Minimising pain in farm animals: the 3S approach – ‘Suppress,Substitute, Soothe’

Recently, the French National Institute for Agricultural Research appointed an expert committee to review the issue of pain in food-producing farm animals. To minimise pain, the authors developed a ‘3S’ approach accounting for ‘Suppress, Substitute and Soothe’ by analogy with the ‘3Rs’ approach of ‘Reduction, Refinement and Replacement’ applied in the context of animal experimentation. Thus, when addressing the matter of pain, the following steps and solutions could be assessed, in the light of their feasibility (technical constraints, logistics and regulations), acceptability (societal and financial aspects) and availability. The first solution is to suppress any source of pain that brings no obvious advantage to the animals or the producers, as well as sources of pain for which potential benefits are largely exceeded by the negative effects. For instance, tail docking of cattle has recently been eliminated. Genetic selection on the basis of resistance criteria (as e.g. for lameness in cattle and poultry) or reduction of undesirable traits (e.g. boar taint in pigs) may also reduce painful conditions or procedures. The second solution is to substitute a technique causing pain by another less-painful method. For example, if dehorning cattle is unavoidable, it is preferable to perform it at a very young age, cauterising the horn bud. Animal management and constraint systems should be designed to reduce the risk for injury and bruising. Lastly, in situations where pain is known to be present, because of animal management procedures such as dehorning or castration, or because of pathology, for example lameness, systemic or local pharmacological treatments should be used to soothe pain. These treatments should take into account the duration of pain, which, in the case of some management procedures or diseases, may persist for longer periods. The administration of pain medication may require the intervention of veterinarians, but exemptions exist where breeders are allowed to use local anaesthesia (e.g. castration and dehorning in Switzerland). Extension of such exemptions, national or European legislation on pain management, or the introduction of animal welfare codes by retailers into their meat products may help further developments. In addition, veterinarians and farmers should be given the necessary tools and information to take into account animal pain in their management decisions.     

New insights into pain-related changes in muscle activation revealed by high-density surface electromyography

High-density surface electromyography (HDEMG) is an electrophysiological technique that can be used to quantify the spatial distribution of activity within muscles. When pain-free individuals perform sustained or repetitive tasks, different regions within a muscle become progressively more active; this is thought to reflect a strategy to redistribute the load to different regions, thus limiting localised muscle fatigue. The use of HDEMG has revealed that when people with musculoskeletal pain perform the same tasks, the distribution of activity within the same muscle is usually different, and the same muscle region tends to be active throughout the whole task without progressive activation of different muscle regions. This potentially results in a focal overload of a muscle region, and may contribute to fatigue, localised muscle pain and potentially pain persistence and/or recurrence over time. Interestingly, not all patients with musculoskeletal pain present with this regional alteration in muscle activation, reflecting the heterogeneity of patient presentations. This article will briefly review the technique of HDEMG followed by a review of studies demonstrating spatial redistribution of muscle activity in asymptomatic people during both isometric and dynamic conditions, including functional tasks. Lastly, the article will provide a review of HDEMG studies with a focus on changes in the behaviour of the lumbar erector spine and upper trapezius in people with spinal pain. These studies have revealed subtle changes in the distribution of muscle activity in people with spinal pain, which may have relevance for onset, persistence or recurrence of symptoms and could become a target of novel therapeutic approaches.     

Mechanisms of ATP release in pain: role of pannexin and connexin channels

Pain is a physiological response to bodily damage and serves as a warning of potential threat. Pain can also transform from an acute response to noxious stimuli to a chronic condition with notable emotional and psychological components that requires treatment. Indeed, the management of chronic pain is currently an important unmet societal need. Several reports have implicated the release of the neurotransmitter adenosine triphosphate (ATP) and subsequent activation of purinergic receptors in distinct pain etiologies. Purinergic receptors are broadly expressed in peripheral neurons and the spinal cord; thus, purinergic signaling in sensory neurons or in spinal circuits may be critical for pain processing. Nevertheless, an outstanding question remains: what are the mechanisms of ATP release that initiate nociceptive signaling? Connexin and pannexin channels are established conduits of ATP release and have been suggested to play important roles in a variety of pathologies, including several models of pain. As such, these large-pore channels represent a new and exciting putative pharmacological target for pain treatment. Herein, we will review the current evidence for a role of connexin and pannexin channels in ATP release during nociceptive signaling, such as neuropathic and inflammatory pain. Collectively, these studies provide compelling evidence for an important role of connexins and pannexins in pain processing.     

