Pain without Nociceptors? Nav1.7-Independent Pain Mechanisms

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How Well Do Clinical Pain Assessment Tools Reflect Pain in Infants?

Background

Pain in infancy is poorly understood, and medical staff often have difficulty assessing whether an infant is in pain. Current pain assessment tools rely on behavioural and physiological measures, such as change in facial expression, which may not accurately reflect pain experience. Our ability to measure cortical pain responses in young infants gives us the first opportunity to evaluate pain assessment tools with respect to the sensory input and establish whether the resultant pain scores reflect cortical pain processing.

Methods and Findings

Cortical haemodynamic activity was measured in infants, aged 25–43 wk postmenstrual, using near-infrared spectroscopy following a clinically required heel lance and compared to the magnitude of the premature infant pain profile (PIPP) score in the same infant to the same stimulus (n = 12, 33 test occasions). Overall, there was good correlation between the PIPP score and the level of cortical activity (regression coefficient = 0.72, 95% confidence interval [CI] limits 0.32–1.11, p = 0.001; correlation coefficient = 0.57). Of the different PIPP components, facial expression correlated best with cortical activity (regression coefficient = 1.26, 95% CI limits 0.84–1.67, p < 0.0001; correlation coefficient = 0.74) (n = 12, 33 test occasions). Cortical pain responses were still recorded in some infants who did not display a change in facial expression.

Conclusions

While painful stimulation generally evokes parallel cortical and behavioural responses in infants, pain may be processed at the cortical level without producing detectable behavioural changes. As a result, an infant with a low pain score based on behavioural assessment tools alone may not be pain free.     

Pain and suffering in invertebrates?

All animals face hazards that cause tissue damage and most have nociceptive reflex responses that protect them from such damage. However, some taxa have also evolved the capacity for pain experience, presumably to enhance long-term protection through behavior modification based on memory of the unpleasant nature of pain. In this article I review various criteria that might distinguish nociception from pain. Because nociceptors are so taxonomically widespread, simply demonstrating their presence is not sufficient. Furthermore, investigation of the central nervous system provides limited clues about the potential to experience pain. Opioids and other analgesics might indicate a central modulation of responses but often peripheral effects could explain the analgesia; thus reduction of responses by analgesics and opioids does not allow clear discrimination between nociception and pain. Physiological changes in response to noxious stimuli or the threat of a noxious stimulus might prove useful but, to date, application to invertebrates is limited. Behavior of the organism provides the greatest insights. Rapid avoidance learning and prolonged memory indicate central processing rather than simple reflex and are consistent with the experience of pain. Complex, prolonged grooming or rubbing may demonstrate an awareness of the specific site of stimulus application. Tradeoffs with other motivational systems indicate central processing, and an ability to use complex information suggests sufficient cognitive ability for the animal to have a fitness benefit from a pain experience. Available data are consistent with the idea of pain in some invertebrates and go beyond the idea of just nociception but are not definitive. In the absence of conclusive data, more humane care for invertebrates is suggested.     

Are Pain-Related Fears Mediators for Reducing Disability and Pain in Patients with Complex Regional Pain Syndrome Type 1? An Explorative Analysis on Pain Exposure Physical Therapy

Objective

To investigate whether pain-related fears are mediators for reducing disability and pain in patients with Complex Regional Pain Syndrome type 1 when treating with Pain Exposure Physical Therapy.

Design

An explorative secondary analysis of a randomised controlled trial.

Participants

Fifty-six patients with Complex Regional Pain Syndrome type 1.

Interventions

The experimental group received Pain Exposure Physical Therapy in a maximum of five treatment sessions; the control group received conventional treatment following the Dutch multidisciplinary guideline.

Outcome measures

Levels of disability, pain, and pain-related fears (fear-avoidance beliefs, pain catastrophizing, and kinesiophobia) were measured at baseline and after 3, 6, and 9 months follow-up.

Results

The experimental group had a significantly larger decrease in disability of 7.77 points (95% CI 1.09 to 14.45) and in pain of 1.83 points (95% CI 0.44 to 3.23) over nine months than the control group. The potential mediators pain-related fears decreased significantly in both groups, but there were no significant differences between groups, which indicated that there was no mediation.

Conclusion

The reduction of pain-related fears was comparable in both groups. We found no indication that pain-related fears mediate the larger reduction of disability and pain in patients with Complex Regional Pain Syndrome type 1 treated with Pain Exposure Physical Therapy compared to conventional treatment.

