Anatomy and Physiology of Pain

1. Anatomy and Physiology of Pain • “Pain is a more terrible lord of mankind than even death itself.” • Albert Schweitzer

2. Pain definitions:(The International Association for the Study of Pain (IASP) • An unpleasant sensory and emotional experienceassociated with actual or potential tissue damage • May not be directly proportional to amount of tissue injury • This definition recognizes that pain is a perception and not a sensation!!

3. Pain definitions:(hierarchical model of pain) • Pain is whatever the experiencing person says it is

4. Pain definitions - implication of both the IASP and the hierarchical model of pain • As a perception, pain may or may not correlate with an identifiable source of injury • The activity in the body’s “nociceptive” system, • which senses noxious stimuli and • generates a physiological and behavioral response, • can be initiated by injury and sustained by neuroplastic changes even after healing • activity in this system can occur in the absence of any discrete injury but in associationwith a recognizable disease

5. Pain definitions - implication of both the IASP and the hierarchical model of pain • In some cases, pain can develop and be unrelated to any identifiable physical process • In all cases, the reality that pain is a perception indicates the potential for: • profound influence of psychological and emotional factors, cognitions • and varied external events

6. Pain definitions - implication of both the IASP and the hierarchical model of pain - concept of pain as perception • It is almost always best to believe that the patient is experiencing what is being reported. • Because there is no objective indicator for pain, experts agree that the best clinical approach in most circumstances is to assume that the patient is reporting a true experience, even in the absence of aclear explanation. • Importantly, accepting a patient’s complaint of pain as valid does not require clinical identification of a physical cause, or demand the initiation of a specific treatment.

7. Pain definitions - implication of both the IASP and the hierarchical model of pain - concept of pain as perception • Almost always, it is a sound foundation for assessment and an important beginning in developing an effective physician-patient dialogue. • The risk that rare cases of malingering or factitious disorder may lead the credulous physician to initial error is more than balanced by the benefits associated with a stance of compassionate acceptance and concern.

8. Types of Pain • 1. Acute - a protective mechanism that alerts the individual to a condition or experience that is immediatelyharmful to the body; • Onset - usually sudden • 2. Chronic - is persistent or intermittent • usually defined as lasting at least 6 months

9. Types of PainResponses to acute pain diaphoresis pallor or flushing increased heart rate elevated blood pressure  blood flow to the viscera, kidney and skin  gastric acid secretion  gastric motility nausea occasionally occurs increased respiratory rate dilated pupils  blood sugar fear general sense of unpleasantness anxiety

10. Types of Pain - response to chronic pain Psychological response Intermittent pain produces a physiologic response similar to acute pain Persistent pain allows for adaptation (functions of the body are normal but the pain is not reliefed) Chronic pain producessignificant behavioural and psychological changes: depression an attempt to keep pain - related behaviourto a minimum sleeping disorders preoccupation with the pain tendency to deny pain

11. Pain threshold and pain tolerance • The pain threshold - the point at which a stimulus is perceived as pain. • It does not vary significantly among healthy people or in the same person over time • Perceptual dominance-intense pain at one location may cause an increase in the pain threshold in another location • The pain tolerance - duration of time or the intensity of pain that an individual will endured before initiation overt pain responses. • It is influenced by: • - persons cultural prescriptions • - expectations • - role behaviours • - physical and mental health

12. Pain threshold and pain tolerance • Pain tolerance is generally decreased: • with repeated exposure to pain • by fatigue, anger, boredom, apprehension • sleep deprivation • Tolerance to pain may be increased: • by alcohol consumption • medication, hypnosis • warmth, distracting activities • strong beliefs or faith • Pain tolerance varies greatly • among people • in the sameperson over time • a decrease in pain tolerance is also evident in the elderly • women appear to be more tolerant to pain than men

13. Age andperception of pain • Children and the elderlymay experience or express pain differently than adults: • Infants in the first 1 to 2 daysof life are less sensitive to pain (or they simply lack the ability to verbalise the pain experience) • A full behavioural response to pain is apparent at 3 to 12 month of life • Older children, between the ages of 15 and 18 years, tend to have a lower pain threshold than do adults • Pain threshold tends to increase with ageing • this change is probably caused by peripheral neuropathies • and changes in the thickness of the skin

14. Clasification of Pain - by pathophysiology • Nociceptive pain (stimuli fromsomaticand visceral structures) • Neuropathic pain (stimuli abnormally processed by the nervous system) • Psychogenic pain is pain for which there is unknown physical causebut processing of sensitive information in CNS is dysturbed • mixed pain • idiopathic pain

