Physiology of pain pathways

PHYSIOLOGY OF PAIN PATHWAY AND ITS MODULATION. THE PHYSIOLOGICAL BASIS OF PAIN PATHWAY. ANAESTHETIC CONSIDERATION AND THE BASIS OF NERVE BLOCKS.

1. PHYSIOLOGY OF PAIN PATHWAYS AND ITS MODULATION DR HASSAN

2. What is Pain ??? The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage ."

3. Derived from Latin -“ Poena ” meaning Penalty/punishment from God . JCAHO declared pain as fifth vital sign (1999). Net effect of a complex interaction of the ascending and descending nervous systems involving biochemical, physiologic, psychological and neocortical processes.

4. Classification Of Pain:- Basis Types of pain Duration Acute Chronic Acute on chronic Cause Cancer Non cancer Mechanism Nociceptive (physiological) Neuropathic (pathological)

5. ACUTE PAIN:- P ain that is caused by noxious stimulation due to injury, a disease process, or the abnormal function of muscle or viscera . Two types of acute (nociceptive) pain somatic and visceral .

6. CLASSIFICATION OF ACUTE PAIN ACUTE PAIN SOMATIC ( somasthetic) VISCERAL (from viscera) e.g . angina pectoris , peptic ulcer, intestinal colic, renal colic, etc Superficial (from skin & subcutaneous tissue) e.g. superficial cuts/burns, etc. Deep (from muscles / bones/ fascia/ periosteum ) e.g. fractures/arthritis/fibrositis, rupture of muscle belly 6

7. CHRONIC PAIN:- Pain that extends 3 or 6 months beyond onset or beyond the expected period of healing. It may be nociceptive , inflammatory, neuropathic or functional in origin. A distinguishing feature is that psychological mechanisms or environmental factors frequently play a major role .

8. ACUTE VS CHRONIC PAIN Acute pain Chronic pain Onset & timing Sudden, short duration Resolves /disappears when tissue heals Insidious onset Pain persists despite tissue healing Signal Warning sign of actual or potential tissue damage Not a warning signal of damage False alarm Severity Correlates with amount of damage Severity not correlated with damage CNS involvement CNS intact- acute pain is a symptoms CNS may be dysfunctional- chronic pain is a disease Psychological effects Less, but unrelieved pain  anxiety and sleeplessness (improves when pain is relieved) Often associate with depression, anger, fear, social withdrawal etc.

9. Neuropathic Pain:- Definition : Pain that is caused by a lesion or disease of the somatosensory system (PNS or CNS) Peripheral Nerves Traumatic brachial plexus injury Diabetes Mellitus Carpel tunnel syndrome Post herpetic neuralgia Central Nervous System Central post stroke pain Neuropathic associated with spinal cord injury

10. MECHANISM OF NEUROPATHIC PAIN Nerve Damage/ Persistent Stimulation Rewiring Of Pain Circuits Both Anatomically & Biochemically Spontaneous Nerve Stimulation Autonomic neuronal stimulation Increased Discharge Of Dorsal Horn Neurons NEUROPATHIC PAIN Results in causing Finally leading to

11. NOCICEPTIVE VS NEUROPATHIC PAIN NOCICEPTIVE PAIN NEUROPATHIC PAIN Well localized Not well localized Sharp Worse with movement Burning Shooting Numbness Pins and needles Obvious tissue injury or illness Tissue injury may not be obvious Inflammation Nerve injury Changes in wiring Abnormal firing Loss modulation Physiological pain * Pathological pain

12. REFERRED PAIN Pain that is perceived at the site different from its point of origin but innervated by the same spinal segment . Usually applies to pain that originates from the viscera. Eg . The pain associated with MI commonly is referred to the left arm, neck & chest.

