PATHOPHYSIOLOGY AND MANAGEMEMENT OF PAIN

DR. SUBODH KUMAR MAHTO,
DEPT. OF MEDICINE
PGIMER,DR.RML HOSPITAL.
NEW Delhi

1. PATHOPHYSIOLOGY AND MANAGEMEMENT OF PAIN DR . SUBODH KUMAR MAHTO, DEPT . OF MEDICINE PGIMER,DR.RML HOSPITAL. NEW Delhi

2. OBJECTIVES INTRODUCTION NEUROANATOMY PATHOPHYSIOLOGY TYPES OF PAIN HISTORY ASSESSMENT OF PAIN MANAGEMENT

3. Pain is an unpleasant , sensory and emotional experience usually associated with noxious stimuli Pain is Subjective Protective And it is modified by developmental, behavioral personality and cultural factors

4. The word “pain” is derived from the Latin word “ poena ” meaning fine, penalty, or punishment. Pain Threshold – level of noxious stimulus required to alert an individual of a potential threat to tissue Pain Tolerance – amount of pain a person is willing or able to tolerate

5. A person experience pain through Sensory- discriminative system : this processes the information about the strength, intensity, quality, spatial, temporal aspects of pain. Motivational- affective system : It determines the individuals avoidance- approach behavior. Cognitive –evaluative system : It overlies the individuals learned behavior concerning the experience of pain. It may block, modulate or enhance the perception of pain.

6. Types of nerve fibers

7. Large fibre Small fibre Unmyelinated Myelinated Slow conducton Fast conduction Responds to thermal chemical and mechanical stimuli Responds to mechanical and mechanothermal stimuli Produces sensation of sharp pain( epicritic pain) Produces sensation of dull pain( protopathic pain)

8. Neuroanatomy of pain The areas of nervous system responsible for pain pathways are: Afferent pathways CNS efferent pathways

9. Pain pathway Afferent pathways terminate in the dorsal horn of the spinal cord(1 st order neuron) The nerve fibers from the dorsal root ganglia enter the spinal cord through dorsal root and send branches 1-2 segments up and down the spinal cord. Second order neurons transmit the impulse from the substantia gelatinosa and lamina through the ventral and lateral horn crossing the same or adjacent segment to the other side of the cord.

10. Pain pathway The impulse is then carried through the spinothalamic tract to the somatosensensory cortex, frontal cortex and cingulate gyrus . There are two divisions of spinothalamic tract which transmit in different areas of brain. Neospinothalamic tract Paleospinothalamic tract Neospinothalamic tract projects to VPL nucleus of thalamus. Paleospinothalamic tract projects to central nuclei of Thalamus.

11. PHYSIOLOGY OF PAIN

12. Peripheral mechanisms of pain

13. Mediators

14. Neurotransmitters Pain Initiators Glutamate - Central Substance P - Central Brandykinin - Peripheral Prostaglandins - Peripheral Pain Inhibitors Serotonin Endorphins Enkephalins Dynorphin

15. Sensitization When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activation is lowered, and the frequency of firing is intensified. mediators - bradykinin , nerve-growth factor, and leukotriene Sensitization occurs At peripheral nerve terminal ( peripheral sensitization) In damaged or inflamed tissues an increase in the production, transport, and membrane insertion of chemically gated and voltage-gated ion channels occurs. At the dorsal horn of the spinal cord ( central sensitization).

16. Pain modulation pathway

17. Endogenous Opioid Systems

18. Gate-Control Theory – Ronald Melzack (1960s) Described physiological mechanism by which psychological factors can affect the experience of pain. Neural gate can open and close thereby modulating pain. Gate is located in the spinal cord in SG. When the gate is closed signals from small diameter pain fibres do not excite the dorsal horn transmission neurons. When the gate is open pain signals excite dorsal horn transmission cells

19. Gate control theory

20. Three Factors Involved in Opening and Closing the Gate The amount of activity in the pain fibers. The amount of activity in other peripheral fibers. Messages that descend from the brain.

