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Salon 1 14 kasim 09.30 10.30 eli̇zabeth papathanassoglou
- 1. Elizabeth PPaappaatthhaannaassssoogglloouu CCyypprruuss UUnniivveerrssiittyy ooff TTeecchhnnoollooggyy,, DDeeppaarrttmmeenntt ooff NNuurrssiinngg
- 2. Aim • To discuss evidence on: • a) the neural circuitry of nociception (sensory and affective pathways), • b) the diverse mediators elicited in pain, as well as the downstream intracellular signaling and pertinent cellular outcomes.
- 3. Pain/ nociception • Complex alarm system aiming to promote survival, healing & adaptation (physical & psychosocial). • Can become maladaptive • Highly integrated neuro-physiological and psycho-social response – Not only about injury – How others react to pain – Emotional responses
- 4. Acute Persistent Pain in critical illness • #1 stressor recalled by critically ill patients • Intricate problem due to limitations in patient communication • The majority of critically ill patients reports pain • 4 in every 6 critically ill patients experience moderate to severe pain (Puntillo et al., 2014). • Pain is attributed to pathophysiological processes and routine procedures (Puntillo 1990-2013, Barr 2013)
- 5. Transition to chronicity: post-ICU syndrome • Risk factor for the post-intensive care syndrome: – “new or worsening impairments in physical, cognitive or mental health status arising after critical illness and persisting beyond acute care hospitalization” (Davidson et al., 2013).
- 6. Pain Pathways 1ary, 2ary somatosensory cortexes, posterior insula (discriminative aspects of pain) dACC anterior insula limbic system
- 7. Sedation suppresses cognition NOT neural circuitry of pain 1ary, 2ary somatosensory cortexes anterior insula dACC posterior insula limbic system TMN
- 8. Interactive loops of pain Sensory Pathway Intracellular signaling Cellular alarm Inflammation Affective Pathway Stress Response Neuropeptides Cytokines
- 9. Inflammation is emotionally painful too • Inflammation increases negative affect and social pain: – Healthy volunteers exposed to endotoxin showed an increase in feelings of social disconnection and neural sensitivity to social pain Eisenberger et al., 2010 Critically ill patients may get entrapped in a vicious circle of heightened physical and social pain
- 10. Sensory pathway: Intra-cellular signaling GPCR LGICs NTRs CR MMAAPPKK AAccttiivvaattiioonn EERRKK pp3388 JJNNKK Transcriptional regulation Alarm molecules DAMPs Oxidative stress Cytokines- Neuropeptides Transcriptional regulation
- 11. Mitochondrial alarm molecules (alarmins, DAMPs) • Upon intense organismic stress, the mitochondrion releases primitive peptides (DAMPs, alarmins) • They convey alarm signals within the cell (nucleus) and inter-cellularly promoting inflammation
- 12. HMGB-1 (high-mobility group Box-1) • Alarm nuclear molecule • Released from distressed and damaged cells • Secreted by ΜΦ, NK, endothelial, neuron & glial cells • Mediator of innate and specific immunity • It binds to DNA and commences the inflammatory cascade • Involved in hypersensitivity and pain responses – Agalave & Svensson, 2014
- 13. HMGB-1 Involved in every aspect of sepsis and MODS pathophysiology – Inflammation – Cell death – Organ PMN infiltration – Oxidative stress Elicits secretion of TNF & Cytokines -feeds back to exaggerated inflammation state Wang et al., 1999, Science; 285.