13. Convergence Theory : This type of referred pain occurs because both visceral and somatic afferents often converge on the same interneurons in the pain pathways. so we “ refer ” the location of visceral receptor activation to the somatic source even though in the case of visceral pain. The perception is incorrect . The convergence of nociceptor input from the viscera and the skin. REFERRED PAIN

14. BREAKTHROUGH PAIN:- Pain is intermittent, transitory & an increase in pain occurs at a greater intensity . Usually lasts from minutes to hours and can interfere with functioning. Eg . Neuropathic pain Lower back pain

15. What are the consequences of not treating acute pain ?

16. Adverse Effects Of Severe Acute Pain System Adverse effects Cardiovascular  Heart rate, BP Risk of m yocardial ischaemia Psychological Anxiety Insomnia Economic Increased in-hospital complications Prolonged length of stay in the hospital Increased health care utilization and costs Gastrointestinal ileus Chronic pain Higher risk of developing chronic pain e.g. post surgical pain syndrome System Adverse effects Psychological Anxiety Insomnia Economic Increased in-hospital complications Prolonged length of stay in the hospital Increased health care utilization and costs

17. Peripheral Receptor ( Nociceptor ) Nociceptors are free nerve endings that sense heat, mechanical and chemical tissue damage . Characteristic of nociceptors - High threshold for activation Encode the intensity of stimulation by increasing their discharge rates in a graded fashion. These receptive endings are widely distributed in- Skin,Dental pulp,Periosteum,Meninges .

18. Types :- Mechano nociceptors (pinch and pinprick) Silent nociceptors (inflammation) Polymodal mechanoheat nociceptors :- {M ost prevalent and respond to excessive pressure, extremes of temperature (> 42°C and < 18°C), and alogens (pain-producing substances) }.

19. Types of Fibers involved in Pain C fibers Small diameter, unmyelinated , slow conduction velocity Normally activated by noxious stimuli (responsible for secondary pain, normally burning , aching pain) Harrison’s Textbook of Medicine Vol 1, Part II, Chap 11 Aβ fibers Large diameter, myelinated , fast conduction velocity Mechanoreceptors normally activated by non-noxious mechanical stimuli (touch) Aδ fibers Medium diameter, myelinated , intermediate conduction velocity Normally activated by noxious stimuli (transmit sharp pain) 20

20. SOMATIC NOCICEPTORS:- Somatic nociceptors include those in skin and deep tissues (muscle, tendon, fascia and bone) whereas. Deep somatic nociceptors are less sensitive to noxious stimuli than cutaneous nociceptors but are easily sensitized by inflammation. 21

21. VISCERAL NOCICEPTORS:- visceral nociceptors include those in internal organs. Visceral organs are generally insensitive tissues that mostly contain silent nociceptors . Most organs such as the intestine are innervated by polymodal nociceptors that respond to smooth muscle spasm, ischemia and inflammation . These receptors generally don’t respond to cutting ,burning or crushing that occurs during surgery. 22

22. Noxious sensations can often be broken down into two components(DOUBLE PAIN):- A fast (sharp) and a slow (burning) sensation . The fast phase is mediated by myelinated fibers (A  ). The slow and delayed pain is mediated by unmyelinated fibers (C-fibers). This distinction has been used to explain the phenomenon of double-pain . 23

23. Afferent activity from these neurons enters the spinal cord between T1 and L2 . F ibers from the esophagus, larynx, and trachea travel with the vagus nerve to enter the nucleus solitarius in the brain stem . F ibers from the bladder, prostate, rectum, cervix and urethra, and genitalia are transmitted into the spinal cord via parasympathetic nerves at the level of the S 2–S4 nerve roots.

24. FAST PAIN Felt about 0.1 sec after a pain stimulus is applied. It is described as sharp pain, pricking pain, acute & electric pain. Fast sharp pain is not felt in most deeper tissues of the body. SLOW PAIN Usually begins after 1 sec or more and may range from seconds to minutes. Described as slow, burning, aching, throbbing, nauseous pain and chronic pain. Associated with tissue destruction.

25. Glutamate - Central Substance P - Central Brandykinin - Peripheral Prostaglandins – Peripheral Aspartate Pain Initiators Serotonin Endorphins Enkephalins Dynorphin GABA Glycine Pain Inhibitors NEUROTRANSMITTERS

26. THREE NEURONS DUAL ASCENDING PATHWAY 27

27. First Order Neuron:- Pseudounipolar cell (dorsal root ganglion) , divides into central and peripheral branch. Impulses are transmitted by A δ fibre or C fibres . Cell bodies located in dorsal root ganglia . These impulses are transmitted through the axons to spinal cord. axons of first order neurons may synapse with interneurons , sympathetic neurons and ventral motor neurons.