21. Conditions that Open the Gate Conditions That Close the Gate Physical conditions Extent of injury Inappropriate activity level Emotional conditions Anxiety Tension Depression Mental Conditions Focusing on pain Boredom Physical conditions Medications Counter stimulation (e.g., heat, massage) Emotional conditions Positive emotions Relaxation, Rest Mental conditions Intense concentration or distraction Involvement and interest in life activities

22. Types Pain can be categorized according to inferred pathology: Nociceptive pain Somatic - Skin, tendons, ligaments, bone etc.. Visceral – Organs, cavity linings Neuropathic pain- stimuli abnormally processed by the nervous system. Ex- diabetic neuropathy, phantom limb pain. Referred pain By duration: Acute Chronic

23. Somatic pain Source: Skin, muscle, and connective tissue Examples: Sprains, headaches, arthritis Description: Localized, sharp/dull, worse with movement or touch Pain med: Most pain meds will help, if severe, need a stronger medication

24. Visceral pain Causes Abnormal distention and contraction of the hollow viscera muscle walls Rapid stretching of the capsule Abrupt anoxemia Direct action of chemical stimuli (oesophagus) Traction or compression of ligaments and vessels Inflammatory processes and Necrosis of some structures (myocardium)

25. Visceral pain Characteristic features of visceral pain It is dull aching, deep, not well defined, and differently described by the patients Difficult to locate Induces strong autonomic reflex phenomena Much more pronounced than in pain of somatic origin (psychic alarm reaction - " angor animi " - in angina pectoris)

26. Referred pain Figure 10-13b Skin (usual stimulus) Kidney (uncommon stimulus) Primary sensory neurons Secondary sensory neuron Ascending sensory path to somatosensory cortex of brain (b)

27. Acute pain It is a protective mechanism that alerts the individual to a condition that is immediately harmful to the body. Which leads to the following responses: Increased HR & RR Elevated BP Pallor or flushing , dilated pupils Psychological and behavioural response to acute pain Fear General sense of unpleasantness Anxiety

28. Chronic pain It is persistent or intermittent usually defined as lasting at least 3- 6 months The cause is often unknown, often develops insidiously, v ery often is associated with Depression. Chronic pain produces significant behavioural and psychological changes: depression an attempt to keep pain - related behaviour to a minimum sleeping disorders preoccupation with the pain tendency to deny pain

29. Common pain syndrome Neuropathic pain Peripheral nerve pain Central pain CRPS Pain in association with psychiatric disease Chronic pain of indeterminate cause Cancer pain Post stroke pain syndrome Cervicogenic headache Low back pain Migraine Phantom limb pain. Neuralgias

30. Neuropathic pain Dysesthesia - Any abnormal sensation described as unpleasant by the patient  Hyperalgesia - Exaggerated pain response from a normally painful stimulus Hyperesthesia ( hypesthesia ) - Exaggerated perception of touch stimulus  Allodynia - Abnormal perception of pain from a normally nonpainful mechanical or thermal stimulus Analgesia - Reduced perception of pain stimulus  Paresthesia - Mainly spontaneous abnormal sensation that is unpleasant; usually described as "pins and needles" 

31. Mechanism of neuropathic pain Denervation hypersensensitivity : Primary afferents are highly sensitive to mechanical stimulation and may generate impulses in the absence of stimulation. Sodium channels accumulate at the regenerating neuroma and all along the axon after nerve injury, and that this gives rise to ectopic and spontaneous activity of the sensory nerve cell and its axons.

32. Complex regional pain syndrome Old terminology - Casualgia . It is a painful condition that includes regional pain, sensory changes, abnormal sudomotor activity , skin changes, edema following an inciting event such as trauma. Commonly seen in females in 3 rd n 4 th decade Precipitating factors: -Fracture -Strain/ sprain -Post surgery -Crush injury

33. Types CRPS I- No definable nerve lesion CRPS II- Involves nerve lession . C LINICAL FEATURES: Excruciating pain Edema of affected limbs. Autonomic dysfunction. Motor dysfunction.

34. Cancer pain Mechanism Direct tumour invasion of local tissues. Metastatic bone pain. Osteoporotic bone and degenerative joint pain in older people. Visceral obstruction. Nerve compression and plexus invasion. Ischaemia . Inflammatory pain. Chemotherapy induced neuropathy, paraneoplastic neuropathy and arthropathy . Post-surgical pain and radionecrosis .