Trial registration

International Clinical Trials Registry NCT00817128     

Is Pain Intensity Really That Important to Assess in Chronic Pain Patients? A Study Based on the Swedish Quality Registry for Pain Rehabilitation (SQRP)

Background

Incorporating the patient''s view on care and treatment has become increasingly important for health care. Patients describe the variety of consequences of their chronic pain conditions as significant pain intensity, depression, and anxiety. We hypothesised that intensities of common symptoms in chronic pain conditions carry important information that can be used to identify clinically relevant subgroups. This study has three aims: 1) to determine the importance of different symptoms with respect to participation and ill-health; 2) to identify subgroups based on data concerning important symptoms; and 3) to determine the secondary consequences for the identified subgroups with respect to participation and health factors.

Methods and Subjects

This study is based on a cohort of patients referred to a multidisciplinary pain centre at a university hospital (n = 4645, participation rate 88%) in Sweden. The patients answered a number of questionnaires concerning symptoms, participation, and health aspects as a part of the Swedish Quality Registry for Pain Rehabilitation (SQRP).

Results

Common symptoms (such as pain intensity, depression, and anxiety) in patients with chronic pain showed great variability across subjects and 60% of the cohort had normal values with respect to depressive and anxiety symptoms. Pain intensity more than psychological symptoms showed stronger relationships with participation and health. It was possible to identify subgroups based on pain intensity, depression, and anxiety. With respect to participation and health, high depressive symptomatology had greater negative consequences than high anxiety.

Conclusions

Common symptoms (such as pain intensity and depressive and anxiety symptoms) in chronic pain conditions carry important information that can be used to identify clinically relevant subgroups.     

Chest Pain in Adolescents—Functional Consequences

In prospectively evaluating 100 cases of adolescents with chest pain (along with two control groups), 91 were found to have recurrent chest pain; fewer than 5 had a serious organic cause. Significantly higher school absenteeism occurred in patients with either chest or abdominal pain than in patients without pain. Adolescents with chest and abdominal pain were more likely to be high users of medical services than those with no pain. Most adolescents believed that persons their age could have attacks; 44 of those with chest pain thought their symptom was due to a heart attack. The occurrence of chest pain was not influenced by an adolescent''s age, sex, race, smoking status or family structure, nor was it consistently associated with depression. Chest pain is thus a common problem of adolescence that produces considerable functional impairment not attributable to serious underlying disease.     

Is Altered Central Pain Processing Related to Disease Stage in Chronic Pancreatitis Patients with Pain? An Exploratory Study

Background

The most dominant feature in chronic pancreatitis is intense abdominal pain. Changes in spinal and/or supraspinal central nervous system pain processing due to visceral nociceptive input play an important role in this pain. How altered pain processing is related to disease stage still needs study.

Methodology/Principal Findings

Sixty chronic pancreatitis patients were compared to 15 healthy controls. Two subgroups of pancreatitis patients were defined based on the M-ANNHEIM severity index of chronic pancreatitis; i.e. moderate and severe. Pain detection and tolerance thresholds for pressure and electric stimuli were measured in six selected dermatomes (C5, T4, T10, L1, L4 and T10BACK). In addition, the conditioned pain modulation response to cold pressor task was determined. These measures were compared between the healthy controls and chronic pancreatitis patients. Severe pancreatitis patients showed lower pain thresholds than moderate pancreatitis patients or healthy volunteers. Healthy controls showed a significantly larger conditioned pain modulation response compared to all chronic pancreatitis patients taken together.

Conclusions/Significance

The present study confirms that chronic pancreatitis patients show signs of altered central processing of nociception compared to healthy controls. The study further suggests that these changes, i.e. central sensitization, may be influenced by disease stage. These findings underline the need to take altered central pain processing into account when managing the pain of chronic pancreatitis.     

Pain and distress: what really matters?

Federal regulations mandate the minimization of both pain and distress in laboratory animals. That no clear definition exists for 'distress' complicates its recognition, quantification, and alleviation. The author argues that IACUCs and investigators should shift their focus from pain to distress, and that in doing so both problems will be better dealt with. She discusses criteria for defining 'significant' distress, and offers suggestions for the conduct of studies to determine levels of distress.     

Pain: A Distributed Brain Information Network?

Understanding how pain is processed in the brain has been an enduring puzzle, because there doesn''t appear to be a single “pain cortex” that directly codes the subjective perception of pain. An emerging concept is that, instead, pain might emerge from the coordinated activity of an integrated brain network. In support of this view, Woo and colleagues present evidence that distinct brain networks support the subjective changes in pain that result from nociceptive input and self-directed cognitive modulation. This evidence for the sensitivity of distinct neural subsystems to different aspects of pain opens up the way to more formal computational network theories of pain.On the surface, pain should have been one of the easier brain systems to understand. Its fundamental importance in organism defence means that its anatomy should be well conserved across species, unlike systems for language, for instance. And its relatively simple scalar signal (from less pain to more pain) should not require extensive computational processing, unlike sound or vision. However, since Penfield''s failure to convincingly locate a “pain cortex” during his classic awake brain stimulation studies in the 1950s [1], trying to piece together the pain system in the brain has been a story of frustration and debate.     

