mainly about neuropathic pain management

1. Neuropathic pain
management
Dr D.Ramu

2. IASP Definition of Pain
“Pain is an unpleasant sensory
and emotional experience
associated with actual or potential tissue
damage or described in
terms of such damage.”

3. Acute vs Chronic Pain
Characteristic Acute Pain Chronic Pain
Cause Generally known Often unknown
Duration of pain Short,
well-characterized
Persists after healing,
3 months
Treatment
approach
Resolution of
underlying cause,
usually self-limited
Underlying cause and pain
disorder; outcome is often
pain control, not cure

4. Possible Descriptions of Neuropathic Pain
• Sensations
• numbness
• tingling
• burning
• paresthetic
• paroxysmal
• lancinating
• electriclike
• raw skin
• shooting
• deep, dull, bonelike ache
• Signs/Symptoms
• allodynia: pain from a
stimulus that does not
normally evoke pain
• thermal
• mechanical
• hyperalgesia: exaggerated
response to a normally painful
stimulus

5. Physiology of Pain Perception
• Transduction
• Transmission
• Modulation
• Perception
• Interpretation
• Behavior
Injury
Descending
Pathway
Peripheral
Nerve
Dorsal
Root
Ganglion
C-Fiber
A-beta Fiber
A-delta Fiber
Ascending
Pathways
Dorsal
Horn
Brain
Spinal Cord
Adapted with permission from WebMD Scientific American® Medicine.5

6. Pathophysiology of Neuropathic Pain
• Chemical excitation of nonnociceptors
• Recruitment of nerves outside of site of injury
• Excitotoxicity
• Sodium channels
• Ectopic discharge
• Deafferentation
• Central sensitization
• maintained by peripheral input
• Sympathetic involvement
• Antidromic neurogenic inflammation

7. Multiple Pathophysiologies May Be Involved
in Neuropathic Pain
• More than one mechanism of action likely involved
• Neuropathic pain may result from abnormal peripheral nerve function and
neural processing of impulses due to abnormal neuronal receptor and
mediator activity
• Combination of medications may be needed to manage pain: topicals,
anticonvulsants, tricyclic antidepressants, serotonin-norepinephrine
reuptake inhibitors, and opioids
• In the future, ability to determine the relationship between the
pathophysiology and symptoms/signs may help target therapy

8. What Are the Goals of Clinical Assessment?
• Achieve diagnosis of pain
• Identify underlying causes of neuropathy
• Identify comorbid conditions
• Evaluate psychosocial factors
• Evaluate functional status (activity levels)
• Set goals
• Develop targeted treatment plan
• Determine when to refer to specialist or multidisciplinary team (pain
clinic)

9. Assessing the Patient With Pain
• Onset and duration
• Location/distribution
• Quality
• Intensity
• Aggravating/relieving factors
• Associated features or secondary signs/symptoms
• Associated factors
• mood/emotional distress
• functional activities
• Treatment response

14. • Chemotherapy-induced neuropathy is usually a dose-dependent,
cumulative side-effect with a ‘glove-and- stocking’ distribution
• Oxaliplatin-induced neuropathy is associated with an acute phase of
allodynia and pricking dys- aesthesia affecting the hands and feet and
also pharyngo- laryngeal dysaesthesia with sensations of shortness of
breath or swallowing difficulties induced by cold drinks

16. • Cancer-related neuropathic pain is chronic and often consists of a
background pain with acute exacerbations, peaking several times a
day.
• These exacerbations are often spontaneous but can also be triggered.
• Such spontaneous and evoked types of pain are perceived in areas of
sensory abnormality (hyposensitivity, hypersensitivity, or both).
• Spontaneous pain may be ongoing, with a constant or fluctuating pain
intensity, or dominated by pain paroxysms of short duration with
pain-free intervals or a less intense background pain.
• Other sensations, such as paraesthesia (abnormal sensa- tion that is
not painful or unpleasant) and dysaesthesia (unpleasant abnormal
sensation) may be present spontan- eously or occur only when
evoked by a stimulus

17. Pain Treatment Continuum
Least
invasive
Most
invasive
Psychological/physical approaches
Topical medications
*Consider referral if previous treatments were unsuccessful.
Systemic medications*
Interventional techniques*
Continuum not related to efficacy

18. Nonpharmacologic Options
• Biofeedback
• Relaxation therapy
• Physical and occupational therapy
• Cognitive/behavioral strategies
• meditation; guided imagery
• Acupuncture
• Transcutaneous electrical nerve stimulation

