management of neuropathic pain

1. Current Therapies
in Management of
Neuropathic Pain
Dr Purnendu Mandal
MD PGT
PHARMACOLOGY
BSMC

2. DEFINITION
• The word pain is derived from the Latin word Peone and the
Greek word Poine meaning penalty or punishment
• Pain is an unpleasant sensation localized to a part of the body.
• It is often described in terms of a penetrating or tissue-destructive process
(e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or
emotional reaction (e.g., terrifying, nauseating, sickening.
• 2 components-
• Nociceptive
• Affective

3. PAIN RECEPTORS
• NOCICEPTORS or PAIN RECEPTORS are sensory
receptors that are activated by noxious insults to
peripheral tissues
 The receptive endings of the peripheral pain fibres are
free nerve endings
 These receptive endings are widely distributed in the
 Skin
 Dental pulp
 Periosteum
 Meninges

5. SKIN RECEPTORS FOR PAIN
HIGH THRESHOLD
MECHANORECEPTORS
( HTMS)
POLYMODAL RECEPTORS
 These receptors detect
local deformation
Eg: Touch
 These receptors detect a
variety of stimuli causing
injury
Eg: Heat
Noxious stimulation
 These do not have a
specialized and simple
nerve endings in the
periphery

6. NERVE FIBRES INVOLVED IN PAIN TRANSMISSION
A FIBRES C FIBRES
A – BETA
FIBRES
A – DELTA FIBRES
 Large
 Myelinated
 Fast conducting
 Low stimulation
threshold
 Respond to light
touch
 Small
 Lightly Myelinated
 Slow conducting
 Respond to heat,
pressure, cooling &
chemicals
 sharp sensation of
pain
 Small & unmyelinated
 Very slow conducting
 Respond to all types of
noxious stimuli
 Transmit prolonged dull
pain
 Require high intensity
stimuli to trigger a
response

7. Peripheral nerve
Sympathetic
postganglionic
Sympathetic
preganglionic
Spinal
cord
Aß
A-delta
C
Dorsal root
ganglion

9. Nociceptive pathway

12. Stimulation Of Nociceptors BRADYKININ
Substances Exiting
Nociceptors
HISTAMINE ,POTASSIUM
ATP
Sensitization Of Nociceptors PGE2. PGI2
Activation Of Nociceptors By
Interacting With Other
Chemical Mediators
PGI2 ,LTs
Discharge Of Pain Releasing
Substances By Nociceptors
SUBSTANCE – P
GLUTAMATE
Neurotransmitters Involved In Pain

14. ENDOGENOUS ANALGESIC MECHANISMS
 The endogenous analgesic mechanism comprises of
endogenously synthesized opioid peptides, which are MORPHINE
like substances
 The opioid like substances are found at different points of the
brain which are breakdown products of 3 large protein molecules
 Pro – opiomelanocortin: β – endorphin
 Pro – encephalin: Met – enkephalin & Leu –
enkephalin
 Prodynorphins: Dynorphins
 These are found in peripheral processes of 10 afferent neurons,
human synovia, many regions of CNS

16. MECHANISMS OF PAIN
Pain sensation involves a series of complex
interactions between peripheral nerves & CNS
Pain sensation is modulated by excitatory and
inhibitory NTs released in response to stimuli
Sensation of pain is composed of 4 basic processes
 Transduction
 Transmission
 Modulation
 Perception

17. CLASSIFICATION OF PAIN
Based on source/ location/ referral & duration
ACUTE PAIN /
TRAUMATIC PAIN
CHRONIC PAIN
VISCERAL
/SPLANCN
IC PAIN
SOMATIC PAIN MALIGNANT PAIN
OR
CANCER PAIN
NON – MALIGNANT
PAIN
OR
BENIGN PAIN
SUPERFICIAL PAIN
OR
CUTANEOUS PAIN
DEEP SOMATIC
PAIN
MUSCULOSKELE
TAL PAIN
NEUROPATHIC
PAIN