15. Nociceptive Pain and its Mechanisms • Clinically, pain can be labeled “nociceptive” if it is inferred that the pain is due to ongoing activation of the nociceptive system by tissue injury. • Although neuroplastic changes (such as those underlying tissue sensitization) are clearly involved, nociceptive pain is presumed to occur as a result of the normal activation of the sensory system by noxious stimuli, a process that involves4 basicprocesses • Transduction • Transmission • Perception of pain • Modulation of pain

16. Nociceptive Pain and its Mechanisms • Tissue injury activates primary afferent neurons called nociceptors,which are small diameter afferent neurons (with A-delta and C-fibers) • Nociceptors respond to noxious stimuli • Nociceptors are found in • skin • muscle • joints • and some visceral tissues.

17. Nociceptive Pain and its Mechanisms Nociceptive primary afferent neurons are varied: • Most are “silent”- active only when suprathreshold stimuli impinge • Some are specificto one type of stimulus, such as • mechanical • or thermal • but most are polymodal • The number and size of the receptive fields served by each fiber may be small or large, respectively

18. Nociceptive Pain and its Mechanisms • nociceptors free nerve endings has capacity to distinguish between noxious and innocuous stimuli whenexposed to • mechanical (incision or tumor growth) • thermal (burn) • chemical (toxic substance) stimuli • tissue damage occurs • substances are released by the damaged tissue which facilitates the movement of pain impulseto the spinal cord

19. Substances released • The substances released from the traumatized tissue are: • prostaglandins • bradykinin • serotonin • substance P • Histamine • Protons • NGF The role of this substances provide opportunities for the developmentof new analgesic drugs

20. So, for instance • Non-steroidal anti-inflammatories, such as ibuprofen, are effective in minimizing pain because they minimize the effects of these substances released, especially prostaglandins • Corticosteroids, such as dexamethasone used for cancer pain, also interferes with the production of prostaglandins

21. 1. Transduction • sufficient amounts of noxious stimulation cause the cell membrane of the neuron (nervous system cell) to become permeable to sodium ions,allowing the ions to rush into the cell and creating a temporary positive charge • then potassium transfers back into the cell, thus changing the charge back to a negative one • with this depolarization and repolarization, the noxious stimuli is converted to an impulse • this impulse takes just milliseconds to occur

22. Some analgesics relieve pain primarily by decreasing the sodium and potassium transfers at the neuron level, thereby slowing or stopping pain transmission • Examples—local anesthetics, anticonvulsants used for neuropathic pain, migraines

23. 2.Transmission • Once depolarization occurs, • transmission of information proceeds proximally along the axon to the spinal cord and then on to higher centers.

24. 2.Transmission • Transmission across the first central synapse may be influenced by activity in the primary afferent itself and modulatory neural pathways • that originate segmentally or supraspinally • further modulation results from processes initated by glial cells.

25. 2.Transmission • Impulse spinal cord brain stem thalamus central structures of brain pain is processed • Neurotransmitters are needed to continue the pain impulse from the spinal cord to the brain

26. 3. Perception of Pain • the end result of the neural activity of pain transmission • it is believed pain perception occurs in the cortical structures • behavioral strategies and therapy can be applied to reduce pain • brain can accommodate a limited number of signals— • distraction, imagery, relaxation signals may get through the gate, leaving limited signals (such as pain) to be transmitted to the higher structures

27. 4.Modulation of Pain • The neurochemistry of these processes involves an extraordinary array of compounds, including • endorphins, • neurokinins, • prostaglandins, • biogenic amines, • GABA, • neurotensin, • cannabinoids, • purines, • and many others.

28. 4.Modulation of Pain • The endorphinergic pain modulatory pathways are characterizedby multiple endogenous ligands and different types of opioid receptors:mu, delta, and kappa. • Endorphins are present in the periphery, • on nerve endings, • immune-related cells • and other tissues, • Endorphins are widely distributed in the central nervous system (CNS). • They are involved in many neuroregulatory processes apart from pain control, including • the stress response • and motor control systems. • Opioid drugs mimic the action of endogenous opioid ligands. Most of the drugs used for pain are full mu receptor agonists.

29. 4.Modulation of Pain • Other pain modulating systems, such as those that use • monoamines(serotonin, norepinephrine and dopamine), • histamine, • acetylcholine, • cannabinoids, • growth factors • and other compounds, • are targets for nontraditional analgesics, such as specific • antidepressants and • anticonvulsants. It is likely that entirely novel analgesic compounds will become commercially available in the future as drug development programs target these systems.

