Elizabeth PapathanassoglouElizabeth PapathanassoglouCyprus University of Technology, Department of NursingCyprus University of Technology, Department of Nursing

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.

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

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) 

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).

Pain Pathways

1ary, 2ary somatosensory cortexes,

posterior insula (discriminative aspects of

pain)

dACC anterior insula limbic system

Sedation suppresses cognition NOT neural circuitry of pain

1ary, 2ary somatosensory cortexes

posterior insula dACCanterior insula

limbic system

TMN

Interactive loops of pain

Sensory Pathway

Intracellular signaling

Cellular alarmInflammation

Affective Pathway

Stress Response

NeuropeptidesCytokines

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

Sensory pathway: Intra-cellular signaling

MAPK ActivationMAPK ActivationERK p38 JNKERK p38 JNK

LGICsNTRs CRGPCR

Transcriptional regulation

Alarm moleculesDAMPs

Oxidative stress

Cytokines- Neuropeptides

Transcriptional regulation

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

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

HMGB-1Involved 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.

Cellular responses & the brain

MAPK ActivationMAPK ActivationERK p38 JNKERK p38 JNK

LGICs NTRs CRGPCR

Transcriptional regulation

Alarm moleculesDAMPs

Oxidative stress

Cytokines- Neuropeptides

Transcriptional regulation

Affective pathwayAffective pathwaySensory pathwaySensory pathway

Agnello et al 2002

Unrelieved pain promotes sensitization

MAPK ActivationMAPK ActivationERK p38 JNKERK p38 JNK

LGICs NTRs CRGPCR

Transcriptional regulation

Alarm moleculesDAMPs

Oxidative stress

Cytokines- Neuropeptides

Transcriptional regulation

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)

Pain promotes cell death

• Persistent pain activates the JNK pathway

• JNK is a stress-activated pathway implicated in inflammation and apoptosis

Gao & Gi, 2008

Pain ratings in critically ill patients associate with death molecules on T and B cells

Papathanassoglou et al (in press)

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)

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).

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

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

Family pictures!• Viewing pictures of one’s partner

appears to lower the intensity of painEisenberger et al., 2011

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

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]

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).

Prevention of pain persistence & chronicity

• Early detection and management • Early psychological and social support

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.

THANK YOU!!!