1. Pathophysiology

2. Overview

3. Pain Is the 5th Vital Sign
Temperature
Respiration
Pulse
Blood pressure
Pain
Speaker’s Notes
In 2000, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) unveiled new pain management standards. Central to these new standards was the concept of pain as the fifth vital sign – something that should be regularly monitored in all patients. While there is some controversy regarding whether pain should in fact be monitored at every visit, like blood pressure, this concept highlights the fundamental importance of pain in patient care.
Reference
Phillips DM. JCAHO pain management standards are unveiled. Joint Commission on Accreditation of Healthcare Organizations. JAMA 2000; 284(4):428-9.
Phillips DM. JAMA 2000; 284(4):428-9.

4. Overview of Pain Protective role: vital early warning system
Senses noxious stimuli
Triggers withdrawal reflex and heightens sensitivity after tissue damage to reduce risk of further damage
Unpleasant experience:
Suffering – physical, emotional and cognitive dimensions
Continuous unrelieved pain can affect physical (e.g., cardiovascular, renal, gastrointestinal systems, etc.) and psychological states
Maladaptive response:
Neuropathic and central sensitization/dysfunctional pain
Not protective
Lessens quality of life
Speaker’s Notes
The physiologic function of pain is to serve as an early warning system that senses noxious stimuli to provoke a reflexive withdrawal (nociception) and to heighten sensitivity after tissue damage to reduce risk of further damage through movement (inflammation).
However, continuous unrelieved pain can have a detrimental impact on both physical and psychological well-being. Unrelieved pain can lead to sympathetic activation of the pituitary-adrenal, affecting the cardiovascular , renal and gastrointestinal systems, increasing the risk of cardiac ischemia and ileus. Unrelieved pain is also frequently associated with anxiety and depression.
Thus, chronic pain states, often involving neuropathic and/or central sensitization/dysfunctional pathophysiologies are considered to be maladaptive rather than protective and lessen quality of life.
References
Costigan M et al. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009; 32:1-32.
Wells N et al. In: Hughes RG (ed). Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Agency for Healthcare Research and Quality; Rockville, MD: 2008.
Woolf CJ et al. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140(6):
Costigan M et al. Annu Rev Neurosci 2009; 32:1-32; Wells N et al. In: Hughes RG (ed). Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Agency for Healthcare Research and Quality; Rockville, MD: 2008; Woolf CJ et al. Ann Intern Med 2004; 140(6):

5. Acute pain may become chronic
The Pain Continuum
Insult
Time to resolution
Acute pain
Chronic pain
Normal, time-limited response to ‘noxious’ experience (less than 3 months)
Pain that has persisted beyond normal tissue healing time (usually more than 3 months)
Usually obvious tissue damage
Serves a protective function
Pain resolves upon healing
Usually has no protective function
Degrades health and function
Speaker’s Notes
This slide illustrates how acute and chronic pain are often classified along a pain continuum.
Acute pain may be seen as a message that follows an insult to tissue, signaling the presence of a pathologic condition, thus alerting the patient to the need to either seek treatment or protect the involved area from further injury. Most episodes of acute pain are self-limiting. Acute pain becomes chronic when it persists beyond the expected period of healing, usually considered to be three months. Recurrent acute pain is not chronic pain.
Chronic pain has also been defined as pain that ceases to serve a protective function, and instead degrades health and functional capability. Chronic pain conditions may be due to a single pathophysiology, that is nociceptive, neuropathic or central sensitization/dysfunctional pain only, or a may be due to a combination of more than one pathophysiological mechanisms.
It is important to differentiate chronic pain from a condition with recurrent episodes of acute pain because the treatment strategies are very different for these two situations.
References
Chapman CR, Stillman M. In: Kruger L (ed). Pain and Touch. Academic Press; New York, NY: 1996.
Cole BE. Pain Management: classifying, understanding, and treating pain. Hosp Physician 2002; 38(6):23-30.
International Association for the Study of Pain. Unrelieved Pain Is a Major Global Healthcare Problem. Available at: CM/ContentDisplay.cfm&ContentID=2908. Accessed: July 24: 2013.
National Pain Summit Initiative. National Pain Strategy: Pain Management for All Australians. Available at: Accessed: July 24, 2013.
Turk DC, Okifuji A. In: Loeser D et al (eds). Bonica’s Management of Pain. 3rd ed. Lippincott Williams & Wilkins; Hagerstown, MD: 2001.
Acute pain may become chronic
Chapman CR, Stillman M. In: Kruger L (ed). Pain and Touch. Academic Press; New York, NY: 1996; Cole BE. Hosp Physician 2002; 38(6):23-30; International Association for the Study of Pain. Unrelieved Pain Is a Major Global Healthcare Problem. Available at: Accessed: July 24: 2013; National Pain Summit Initiative. National Pain Strategy: Pain Management for All Australians. Available at: Accessed: July 24, 2013; Turk DC, Okifuji A. In: Loeser D et al (eds.). Bonica’s Management of Pain. 3rd ed. Lippincott Williams & Wilkins; Hagerstown, MD: 2001.