18. Nociceptive vs. Neuropathic Pain
Nociceptive
•Usually aching or throbbing
and well-localized
•Usually time-limited (resolves
when damaged tissue heals),
but can
be chronic
•Generally responds to
conventional analgesics
Neuropathic
•Pain often described as
tingling, shock-like, and
burning – commonly
associated with numbness
•Almost always a
chronic condition
•Responds poorly to
conventional analgesics

19. NEUROPTHIC PAIN
Neuropathic pain is the pain arising as a direct consequence
of a lesion or disease affecting the somatosensory system.
It is described as
 Aching
 Throbbing
 Burning
 Shooting
 Stinging
 Tenderness/ sensitivity of skin

20. Positive
symptom
Definition
Spontaneous pain Painful sensations felt with no evident stimulus
Allodynia
Pain due to a stimulus that does not normally provoke pain
(e.g., touching, movement, cold, heat)
Hyperalgesia
An increased response to a stimulus that is normally painful
(e.g., cold, heat, pinprick)
Dysesthesia
An unpleasant abnormal sensation, whether spontaneous or
evoked (e.g., shooting sensation)
Paresthesia
An abnormal sensation, whether spontaneous or evoked (e.g.,
tingling)
Sensory symptoms
of neuropathic pain

21. PERIPHERAL SENSITISATION CENTRAL SENSITISATION
•Increase expression of Na,Ca channels
•Neuroma formation
•Increased general excitability of
multi-receptive spinal cord neurones.
•Dysfunction of descending
inhibitory serotonergic and
noradrenergic pathway

23. causes
Central Peripheral
Post-stroke pain (Thalamic
pain syndrome)
Multiple Sclerosis
Spinal cord injury
Spinal cord tumor
Syringomyelia
Spinal infarction
Painful diabetic polyneuropathy (PDPN)
Painful non-diabetic polyneuropathy
Post-Herpetic Neuralgia (PHN)
Trigeminal Neuralgia
Entrapment neuropathy (i.e. Carpal Tunnel
Syndrome)
Radicular pain following nerve root compression
Drug induced neuropathy (Chemotherapy/
Antiretroviral drugs)
Nutritional (Vitamin B deficiency)
Heavy metals (i.e. thallium/arsenic)
Post-amputation pain (Stump pain/Phantom limb
pain)
Ischaemic neuropathy
Complex regional pain syndrome(CRPS) type II
HIV associated sensory neuropathy
Chronic alcoholism
Uraemia
Fabry disease

24. Signs and Symptoms
Spontaneous pain - It can be both continuous or paroxysmal
a) Burning or intense tightness with superimposed shooting or lancinating pain.
b) Electric shock like sensation
c) Tingling sensation or ant crawling sensation
d) Pin & needles sensation
e) Itching
Induced pain -
a) Allodynia- pain in response to a normally non-painful stimulus (Light breeze, during clothing, change
of temperature)
b) Hyperalgesia- increased pain in response to a normally painful stimulus
c) Superimposed autonomic features, such as alterations in temperature, color and sweating, as well as
the development of trophic changes, suggesta diagnosis of reflex sympathetic dystrophy or complex
regional pain syndrome

25. ASSESSMENT OF PAIN
METHOD OF PAIN ASSESSMENT
 Comprehensive history intake
 Medical history
 Physical history
 Family history
 Physical exam
Questioning on characteristic of pain – onset,
duration, location, quality, severity & intensity
 Evaluation of psychological status

26. PAIN ASSESSMENT PNUEMONIC
 P – Palliative/ Provocative/ Precipitating
 Q – Quality
 R – Radiation/ Region
 S – Severity
 T – Temporal/ Time related
The impact of pain on the patients functional status, behaviour
and psychological status should also be assessed

27. PAIN ASSESSMENT TOOLS
 Pain may be accompanied by physiologic signs and symptoms
and there are no reliable objective markers of pain
 The severity of pain can be assessed by rating scales &
multidimensional scales.
RATING SCALES
Provide a simple way to
classify the intensity of pain
and should be selected based
on the patients ability to
communicate
MULTIDIMENSIONAL SCALES
Helpful in obtaining
information about the pain
and impact on QOL, but are
more often time consuming to
complete

