Pain and Analgesic Pathways

1. Pain and Analgesic Pathways Robert B. Raffa, Ph.D. Professor of Pharmacology Temple University School of Pharmacy & School of Medicine

2. Current Knowledge • Different ‘types’ of pain, not just different degrees of pain • Multiple chemical mediators of pain • Optimal therapy matches the analgesic(s) with the type(s) of pain

3. Types of Pain ‘Nociceptive’ • normal physiology (mechanisms known) • beneficial • treated with conventional analgesics (NSAIDs, acetaminophen, opioids) • unrelieved, it becomes deleterious ‘Neuropathic’ • aberrant physiology (mechanisms unknown) • poor quality of life • difficult to treat

4. cortex Normal Pain Pathways thalamus • Tissue injury • histamine • bradykinin • etc. lateral spino- thalamic tract dorsal root ganglion primary afferent Fig 3-25

5. Normal Pain Pathways PAG (periaqueductal gray) locus ceruleus raphe nuclei Enkephalin-containing interneuron Fig 3-25

6. Primary (1o) Afferents ‘sharp’localized ‘dull’vague Ad C

7. REVIEW QUESTION Which is/are TRUE? • Pain can be beneficial • Pain can be harmful • Nociception is normal • C-fibers transmit sharp, localized pain

8. Multiple types in injury In many injuries and chronic disorders (e.g., arthritis, cancer), there are multiple sources and types of tissue injury and, thus, multiple sources and causes (‘types’) of pain.

9. Current Analgesics Options • NSAIDs: 1970’s • opioids: 1970’s • tramadol: 1980’s & 1990’s • COX-2 inhibitors: 1990’s • acetaminophen: unknown • combinations • adjuncts

10. WHO Analgesic ‘Ladder’ Step 3 Strong opioids (e.g., morphine) with or without non-opioids Severe Moderate Mild Step 2 Weak opioids (e.g., codeine) with or without non-opioids Step 1 Non-opioids (e.g., NSAIDs, acetaminophen = paracetamol)

11. Underutilization and Control

12. NSAIDs Aa PGs COX Sites of Action

13. Sites of Action Local Anesthetics (voltage-gated Na+ channels)

14. Sites of Action Opioids (m, d, k)

15. Sites of Action Acetaminophen ?

16. REVIEW QUESTION The WHO analgesic ladder is a guide to the proper dose of analgesic: • True • False

17. ‘Resistant’ Pains • Migraine • Neuropathic pain • Sickle cell pain • etc.

18. Migraine • Periodic, pulsatile headaches. Familial disorder that usually begins in childhood or early adulthood and tends to decrease in frequency in later life. • Possible causes: (1) humoral disturbance that alters vascular responsiveness which in turn elicits pain, or (2) a neurological disturbance in the meninges, from which pain and vasomotor changes result. More specifically, could be due to vascular changes triggered by 5-HT release, to a neuronal abnormality, or excess activity of peptidergic nerve terminals in meningeal vessels. The release of 5-HT also leads to local inflammatory response and the release of other mediators (e.g., bradykinin and prostaglandins) that act on nociceptive nerve terminals, causing pain and also releasing neuropeptides which further reinforce and prolong the pain. Afferent nerve terminals in blood vessel walls may become hypersensitive to vascular distension, thus accounting for the fact that many anti-migraine drugs are vasoconstrictors.

19. Migraine Pharmacologic management • Acute attack • analgesics (e.g., NSAIDs, APAP) • ‘triptans’ (5-HT agonists) • Prophylaxis • ß blockers • anticonvulsants • Ca2+ channel blockers • etc.

20. Neuropathic Pain Common types • diabetic neuropathy • post-herpetic neuralgia • ‘phantom limb’ • etc. Pharmacologic management • opioids • tramadol • topical anesthetics • antidepressants • anticonvulsants

21. Possible Mechanisms • ‘Central sensitization’. Overactivity of a 2o neuron in the dorsal horn leads to enhanced pain transmission characterized by a lowered threshold for activation and expanded receptive fields, leading to the activation of key excitatory amino acid receptors such as the N-methyl-D-aspartate (NMDA) receptor. • Disinhibition. Reduced activation of central inhibitory inputs from endogenous opioid, 5-HT, and norepinephrine pathways. • Sympathetic activation. Sympathetic nerve endings sprout from a nearby blood vessel toward the site of injury and can enhance signal transmission in the DRG. Catecholamine release and up-regulation of adrenoceptors on free nerve endings also contribute to sympathetically mediated pain. • Peripheral sensitization. Injury to peripheral nerves may lead to hyperexcitability of peripheral nerve terminals (nociceptors). This may be due to altered expression of Na+ channels, Ca2+ channels, or adrenoceptors in peripheral nerves and DRG.

22. Mechanisms of Pain Normosensitivity

23. Mechanisms of Pain Central Sensitization

24. Mechanisms of Pain Neuropathic

25. Mechanisms of Pain Hyperalgesia

26. Mechanisms of Pain Allodynia

27. Combination Analgesics Possible rationales • No single perfect analgesic • Complementary PK • Multiple sites/mechanisms of action target multiple pain pathways • Potentially synergistic analgesia • Comparable efficacy, but reduced AE profile Raffa, RB. J Clin Pharm Ther. 2001;26:257-64.

28. REVIEW QUESTION ‘Triptans’ are most associated with: • Diabetic neuropathy • Migraine headache • Neuropathic pain

29. REVIEW QUESTION Central sensitization and up-regulation are the same thing: • True • False

30. REVIEW QUESTION Almost everyone experiences: • Hyperalgesia • Allodynia

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