35. Post stroke pain syndrome Patients complaints of spontaneous severe paroxysmal and burning type pain sensation. It has been postulated that damaged sensory pathways or damage to the central inhibitory may be responsible for pain. Following stroke about 40- 60 % patients develop shoulder pain. It usually improves following physiotherapy.

36. Phantom limb pain Phantom = ghost. Phantom limb feels real. Sometimes amputees try to walk on their phantom limb. Several studies have shown that 75% of patients with PLP develop pain within the first few days after amputation. Usually intermittent; only few patient’s are in constant pain. Located in distal parts of the missing limb. Mechanism- stump neuroma , spinal plasticity , cerebral reorganization. Treatment – multi disciplinary approach. TCAs, TENS, Mirror box therapy etc..

37. Cerebral reorganization.

38. Mirror box therapy Persons with amputated limb use either a mirror or mirror box to reflect an image of the intact limb. It is hypothesized that this works by preventing cortical restructuring

39. History Site of pain Primary location Radiation Circumstances associated with pain onset including details of trauma or surgical procedures Character of pain - Sensory descriptions eg sharp, throbbing, aching Intensity of pain At rest Movement

40. Temporal factors Duration Current pain, during last week Aggravating or Relieving factors Associated symptoms ( eg nausea) Effect of pain on activities and sleep Treatment history Current and previous medications Other treatment eg . transcutaneous electrical nerve stimulation

41. Assesment of pain McGill pain questionnaire Part I - To localize the pain Part II- Incorporates the visual analogue scale. Part III- The pain rating index. It includes 20 categories and 76 descriptions.

42. VISUAL ANALOG SCALE

43. Neuropathic pain questionnaire

44. Treatment

45. Classes of medication Non narcotic analgesics Narcotics analgesics Anti depressants Anti convulsants Anti arrythmics Muscle relaxants Complementary and alternate medicine: Hyperbaric oxygen. Acupuncture. Electrical stimulation devices. Trigger point injections.

46. Pain ladder approach

47. Adjuvant therapy ‐ Tricyclic anti‐depressants Anticonvulsant medications – Gabapentin , Pregabalin , and Carbamazepine NSAIDs (non‐steroidal anti‐ inflammatories ) ‐ can be used as co‐analgesics and are useful in reducing inflammation

48. NSAIDS Drugs dosages Adverse effects Uses Acetylsalicylic acid 650 mg PO Reye’s syndrome in children Avoid in women in late pregnancy, kidney or liver disease, asthma, high blood pressure, or bleeding disorders. Peptic ulcer. Headache, muscle ache, backache, fever, and arthritis menstrual cramps . Acetaminophen 650 mg PO May be harmful for people with kidney or liver disease or those who drink alcohol heavily Headache, muscle ache, backache, fever, and arthritis. Ibuprofen 400 mg PO May be harmful for people with kidney or liver disease, asthma, bleeding disorders, or those who drink alcohol heavily. Headache, muscle ache, fever, sprains, menstrual cramps, backache, and arthritis pain. Naproxen 250-500 mg PO Not recommended for children without a health care professional’s supervision Cardio vascular risks and G.I toxicity Headache, muscle ache, fever, menstrual cramps, backache, arthritis pain and inflammation.

49. Drugs Dosages Adverse effects uses Celecoxib 100-200 mg PO Generally well-tolerated Muscle aches, joint pain, arthritis, pain and inflammation Ketorolac 15-60 IM/IV May be harmful for people with kidney or liver disease or those who drink alcohol heavily. Not recommended for children Headache, muscle ache, fever, menstrual cramps, cold or flu aches

50. OPIOIDS Most potent analgesics It produces analgesia by activating pain-inhibitory neurons and directly inhibit pain-transmission neurons. Modes of delivery: Oral IV and IM Nasal spray Transdermal & transmucosal patch Sublingual route Suppository Epidural & Intrathecal route

51. Short acting opiods Peak effect - 1–2 hrs Duration – 4 hrs Uses Acute pain - in moderate to severe chronic pain. Rescue medication for break through pain. Eg – Codeine( 30- 60 mg PO QID) Tramadol (50- 100 mg PO QID) Morphine( 30 mg PO QID , 5 mg 4 hourly IV)