Pain trends and pain growth disparities, 2009–2021

Physical pain is a major public health concern. Yet evidence on trends in physical pain around the world barely exists. Using nationally representative data from 146 countries (N = 1.6 million respondents), this paper finds that, all over the world, the percentage of people in pain increased from 26.3 in 2009 to 32.1 in 2021. This rising trend was present in both higher- and lower-income countries. This article also documents pain disparities: In the worldwide population, pain grew faster among women, the less educated, and the poor. Although the aggregate level of pain was greater among the elderly (> 60 years old), the growth in pain was faster among the younger (< 35 years old). These findings hold after controlling for sociodemographic factors. Disparities of pain growth in higher- and lower-income nations and potential explanatory factors are also discussed. Understanding how the level of pain varies over time and across demographic groups is crucial to evaluate and shape public health policies.     

Do Laying Hens with Keel Bone Fractures Experience Pain?

The European ban on battery cages has forced a change towards the use of non-cage or furnished cage systems, but unexpectedly this has been associated with an increased prevalence of keel bone fractures in laying hens. Bone fractures are acutely painful in mammals, but the effect of fractures on bird welfare is unclear. We recently reported that keel bone fractures have an effect on bird mobility. One possible explanation for this is that flying becomes mechanically impaired. However it is also possible that if birds have a capacity to feel pain, then ongoing pain resulting from the fracture could contribute to decreased mobility. The aim was to provide proof of concept that administration of appropriate analgesic drugs improves mobility in birds with keel fracture; thereby contributing to the debate about the capacity of birds to experience pain and whether fractures are associated with pain in laying hens. In hens with keel fractures, butorphanol decreased the latency to land from perches compared with latencies recorded for these hens following saline (mean (SEM) landing time (seconds) birds with keel fractures treated with butorphanol and saline from the 50, 100 and 150 cm perch heights respectively 1.7 (0.3), 2.2 (0.3), p = 0.05, 50 cm; 12.5 (6.6), 16.9 (6.7), p = 0.03, 100 cm; 20.6 (7.4), 26.3 (7.6), p = 0.02 150 cm). Mobility indices were largely unchanged in birds without keel fractures following butorphanol. Critically, butorphanol can be considered analgesic in our study because it improved the ability of birds to perform a complex behaviour that requires both motivation and higher cognitive processing. This is the first study to provide a solid evidential base that birds with keel fractures experience pain, a finding that has significant implications for the welfare of laying hens that are housed in non-cage or furnished caged systems.     

How Does Anodal Transcranial Direct Current Stimulation of the Pain Neuromatrix Affect Brain Excitability and Pain Perception? A Randomised,Double-Blind,Sham-Control Study

Background

Integration of information between multiple cortical regions of the pain neuromatrix is thought to underpin pain modulation. Although altered processing in the primary motor (M1) and sensory (S1) cortices is implicated in separate studies, the simultaneous changes in and the relationship between these regions are unknown yet. The primary aim was to assess the effects of anodal transcranial direct current stimulation (a-tDCS) over superficial regions of the pain neuromatrix on M1 and S1 excitability. The secondary aim was to investigate how M1 and S1 excitability changes affect sensory (STh) and pain thresholds (PTh).

Methods

Twelve healthy participants received 20 min a-tDCS under five different conditions including a-tDCS of M1, a-tDCS of S1, a-tDCS of DLPFC, sham a-tDCS, and no-tDCS. Excitability of dominant M1 and S1 were measured before, immediately, and 30 minutes after intervention respectively. Moreover, STh and PTh to peripheral electrical and mechanical stimulation were evaluated. All outcome measures were assessed at three time-points of measurement by a blind rater.

Results

A-tDCS of M1 and dorsolateral prefrontal cortex (DLPFC) significantly increased brain excitability in M1 (p < 0.05) for at least 30 min. Following application of a-tDCS over the S1, the amplitude of the N20-P25 component of SEPs increased immediately after the stimulation (p < 0.05), whilst M1 stimulation decreased it. Compared to baseline values, significant STh and PTh increase was observed after a-tDCS of all three stimulated areas. Except in M1 stimulation, there was significant PTh difference between a-tDCS and sham tDCS.

Conclusion

a-tDCS of M1 is the best spots to enhance brain excitability than a-tDCS of S1 and DLPFC. Surprisingly, a-tDCS of M1 and S1 has diverse effects on S1 and M1 excitability. A-tDCS of M1, S1, and DLPFC increased STh and PTh levels. Given the placebo effects of a-tDCS of M1 in pain perception, our results should be interpreted with caution, particularly with respect to the behavioural aspects of pain modulation.

Trial Registration

Australian New Zealand Clinical Trials, ACTRN12614000817640, http://www.anzctr.org.au/.     