Oral transmucosal fentanyl citrate in cancer pain management: a practical application of nanotechnology

Pain is experienced by most cancer patients and represents an important issue in the clinical setting. Breakthrough pain is a transitory flare of pain that occurs in most cancer patients on a background of otherwise controlled persistent pain. Treatment of breakthrough pain is a challenging phenomenon. Oral transmucosal fentanyl citrate (OTFC; Actiq, Cephalon, UK), a new opioid formulation with a unique delivery system, utilizing the advantages that nanotechnology offers, reflects the characteristics of breakthrough pain (rapid onset of action and short duration), which makes it an effective treatment to cancer patients who are already receiving opioids and continue to experience such flares of pain. Oral transmucosal fentanyl citrate is specifically developed and approved for the management of breakthrough pain in cancer patients and it has the potential to be a useful tool for clinicians.     

Effect of experimental low back pain on neuromuscular control of the trunk in healthy volunteers and patients with chronic low back pain

Studies of electromyographic (EMG) activity and lumbopelvic rhythm have led to a better understanding of neuromuscular alterations in chronic low back pain (cLBP) patients. Whether these changes reflect adaptations to chronic pain or are induced by acute pain is still unclear. This work aimed to assess the effects of experimental LBP on lumbar erector spinae (LES) EMG activity and lumbopelvic kinematics during a trunk flexion–extension task in healthy volunteers and LBP patients. The contribution of disability to these effects was also examined. Twelve healthy participants and 14 cLBP patients performed flexion–extension tasks in three conditions; control, innocuous heat and noxious heat, applied on the skin over L5 or T7. The results indicated that noxious heat at L5 evoked specific increases in LES activity during static full trunk flexion and extension, irrespective of participants’ group. Kinematic data suggested that LBP patients adopted a different movement strategy than controls when noxious heat was applied at the L5 level. Besides, high disability was associated with less kinematic changes when approaching and leaving full flexion. These results indicate that experimental pain can induce neuromechanical alterations in cLBP patients and healthy volunteers, and that higher disability in patients is associated with decreased movement pattern changes.     

疼痛患者脊髓脑脊液中强啡肽含量的分析

本文观察了疼痛患者脊髓脑脊液中强啡肽含量的变化。共收集３１例急性疼痛患者和１４例慢性疼痛患者的脊髓脑脊液,测定其中的强啡肽含量,与２７例无痛患者的结果进行比较,并结合被测者的性别、年龄、体重、血压、脉搏、体温等一般情况进行分析。结果表明,慢性痛患者脑脊液中强啡肽含量显著升高,而急性痛患者则略有降低。判别分析表明,急性痛患者的强啡肽含量及其他临床资料有明显的特点（判别准确率８２％）;慢性痛患者未见明显特征。作者认为,在更广泛地收集临床资料和检验结果的基础上,进一步研究不同病因的疼痛患者的临床特征,可能有助于对疼痛疾病进行鉴别诊断     

Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5

Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.     

A Psychophysical Comparison of Sensory and Affective Responses to Four Modalities of Experimental Pain

It is generally accepted that the sensory and affective components of pain may be differentially associated with various acute and chronic diseases, and that some treatment regimens are best directed toward certain aspects of the pain experience. In addition, experimental animal models have been described that presume to assess either the sensory-discriminative aspects of phasic pain or the affective responses associated with tonic pain. The present psychophysical experiment directly compares the perceived intensity and unpleasantness of sensations evoked by four types of experimental noxious stimuli: contact heat, electric shock, ischemic exercise, and cold-pressor pain. A novel pain measurement technique is described that incorporates unbounded magnitude-estimation/category scales; this technique allows precise ratio responses, while minimizing within- and between- subject variability. We observe that, relative to the perceived intensity of the individual stimuli, subjects consistently differentiate among the degrees of unpleasantness evoked by the four stimulus modalities. Ischemic exercise and cold-pressor pain evoke higher estimates of unpleasantness, and thus may better mimic the pain of chronic disease. The relative unpleasantness produced by contact heat is significantly less than that of the other modalities tested, and therefore contact heat stimuli may be ideally suited for assessing sensory-discriminative aspects of pain perception. Possible neurophysiological mechanisms underlying the observed differences in perceived unpleasantness are discussed in relation to the growing body of literature concerning tonic and phasic pain stimuli.     