6. Acute vs. Chronic Pain Acute Chronic Sudden, sharp, intense, localized
Usually self-limited (<6 months)
May be associated with physiologic changes (e.g., sweating, increased heart rate, elevated blood pressure)
Gnawing, aching, diffuse
No definite beginning or end
Varies in intensity; may remit briefly
Associated with psychological and social difficulties
Acute pain may be superimposed
Speaker’s Notes
Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the onset of pain, though some theorists and researchers have placed the transition from acute to chronic pain at 12 months. Others apply acute to pain that lasts less than 30 days, chronic to pain of more than six months duration, and subacute to pain that lasts from one to six months A popular alternative definition of chronic pain, involving no arbitrarily fixed durations is "pain that extends beyond the expected period of healing."
Acute and chronic pain have distinct characteristics, as shown on this slide. Acute pain tends to be sudden, sharp, intense, and localized. It is usually self-limited, lasting <6 months. Acute pain may be associated with physiologic features, such as sweating, increased heart rate, and elevated blood pressure.
Chronic pain, on the other hand, is often described as gnawing or aching and is generally diffuse. There is no definite beginning or end to the pain. Intensity may vary or there may be brief periods of remissions. Chronic pain results in psychological and social difficulties. Acute pain may be superimposed on chronic pain.
References
Siddall PJ et al. In: Cousins MJ, Bridenbaugh PO (eds). Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Lippincott Williams & Wilkins; Philadelphia, PA: 1998.
Thienhaus O, Cole BE. Classification of pain. In: Weiner R. Pain Management: A Practical Guide for Clinicians. CRC Press; Boca Raton, FL: 2002.
Siddall PJ et al. In: Cousins MJ, Bridenbaugh PO (eds). Neural Blockade in Clinical Anesthesia and Management of Pain. 3rd ed. Lippincott Williams & Wilkins; Philadelphia, PA: 1998; Thienhaus O, Cole BE. Classification of pain. In: Weiner R. Pain Management: A Practical Guide for Clinicians. CRC Press; Boca Raton, FL: 2002.

7. Acute Pain Can Become Chronic
Pathophysiological
processes
Pathophysiological
maintaining factors
Sensory
component
Sensory
component
Acute
pain
Chronic
pain
Affective/cognitive
component
Affective/cognitive
component
Speaker’s Notes
This slide presents a simplified conceptual model of the role of acute pain in the development of chronic pain.
An individual’s experience of pain comprises both sensory and affective/cognitive components. There is a school of thought that the severity and quality of acute sensory pain reflect the severity and nature of the underlying pathophysiological processes whereas the severity and quality of acute affective/cognitive pain reflect the severity and nature of any psychosocial antecedents.
Research to date suggests that chronic pain is more likely to develop when an individual’s overall experience of acute pain is more severe, when there is greater physical pathology, and greater psychosocial distress. Accordingly, chronic pain can persist independently of the pathophysiological and psychosocial determinants of the acute pain experience (e.g., phantom pain).
Although pathophysiological processes and psychosocial factors may contribute to the maintenance of chronic pain once it is established, severe acute pain is considered as the “final common pathway” through which these factors contribute to the development of chronic pain. Consequently, minimization of acute pain and psychosocial distress can in turn prevent chronic pain.
Reference
Dworkin RH. Which individuals with acute pain are most likely to develop a chronic pain syndrome? Pain Forum 1997; 6(2):
Psychosocial
antecedents
Psychosocial
maintaining factors
Dworkin RH. Pain Forum 1997; 6(2):

