were hand and lower back. Low back pain as the main pain manifestation was significantly more frequent in patients with very early SSc (p = 0.01); those patients also showed worse HADS and MFHW scores. Regarding pain chronification, 34.8% were in stage I according to the MPSS, 45.2% in stage II and 20.0% in stage III. There was no significant correlation between chronification grade and disease severity, but advanced chronification was significantly more frequent in patients with low back pain (p = 0.024). It was also significantly associated with pathological HADS scores (p < 0.0001) and linked with decreased well-being and higher use of analgesics. Conclusions Our study implies that also non-disease-specific symptoms such as low back pain need to be considered in SSc patients, especially in early disease. Since low back pain seems to be associated with higher grades of pain chronification and psychological problems, our study underlines the importance of preventing pain chronification in order to enhance the quality of life.

Abdominal Hernia Pain: Chronification Mechanisms after Hernia Surgery

Groin pain is the most common cause of surgical intervention. There are 3 parameters that increase the chances of chronic pain. On the one hand, starting the surgery with high intensity pain that has not been previously controlled. On the other, insufficient anesthetic and analgesic control during the surgical procedure. Finally, an inadequate management of acute postoperative pain. The presence of groin pain and its poor control before the intervention predisposes to difficulties during the perioperative process. Thus, the appearance of acute postoperative pain not adequately controlled will prevent its remission in a natural way in the usual period (approximately 1 month) and will cause it to progress in intensity and continuity (from 1 month to 3 months after surgery), transforming into a chronic pain (from 3 months after the intervention). In this process of chronification, in which pain goes from nociceptive to neuropathic, different physiological sensitization mechanisms are involved, both peripheral and central. The chronification of the painful process and, ultimately, the therapeutic approach that we will have to use to try to prevent this process depends to a large extent on these modifications that facilitate the change in the nature of pain.

Investigation of Risk Factors for Pain Chronification in Patients Suffering from Infections of the Spine

Background: Spinal infections represent a therapeutic challenge. The often protracted course of the disease is accompanied by pain, which can lead to a chronic pain experience even after the infectious disease has been treated successfully. The aim of this study was to investigate possible risk factors of pain chronification. Methods: In a prospective study, 14 patients with spinal infections were examined at admission (T1), at discharge from inpatient therapy (T2), and three to eight months postoperatively (T3) byquestionnaires on risk factors for pain chronification and by quantitative sensory testing (QST). Results: In-patient treatment lasted on average 45.3 days (±33.13). The patients complained of pain for 3.43 months (±2.77) prior to inpatient treatment. The visual analogue scale (VAS) for pain (0–10) and the Oswestry Disability Index detected significant improvement in the course of the study. However, patients also reported catastrophic thinking, as well as fear of movement and (re)-injury. Conclusion: In summary, our results demonstrate that patients with spinal infections did not suffer from pain chronification, but might benefit from an interdisciplinary therapeutic approach, which emphasizes promoting active pain-coping strategies, as well as addressing fear of movement and catastrophic thinking.