- 15. Cellular responses & the brain AAffffeeccttiivvee ppaatthhwwaayy SSeennssoorryy ppaatthhwwaayy GPCR LGICs NTRs CR MMAAPPKK AAccttiivvaattiioonn EERRKK pp3388 JJNNKK Transcriptional regulation Alarm molecules DAMPs Oxidative stress Cytokines- Neuropeptides Transcriptional regulation Agnello et al 2002
- 16. Unrelieved pain promotes sensitization GPCR LGICs NTRs CR MMAAPPKK AAccttiivvaattiioonn EERRKK pp3388 JJNNKK Transcriptional regulation Alarm molecules DAMPs Oxidative stress Cytokines- Neuropeptides Transcriptional regulation
- 17. Pain affects immunity • Acute pain in experimental models causes suppression of splenic NK activity (Sakaue, et al., 2011) • Adequate pain control: inhibits the expected supression of lymphoproliferation and of reduction of NK activity (Sacerdote et al, 2000; Pollock et al 1991; Page et al, 2001) • Chronic pain: ↓cytotoxic CD8+ lymphocytes ↓T-helper type 1 response. ↓NK activity (Kaufmann, Eisner, et al, 2007; Brennan 1994)
- 18. Pain promotes cell death • Persistent pain activates the JNK pathway • JNK is a stress-activated pathway implicated in inflammation and apoptosis Gao & Gi, 2008
- 19. Pain ratings in critically ill patients associate with death molecules on T and B cells Papathanassoglou et al (in press)
- 20. Pain intensity associates with circulating cell death markers • Pain intensity correlates with sFas (r=0.385, p=0.001) and sFasL (r=0.268, p=0.011) (controlled for disease severity) in critically ill patients with and without apparent tissue injury. • Significant increases in sFas 30 min after sedation break (p=0.013), • Significant differences between the two groups (p=0.031). WFCCN Congress, 2013 Kletsiou & Papathanassoglou (in press)
- 22. Pain: it’s no metaphor • “Pain” of loss and isolation activates the 2ary somatosensory cortex similarly to physical pain (Kross et al., 2011). • Analgesic agents (acetaminophen) also reduce social pain (Dewall et al., 2010). (Kross et al., 2011).
- 23. Social Isolation is Painful! • The affective pathway of nociception gets activated even by simple social exclusion conditions, such as being ignored or excluded from a game. • Patients that feel isolated, lonely or ignored may be at risk for higher pain intensity, as well as lower pain threshold. Eisenberger et al., 2003
- 24. Social support: a universal painkiller • Individuals with more social support show attenuated neural responses to social exclusion Masten et al., 2012 • Presence of a significant other lowers pain intensity and sensitivity and decreases pain-related neural activation –Montoya et al., 2004
- 25. Family pictures! • Viewing pictures of one’s partner appears to lower the intensity of pain Eisenberger et al., 2011
- 26. Pain & Agression • inadequate analgesia is linked to the onset of delirium Robinson & Volmer, 2010 • Interconnection between pain, agitation and delirium Barr et al., 2013 • Interpretable in evolutionary terms: when harmed one may need to defend oneself and attack. • Social exclusion, by activating overlapping neural pathways may also trigger defensive/ aggressive behavior Warburton et al., 2006
- 27. Chronic pain post-ICU • ICU pain commonly persists after discharge [Kyranou & Puntillo, 2012] • Pain frequency, intensity higher in survivors of ARDS and severe sepsis [Dowdy et al., 2006; Zimmer at al 2006] • Surgical ICU patients: At 8 years, pain and discomfort in 57% [Timmers et al., 2011] • General ICU patients: 6 -12 months post-ICU, chronic pain was reported by 44% of respondents. shoulder was the most commonly reported joint affected (22%). [Battle et al., 2013]
- 28. Transition to chronicity: neurophysiological evidence • Fear of pain, may be important for the transition to chronicity. • The amygdala integrate negative emotion, anxiety and nociceptive information • Amygdalic hyperactivity during early stages of pain contributes to pain persistence and chronicity (Li et al., 2013).
- 29. Prevention of pain persistence & chronicity • Early detection and management • Early psychological and social support
- 30. Conclusion • Cellular responses to persistent pain may put critically ill patients at risk for sepsis and multiple organ dysfunction. • Social support and emotion are important in modulating both acute and persistent pain in critically ill patients, as well as the transition to chronic pain therefore they need to be targeted specifically in order to improve patient outcomes.
- 31. THANK YOU!!!
Editor's Notes
- To discuss evidence on…. From the viewpoint of critically ill patients’ outcomes
- The perception of pain is a complex alarm system aiming to promote survival, healing & adaptation, both physical as well as psychosocial. I want to highlight how highly integrated a phenomenon pain is, which is at the same time a neuro-physiological and psycho-social response, and what are the implications of this for critically ill patients Pain is not only about tissue injury, it is about emotions, but also about how others react to it. It is actually a complex psychosocial phenomenon. For the sake of this presentation I would like us to bracket for a little bit everything we know about pain, either being professional knowledge and/ or personal experience, and just follow the line of evidence, in order to realize how highly integrated a phenomenon pain is, which is at the same time a neuro-physiological and psycho-social response.