8. Acute Pain Can Become Chronic
Life Cycle Factors Associated with Development of Chronic Pain
From birth
Genetics Female sex
Minority race/ethnicity Congenital disorders Prematurity
Parental anxiety
Irregular feeding/sleeping
Parents’ pain exposure and reactions
Personality
Childhood
Physical/sexual abuse and other traumatic events
Low socioeconomic status
Emotional, conduct and peer problems
Hyperactivity
Serious illness or injury
Separation from mother
Acute or recurrent pain experience
Adolescence
Changes of puberty Gender roles
Education level
Injuries
Obesity
Low levels of fitness
Adulthood
Vivid recall of childhood trauma
Lack of social support
Accumulated stress
Surgery
Overuse of joints and muscles
Occupation
Chronic disease
Aging
Speaker’s Notes:
This slide shows the individual factors throughout a person’s lifespan that could contribute to the eventual development of chronic pain.
Reference
Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies Press; Washington, DC: 2011.
Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies Press; Washington, DC: 2011.

9. Risk Factors for Chronic Post-operative Pain
Pre-operative factors
Moderate to severe pain, lasting >1 month
Repeat surgery
Psychologic vulnerability (e.g., catastrophizing)
Pre-operative anxiety
Female gender
Younger age (adults)
Workers’ compensation
Genetic predisposition
Inefficient diffuse noxious inhibitory control
Intra-operative factors
Surgical approach with risk of nerve damage
Post-operative factors
Moderate to severe acute pain
Radiation therapy to area
Neurotoxic chemotherapy
Depression
Psychological vulnerability
Neuroticism
Anxiety
Speaker’s Notes:
This slide lists peri-operative risk factors for the development of chronic post-operative pain.
Reference
Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management: Scientific Evidence. 3rd ed. ANZCA & FPM; Melbourne, VIC: 2010.
Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management: Scientific Evidence. 3rd ed. ANZCA & FPM; Melbourne, VIC: 2010.

10. Etiology

11. Common Causes of Acute Pain
Fractures2,3
Dental procedures1
Surgery4
Acute pain
Renal colic7
Strains and sprains5,6
Speaker’s Notes
There are many common sources of acute pain, including:
Dental procedures,1 which may cause toothache, pain in teeth associated with hot, cold, or sweet sensations and pain and discomfort in the mouth, teeth, or gums
Fractures, for instance of the rib2 or clavicle, humerus, radius or ulna, hand, femur, tibia or fibula, foot, or other fractures seen in hospital emergency departments3
Surgery,4 leading to post-operative pain
Strains and sprains (tendon injuries)5
Renal colic,7 which is characterized by an abrupt onset of unbearable pain due to an acute urinary tract obstruction
Burns8
Inflammation9
Abdominal pain,10 the leading illness-related diagnosis in the emergency department according to data on emergency department visits in the United States in 20056
References
Pau AK et al. Prevalence estimates and associated factors for dental pain: a review. Oral Health Prev Dent 2003; 1(3):
Karmakar MK et al. Acute pain management of patients with multiple fractured ribs. J Trauma 2003; 54(3):
Brown JC et al. Emergency department analgesia for fracture pain. Ann Emerg Med 2003; 42(2):
Apfelbaum JL et al. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg 2003; 97(2):
Wilson JJ et al. Common overuse tendon problems: a review and recommendations for treatment. Am Fam Physician 2005; 72(5):811-8.
Nawar EW et al. National Hospital Ambulatory Medical Care Survey: 2005 emergency department summary. Adv Data 2007; 29(386):1-32.
Heid F et al. The treatment of pain in urology. BJU Int 2002; 90(5):481-8.
Pal SK et al. Adjunctive methods of pain control in burns. Burns 1997; 23(5):
Lee Y et al. The role of COX-2 in acute pain and the use of selective COX-2 inhibitors for acute pain relief. Curr Pharm Des 2005; 11(14):
Cartwright SL et al. Evaluation of acute abdominal pain in adults. Am Fam Physician 2008; 77(7):971-8.
Burns8
Abdominal pain6,10
Inflammation9
1. Pau AK et al. Oral Health Prev Dent 2003; 1(3):209-20; 2. Karmakar MK et al. J Trauma 2003; 54(3):615-25; 3. Brown JC et al. Ann Emerg Med 2003; 42(2): ; 4. Apfelbaum JL et al. Anesth Analg 2003; 97(2):534-40; 5. Wilson JJ et al. Am Fam Physician 2005; 72(5):811-8; 6. Nawar EW et al. Adv Data 2007; 29(386):1-32; 7. Heid F et al. BJU Int 2002; 90(5):481-8; 8. Pal SK et al. Burns 1997; 23(5): ; 9. Lee Y et al. Curr Pharm Des 2005; 11(14): ; 10. Cartwright SL et al. Am Fam Physician 2008; 77(7):971-8.

