Pain And Analysis

Pain Pain and and Analgesic Analgesic Pathways Pathways

Robert Robert B. B. Raffa, Raffa, Ph.D. Ph.D. Professor Professor of of Pharmacology Pharmacology Temple Temple University University School School of of Pharmacy Pharmacy & & School School of of Medicine Medicine

Current Knowledge

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

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

Normal Pain Pathways cortex thalamus

Tissue injury • histamine • bradykinin • etc. dorsal root ganglion

primary afferent

lateral spinothalamic tract

Fig 3-25

Normal Pain Pathways

PAG (periaqueductal gray) locus ceruleus raphe nuclei

Enkephalin-containing interneuron

Fig 3-25

Primary (1o) Afferents ‘sharp’ localized

Aδ

‘dull’ vague

C

REVIEW QUESTION Which is/are TRUE? 1. Pain can be beneficial 2. Pain can be harmful 3. Nociception is normal 4. C-fibers transmit sharp, localized pain

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.

Current Analgesics Options • • • • • • •

NSAIDs: 1970’s opioids: 1970’s tramadol: 1980’s & 1990’s COX-2 inhibitors: 1990’s acetaminophen: unknown combinations adjuncts

WHO Analgesic ‘Ladder’ Severe

Moderate

Mild

Step 3 Strong opioids (e.g., morphine) with or without non-opioids Step 2 Weak opioids (e.g., codeine) with or without non-opioids Step 1 Non-opioids (e.g., NSAIDs, acetaminophen = paracetamol)

Underutilization and Control

Sites of Action NSAIDs

Aa

COX

PGs

Sites of Action

Local Anesthetics (voltage-gated Na+ channels)

Opioids (µ , δ , κ )

Sites of Action

Sites of Action

Acetaminophen ?

REVIEW QUESTION The WHO analgesic ladder is a guide to the proper dose of analgesic: 1. True 2. False

‘Resistant’ Pains • • • •

Migraine Neuropathic pain Sickle cell pain etc.

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

Migraine Pharmacologic management • Acute attack – analgesics (e.g., NSAIDs, APAP) – ‘triptans’ (5-HT agonists)

• Prophylaxis – ß blockers – anticonvulsants – Ca22++ channel blockers – etc.

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

Possible Mechanisms •• ‘Central ‘Central sensitization’. sensitization’. Overactivity Overactivity of of aa 22oo neuron neuron in in the the dorsal dorsal horn horn leads leads to to enhanced enhanced pain transmission characterized by aa lowered lowered threshold threshold for for activation activation and and expanded expanded receptive receptive fields, fields, leading leading to to the the activation activation of of key key excitatory excitatory amino amino acid acid receptors receptors such such as as the the N-methylN-methyl-DD-aspartate -aspartate (NMDA) (NMDA) receptor. receptor. •• Disinhibition. Disinhibition. Reduced Reduced activation activation of of central central inhibitory inhibitory inputs inputs from from endogenous endogenous opioid, opioid, 5-HT, 5-HT, and and norepinephrine norepinephrine pathways. pathways. •• Sympathetic Sympathetic activation. activation. Sympathetic nerve nerve endings sprout from from aa nearby nearby blood blood vessel vessel toward toward the the site site of of injury injury and and can can enhance enhance signal signal transmission transmission in in the the DRG. DRG. Catecholamine Catecholamine release release and and up-regulation up-regulation of of adrenoceptors adrenoceptors on on free free nerve nerve endings endings also also contribute contribute to to sympathetically sympathetically mediated mediated pain. pain. •• Peripheral Peripheral sensitization. sensitization. Injury Injury to to peripheral peripheral nerves nerves may may lead lead to to hyperexcitability hyperexcitability of of peripheral peripheral nerve nerve terminals terminals (nociceptors). (nociceptors). This This may be be due to to altered altered expression expression of of Na Na++ channels, channels, Ca Ca2+2+ channels, channels, or or adrenoceptors adrenoceptors in in peripheral peripheral nerves nerves and and DRG. DRG.

Mechanisms of Pain Normosensitivity

Mechanisms of Pain Central Sensitization

Mechanisms of Pain Neuropathic

Mechanisms of Pain Hyperalgesia

Mechanisms of Pain Allodynia

Combination Combination Analgesics Analgesics Possible rationales No No single single perfect perfect analgesic analgesic –– Complementary PK Complementary PK –– Multiple sites/mechanisms of action target multiple pain pathways Multiple sites/mechanisms of action target multiple pain pathways –– Potentially synergistic analgesia Potentially synergistic analgesia –– Comparable efficacy, but reduced AE profile Comparable efficacy, but reduced AE profile ––

Raffa, RB. J Clin Pharm Ther. 2001;26:257-64.

REVIEW QUESTION ‘Triptans’ are most associated with: 1. Diabetic neuropathy 2. Migraine headache 3. Neuropathic pain

REVIEW QUESTION Central sensitization and up-regulation are the same thing: 1. True 2. False

REVIEW QUESTION Almost everyone experiences: 1. Hyperalgesia 2. Allodynia

end