Pain & Neuropathic

Pain - Basics

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 Pain
• An unpleasant sensation and associated negative feelings which we get when
there is actual or likely damage to any body part
• Protective in nature - acts as a warning signal against disturbance in body
• Felt by sufferer alone – severity can’t be felt or measured by others
• Can be acute (lasting 1 month max.) / subacute (1-6 months) / chronic (>6 months)

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 Pain: Clinical Types
On the basis of nature and site of tissue damage
 Nociceptive pain
• Usual clinical pain resulting from inflammation of tissues but the nerves are not affected
• Sharp throbbing or aching in quality
• Pain stops after damaged tissue has healed
• Sensory nerves are functioning normally
• Responds well to routinely used analgesics & anti-inflammatory drugs (NSAIDs, opioids, steroids)
 Neuropathic pain
• Results from damage to sensory nerves
• Often chronic (continuous or off-and-on) and very distressing in nature
• Pain qualities: burning / stabbing / shooting / numbness / coldness / electric shock-like / itchiness
• Abnormal sensations like paresthesia & dysesthesia may be present
• Often difficult to treat - does not respond well to routine pain killers
 Mixed-origin pain → combination of nociceptive + neuropathic (e.g., low back pain)
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Painful Neuropathy: Symptoms

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 Painful Neuropathy: Important Types

• Diabetic neuropathy (caused by diabetes mellitus)

• Post-herpetic neuralgia or shingles [caused by Varicella zoster (chicken pox virus) infection]
• Cancer-related
• Local nerve-injury related – traumatic / surgical / compression / toxic substances / nutritional deficiency /
chemotherapy / radiation
• Post-stroke
• Spinal cord injury-related
• HIV-associated
• Reflex sympathetic dystrophy
• Phantom limb pain
• Trigeminal neuralgia
• Multiple sclerosis

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Pain Transmission & Modulation Pathways (Simplified)
Ascending pain transmission pathway
 Carries pain impulses (generated when pain receptors
activated due to damage or irritation in nearby area)
Thalamus from the site of origin to brain through spinal cord
Descending pain modulation pathway
 Interferes with pain impulses entering spinal cord
 Decreases pain impulses going to brain through
spinal cord
Descending pain modulation pathway
Ascending pain transmission pathway Nociceptive pain caused by:
 Tissue damage (inflammation / irritation)
 Ascending pathway functioning normally
 Descending pathway functioning normally
Neuropathic pain caused by:
 Part of sensory nerve damaged / compressed →
generate excessive pain impulses
 Ascending pathway abnormally active
 Descending pathway abnormally inactive

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 NePn Types: Based on Site of Origin

 Peripheral NePn
• Peripheral = outside of brain or spinal cord (outside CNS)
• Pain due to damage or irritation of peripheral sensory nerves
• Causes of damage: disease / injury# / anatomical anomaly
 Central NePn
• Central = inside of brain or spinal cord (inside CNS)
• Pain due to damages in the spinal cord or brain
• Causes of damage: injury# / disease (stroke / multiple sclerosis)
# mechanical / chemical / physical / biological (infection)

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 NePn: Clinical Examples
Peripheral NePn Conditions

Central NePn Conditions

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 NePn Management: Concerns

• Multiple –ve effects of NePn on patients’ functioning

 Impairs mood, quality of life, daily activities, occupational performance, sleep
• Health-care costs of NePn  3X higher vs. those without it
• Tx often less than satisfactory
 Inadequate pain relief
 Tolerability problems (from drug side effects  high drug dose doesn’t give better
pain relief, but side effects can ↑ disproportionately)

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 NePn: Drug Therapy
Antidepressants
TCA Amitriptyline, nortriptyline,
desipramine, imipramine, doxepine
SNRI Duloxetine*, venlafaxine
Anticonvulsants Pregabalin*, gabapentin*,
carbamazepine*, valproate,
lamotrigine, oxcarbazepine
Topical Agents Lidocaine patch 5%*, capsaicin
Opioids Oxycodone, tramadol, fentanyl,
morphine, hydrocodone
Intrathecal Ziconotide, opioids
Antidepressants and anticonvulsants are considered the first choice of treatment in neuropathic
pain syndrome

* Approved by the US FDA use in various neuropathic pain disease states

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NePn: Drug Therapy

Murnion BP. Aust Prescr. 2018;41:60-3.

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 Drug Monotherapy for NePn: Limitations

• Incomplete pain relief [1]

 rarely  pain severity by >60%
 limited proportion of responders# → 40-60% of patients; remainder do not
benefit
• Dose-limiting side-effects
 high dose monotherapy can cause intolerable SEs [2]
• Majority of patients receive multiple concurrent treatments to
overcome limitations of monotherapy [3]
# Persons in whom pain severity has reduced by at least 30% with treatment, compared to that at baseline, i.e., before the start of treatment

1. Ann Rheum Dis 2008;67:536-61.

2. JAMA 2004;292:2388-95.
3. Int J Clin Pract 2007;61:1498-1508.
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 Drug Combinations for NePn: Rationale

• NePn is widely prevalent  >2-3% of general population affected

• Pregabalin (PGB) & Duloxetine (DLX)  2 of several 1st-line drugs with the most
favourable therapeutic profiles
• Monotherapy with PGB / DLX: limitations
– Incomplete pain relief
• rarely  pain severity by >60%
• responders: 40-60% of patients
– Dose-limiting side-effects
• Combination of different drugs could provide additive or synergistic analgesia, thus
leading to d efficacy or tolerability, or both
• Studies have shown superior pain relief with drug combinations than individual
drugs given alone
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