12. Nociceptive Pain Visceral Trauma Musculoskeletal injury
Ischemic, e.g., myocardial infarction
Abdominal colic
Speaker’s Note:
In our daily life there are many forms of acute pain, such as “somatic pain” of musculoskeletal origin due to sports injury /trauma, burn, incision (such as in post-operative pain) or infectious diseases (such as in pharingitis, otitis, etc.).
It may also be a “visceral pain” due to vascular occlusion such as in myocardial ischemia, visceral nociceptive/inflammatory pain due to stretching, hypoxia or inflammation of the hollow organs such as in abdominal colic, dysmenorrhea, etc. Trigeminal or C2-C3 nerve root irritation may lead to neurovascular inflammation in acute episodic headaches such as migraine.
Reference
Fishman SM et al (eds). Bonica’s Management of Pain. 4th ed. Lippincott, Williams and Wilkins; Philadelphia, PA: 2010.
Post-operative pain
Burn pain
Infection, e.g., pharyngitis
Dysmenorrhea
Fishman SM et al (eds). Bonica’s Management of Pain. 4th ed. Lippincott, Williams and Wilkins; Philadelphia, PA: 2010.

13. Pathophysiology

14. Acute Pain: Normal Nociception Is Modified by Inflammation
Tissue damage zone
Activation and sensitization
PGs, H+
Cytokines
TNF, IL1, IL6
Growth factors
NGF, BDNF, etc.
ATP, Bk
5HT
C fiber
NGF
SP, CGRP
Speaker’s Notes
In acute pain, normal nociception is modified by inflammation. This inflammation is not limited to the site of the injury or lesion. Inflammatory mediators are also active at other sites along the pathways for the conduction and transmission of the noxious action potentials. Inflammation is the key driving force in the development of sensitization to nociception. If not treated appropriately, it may lead to structural modifications of the neuron that evolve into chronic pain syndromes.
Tissue lesions result in cell damage. The damaged cells and the surrounding mast cells, neutrophils and macrophages release a variety of algogenic substances (e.g., Bk, H+, ATP) that activate terminal sensory nerve endings in the vicinity. Furthermore, mast cells, neutrophils and macrophages release many inflammatory mediators (e.g., IL1, IL6, TNF) that in turn stimulate formation of prostaglandins from the damaged cell membranes.
All these mediators activate the sensory (A and C) nerve endings and their persistence produces sensitization of these nerve endings. In response to the activation, the nerve cell body in the dorsal root ganglion produces neurotransmitters (e.g., substance P, CGRP) that are sent to the nerve endings by axonal transport, together with nerve growth factors. Some of these neurotransmitters affect local blood vessels, and produce vasodilatation and plasma extravasation, the so-called neurogenic edema.
References
Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J Anaesth 2001; 87(1):3-11.
Oprée A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci 2000; 20(16):
Blood
vessel
Vasodilation + plasma extravasation
5HT = serotonin; ATP = adenosine triphosphate; BDNF = brain-derived neurotrophic factor; Bk = bradykinin; CGRP = calcitonin gene-related peptide ; IL = interleukin; PG = prostaglandin; NGF = nerve growth factor; SP = substance P; TNF = tumor necrosis factor
Kidd BL, Urban LA. Br J Anaesth 2001; 87(1):3-11; Oprée A, Kress M. J Neurosci 2000; 20(16):