28. SECOND ORDER NEURONS Second order neurons consist of - Nociceptor specific primarily in LAMINA I W ide Dynamic Range(WDR) neurons primarily in LAMINA V Nociceptive specific neurons serve only noxious stimuli, but WDR neurons also receive non noxious afferent input from A β , A ∂ and C fibers. Cell body in the Spinal Cord or medulla oblongata.

29. Spinal cord grey matter was divided by REXED into ten lamina . The first six lamina , which make up the dorsal horn, receive all afferent neural activity, and represent the principal site of modulation of pain by ascending and descending neural pathways .

30. Lamina II also called the SUBSTANSIA GELATINOSA ,contains many interneurons It is believed to be a major site of action for opioids . Lamina V contains WDR neurons ,responds to both noxious and non noxious sensory input and receives both visceral and somatic pain afferents . Thus responsible for referred pain .

31. THIRD ORDER NEURON:- located in the thalamus and send fibers to somatosensory areas 1 and 2 in the postcentral gyrus of the parietal cortex and the superior wall of the sylvian fissure respectively. Perception and discrete localization of pain take place in this cortical areas.

32. SPINOTHALAMIC TRACT The axons of most second order neurons cross the midline close to their level of origin to the contralateral side before they form the spinothalamic tract They s end their fibres to the thalamus ,the reticular formation, the nucleus raphe Magnus and the peri aqueductal grey matter . The tract can be divided into a lateral and medial tract . 34

33. The lateral spinothalamic tract projects mainly to the ventralposterolateral nucleus of the thalamus and carries discriminative aspects of the pain such as location ,intensity and duration and Thermal sensation . The medial spinothalamic tract projects to the medial thalamus and is responsible for mediating the autonomic and unpleasant emotional perception of the pain, Touch and Pressure . 35

34. Although most neurons from the lateral thalamic nuclei project to the primary somatosensory cortex . T hose from the intralaminar and medial nuclei project to the anterior cingulate gyrus and mediate the suffering and emotional components of pain .

35. ALTERNATE PAIN PATHWAYS Pain fibres ascend diffusely ipsilaterally and contralaterally, hence some patients continue to receive pain following ablation of the contralateral spinothalamic tract. The spinoreticular tract is thought to mediate arousal and autonomic responses to pain. The spinomesencephalic tract may be important inactivating anti-nociceptive because it has some projection to the periaqueductal grey matter .

36. The spinohypothalamic and spinotelencephalic tract activates the hypothalamus and evoke emotional behavior . The spinocervical tract ascends uncrossed to the lateral cervical nucleus which relays the fibres to the contralateral thalamus . This tract is likely a major alternative pathway for pain.

37. MECHANISMS OF PAIN Pain sensation involves a series of complex interactions between peripheral nerves & CNS. Pain sensation is modulated by excitatory and inhibitory NTs released in response to stimuli. Sensation of pain is composed of :-- - Transduction;-Transmission; - Modulation;-Perception

38. MODULATION OF PAIN

39. Modulation of pain occurs - peripherally at the nociceptors , - spinal cord - supraspinal structure . This modulation can either inhibits or facilitates pain. The major site of modulation is dorsal horn of spinal cord. 42

40. PERIPHERAL MODULATION Nociceptors and their neurons display sensitization following repeated stimulation . It occurs by two mechanisms: PRIMARY HYPERALGESIA (exaggerated response to pain at site of injury ) SECONDARY HYPERALGESIA (response to pain outside the site of injury ) 43

41. PRIMARY HYPERALGESIA Sensitization of nociceptors commonly occurs with injury and following application of heat . Primary hyperalgesia is mediated by the releaseof alogens from damaged tissues:- 1) Bradykinin - macrophages 2) Histamine- platelets and mast cells 3) Serotonin 4) Prostaglandin 44

42. Innocuous/Noxious stimulus Reduced Transduction Threshold primary sensory neuron central neuron Peripheral Sensitization Primary hyperalgesia Primary heat allodynia Inflammation