28. RATING SCALES
SIMPLE DESCRIPTIVE PAIN INTENSITY SCALE
NO PAIN MILD
PAIN
MODERATE
PAIN
SEVERE
PAIN
VERY
SEVERE
PAIN
WORST
POSSIBLE
PAIN
NUMERIC SCALE

29. VISUAL ANALOG SCALE (VAS)
FACES SCALE

30. VERBAL RATING SCALE
PAIN THERMOMETER

31. MULTIDIMENSIONAL ASSESSMENT SCALES
 The following are the types of MAS
 Initial pain assessment tools
 Brief pain inventory
 McGill pain questionnaire
 The neuropathic pain scale
 The Oswestry disability index

32. DIAGNOSIS OF CHRONIC PAIN

33. Diagnosing Neuropathic Pain
Is Challenging
Diagnostic
challenges
Multiple,
complex
mechanisms
Diverse
symptoms
Difficulties in
communicating and
understanding symptoms
Recognition of
comorbidities

34. • Pharmacological
• Physical Therapy
• Behavioural Therapy
• Neuromodulation
• Interventional Approaches
Approach to treatment

35. 1. Initial management - treatment targeted to the
specific diagnosis. Eg.- Control of Diabetes,
Removing offending drug ,Releiving compression
2. Simple Analgesics Acetaminophen /Nsaids rarely
helpful
3. Despite treatment – 3o -50 % reduction
4. Start at lowest dose increase every 3 to 7 days to
max tolerated dose
5. Physical, psychological, environmental and
behavioural factors
IMPORTANT CONSIDERATIONS

36. Principles of pharmacotherapy
The severity of the pain, and its impact on
lifestyle, daily activities.
To find out the underlying cause of the pain.
Particular pharmacological treatment .
 The benefits and possible adverse effects of
pharmacological treatments.
Optimise drug dose
 Coping strategies for pain and for possible
adverse effects of treatment .
Non-pharmacological treatments.
• physical and psychological therapies
(rehabilitation service)
• surgery

37. Targets
1. Ectopic activity of
damaged peripheral
nerves
2. Increased excitability of
spinal dorsal horn
neurones
3. Restoration/augmentation
of GABArgic inhibition
4. Supraspinal and affective
Mechanisms
5. Alteration of Sympathetic
Nervous System
6. Spinal peptidergic
mechanisms
7. Spinal excitatory amino
acid receptors

38. 1. α2δ-ligands (pregabalin and
gabapentin)
2. TCA (low-dose amitriptyline
or other TCA)
3. SNRIs (duloxetine and
venlafaxine) and
4. Opioids (tramadol,
methadone and morphine).
Classes of Drugs
Peripheral neuropathic pain

39. Central neuropathic pain
 First line drugs-
Pregabalin
Gabapentin
TCAs (specifically amitriptyline)
spinal cord injury (SCI) and post-stroke pain
 Second line drugs-
• All above + Tramadol and stronger opioids as second-line
• Cannabinoids are suggested in multiple sclerosis (MS) if
other treatments fail
• Mixed evidence for Lamotrigine in SCI(spinal cord injury)
and post-stroke pain.

40. Gabapentin and pregabalin bind to the voltage-gated calcium channels at the
alpha 2-delta subunit .
Pregabalin and Gabapentin
Pregabalin Gabapentin
Starting dose 25mg/day
Titrated upto 300-450mg/day in 2 divided
doses
Max dose 3600mg/day in 3 divided
doses.
shorter titration period
S/E
Dose dependant dizziness and sedation.
Both need dose reduction in Renal Failure.