30. 4.Modulation of Pain • changing or inhibiting pain impulses in the descending tract (brain spinal cord) • descending fibers also release substances such as norepinephrine and serotonin (referred to as endogenous opioids or endorphins) which have the capability of inhibiting the transmission of noxious stimuli • cancer pain responds to antidepressants which interfere with the reuptake of serotonin and norepinephrine which increases their availability to inhibit noxious stimuli

31. Clinical Characteristics of Nociceptive Pain • acute (short-lived, remitting) • persistent (long-lived, chronic), • primarily involve injury to somatic • or visceral tissues. • “somatic pain”- pain related to ongoing activation of nociceptors that innervate somatic structures, such as • bone, • joint, • muscle • and connective tissues, • this pain is recognized by identification of a lesion • characterisitics typically include a well localized site and an experience described as aching, squeezing, stabbing, or throbbing.

32. Clinical Characteristics of Nociceptive Pain • Arthritis and metastatic bone pain are examples of somatic pain. • Pain arising from stimulation of afferent receptors • in the viscera is referred to as visceral pain. • Visceral pain caused by • obstruction of hollow viscus is poorly localized and is often described as cramping and gnawing, with a daily pattern of varying intensity. • when organ capsules or other structures such as myocardium, are involved, however, the pain usually is well localized and described as sharp, stabbing or throbbing, • descriptors similar to those associated with somatic pain.

33. Clinical Characteristics of Nociceptive Pain • Nociceptive pain may involve acute or chronic inflammation. • The physiology of inflammation is complex. • an immune component • retrograde release of substances from C polymodal nociceptors - “neurogenicinflammation” - involves the release from nerve endings of compounds such as • substance P, • serotonin, • histamine, • acetylcholine, • and bradykinin. • these substances activate and sensitize other nociceptors. • Prostaglandins produced by injured tissues also may enhance the nociceptive response to inflammation by lowering the threshold to noxious stimulation.

34. Neuropathic Pain and its Mechanisms • abnormal processing of the impulses either • by the peripheral • or central nervous system • may be caused by • injury (amputation and subsequent phantom limb pain) • scar tissue from surgery (back surgery high risk) • nerve entrapment (carpal tunnel) • damaged nerves (diabetic neuropathy) • unclear why depolarization and transmission of pain impulse are • spontaneous • and repetitive

35. Neuropathic Pain and its Mechanisms • It occurs as a result of injury to or dysfunction of the nervous system itself, peripheral or central • Deaferentation pain- form of neuropathic pain: a term implyingthat sensory deficit in the painful area is a prominent feature (anesthesia dolorosa) • Phantom pain-pain localised into non-existing organ (tissue) • Long-lasting painafter short-lasting pain stimulus

36. Clinical Manifestation of Pain • Acute Pain • Somatic • Visceral • Reffered pain • Somatic pain is superficialcoming from the skin or close to the surface of the body. • Visceral painrefers to pain ininternal organs, the abdomen, or chest. • Referred painis pain that is present in an arearemoved or distant from its point of origin. • Thearea of referred painis suppliedby the nerves from the same spinal segmentas the actual site of pain.

37. Different types of chronic somatic pain I. Nervous system intact 1. nociceptive pain 2. nociceptive - neurogenic pain (nerve trunk pain) II. Permanent functional and/or morphologicalabnormalitiesof the nervous system(preganglionic, spinal - supraspinal) 1.neurogenic pain 2. neuropathic pain 3. deafferentation pain

38. The most common chronic pain • Persistent low back pain • result of poor muscle tone, • inactivity, • muscle strain, • sudden vigorous exercise • 2. Chronic pain associated with cancer

39. The most common chronic pain • 3. Neuralgias- results from damages of peripheral nerves • Causalgia- severe burning pain appearing1 to 2 weeks after • the nerve injury associated with discoloration • and changes in the texture of the skin • in the affected area. • Reflex sympathetic dystrophies- occur after peripheral • nerve injury and is characterised bycontinuous • severe burning pain.Vasomotor changes are • present (vasodilatation vasoconstriction  • cool cyanotic and edematous extremities).