15. What is nociceptive pain?
Definition
Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors
Can be somatic or visceral
Pain Quality
Usually aching or throbbing
Usually time-limited (resolves when damaged tissue heals)
Usually well localized if somatic
May be referred if visceral
Can become chronic
Speaker’s Notes
Nociceptive pain is a sensory experience that occurs when specific sensory neurons, called nociceptors, respond to noxious stimuli. With nociceptive pain, the painful region is typically localized to the site of injury and the pain is often described as throbbing, aching or pressure-like. Nociceptive pain is usually time limited and resolves when the damaged tissue heals (e.g., bone fractures, burns, and bruises).
Somatic pain originates with the musculoskeletal or cutaneous nociceptors and is often well localized. Visceral pain originates in nociceptors located in the hollow organs and smooth muscles; it is often referred.
Although nociceptive pain is generally self-limiting, it can become chronic. Treatment with conventional analgesics is usually appropriate.
References
Felson DT. Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther 2009; 11(1):203.
International Association for the Study of Pain. IASP Taxonomy. Available at: Accessed: July 15, 2013.
McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3 Suppl):S2-15.
Felson DT. Arthritis Res Ther 2009; 11(1):203; International Association for the Study of Pain. IASP Taxonomy. Available at: Accessed: July 15, 2013; McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Woolf CJ. Pain 2011;152(3 Suppl):S2-15.

16. Somatic vs. Visceral Pain
Nociceptors are involved
Often well localized
Usually described as throbbing or aching
Can be superficial (skin, muscle) or deep (joints, tendons, bones)
Involves hollow organ and smooth muscle nociceptors that are sensitive to stretching, hypoxia and inflammation
Pain is usually referred, poorly localized, vague and diffuse
May be associated with autonomic symptoms (e.g., pallor, sweating, nausea, blood pressure and heart rate changes)
Speaker’s Notes
Nociceptive pain can have either a somatic or a visceral origin. Somatic pain, originating in the skin, muscles, joints, tendons or bones, is the better known of the two types and is what is often meant when people refer to nociceptive pain. However, visceral pain originating in the hollow organs and/or smooth muscles is also quite common, as exemplified by dysmenorrhea, infective cystitis and functional gastrointestinal disorders. Unlike somatic pain, visceral pain is usually diffuse rather than well localized. It may also be referred (i.e., experienced in a part of the body not associated with the initial injury or dysfunction).
References
McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
Sikandar S, Dickenson AH. Visceral pain: the ins and outs, the ups and downs. Curr Opin Support Palliat Care 2012; 6(1):17-26.
McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Sikandar S, Dickenson AH. Curr Opin Support Palliat Care 2012; 6(1):17-26.

17. Referred Pain Speaker’s Notes
In the spinal cord, there is a convergence of visceral and somatic cutaneous afferent fibers. The ascending axons transmit the message to the brain. Thus, visceral nociceptor stimulation misinterprets the location of the pain as being in the skin.
The image shown on this slide depicts the regions of referred visceral pain.
References
Hudspith MJ et al. In: Hemmings HC, Hopkins PM (eds). Foundations of Anesthesia. 2nd ed. Elsevier; Philadelphia, PA: 2006.
Schmitt WH Jr. Visceral referred pain areas. Uplink 1998; 10:1-3.
Hudspith MJ et al. In: Hemmings HC, Hopkins PM (eds). Foundations of Anesthesia. 2nd ed. Elsevier; Philadelphia, PA: 2006; Schmitt WH Jr. Uplink 1998; 10:1-3.

18. Nociception: Neural Process of Encoding Noxious Stimuli
Somatosensory
cortex
Thalamus
Perception
Noxious stimuli
Descending modulation
Ascending input
Speaker’s Notes
This slide illustrates some central and peripheral pathways by which painful stimuli are normally processed (nociceptive pain).
Transduction is the conversion of a noxious thermal, mechanical or chemical stimulus into electrical activity in the peripheral terminals of nociceptor sensory fibers. This process is mediated by specific receptor ion channels expressed only by nociceptors.
Conduction is the passage of action potentials from the peripheral terminal along axons to the central terminal of nociceptors in the central nervous system.
Transmission is the synaptic transfer and modulation of input from one neuron to another. Peripheral nerve fibers involved in pain include unmyelinated slowly conducting C fibers and thinly myelinated A fibers.
In the superficial layers of the dorsal horn, these fibers make synaptic connection with second-order neurons that transmit the impulses through the spinal cord to the brain (ascending transmission pathway). In the brain, the thalamus and certain specific cortical areas are critical for the sensory experience of pain. Transmission and processing of pain impulses is also modulated by descending pathways.
Reference
Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002; 5(Suppl):
Conduction
Transmission
Transduction
Nociceptive afferent fiber
Spinal cord
Consequences of encoding may be autonomic (e.g., elevated blood pressure) or behavioral (motor withdrawal reflex or more complex nocifensive behavior). Pain perception is not necessarily implied.
Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):