- Recently, pain has been recognized as a risk factor for the post-intensive care syndrome which encompasses “new or worsening impairments in physical, cognitive or mental health status arising after critical illness and persisting beyond acute care hospitalization” (Davidson et al., 2013).
- It has long been recognized that pain has both sensory and affective components, Early clinical observations alluded to the existence of separate neural circuitries, since thalamic lesions that inhibit nociception may still leave one’s emotional and autonomic response to pain intact, despite inability to “sense” pain (Jaillard and Ropper, 2013). Further, lesions at the insula or cingulate cortex that inhibit emotional responses to pain render individuals indifferent to the experience of pain despite their ability to sense and localize pain (Foltz and White, 1968; Berthier et al., 1988). More recently functional magnetic resonance imaging (fMRI) studies showed two components of the neural pathway for physical pain: a sensory component in the primary and secondary somatosensory cortexes and posterior insula coding for discriminative aspects of pain, and an affective component involving the dorsal anterior cingulate cortex (dACC), anterior insula and the limbic system (Eisenberger, 2012). What is important to note is that these two systems feed back to each other. Even more remarkably, the sensory and affective pathways are activated not only by physical noxious stimuli (eg burn or injury), but also by psychosocial noxious stimuli (eg rejection).
- It is important to note here, that By virtue of where these brain structures are localized it is evident that although sedation can suppress cognitive recollection of pain, it cannot effect the neural circuitry of pain which gets triggered either in sleep or wakefulness alike. For example, sedatives produce their sedative effect by locking on to a specific type of neurotransmitter receptor in the tuberomammillary nucleus TMN called GABA-A, which really does not affect at all the pain pathway That means that critically ill patients may be in pain and their stress systems activated as a result of pain, although we are unable to observe any signs of pain, and even they will not be able to remember being in pain later.
- So the experience of pain is mediated by two distinct, yet highly interactive pathways which constantly feed back to each other and produce more of the conditions that enhance pain perception. For example, activation of the sensory pathway results in specific intracellular signaling which promotes inflammation and cellular stress which produce even more noxious stimuli At the same time activation of the affective pathway, produces a stress response which feeds back to intracellular signaling and with the ensuing release of cytokines and neuropeptides augments the perception of pain.
- Moreover, the inflammatory response appears to feed back to the affective pathway and to increase negative affect and social pain as well Healthy volunteers that were exposed to endotoxin vs., placebo showed an increase in feelings of social disconnection and neural sensitivity to social pain (Eisenberger et al., 2010). Based on such observations, critically ill patients may get entrapped in a vicious circle of heightened physical and social pain that they mutually feed-back to each other.
- Lets have a look at the cellular events downstream the sensory pathway. Here is the picture of a neuron and of synaptic signaling. Activation starts with increased presynaptic release of nociceptive transmitter-mediators from presynaptic neuron terminals or glia such as neuropeptides: SP (substance P) or CGRP (calcitonin gene related product); amino acids: Glu (glutamate); neurotrophins: NGF (nerve growth factor) or BDNF (brain-derived neurotrophic factor); chemokines: fractalkine; or cytokines: TNF (tumor necrosis factor), as examples. The activation process continues with the postsynaptic stimulation of nociceptors located on neurons or glia that include: GPCRs (G-protein coupled receptors) that bind neuropeptides (e.g. SP and CGRP) and chemokines (e.g. fractalkine); LGICs (ligand-gated ion channels) that bind amino acids (e.g. Glu); NTR (neurotrophin receptor) tyrosine kinases that bind the neurotrophins (e.g. NGF and BDNF) and cytokine receptors that bind TNF. Nociceptor stimulation leads to the activation of various second-messenger signal transduction that converge to ‘‘turn-on’’ MAPKs via phosphorylation, regarded as a key component in nociceptive sensitization. Activation (phosphorylation) of MAPKs, that include ERK, p38 and JNK, leads to transcriptional regulation, such as activation of TREs (transcription factor response elements) on DNA producing gene products, as well as non-transcriptional regulation that together enhances the excitatory properties of nociceptive activation and sensitization Activation of transcription factors results in the production of cytokines and neuropeptides, that activate more transcription factors, enhance inflammation and feed back to nociceptive signaling. At the same time, cells may undergo oxidative stress and release alarm molecules which also account for transcriptional activation and feeding back to the vicious circle of pain signaling. MAPK (mitogen-activated protein kinases, originally called ERK, extracellular signal-regulated kinases), Biochemical and pharmacological assessment of MAP-kinase signaling along pain pathways in experimental rodent models: a potential tool for the discovery of novel antinociceptive therapeutics Rebecca M. Edelmayer, Jill-Desiree Brederson, Michael F. Jarvis, Robert S. Bitner * Biochemical Pharmacology 87 (2014) 390–398