Interrelated hypoalgesia,creep, and muscle fatigue following a repetitive trunk flexion exposure

Repetitive trunk flexion can damage spinal tissues, however its association with low back pain in the workplace may be confounded by factors related to pain sensitivity. Muscle fatigue, exercise-induced hypoalgesia, and creep-induced neuromuscular changes following repetitive trunk flexion may all affect this assumed exposure-pain relationship. This study’s purpose was to determine how mechanical pain sensitivity in the low back is affected by a repetitive trunk flexion exposure and identify factors associated with changes in low back pain sensitivity. Pressure pain thresholds, perceptions of sub-threshold stimuli, and muscle fatigue in the trunk and tibia, as well as lumbar spine creep were tracked in 37 young healthy adults before and up to 40 min after a 10-min repetitive trunk flexion exposure. Pressure pain thresholds (p = 0.033), but not perceptions of sub-threshold stimuli (p > 0.102) were associated with approximately a 12.5% reduction in pain sensitivity 10 min after completing the exposure, while creep and local muscle fatigue effects were only observed immediately following the exposure. Creep and fatigue interactions and the corresponding tibial measure co-varied with individual low back pressure pain thresholds. The net hypoalgesic effects of repetitive trunk flexion have the potential to partially mask possibly injurious loads, which could contribute to the severity or incidence of lower back injuries related to these exposures.     

Influence of surface anesthesia on the pressure pain threshold measured with different-sized probes

Transcutaneous pressure with pressure probes of arbitrary diameters have been commonly used for measuring the threshold and magnitude of muscle pain, yet this procedure lacks scientific validation. To examine the valid probe dimensions, we conducted physiological experiments using 34 human subjects. Pin-prick pain, pressure pain threshold (PPT) to pressure probes of various diameters, heat pain threshold, and electrical pain threshold of deep tissues were measured before and after application of surface lidocaine anesthesia to the skin surface over the brachioradial muscle in a double-blinded manner. The anesthesia neither affected PPT with larger probes (diameters: 1.6 and 15?mm) nor increased electric pain threshold of deep structures, whereas it diminished pain count in pin-prick test and PPT with a 1.0?mm diameter probe, suggesting that mechanical pain thresholds measured with 1.6 and 15?mm probes reflect the pain threshold of deep tissues, possibly muscle. Pain thresholds to heat did not change after application of the anesthesia. These results suggest that larger pressure probes can give a better estimation of muscular pain threshold.     

Dynamic changes to the endocannabinoid system in models of chronic pain

The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.     

Comparing the efficacy of pain managements after total hip arthroplasty: A network meta-analysis

The aim of our current study is to compare efficiency of various interventions implemented for pain management after total hip arthroplasty (THA). PubMed and EMBASE were searched for randomized clinical trials (RCTs) reporting the pain scales for evaluate the efficacy of pain control after THA including at least one pair of direct control groups. Pain scale values and the associated 95% credible interval (CrI) were used to describe efficacy. Surface under the cumulative ranking curve (SUCRA) of each means of pain control was calculated to compare the relative ranking of different interventions. Thirty-five eligible literatures were involved in data analysis. The interventions for postoperative pain management we examined were psoas compartment block (PCB), posterior nerve block (PNB), fascia iliaca block (FIB), periarticular injection (PAI), femoral nerve block (FNB), lumbar plexus block (LPB), spinal anesthesia (SA), epidural analgesia (EPI), intrathecal morphine (IA), intravenous patient-controlled analgesia (IV-PCA), patient-controlled analgesia (PCA), onsteroidal anti-inflammatory drug (NSAID), local infiltration analgaesia (LIA), and reverse LIA (rLIA). In 0 to 6 hours analysis, patients under SA were found to have significantly lower pain score and SA was ranked the best. In 6 to 12 hours analysis, SA was found to be significantly more effective than other interventions and its SUCRA was the highest. No intervention showed a significant effect on reducing pain score for 12 to 24 hours and 24 to 48 hours after THA. SA is the best intervention to reduce THA postoperative pain in the first 24 hours. LPB is a better choice to reduce pain 12 to 48 hours after THA.     