19. Nociceptive Pain + NOCICEPTIVE PAIN
Transduction
Transduction of noxious mechanical and chemical stimuli into electrical signals in nociceptors
Transmission
Neuronal signals are transmitted up via the spinal cord to higher centers where they are perceived as “pain”
Modulation
Nervous system can alter pain sensitivity via inhibition or facilitation +
Speaker’s Notes
Nociception is the transduction of noxious mechanical and chemical stimuli into electrical signals in nociceptors:
In transduction, different receptors and channels detect different types of noxious stimuli:
Transient receptor potential cation channel subfamily V member 1 (TRPV1) ion channel-linked receptors detect noxious heat (>43°C)
Transient receptor potential cation channel subfamily A member 1 (TRPA1) ion channel-linked receptors detect noxious cold
Acid-sensing ion channels (ASICs) detect noxious pH
Degerin/epithelial sodium channels (DEG/ENaC) detect mechanical stimuli
Transmission occurs when neuronal signals are transmitted up via the spinal cord to higher centers where they are perceived as “pain”.
Modulation refers to the ability of the nervous system to alter pain sensitivity via inhibition or facilitation.
References
Caterina MJ et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389(6653):
Julius D. Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413(6852):
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168):
NOCICEPTIVE PAIN
Caterina MJ et al. Nature 1997; 389(6653): ; Julius D. Basbaum AI. Nature 2001; 413(6852):203-10; Woolf CJ, Salter MW. Science 2000; 288(5472):

20. Transduction via Endogenous Mediators
Noxious stimuli
Mediators
Prostaglandins
Leukotrienes
Substance P
Histamine
Bradykinin
Serotonin
Hydroxyacids
Reactive oxygen species
Inflammatory cytokines and chemokines
Receptors/channels on nociceptors
Mechanical
Thermal
Chemical
Speaker’s Notes
Pain is transduced via various endogenous mediators, such as prostaglandins and substance P, which bind to receptors and/or channels on nociceptors to transform noxious stimuli into electrical signals.
Different receptors and channels detect different types of noxious stimuli:
Transient receptor potential cation channel subfamily V member 1 (TRPV1) ion channel-linked receptors detect noxious heat (>43°C)
Transient receptor potential cation channel subfamily A member 1 (TRPA1) ion channel-linked receptors detect noxious cold
Acid-sensing ion channels (ASICs) detect noxious pH
Degerin/epithelial sodium channels (DEG/ENaC) detect mechanical stimuli
References
Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413(6852):
Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002; 5(Suppl):
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
Julius D, Basbaum AI. Nature 2001; 413(6852):203-10; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):1062-7; Woolf CJ, Salter MW. Science 2000; 288(5472):

21. Transmission via Neurotransmitters
Impulses reach terminals of presynaptic neuron
Glutamate is released into synaptic cleft
Glutamate binds to AMPA receptor
Impulse is transmitted to postsynaptic neuron
Presynaptic
neuron
Substance P
Glutamate
NMDA receptor blocked by Mg2+
Speaker’s Notes
This slide contains an animated build to illustrate the normal sequence of events occurring during transmission at spinal dorsal horn synapses. Click on this slide to advance the sequence:
Pain is conducted and transmitted via various excitatory and inhibitory neurotransmitters. Once the action potential from the periphery reaches the first synapse at the dorsal horn of the spinal cord, a number of neuroactive substances are released. These include several excitatory and inhibitory neurotransmitters, such as substance P, calcitonin gene-related peptide, aspartate and glutamate (excitatory) and glycine and somatostatin (inhibitory). The first part of the animation sequence on this slide shows the presynaptic terminal being depolarized following impulse arrival and glutamate being released into the synaptic cleft.
Glutamate then diffuses across the cleft and binds to the AMPA receptors, activating postsynaptic second-order nociceptive neurons
NMDA receptors on the postsynaptic membrane are not activated because they are blocked by magnesium ions
Local anesthetics act to reduce pain at the level of transmission
References
Fields HL et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413(6852):
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
Synaptic cleft
Postsynaptic
neuron
NMDA receptor
NK-1
AMPA
receptor
AMPA = 2-amino-3-(3-hydroxy- 5-methyl-isoxazol-4-yl) propanoic acid; NK = neurokinin; NMDA = N-methyl-D-aspartate
Fields HL et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Julius D, Basbaum AI. Nature 2001; 413(6852):203-10; Woolf CJ, Salter MW. Science 2000; 288(5472):