43. Prostaglandins:- Prostaglandins are produced following tissue damage by the action of phospholipase A 2 on phospholipids released from cell membranes to form arachidonic acid . The cyclooxygenase (COX) pathway then converts the latter into endoperoxides , which in turn are transformed into prostacyclin and prostaglandin E 2 (PGE 2 ). PGE 2 directly activates free nerve endings , whereas prostacyclin potentiates the edema from bradykinin . 46

44. Pharmacological agents such as acetylsalicylic acid (ASA, or aspirin), acetaminophen , and nonsteroidal antiinflammatory drugs (NSAIDs) produce analgesia by inhibition of COX. A nalgesic effect of corticosteroids likely the result of inhibition of prostaglandin production through blockade of phospholipase A 2 activation . 47

45. SECONDARY HYPERALGESIA (Neurogenic inflammation) It is manifested by the “ triple response ’’ of a red flush at the site of injury(flare), local tissue edema, and sensitization to noxious stimuli. Secondary hyperalgesia is primarily due to release of s ubstance P (and probably CGRP) from collateral axons of the primary afferent neuron. 49

46. Substance P Substance P is an peptide that is synthesized and released by first order neurons both peripherally and in the dorsal horn . It degranulates histamine and 5-HT, vasodilates blood vessels, causes tissue edema, and induces the formation of leukotrienes. The compound capsaicin , degranulates and depletes s ubstance P . When applied topically, capsaicin diminishes neurogenic inflammation and appears to be useful for some patients with postherpetic neuralgia . 50

47. Tissue injury causes release of chemicals. They sensitize or activate receptors. Neurons release substance P , which stimulates mast cells and blood vessels. Histamine released from mast cells and bradykinin released from blood vessels add to pain stimulus. 51

48. What are the Modulators Of peripheral Sensitisation ?

49. Noxious stimulus Increased Pain Responsiveness primary sensory neuron central neuron Central Sensitization Secondary hyperalgesia Tactile allodynia Irritants Tissue damage Inflammation

50. CENTRAL MODULATION FACILITATION T hree mechanisms are responsible for central sensitization in the spinal cord:- (1 ) Wind up and sensitization of second order neurons . WDR neurons increase their frequency of discharge with same repeated stimuli and exhibit prolonged discharge even after afferent C fiber input has stopped. 55

51. (2 ) Receptor Field Expansion Dorsal horn neurons increase their receptive fields such that adjacent neurons become responsive to stimuli to which they were previously unresponsive . ( 3) Hyperexcitability of flexion reflexes 56

52. Neurochemical Mediators Of Central Sensitization :- Substance P Vasoactive Intestinal Peptide (VIP) Cholecystokinin (CCK) Angiotensin  L-glutamate L-aspartate 57

53. Mechanism Of Action:- These substances trigger changes in membrane excitability by interacting with G protein–coupled membrane receptors on neurons, activating intracellular second messenger s, which in turn phosphorylate substrate proteins . A common pathway is an increase in intracellular calcium concentration . 58

54. Glutamate and aspartate receptors play an important role in wind up via activation of NMDA and non NMDA receptor mechanism. These amino acids are believed to be largely responsible for the induction and maintenance of central sensitization.

55. The spreading flare of pain, allodynia , and hyperalgesia is explained by activated NMDA receptors in the dorsal horn which increases calcium conductance , leading to activation of protein kinases and to activation of the enzyme nitric oxide synthase , leading to nitric oxide synthesis. These actions also depend on activation of secondary messenger systems

56. Both prostaglandins and nitric oxide facilitate the release of excitatory amino acids in the spinal cord. Thus, COX inhibitors such as ASA and NSAIDs also appear to have important analgesic actions in the spinal cord.