52. Long acting opiods Steady pain relief for 12 hours. Used for chronic pain. Eg - Hydromorphone (2-4 mg PO QID) Methadone(5-20 mg PO/IV TDS) Buprenorphine Fentanyl ( 25-100 µg/hour transdermal patch for 72 hour) Oxy codone (5-10 mg POQID)

53. What Dose to Give an Opioid Naïve Patient? For opioid naïve start at a morphine equivalent of 2 to 5 mg IV or 10 mg PO Dose escalation should be more than 30 to 50% of base dose to observe a meaningful change. Frequency of parenteral dosing can be as often as every 15 to 30 minutes until adequate analgesia is achieved

54. Opiod Analgesic Usual Starting Dose Drug Equianalgesic parenteral dose Starting iv dose iv:po ratio Starting dose po /transdermal Duration of Action Morphine 10 mg Bolus dose=0.05-0.1 mg /kg q 2-4 hours Continuous infusion=0.01-0.04 mg/kg/hr 1:3 0.15-0.3 mg/kg/dose q 4 hours 3-4 hours Hydromorphone 1.5 mg 0.015-0.02 mg/kg q 4 1:5 0.06 mg/kg q 3 to 4 hours 2-4 hours Oxycodone 5-10 mg N/A 0.1-0.2 mg/kg q 3 to 4 3-4 hours Fentanyl 100mcg 1 to 2 mcg/kg/hr as continuous infusion 25 mcg patch/hour 72 hours Methadone 10 mg 0.1 mg/kg q 4 to 8 hours 1:2 0.2 mg/kgq 4 to 8 hours 12 to 150 hours

55. Opioid -responsiveness – It is the ability to achieve pain relief with evidence of improved function without the development of unmanageable or intolerable side effects. Addiction- Compulsive use and preoccupation with the drug and its supply. Inability to consistently Control the quantity used. Craving the psychological effects of the drug. Continued use despite adverse effects from the drug.

56. Physical dependence - manifested by a withdrawal syndrome which includes Sleeplessness - Anxiety and agitation – Anxiolytics Stomach cramps - Dicyclomine Body aches (flu-like symptoms) - Anti-inflammatory pain relievers Muscle cramps - Muscle relaxants Nausea, vomiting, diarrhea, sweating and skin crawling Alternative opioids - during detoxification. Methadone Buprenorphine decrease by 10-20 % per week. Tramadol

57. Therapeutic monitoring Four A’s: A nalgesia (pain relief – often measured by a 10-point rating scale). A ctivities of daily living (physical, psychological, and social functioning). A dverse effects. A berrant or abnormal drug-related behaviors.

58. Is the person’s day centered around taking medication? Does the person take pain medication only on occasion, perhaps three or four times per week? Have there been any other chemical (alcohol or drug) abuse problems in the person’s life? Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? Is the person in pain able to function (work, household chores, and play) with pain medication in a way that is clearly better than without?

59. Three Complications of Chronic High Dose Opioid Therapy Neurotoxicity Tolerance Opioid Induced Hyperalgesia Tolerance Due to prolonged use of opiates It occurs when there is a progressive lack of response to a drug requiring increased dosing Higher doses of opiates are required to elicit same amount of analgesia

60. Opioid -induced Neurotoxic ity Mediated through non- opioidergic mechanisms Due to neuro -excitatory metabolites of opioids (morphine-6-glucuronide, oxymorphone-3-glucuronide) Causes spectrum of symptoms ranging from mild confusion or drowsiness to hallucinations, delirium and seizures Typically develops on initiation to a week of initiating an opioid or reaching a dose that causes metabolite buildup.

61. Opioid Induced Hyperalgesia Clinical features- Hyperalgesia , allodynia,Myoclonus , Confusion etc.. Related to but different from tolerance Different from opioid neurotoxicity Has been observed and documented in literature since 19 th century (Observed by Albutt in 1870) Treatment – dose reduction, Utilize NMDA antagonists, Interventional pain techniques or neurosurgical procedures

62. Anti Depressants Tricyclic anti depressants: Amitriptyline (25- 300 mg PO) Imipramine (75-400 mg PO) Desipramine (50- 300 mg PO) Nortriptyline (40- 150 mg PO) Adverse effects- Dry mouth, Blurred vision, Constipation, Difficulty urinating , Worsening of glaucoma, Palpitations, Wt gain and hypotension.