22. Ascending Nociceptive Descending Inhibitory/facilitatory
Pain Modulation
Brain
Pain is modulated via ascending nociceptive and descending inhibitory/facilitatory spinal tracts
Ascending Nociceptive
Descending Inhibitory/facilitatory
C fibers
Aδ fibers
Serotonin
Norepinephrine
Dopamine
Descending modulation
Ascending input
Speaker’s Notes
Ascending nociceptive pain pathways consist of nerve fibers with unmyelinated (C fibers) or thinly myelinated (Aδ fibers) axons. Aδ and C fiber nociceptors are usually activated by noxious stimuli. Activated Aδ fibers transmit sharp pain, while activated C fibers are responsible for secondary pain, which is usually described as aching or burning.
Ascending nociceptive pain input is modulated by descending control mechanisms involving various monoamine neurotransmitters, such as serotonin, norepinephrine and dopamine. Descending modulation originates from prefrontal cortex, anterior cingulate cortex (ACC), insular cortex, amygdala and hipotalamus. They project down to the brainstem pain modulatory connections such as : periaquaductal grey (PAG), rostral ventral medulla (RVM) and dorsolateral pontin tegmentum (DLPT). Different monoaminergic neurotransmitters bind to different receptors in the descending pathways and thus have different effects on the perception of pain, with some inhibiting and some facilitating pain.
References
Benarroch EE. Descending monoaminergic pain modulation: bidirectional control and clinical relevance. Neurology 2008; 71(3):
Fields HL et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006.
Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002; 5(Suppl):
Spinal cord
Benarroch EE. Neurology 2008 ; 71(3):217-21; Fields HL et al. In: McMahon SB, Koltzenburg M (Eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):

23. Pain Perception
Perception
Spinal cord transmits pain signals to specific nuclei in the thalamus, and from there to wide variety of regions in the brain – collectively known as the “pain matrix”
Pain perception can also be altered without any external stimuli (i.e., through emotion, distraction, placebo, etc.)
Brain
matrix
Speaker’s Notes
Pain is a complex, multidimensional experience involving many areas of the brain, including the thalamus; mid/rostral anterior cingulate cortex; primary and secondary somatosensory cortex; anterior, mid and posterior divisions of the insular cortex; dorsal, mid and ventral prefrontal cortices; brainstem nuclei and parts of the basal ganglia – collectively known as the “pain matrix”.
Lateral systems consists of the somatosensorial cortex S1 and S2, lateral thalamus and posterior insula. They are involved in the sensory aspects of pain, such as the differentiation of the localization and intensity of pain.
Medial systems consists of the anterior cingulate cortex (ACC) and anterior insular cortex, which are known to be components of the limbic system, and the medial thalamus. They are involved in the emotional, attentional, decision-making and cognitive aspects of pain perception.
Thalamic nucleic transmit information to both these areas simultaneously, leading to the complex interplay between external stimuli and internal processing that results in the very personal experience we call pain.
Reference
Tracey A, Dickenson A. Snapshot: pain perception. Cell 2012; 148(6):1308-e2.
Tracey A, Dickenson A. Cell 2012; 148(6):1308-e2.