Companion-Animals’ Effectiveness in Managing Chronic Pain in Adult Community Members

ABSTRACT

Therapy animals have been found to alleviate pain in healthcare settings, but companion-animal owners report greater discomfort and use more analgesics than people who do not own one or more companion animals. To investigate this anomaly, 173 adults completed an online survey that included questions about themselves and any companion animal they owned, the Depression Anxiety and Stress Scales, the Numeric Pain Rating Scale, and a modified version of the Chronic Pain Coping Inventory-42. Participants were also invited to contact the researchers to expand on their responses in a semi-structured interview, to which seven owners responded. There was no significant difference between reported pain levels in owners versus non-owners. However, companion-animal owners who reported actively using human–animal interactions to manage their pain rated this as moderately helpful and reported lower pain levels than other owners. There were also no significant differences between owners’ and non-owners’ anxiety or stress levels. Companion-animal owners reported more depressive symptoms than non-owners, but owners with animals perceived as more friendly reported fewer depressive symptoms. Dog owners comprised most of the sample and, for these participants, there was a negative association between perceived dog friendliness and levels of depression and anxiety. Those with more disobedient dogs also experienced greater stress. Interviewees reported that their companion animals helped them cope with pain in many ways, including provision of social and emotional support and by providing a sense of purpose in life. These findings indicate that some, but not all, companion animals may be beneficial for participants with chronic pain. Since the benefits appear to be associated with the species and personality of the animal, and with whether the person actively uses human–animal interactions as a pain-coping mechanism, care should be taken before recommending companion-animal ownership to persons suffering from chronic pain.     

The Controversy on Fish Pain: A Veterinarian’s Perspective

Fish welfare is still a relatively new field. As such, regulations and protocols to ensure fish welfare are currently limited and vary considerably in different jurisdictions. This is in part because of the ongoing controversy as to whether or not fish feel pain. This controversy has persisted for several years, yet veterinarians have been mostly absent from the discussion so far. This essay aims to address this issue. Here, it is argued that while this controversy has its place, it is unlikely to be resolved in the near future. Fish welfare could instead be improved by pursuing more clinically applicable research to increase knowledge of fishes’ behavior and physiology. Such research would assist in learning the optimal environment for their specific needs, as well as compiling some verified indicators of pain in fish. This would then lead to improved studies that could help to determine if and when analgesic drugs can be beneficial in fish, as they are in many other species.     

Computer-Assisted Diagnosis of Abdominal Pain using “Estimates” Provided by Clinicians

This paper reports a comparison between two modes of computer-aided diagnosis in a real-time prospective trial involving 472 patients with acute abdominal pain. In the first mode the computer-aided system analysed each of the 472 patients by referring to data previously collated from a large series of 600 real-life patients. In the second mode the system used as a basis for its analysis “estimates” of probability provided by a group of six clinicians. The accuracy and reliability of both modes were compared with the performance of unaided clinicians.Using “real-life” data the computer system was significantly more effective than the unaided clinician. By contrast, when using the clinicians'' own estimates the computer-aided system was often less effective than the unaided clinician—especially when diagnosing less common disorders. It seems, firstly, that future systems for computer-aided diagnosis should employ data from real-life and not clinicians'' estimates, and, secondly, that clinicians themselves cannot analyse cases in a probabilistic fashion, since often they have little idea of what the “true” probabilities are.     

Transforming Growth Factor-β in Normal Nociceptive Processing and Pathological Pain Models

The transforming growth factor-β (TGF-β) superfamily is a multifunctional, contextually acting family of cytokines that participate in the regulation of development, disease and tissue repair in the nervous system. The TGF-β family is composed of several members, including TGF-βs, bone morphogenetic proteins (BMPs) and activins. In this review, we discuss recent findings that suggest TGF-β function as important pleiotropic modulators of nociceptive processing both physiologically and under pathological painful conditions. The strategy of increasing TGF-β signaling by deleting “BMP and activin membrane-bound inhibitor” (BAMBI), a TGF-β pseudoreceptor, has demonstrated the inhibitory role of TGF-β signaling pathways in normal nociception and in inflammatory and neuropathic pain models. In particular, strong evidence suggests that TGF-β1 is a relevant mediator of nociception and has protective effects against the development of chronic neuropathic pain by inhibiting the neuroimmune responses of neurons and glia and promoting the expression of endogenous opioids within the spinal cord. In the peripheral nervous system, activins and BMPs function as target-derived differentiation factors that determine and maintain the phenotypic identity and circuit assembly of peptidergic nociceptors. In this context, activin is involved in the complex events of neuroinflammation that modulate the expression of pain during wound healing. These findings have provided new insights into the physiopathology of nociception. Moreover, specific members of the TGF-β family and their signaling effectors and modulator molecules may be promising molecular targets for novel therapeutic agents for pain management.