40. The most common chronic pain • 4. Myofascial pain syndromes- second most common causeof chronic pain. • include:myositis, fibrositis, myalgia,musclestrain, injury to the muscle and fascia • The pain is a result ofmuscle spasm, tenderness • and stiffness

41. The most common chronic pain • 5. Hemiagnosia • a loss of ability to identify the sourceof pain on one side • (the affected side) of the body. • Application of painful stimulito the affected side thus producesanxiety, moaning, agitation and distress but no attempt to withdrawalfromor push asidethe offending stimulus. • Emotional andautonomic responses to the painmy be intensified. • ● Hemiagnosia is associated with stroke that produces • paralysis and hypersensitivity to painful stimuli in the • affected side 6. Phantom limb pain - is pain that an individual feels in amputated limb

42. Pathophysiology of muscle pain (MP) • MP-a part ofsomatic deep pain, • it is commoninrheumathology and sports medicine • is rather diffuse and difficult to locate • MP is not a prominent feature of the serious progressive diseases • affecting muscle, e.g. the muscular dystrophies, denervation, • or metabolic myopathies,but it is a feature of • rhabdomyolysis • Muscles are relatively insensitive to pain when elicited by needle • prickor knife cut,but overlying fascia is very sensitive to pain. • Events, processes which may lead to muscular pain are: • metabolic events: • metabolic depletion ( ATP  muscular contracture) • accumulation of unwanted metabolities(K+, bradykinin)

43. Pathophysiology of visceral pain • Visceral pain: • Types- angina pectoris, myocardial infarction, acute • pancreatitis, cephalic pain, prostatic pain, • nephrlolytiatic pain • Receptors:unmyelinated C – fibres • For human pathophysiology the kinds of stimuli apt to • induce pain in the viscera are important. • It is well-known that the stimuli likely toinduce cutaneous • pain are not algogenicinthe viscera. This explains why in • the past the viscera wereconsidered to be insensitive • to pain

44. Adequate stimuliof inducing visceral pain: • 1. abnormal distention and contraction of the hollow • viscera muscle walls • 2. rapid stretching of the capsule of such solid visceral • organs as are the liver, spleen, pancreas... • 3. abrupt anoxemia of visceral muscles • 4. formation and accumulation of pain - producing • substances • 5. direct action of chemical stimuli (oesophagus, stomach) • 6. traction or compression of ligaments and vessels • 7. inflammatory processes • 8. necrosis of some structures (myocardium, pancreas)

45. Characteristic feature of true visceral pain a) it is dull, deep, not well defined, and differently described by the patients b) sometimes it is difficult to locatethis type of pain because it tends to irradiate c) it is often accompanied by a sense of malaise d) it induces strong autonomic reflex phenomena (much more pronounced than in pain of somatic origin) -diffuse sweating, vasomotor responses, changes of arterial pressure and heart rate, and an intense psychic alarm reaction -"angor animi" - in angina pectoris) • There are many visceral sensationthat are unpleasant but below the level of pain, e.g. feeling of disagreeable fullness or acidity of the stomach or undefined and unpleasant thoracic or abdominal sensation. • These visceral sensation may precedethe onset of visceral • pain

46. Refered visceral pain (transferred pain) • Refered pain= when an algogenic process affecting a visceralrecursfrequently or becomes more intense and prolonged, the locationbecomes more exact and the painfull sensation isprogressively felt inmore superficial structures • Refered pain may be accompanied by allodynia and cutaneousand muscular hyperalgesia • Mechanisms involved in refered pain creation: • convergence of impulses from viscera and from the skin • in the CNS: • Sensory impulses from the viscera create an irritable focusin the segment at which theyenter the spinal cord. • Afferent impulsesfrom the skin entering the same segment are therebyfacilitated, giving rise to true cutaneous pain. • senzitization of neurons in dorsal horn

47. Referedvisceral pain (transferred pain) • Painful visceral afferent impulsesactivate anterior horn motor cells to produce rigidity of themuscle (visceromotor reflexes) • A similar activation ofanterolateral autonomic cells induces pyloerection,vasoconstriction, and other sympathetic phenomena • These mechanisms, which in modern terms can be defined aspositive sympathetic and motor feedback loops, are fundamental in refered pain • It is clear that painful stimulation of visceral structures evokes avisceromuscular reflex,so thatsome muscles contract and become a new source of pain

48. Refered visceral pain (transferred pain)  It has been observed that thelocal anesthetic block of the sympathetic ganglialed to the disappearance, or at least to a markeddecrease, of refered pain, allodynia, hyperalgesia. In some conditions,reffered somaticpain is long-lasting, increases progressively, and is accompanied bydystrophy of somatic structures. Possible mechanisms: onset of self-maintainingvicious circleimpulses: peripheral tissue afferent fibers central nervous system peripheral tissue  somatic and sympathetic efferent fibres

50. Intricate conditions - in some types of pain, e.g. chest pain, is difficult to distinguish the true cause of pain because such kind of painmay be related to cervical osteoarthrosis, esophageal hernia, or cholecystitis. • It is difficult to ascertain whether these intricate conditions are due to a simple addition of impulses from different sources in the CNS or tosomatovisceral and viscerosomatic reflex mechanisms.