19. Pharmacologic Treatment Options
• Classes of agents with efficacy demonstrated
in multiple, randomized, controlled trials for neuropathic pain
• topical analgesics (capsaicin, lidocaine patch 5%)
• anticonvulsants (gabapentin, lamotrigine, pregabalin)
• antidepressants (nortriptyline, desipramine)
• opioids (oxycodone, tramadol)
• Consider safety and tolerability when initiating treatment

20. FDA-Approved Treatments for Neuropathic Pain
• Carbamazepine
• trigeminal neuralgia
• Duloxetine
• peripheral diabetic neuropathy
• Gabapentin
• postherpetic neuralgia
• Lidocaine Patch 5%
• postherpetic neuralgia
• Pregabalin*
• peripheral diabetic neuropathy
• postherpetic neuralgia
*Availability pending based upon controlled substance scheduling by the DEA.

21. BRAIN
Pharmacologic Agents Affect Pain Differently
Descending Modulation
Central Sensitization
PNS
Local Anesthetics
Topical Analgesics
Anticonvulsants
Tricyclic Antidepressants
Opioids
Anticonvulsants
Opioids
NMDA-Receptor Antagonists
Tricyclic/SNRI Antidepressants
Anticonvulsants
Opioids
Tricyclic/SNRI Antidepressants
CNS
Spinal
Cord
Peripheral
Sensitization
Dorsal
Horn

22. Topical vs Transdermal Drug Delivery Systems
Systemic activity
Applied away from painful site
Serum levels necessary
Systemic side effects
Peripheral tissue activity
Applied directly over painful site
Insignificant serum levels
Systemic side effects unlikely
Topical
(lidocaine patch 5%)
Transdermal
(fentanyl patch)

23. Lidocaine Patch 5%
• Lidocaine 5% in pliable patch
• Up to 3 patches applied once daily directly over
painful site
• 12 h on, 12 h off (FDA-approved label)
• recently published data indicate 4 patches (18–24 h) safe
• Efficacy demonstrated in 3 randomized controlled trials on postherpetic neuralgia
• Drug interactions and systemic side effects unlikely
• most common side effect: application-site sensitivity
• Clinically insignificant serum lidocaine levels
• Mechanical barrier decreases allodynia

24. Anticonvulsant Drugs for Neuropathic Pain Disorders
• Postherpetic neuralgia
• gabapentin*
• pregabalin *
• Diabetic neuropathy
• carbamazepine
• phenytoin
• gabapentin
• lamotrigine
• pregabalin *
• HIV-associated neuropathy
• lamotrigine
• Trigeminal neuralgia
• carbamazepine*
• lamotrigine
• oxcarbazepine
• Central poststroke pain
• lamotrigine
*Approved by FDA for this use.
HIV = human immunodeficiency virus.

25. Gabapentin in Neuropathic Pain Disorders
• FDA approved for postherpetic neuralgia
• Anticonvulsant: Antagonism of the alfa2beta subunit of voltage-
dependent calcium channels at presynaptic sites
• Limited intestinal absorption
• No significant drug interactions
• Peak time: 2 to 3 h; elimination half-life: 5 to 7 h
• Usual dosage range for neuropathic pain up to 3,600 mg/d (tid–qid)*
*Not approved by FDA for this use.

26. Gabapentin and pregabalin
• Pain relief can be rapid (within the first or second week) and often
accompanied by improvements in sleep and quality of life measures
• Somnolence and dizziness are the most common side-effects;
peripheral oedema, weight gain, nausea, vertigo, asthenia, dry
mouth, and ataxia may occur
• Both gabapentin and pregabalin undergo renal excretion and renal
impairment requires dosage adjustment.
• Pregabalin has anxiolytic effects in patients with generalized anxiety
disorders

27. Other Anticonvulsants
• Carbamazepine, and its analogue oxcarbazepine, is blocking of
sodium channels.
• First-line drugs for tri- geminal neuralgia
• Lamotrigine and valproate have limited roles in the treatment of
neuropathic pain as results from randomized controlled trials are
conflicting

28. Antidepressants in Neuropathic Pain Disorders
• Tricyclic antidepressants (TCAs) (e.g. amitriptyline, desparamine, nortryptiline, clomipramineand
imipramine)
• Selective serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g. duloxetine paroxitine,
citalopram and venlafaxine)
• Multiple mechanisms of action
• Inhibiting the reuptake of norepinephrine and serotonin into presynaptic neurons
• First drug of choice in patients with a coexisting depression
• venlafaxine have been used successfully in the management of hot flushes and can be very useful
in patients with breast cancer with neuropathic pain, menopausal flushes, and depression.
• Randomized controlled trials and meta-analyses demonstrate benefit of tricyclic antidepressants
(especially amitriptyline, nortriptyline, desipramine) for postherpetic neuralgia and diabetic
neuropathy
• Onset of analgesia variable
• analgesic effects independent of antidepressant activity
• Improvements in insomnia, anxiety, depression
• Desipramine and nortriptyline have fewer adverse effects
Not approved by FDA for this use.