57. What are the Modulators Of Central Sensitisation ?

58. INHIBITION SEGMENTAL INHIBITION Activation of large afferent fibers inhibits WDR neuron and spinothalamic tract activity. Moreover, activation of noxious stimuli in noncontiguous parts of the body inhibits WDR neurons at other levels; ie, pain in one part of the body inhibits pain in other parts . These two observations support a gate theory for pain processing in the spinal cord . 64

59. Gate Theory of Pain Melzack & Wall (1965). The gate = spinal cord interneurons that release opioids . The synaptic junctions between the peripheral nociceptor fiber and the dorsal horn cells in the spinal cord are the sites of considerable plasticity . A “ GATE ” can stop pain signals arriving at the spinal cord from being passed to the brain. 65

60. The Gate-Control Theory ofPain Figure 10-12a 66

61. The Gate-Control Theory of Pain Figure 10-12b 67

62. The Gate-Control Theory of Pain Figure 10-12c 68 ACUPUNCTURE AND TENS

63. The introduction of the gate control theory in 1965 [Melzack &Wall 1965] has acted as a catalyst for the global proliferation of the different techniques for pain alleviation based on afferent stimulation, such as transcutaneous electric nerve stimulation [TENS] and ACUPUNTURE.

64. M echanisms O f A ction O f TENS Afferent activity set up by TENS inhibits nociceptive transmission in the spinal cord through pre as well as post synaptic inhibitory mechanisms . Not only the spinal cord but also the thalamic regions may be involved. TENS stimulation may activate mechanisms at both spinal segment and supraspinal centres . 70

65. M echanism O f A ction O f ACUPUNTURE Acupuncture is a mode of peripheral stimulation based on the activation of peripheral receptors, sensory nerve fibers or both . While a needle can mechanically stimulate nerve fibers of many types, the pain relieving effect of acupuncture has been attributed to the activation of A δ and possibly C fibers . 71

66. SUPRA SPINAL INHIBITION Several supraspinal structures send fibers down the spinal cord to inhibit pain in the dorsal horn. Important site of origin for these pathways include the periaqueductal grey, reticular formation and nucleus raphe Magnus(NRM ) Stimulation of the periaqueductal gray area in midbrain produces widespread analgesia in humans . Axons from these tracts act presynaptically on primary afferent neurons and postsynaptically on second-order neurons (or interneurons). 72

67. These pathways mediate their antinociceptive action via α 2 -adrenergic, serotonergic, and opiate ( μ ,∂ and k ) receptor mechanisms . The role of monoamines in pain inhibition explains the analgesic action of antidepressants that block reuptake of catecholamines and seroto nins . 73

68. COGNITIVE MODULATION Cognitive modulation of pain involves the patients ability to relate a painful experience to another event . E xample if a patient in pain concentrate on separate and unrelated images it is possible to decrease the effects of painful sensation. 74

69. PSYCOLOGICAL MODULATION Relaxation – systematic relaxation of the large muscle groups. Hypnosis – effective analgesic, state of inner absorption and focused attention. Reduces pain by distraction, altered pain perception, increased pain threshold. 75

70. NON-PHARMACOLOGICAL MODULATION Massage reduces pain, including release of muscle tension, improved circulation, increased joint mobility, and decreased anxiety . Physical modalities Cold for acute injuries in first 48 hours, to decrease bleeding or hematoma formation, edema, and chronic back pain. Heat works well for relief of muscle aches and abdominal cramping . 76

71. Neurostimulation Neurostimulation uses a small implanted system to send precisely controlled mild electrical impulses to the nervous system –Typically the dorsal horn in the Spinal Cord The patient feels the Neurostimulation as a pleasant tingling sensation, also known as “ paraesthesias ” Neurostimulation is divided into subcategories based upon the type of nerve that is being stimulated. Spinal cord stimulation (SCS ) involves stimulation of the dorsal column of the spinal cord, Peripheral nerve stimulation (PNS ) involves stimulation of a specific nerve branch. SCS is the most effective technique for chronic pain management . SCS PNS 77

72. Intracerebral Stimulation Method of Deep Brain Stimulation . Used for intractable cancer pain , intractable neuropathic pain . for nociceptive pain e lectrodes are implanted into the periaqueductal and periventricular gray areas. For neuropathic pain the electrodes are placed into specific sensory thalamic nuclei . 78

73. “ Those who do not feel pain seldom think that it is felt ” Dr. Samuel Johnson (1709-1784 ) THANK YOU THANK YOU