63. SSRIs(Selective Serotonin reuptake Inhibitors Examples Fluoxetine Sertraline Citalopram Escitalopram Fewer side effects and are less sedating than TCAs. Effective for prevention of migraine but less effective for other types of pain.

64. SNRIs Selective Serotonin and Nor-adrenaline Reptake Inhibitors Duloxetine (30- 60 mgPO ) Venlafaxine (75-400 mg PO) Milnacipran (25-100 mg PO) Serotonin syndrome. Antidepressant medications included in this warning are fluoxetine , sertraline , paroxetine , escitalopram , duloxetine , milnacipran , and venlafaxine . Migraine drugs include Triptans .

65. ANTI CONVULSANT DRUGS Gabapentin ( 600-1200 mg PO) Neuralgia Pregabalin (150- 600 mg PO) Postherpetic neuralgia, diabetic neuropathy, and fibromyalgia Carbamazepine (200- 300 mg PO QID) Trigeminal neuralgia Valproic acid (400- 600 mg PO OD) Prophylaxis of migraine Lacosamide (100 mg PO BD) Diabetic neuropathic pain Topiramate (25- 200 mg PO OD) Prophylaxis of migraine

66. SODIUM CHANNEL BLOCKING & ORAL ANTI-ARRHYTHMIC AGENTS Drugs commonly used are Lidocaine Flecainide Mexilitine Lidocaine has anti- arrhythmics with local anesthetic properties and it is occasionally used in refractory pain. These drugs interrupt premature firing of damaged nerves hence less capability of the nerve to trigger pain.

67. TOPICAL PAIN RELIEVERS Topical agents work locally and must be applied directly over the painful area Transdermal drugs have effects throughout the body and work when applied away from the area of pain Transdermal medication in a patch is absorbed through the skin by the bloodstream over a period of time. Eg – EMLA(Eutectic Mixture of Local Anesthetic; contains lidocaine and prilocaine ) L.M.X.4 (contains lidocaine 4%), Used primarily prior to painful procedures such as while lumbar puncture (spinal tap), and wart removal.

68. DRUGS USED AS MUSCLE RELAXANTS IN CHRONIC PAIN Carisoprodol (200 mg PO BD) Metaxalone (800 mg PO TDS) Chlorzoxazone (250 – 750 mg PO TDS) Baclofen ( 5 mg PO TDS) Tizanidine (4 mg PO TDS)

69. Botulinum toxins Botulinum toxins have been found to be effective in decreasing tone in overactive (hypertonic) muscles It is used for the treatment of the postural abnormalities and pain associated with dystonias . Ex- torticollis . Onabotulinumtoxin A is additionally approved by FDA to prevent headaches in adults with chronic migraine

70. Interventional therapy Intra articular steroid injections Viscosupplementation Spinal cord stimulation Implanted targeted intra thecal drug delivery Epidural analgesia Nerve plexus block

71. Spinal cord stimulation: Chronic radicular pain CRPS type I and II Painful peripheral neuropathies Peripheral vascular disease not amenable to Surgical by pass or conventional therapy. Central pain Phantomb limb pain.

72. Patient control analgesia: Indications: Post operative pain management. Trauma Burns Sickle Cell Crisis

73. Epidural analgesia: Indication: Disk herniation , degeneration, and spondylosis Radiculopathy - cervical thoracic, lumbosacral Spinal stenosis and facet arthropathy Pelvic pain - Aid with pelvic floor physical therapy Labor epidural analgesia

74. TENS TENS is a method of treating pain that is non-invasive and does not use pharmaceuticals. The TENS device sends impulses through the skin that stimulate the nerve Indications: Chronic post operative pain Chronic post traumatic pain

75. Herbal Medications

76. Rules of thumb Use the lowest effective dose by the simplest route. Start with the simplest single agent and maximize it’s potential before adding other drugs. Use scheduled, long-acting pain medications for constant or frequent pain. Treat breakthrough pain with with parentral , short-acting medication

77. Source of information Harrison 18 th edition Bradley neurology ACPA guidelines for pain management WHO guidelines for pain management

78. “Pain is a more terrible lord of mankind than death itself.” Albert Schweitzer THANK YOU