29. Tricyclic Antidepressants: Adverse Effects
• Commonly reported AEs
(generally anticholinergic):
• blurred vision
• cognitive changes
• constipation
• dry mouth
• orthostatic hypotension
• sedation
• sexual dysfunction
• tachycardia
• urinary retention
• Desipramine
• Nortriptyline
• Imipramine
• Doxepin
• Amitriptyline
Fewest
AEs
Most
AEs
AEs = adverse effects.

30. • contraindicated in patients with epilepsy, heart failure, and cardiac
conduction blocks

31. Principles of Opioid Therapy for Neuropathic Pain
• Opioids should be titrated for therapeutic efficacy versus AEs
• Fixed-dose regimens generally preferred
• Opioids can be effective in neuropathic pain
• Most opioid AEs controlled with appropriate specific management (eg, prophylactic bowel
regimen, use of stimulants)

32. Distinguishing Dependence, Tolerance, and Addiction
• Physical dependence: withdrawal syndrome arises if drug discontinued,
dose substantially reduced, or antagonist administered
• Tolerance: greater amount of drug needed to maintain therapeutic
effect, or loss of effect over time
• Pseudoaddiction: behavior suggestive of addiction; caused by
undertreatment of pain
• Addiction (psychological dependence): psychiatric disorder characterized
by continued compulsive use of substance despite harm

33. • N-methyl D-aspartate antagonists
• Ketamine
• Not sufficient evidence to recommend these drugs for any uncontrolled
cancer-related pain and use should be reserved for treatment resistent pain

34. • Cannabinoids
• concerns about abuse and addiction and also legal and regulatory issues
• Antiemetic effects and improve appetite and may therefore be considered for
treating neuro- pathic pain associated with nausea and decreased appe- tite.

35. • Capsaicin
• act via the transient receptor potential vanilloid 1 (TRPV1) receptor and may
deplete substance P from primary afferent nociceptors
• cutaneous patch of capsaicin 8%, has been given marketing authorization in
Europe for ‘treatment of peripheral neuropathic pain in non- diabetic adults’

36. Interventional Treatments for Neuropathic Pain
• Neural blockade
• sympathetic blocks for CRPS-I and II
(reflex sympathetic dystrophy and causalgia)
• Neurolytic techniques
• alcohol or phenol neurolysis
• pulse radio frequency
• Stimulatory techniques
• spinal cord stimulation
• peripheral nerve stimulation
• Medication pumps
CRPS = complex regional pain syndrome.

37. Summary of Advances in Treatments for Neuropathic Pain
• Botulinum toxin: low back pain
• Lidocaine patch 5%: low back pain, osteoarthritis, diabetic and HIV-related
neuropathy, with gabapentin
• CR oxycodone: diabetic neuropathy
• Gabapentin: HIV-related neuropathy, diabetic peripheral neuropathy, others
• Levetiracetam: neuropathic pain and migraine
• Oxcarbazepine: neuropathic pain; diabetic neuropathy
• Bupropion: neuropathic pain
• Transdermal fentanyl: low back pain
*Applications not approved by FDA.

38. Summary
• Chronic neuropathic pain is a disease, not a symptom
• “Rational” polypharmacy is often necessary
• combining peripheral and central nervous system agents enhances pain relief
• Treatment goals include:
• balancing efficacy, safety, and tolerability
• reducing baseline pain and pain exacerbations
• improving function and QOL
• New agents and new uses for existing agents offer additional treatment
options

39. • In neuropathic pain conditions (apart from trigeminal neuralgia), TCA,
SNRIs (duloxetine and venlafaxine) or calcium channel a2d agonists
(gabapentin or pregabalin) are the first drug choices.
• In patients with focal peripheral neuropathy with allodynia, a topical
lidocaine patch is also a first-line drug.
• Antide- pressants may be the first drug choice in patients with
depression
• TCAs and calcium channel a2d agonists may be considered in patients
with sleep disturbances.
• Prega- balin may be the first choice in patients with anxiety.
• Opioids are frequently co-prescribed in cancer neuropathic pain as
the cause can be mixed; neuropathic pain rarely exists in isolation in
active cancer.
• Switching from one opioid to another may improve pain relief.
• Combination therapy may be considered in patients with insufficient
effect from one drug