Pain and analgesic pathways
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Pain and Analgesic Pathways. Robert B. Raffa, Ph.D. Professor of Pharmacology Temple University School of Pharmacy & School of Medicine. Current Knowledge. Different ‘types’ of pain, not just different degrees of pain Multiple chemical mediators of pain

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Pain and analgesic pathways

Pain and Analgesic Pathways

Robert B. Raffa, Ph.D.

Professor of Pharmacology

Temple University

School of Pharmacy & School of Medicine


Current knowledge

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


Types of 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

Normal Pain Pathways

thalamus

  • Tissue injury

  • histamine

  • bradykinin

  • etc.

lateral spino-

thalamic tract

dorsal root

ganglion

primary

afferent

Fig 3-25


Normal pain pathways1

Normal Pain Pathways

PAG

(periaqueductal gray)

locus ceruleus

raphe nuclei

Enkephalin-containing

interneuron

Fig 3-25


Sharp localized

Primary (1o) Afferents

‘sharp’localized

‘dull’vague

Ad

C


Review question

REVIEW QUESTION

Which is/are TRUE?

  • Pain can be beneficial

  • Pain can be harmful

  • Nociception is normal

  • C-fibers transmit sharp, localized pain


Multiple types in injury

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

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

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)


Underutilization and control

Underutilization and Control


Sites of action

NSAIDs

Aa PGs

COX

Sites of Action


Sites of action1

Sites of Action

Local

Anesthetics

(voltage-gated

Na+ channels)


Sites of action2

Sites of Action

Opioids

(m, d, k)


Sites of action3

Sites of Action

Acetaminophen ?


Review question1

REVIEW QUESTION

The WHO analgesic ladder is a guide to the proper dose of analgesic:

  • True

  • False


Resistant pains

‘Resistant’ Pains

  • Migraine

  • Neuropathic pain

  • Sickle cell pain

  • etc.


Migraine

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.


Migraine1

Migraine

Pharmacologic management

  • Acute attack

    • analgesics (e.g., NSAIDs, APAP)

    • ‘triptans’ (5-HT agonists)

  • Prophylaxis

    • ß blockers

    • anticonvulsants

    • Ca2+ channel blockers

    • etc.


Neuropathic pain

Neuropathic Pain

Common types

  • diabetic neuropathy

  • post-herpetic neuralgia

  • ‘phantom limb’

  • etc.

    Pharmacologic management

  • opioids

  • tramadol

  • topical anesthetics

  • antidepressants

  • anticonvulsants


Possible mechanisms

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.


Mechanisms of pain

Mechanisms of Pain

Normosensitivity


Mechanisms of pain1

Mechanisms of Pain

Central Sensitization


Mechanisms of pain2

Mechanisms of Pain

Neuropathic


Mechanisms of pain3

Mechanisms of Pain

Hyperalgesia


Mechanisms of pain4

Mechanisms of Pain

Allodynia


Combination analgesics

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.


Review question2

REVIEW QUESTION

‘Triptans’ are most associated with:

  • Diabetic neuropathy

  • Migraine headache

  • Neuropathic pain


Review question3

REVIEW QUESTION

Central sensitization and up-regulation are the same thing:

  • True

  • False


Review question4

REVIEW QUESTION

Almost everyone experiences:

  • Hyperalgesia

  • Allodynia


Pain and analgesic pathways

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