- PAMPs include things that are unique to bacteria or viruses — cell wall components that are present in bacteria, but not in vertebrate cells, for example; or double-stranded RNA, which is found in lots of viruses but would be unusual in our own cells. “Danger” signals, on the other hand, are indications of cell death — internal components of a cell, for example, that have leaked out as the cell dies. 1 For a while, it looked as if PAMPs were the major signal leading to innate and then adaptive immunity, but more recently it’s become clear that DAMPs are also very important. The Third International DAMPs and Alarmins Symposium was recently held in Pittsburgh, USA.The aim of this meeting was to introduce the emergent understanding of the danger signals also called alarmins or damage associated molecular patterns (DAMPs) by analogy to the pathogen associated molecular patterns (PAMPs). What brought our attention to this meeting is the recent discovery that TLRs play an important role in the immune response initiated by the DAMPs. The major DAMPs are HMGB1 (high mobility group box protein-1), S100A8/S100A9, heat-shock proteins, uric acid and DNA. Among these DAMPs, HMGB1 is the most studied as it has been associated with several diseases, including cancer, sepsis, rheumatoid arthritis, stroke and atherosclerosis. HMGB1 is a very abundant nuclear protein expressed in nearly all cell types. In normal conditions, HMGB1 binds to DNA and bends it to facilitate gene transcription. Under stress conditions, such as injury or infection, HMGB1 is released and promotes inflammation. HMGB1 is passively released by necrotic but not apoptotic death of normal cells and actively secreted by a variety of activated immune and non-immune cells.Contrary to many reports, HMGB1 is not a pro-inflammatory cytokine per se. HMGB1 by itself has little or no proinflammatory activity but it binds to mediators of inflammation such as LPS, DNA or IL-1β and induces signaling pathways leading to NF-κB activation thereby potentiating inflammatory responses. Although the signaling pathways elicited by HMGB1 are not fully defined, there is evidence that the triggering occurs via several receptors including RAGE (receptor for advanced glycation end-products), TLR2, TLR4 and TLR9[1]. HMGB1 binds RAGE to regulate migratory responses, but the use of ultrapure recombinant HMGB1 has demonstrated that it does not bind TLR4 (M. Bianchi, oral communication). However, HMGB1 which is released upon LPS-induced TLR4 activation, binds LPS even if present in very small amounts and carries it to TLR4 therefore perpetuating NF-κB activation and inflammation. A similar mechanism was reported for DNA, which is released into the systemic circulation after traumatic shock or injury, and presented to TLR9 by HMGB1[2]. Thus, HMGB1 is not an endogenous ligand for TLRs but an amplifier of TLR-mediated inflammatory responses. S100A8 (also known as Myeloid-related protein-8, MRP-8) and S100A9 (MRP14) are highly up-regulated in various diseases, such as sepsis, rheumatoid arthritis, inflammatory bowel disease and cancer. These calcium-binding proteins are the most abundant cytoplasmic proteins of neutrophils and monocytes. They are specifically released at sites of inflammation during the activation of phagocytes. S100A8 and S100A9 form complexes in which S100A8 appears to be the active component, while S100A9 modulates the activity of its binding partner. Although the biological functions of these proteins are not completely understood, they seem to depend on interactions with RAGE and TLR4. Similarly to HMGB1, S100A8-S100A9 complexes amplify the LPS-triggered inflammatory responses of phagocytes. But unlike HMGB1 and according to current knowledge, they can bind to both RAGE and TLR4[3]. The list of DAMPs is rapidly increasing with new additions such as granulysin, eosinophil-derived neurotoxin and serum amyloid A (SAA). A recent report suggests that SAA induces inflammation in a TLR2-dependent manner while another report claims that SAA is an endogenous agonist for TLR4[4, 5]. It is clear that DAMPs interact with TLRs, however it is less clear whether they bind to them. Recombinant DAMP proteins may contain traces of lipoproteins or endotoxins that may be sufficent to skew the results.Before this meeting on DAMPs and Alarmins,HMGB1 was thought to be a TLR4 ligand. This highlights how crucial it is to work with DAMP preparations that are totally free of microbial contaminants in order to understand the role of DAMPs in the numerous cellular processes in which they are involved.