42. 1. Neuropathic pain, such as diabetic neuropathy, post-herpetic
neuralgia, complex regional pain syndrome(CRPS) and certain other
types of chronic pain.
2. Generalised Anxiety disorder
3. Fibromyalgia
4. The IASP NeuPSIG guidelines acknowledge the additional efficacy of
gabapentin and pregabalin in sleep disorders, and pregabalin in
anxiety disorders associated with pain.
5. As an antiepileptic used as an adjunct in thetreatment of partial
seizures with or without secondary generalisation.
6. There is growing interest in the use of analgesic adjuvants including
anti-epileptics such as pregabalin to modulate opioid dosage and
efficacy for postoperative pain
Uses

43.  Serotonin and norepinephrine reuptake inhibitors
- Amitriptyline most widely used
- doxepin , imipramine , nortriptyline ,
and desipramine also have been used with success.
- Amitriptyline /nortriptyline may be started at 10-
25 mg/d bedtime and slowly titrated up to an
effective analgesic dose (eg, 75 mg/d).
It can take up to six to eight weeks, including two
weeks at the highest dosage tolerated
 TCA- CARDIOTOXIC
 Amitriptyline- C/I in IHD (AVIODED IN ELDERLY)
Tricyclic antidepressants

45. Condition response to TCA
Post Herpetic Neuralgia
Diabetic Neuropathy
Tension Headache
Migraine Headche
Rheumatiod Arthritis
Chronic Low Back Pain
Cancer
Central Post Stroke Pain

46. 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.

47. • venlafaxine , desvenlafaxine , duloxetine ,
and milnacipran
• 1. Venlafaxine – Fewer side effects than TCAs
Less efficacious max- 150-225mg/day
2. Duloxetine – 60 -120 mg /day . Started at 30
mg/day ADR - nausea, somnolence, dry
mouth, constipation, reduced appetite,
diarrhea, hyperhidrosis, and dizziness,
SNRI Antidepressants

48. • topiramate , lamotrigine , levetiracetam ,phen
ytoin , valproate , zonisamide ,tiagabine ,
have been utilized anecdotally and in
randomized trials for various pain conditions
• in general these agents should be reserved for
second line treatment
• Except Carbamzepine for trigeminal neuralgia
Other antiepileptics

50. • Tramadol
• weak μ-opioid agonist
• most of the international guidelines reserve opioid analgesics as second-
or third-line agents.
• risk of long-term side-effects and possible opioid misuse and addiction.
• Tramadol should be initiated at low dosages, particularly in elderly
patients (50 mg once daily), and then titrated as tolerated. The effective
dosage range is 200–400 mg/day.
• Induces dizziness, dry mouth, nausea, constipation, and somnolence and
can cause or aggravate cognitive impairment, particularly in the elderly.
• There is an increased risk of seizures in patients with previous epilepsy
OPIOIDS

51. • now established that strong opioids (oxycodone,
methadone, and morphine) have efficacy in
peripheral neuropathic pain.
• doses necessary to reach efficacy may be higher
in neuropathic pain than in nociceptive pain
• Longterm morphine administration may be
associated with immunological changes and
hypogonadism
• Long term use –addiction

52. Treatment algorithm for peripheral pain

54. IASP RECOMMENDATIONS(2015)
1ST Line 2nd Line 3rd Line
SNRI High Tramadol Moderate Strong
opioids
Moderate
TCA Moderate Capsaicin 8%
patches
High
Botulinum
toxin A
Moderate
High Lidocaine
patches
LowPregabalin,
Gabapentin,
Gabapentin
extended
release

55. NICE guidelines 2013
 All neuropathic pain (except trigeminal neuralgia)
A choice of amitriptyline, duloxetine, gabapentin or pregabalin is
offered as initial treatment for neuropathic pain (except trigeminal
neuralgia).
 If the initial treatment is not effective or is not tolerated, one of the
remaining 3 drugs may be given, and switching should be done
again if the second and third drugs tried are also not effective or
not tolerated.
 Tramadol is considered only if acute rescue therapy is needed
Capsaicin cream may be given to people with localized neuropathic
pain who wish to avoid, or who cannot tolerate oral treatments.