Long-term and trans-generational effects of neonatal experience on sheep behaviour

Early life experiences can have profound long-term, and sometimes trans-generational, effects on individual phenotypes. However, there is a relative paucity of knowledge about effects on pain sensitivity, even though these may impact on an individual''s health and welfare, particularly in farm animals exposed to painful husbandry procedures. Here, we tested in sheep whether neonatal painful and non-painful challenges can alter pain sensitivity in adult life, and also in the next generation. Ewes exposed to tail-docking or a simulated mild infection (lipopolysaccharide (LPS)) on days 3–4 of life showed higher levels of pain-related behaviour when giving birth as adults compared with control animals. LPS-treated ewes also gave birth to lambs who showed decreased pain sensitivity in standardized tests during days 2–3 of life. Our results demonstrate long-term and trans-generational effects of neonatal experience on pain responses in a commercially important species and suggest that variations in early life management can have important implications for animal health and welfare.     

Pain modulatory network is influenced by sex and age in a healthy state and during osteoarthritis progression in rats

Old age and female sex are risk factors for the development of osteoarthritis (OA) and chronic pain. We investigated the effects of sex and age on pain modulatory networks in a healthy state and during OA progression. We used functional MRI to determine the effects of sex and age on periaqueductal gray functional connectivity (PAG FC) in a healthy state (pre‐OA) and during the early and late phases of monosodium iodoacetate‐induced OA in rats. We then examined how sex and age affect longitudinal changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG FC than males, and this effect was exaggerated with aging. Young males had moderate PAG FC changes during the early phase but recruited additional brain regions, including the rostral anterior cingulate cortex (ACC), during the late phase. Young females exhibited widespread PAG FC in the early phase, which includes connections to insula, caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer regions in the early phase, but they recruited additional brain regions, including NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex and age in a healthy state. A widespread PAG network in the early phase of OA pain may contribute to the transition from acute to chronic OA pain and the increased risk of developing chronic pain for females. Enhanced PAG FC with the reward system may represent a potential mechanism underlying chronic OA pain in elderly patients.     

Religious Coping with Chronic Pain

This study examined the role of religious and nonreligious cognitive-behavioral coping in a sample of 61 chronic pain patients from a midwestern pain clinic. Participants described their chronic pain and indicated their use of religious and nonreligious cognitive-behavioral coping strategies. Results supported a multidimensional conceptualization of religious coping that includes both positive and negative strategies. Positive religious coping strategies were associated significantly with positive affect and religious outcome after statistically controlling for demographic variables. In contrast, measures of negative religious coping strategies were not associated significantly with outcome variables. Several significant associations also were found between nonreligious cognitive-behavioral coping strategies and outcome variables. The results underscore the need for further research concerning the contributions of religious coping in adjustment to chronic pain. Practitioners of applied psychophysiology should assess their chronic pain patients' religious appraisals and religious coping as another important stress management strategy.     