24. Inflammation Changed responsiveness of neurons in CNS
Brain
Damaged tissue
Inflammatory cells
Tumor cells
Prostanoids
Cytokines
Growth factors
Kinins
Purines
Amines
Ions
Inflammatory chemical mediators
Changed responsiveness of neurons in CNS
(central sensitization)
Speaker’s Notes
Inflammation occurs when damaged tissue, inflammatory cells and/or tumor cells release inflammatory chemical mediators, such as cytokines, growth factors, kinins, purines, amines, prostanoids and ions. Some of these mediators directly activate nociceptors, provoking pain. Others heighten the responsiveness of the nociceptors, lowering the pain threshold while the damaged tissue heals – a process known as peripheral sensitization. This in turn changes the responsiveness of neurons in the CNS, which is called central sensitization.
Reference
Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002; 5(Suppl):
Changed responsiveness of nociceptors
(peripheral sensitization)
Nociceptive afferent fiber
Spinal cord
CNS = central nervous system
Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):

25. Central Sensitization
C fiber terminal
GABA Glycine
Glutamate
(+)
PGE2
Inhibitory
Inter-neuron
(-)
NMDA P
Substance P
(-) on
Glycine
receptors
AMPA P
Ca++
PGE2
(+)
Speaker’s Notes
This slide contains an animation sequence: left click or arrow down in presentation mode to show next numbered item. Please wait for the animation to complete running before clicking on the next item.
The sequence is as follows:
Inhibitory inter-neurons (including those using endogenous opioid transmitters) die (disappear), and are replaced by text “Inhibitory inter-neuron cell death”
Animation skips to next slide – make one additional left click or arrow down and the animation will automatically run until completion
Formation of aberrant excitatory synapses between A-fibers (instead of normal C fibers) and the dorsal horn
New afferent neuron appears from top left, NMDA and AMDA receptors appear on dorsal horn; glutamate transmitters are released from new afferent neuron, bind to AMDA and NMDA receptors, opening associated calcium channels which stimulate PKC enzymes to phosphorylate NMDA and AMDA receptors – further opening their associated calcium channels
The result is a long-lasting increase in neuron sensitivity, leading to chronic neuropathic pain, often resistant to opioids.
Reference
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
(+)
PKC
(+)
Na+
PGE2
Dorsal horn neuron
PGE2
COX-2
induction
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate; prostaglandin E; PKC = protein kinase C
Woolf CJ, Salter MW. Science 2000; 288(5472):

26. Central Sensitization
New A fiber forming synapse
C fiber terminal
Inhibitory
inter-neuron
cell death
Glutamate
(+)
PGE2 P
NMDA P
AMPA P
Substance P
Dorsal horn neuron
AMPA P
Ca++
(+)
Loss of inhibitory
effects of inter-neurons
(+)
Establishment of aberrant excitatory
synaptic
connection
Speaker’s Notes
This slide contains an animation sequence continued from the previous slide. The animation should “play” automatically from the previous slide.
Reference
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288(5472):
PKC
(+)
Na+
PGE2
Dorsal horn neuron
PGE2
COX-2
induction
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA = γ-aminobutyric acid; NMDA = N-methyl-D-aspartate; prostaglandin E; PKC = protein kinase C
Woolf CJ, Salter MW. Science 2000; 288(5472):

27. Summary

28. Pathophysiology of Acute Pain: Summary
In acute pain, normal nociception is modified by inflammation
Acute pain may develop into chronic pain through modulation of synaptic transmission
Repeated activation of C fiber nociceptors and peripheral inflammation can lead to increased expression of COX-2, iNOS and c-Fos in the secondary neuron and microglia
Peripheral injury can generate pain hypersensitivity in neighbouring, uninjured tissues (secondary hyperalgesia) via central sensitization
Speaker’s Notes
This slide can be used to summarize the key concepts of this section.
The phenomenon of central sensitization increases neuronal activity within the spinal cord. This is linked to painful sensations such as hyperalgesia and allodynia and the generation of spontaneous pain. Increased peripheral receptive fields of individual spinal neurones, lowered threshold to peripheral stimuli and increased spontaneous firing are also observed. However, it is important to realize that spinal cord sensitization is an activity-dependent process. When the peripheral trigger of inflammation is removed, the modulation of nociceptive signals in the dorsal horn of the spinal cord will return to normal.
This plasticity is of great importance when considering a rational basis for the treatment of both inflammatory and neuropathic pain, where the damage to tissue and nerve leads to alterations in both the peripheral and central mechanisms of pain signaling.
In terms of existing drug therapies, this plasticity, or ability of the nervous system to change in the face of a particular pain syndrome, is one reason for the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in inflammatory conditions.
iNOS = inducible nitric oxide synthase