- Lets have a look at one of these alarm molecules, HMGB1, which has also been studied in relation to sepsis in critical illness. High-mobility group box 1 (HMGB1), a highly conserved protein previously known as a DNA-binding protein involved in maintenance of nucleosome structure and regulation of gene transcription, was recently found to act as a potent proinflammatory cytokine during infection responses.
- So what happens is that pain and inflammation feed back to each other, thus creating the conditions for the onset of multiple organ dysfunction, which is a devastating outcome for critically ill patients.
- At the same time, the soup of cytokines, neuropeptides, alarm molecules and oxygen free radicals signal the central nervous system and they elicit central neurotransmitters that augment pain perception and the characteristic sickness behaviour and negative affect. Then the brain signals back to the periphery through production of even more neuropeptides and cytokines. So a new vicious circle is established. In a model of endotoxemia, passive immunization with anti-HMG-1 antibodies attenuated the development of hypophagia, indicating that HMG-1 is a mediator of sickness behaviour associated with endotoxemia. Agnello et al 2002
- More importantly these events account for both central as well as peripheral sensitization to pain, which is a dual process consisting of activation and sensitization that is ultimately bidirectional and self-perpetuating. Persistent nociceptive signaling after tissue damage results in activity-dependent plasticity or a progressive increase in the response of the system to subsequent stimulation, such that mildly noxious (painful) stimuli are perceived as more painful and non-painful, and innocuous stimuli may now elicit pain
- Lets have a look at pain’s effect on immunity
- Although these results are novel they make sense when previous evidence is taken into account.
- In this study, in a sample of critically ill patients we observed for the first time associations between the intensity of pain, as measured by 4 different scales, including two behavioral scales- and expression of the death receptor Fas on B cells and cytotoxic T cells. This is the first time anybody reports associations between pain and apoptotic markers. What can we conclude of that? Simplistically or not, when critically ill patients are in pain, their immune cells die, so off goes immunity and welcome infections.
- In another repeated-measures correlational study we observed weaker, but still very significant associations between Pain intensity and soluble apoptotic markers, both sfas and sfasL. Also… Which really links these markers to pain and stress
- So pain not only precipitates inflammation but also cell death and immunosuppression, which really set the stage for the development of sepsis as well.
- Pain is never a metaphor! Remarkably, even what we consider metaphorical pain with no apparent sensory component, such as social pain of loss and isolation, activates somatosensory neural circuitry similar to physical pain, to the degree that analgesic agents, such as acetaminophen, along with physical pain also reduce social pain (Dewall et al., 2010). Indeed, intense social pain, such as recalling rejection by a romantic partner activates the secondary somatosensory cortex (Kross et al., 2011).
- The affective pathway of nociception appears to be activated even by simple social exclusion conditions, such as being ignored or excluded from a game (Eisenberger et al., 2003). Patients that feel isolated, lonely or ignored may be at risk for higher pain intensity, as well as lower pain threshold.
- Remarkably, even viewing pictures of one’s partner appears to lower the intensity of pain (Eisenberger et al., 2011), which provides empirical support for the practice of displaying pictures of family and friends close to the bed of critically ill patients (Macnab et al., 1997).
- inadequate analgesia has been linked to the onset of delirium (Robinson & Volmer, 2010) practice guidelines acknowledge the interconnection between pain, agitation and delirium (Barr et al., 2013) Pain’s effect on triggering aggression may be interpretable in evolutionary terms, since when harmed one may need to defend oneself and attack. Similarly, social exclusion, by virtue of activating overlapping neural pathways may also trigger defensive/ aggressive behavior (Warburton et al., 2006). Therefore, both physical pain control and social support are essential in preventing critically ill patients’ irritability, aggression and delirium.
- Lately awareness on chronic pain after discharge from ICU has increased.