疼痛的性别差异

目前已有许多临床流行病学研究和实验研究证实了人类的疼痛存在性别差异。临床迹象表明疼痛存在性别差异,许多慢性疼痛疾病（偏头痛、颞下颌关节痛、纤维肌痛、风湿痛等）的发生率女性明显高于男性。女性对一些实验性疼痛（机械刺激痛、电刺激痛、热刺激痛等）更加敏感,痛阈和对疼痛的耐受性比男性低,而且女性月经周期与疼痛有关。啮齿动物实验研究也发现存在疼痛的性别差异。但是在不同动物研究或不同实验性疼痛刺激下雌雄性别的反应不完全相同,这些差异可能是由很多影响因素所导致的。目前许多研究对疼痛存在性别差异的解释也有所不同,机制尚不清楚,可能的因素包括：生物因素（性激素、内源性镇痛、基因等）、社会心理因素以及两者的相互作用等。     

Zonisamide: Antihyperalgesic efficacy,the role of serotonergic receptors on efficacy in a rat model for painful diabetic neuropathy

Aims

The purpose of this study was to compare the changes of antihyperalgesic effectiveness of zonisamide (25 and 50 mg/kg), an antiepileptic drug, on the early and late phases of neuropathy and to investigate the role of serotonergic descending inhibitory pain pathways in antihyperalgesic effectiveness of zonisamide in the streptozotocin-induced rat model for painful diabetic neuropathy.

Main methods

The hot-plate and tail-immersion, to determine thermal thresholds, and paw pressure withdrawal tests, to determine mechanical thresholds, were performed as hyperalgesia tests. To investigate the role of serotonergic pathway, 1 mg/kg ketanserin (5-HT_2A/2C antagonist) and ondansetron (serotonin 5-HT₃ receptor antagonist) were used.

Key findings

Zonisamide enhanced pain thresholds significantly in the 3rd, 6th and 8th weeks as the reference drugs morphine (5 mg/kg) and carbamazepine (32 mg/kg, tested only in the 3rd week). There were no observed differences on the potency of antihyperalgesic effect between weeks and between doses. Each antagonist reversed the effect of zonisamide in the hot-plate and tail-immersion tests significantly, but, relatively in the paw pressure withdrawal tests.

Significance

These results support the role for zonisamide in the management of diabetic neuropathic pain in all phases. Serotonin 5-HT_2A/2C and 5-HT₃ receptors are involved in the antihyperalgesic effect of zonisamide by enhancement of thermal threshold, and partially by mechanical threshold, so they may not mediate mechanical hyperalgesia in diabetic neuropathy.     

Test–retest reliability of subjective supra-threshold scaling of multiple pressure-pain sensations among healthy individuals: a study using hydraulic pressure algometry

Abstract

Background: Supra-threshold scaling of multiple pressure-pain sensations involves delivery of varied stimulus intensities, either via stimulus-dependent or response-dependent manner, and recording of subjective pain ratings by participants. The focus of this study was to determine the intra- and inter-session reliability of pain intensity and pain unpleasantness ratings related to pressure-pain thresholds (PPTs) of just noticeable pain (JNP), weak pain (WP) and moderate pain (MP) among healthy individuals.

Methods: Fourteen healthy participants (eight women, six men) participated in three sessions of testing at varied intervals over the course of 72?h. In session one, a multiple random staircase method using hydraulic pressure algometry was used to measure PPT of JNP, WP and MP on thumbnail bed. In session 2, ratings of pain intensity and pain unpleasantness were recorded when stimuli at levels corresponding to PPT of JNP, WP and MP were repeatedly applied before and after 20?min of no intervention.

Results: Interclass correlation coefficient (ICC) values for pain ratings of JNP, WP and MP in intra-session reliability were 0.810, 0.826 and 0.881, respectively, whereas the values were 0.817, 0.792 and 0.910, respectively, for inter-session reliability. ICC values for pain unpleasantness were also highly consistent and repeatable. Temporal summation of pain intensity and pain unpleasantness were not related to the repeated application of pressure stimuli.

Conclusions: The findings indicate that the pain intensity and pain unpleasantness ratings for stimuli at levels equal to the thresholds of JNP, WP and MP have good intra- and inter-session reliability.

Significance: This study showed that both pain intensity and pain unpleasantness of JNP, WP and MP have good intra- and inter-session reliability and agreement. Furthermore, the temporal summation of pain or unpleasantness is not related to repeated application of pressure stimuli.

Abbreviations: JNP: Just noticeable pain; WP: Weak pain; MP: Moderate pain; PPTs: pressure-pain thresholds; HPA: Hydraulic pressure algometry; MRSM: multiple random staircase method