56.  Treatments that should not be used
The following should not be given to treat neuropathic pain in non-specialist settings, unless
advised by a specialist to do so:
Cannabis sativa extract
Capsaicin patch
Lacosamide
Lamotrigine
Levetiracetam
Morphine
Ox-carbazepine
Topiramate
Tramadol (this is referring to long-term use)
Venlafaxine.
Trigeminal neuralgia
Carbamazepine is the initial treatment of choice for trigeminal neuralgia.
If initial treatment with carbamazepine is not effective, is not tolerated or is contraindicated, expert
advice from a specialist should be sought and early referral to a specialist pain service or a
condition-specific serviceis considered.

57. LIGNOCAINE PATCH
• 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)
• Efficacy demonstrated in 3 randomized controlled trials on
postherpetic neuralgia
• Most appropriate for patients with well localized neuropathic
pain and Allodynia
• Drug interactions and systemic side effects unlikely
– most common side effect: application-site sensitivity
• Clinically insignificant serum lidocaine levels

58. 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)

59. Capsaicin Patches
• agonist of the transient receptor potential vanilloid receptor
(TRPV1) and activates TRPV1 ligand-gated channels on nociceptive
fibers
• Several days of capsaicin application, TRPV1-containing sensory
axons are desensitized, which inhibits the transmission of pain.
• Can act as counterirritant .
• optimal duration of the patches -Post herpetic neuralgia (60
minutes) and HIV neuropathy (30 minutes).
Emerging Drug Treatments

60. • Adverse effects-local capsaicin-related
reactions at the application site
• (pain, erythema, and sometimes edema and
itching)
• potential risk of high blood pressure during
treatment

61. • long-term efficacy of a series of subcutaneous
injections of BTX-A (from 100 to 200 units)
injected into the painful area in patients with
mononeuropathies.
• (Mainly of traumatic origin) , in patients with
diabetic painful polyneuropathies .
• discrepant data indicate the need for further
large-scale trials
Botulinum Toxin A

62. • 2007 review of studies found that injected)
administration of alpha lipoic acid (ALA) was
found to reduce the various symptoms of
peripheral diabetic neuropathy
• at a dosage of 600 mg once daily over a period of
three weeks, alpha lipoic acid leads to a
significant and clinically relevant reduction in
neuropathic pain
• Isosorbide dinitrite Spray For diabetic
neuropathy – NO generation ,local vasodilating
effect
Other agents

63. • α2- Agonists like clonidine reduce NT release and
decrease postsynaptic transmission.
• Benzodiazepines
• Baclofen – a GABAB receptor agonist
• Botulinum toxin – inhibits Ach release at NMJ.
• Ziconotide- blocks N-type voltage sensitive Ca2+
channel.
Other Analgesics and Adjuvants

64. Interventional treatments
MODALITIES
• 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

65. • TENS — Transcutaneous Electrical Stimulation
(TENS) involves the application of electrical
currents to the skin primarily for the purposes
of pain relief.
TENS

66. • delivery of a low voltage electrical current from a
small battery-operated device to the skin via
surface electrodes
• conventional TENS (high frequency >50hz, short pulse duration, low
intensity);
• acupuncture-like TENS (low frequency <10 hz , long pulse duration, high
intensity);
• burst TENS (high frequency trains of pulses delivered at a low frequency);
• and brief-intense TENS (high frequency and long pulse duration pulses
delivered at a high intensity)
• systematic reviews have found variable and inconclusive results of
efficacy of TENS in chronic pain management
• COCHRANE review 2008 – inconclusive

67. TENS electrodes are contraindicated:
1. Over the eyes due to the risk of increasing intraocular pressure
2. Transcerebrally
3. On the front of the neck due to the risk of an
acute hypotension (through a vasovagal reflex) or even
a laryngospasm
4. Through the chest using an anterior and posterior electrode
positions
5. Avoided if Cardiac Pacemaker present
6. Internally, except for specific applications of dental, vaginal, and
anal stimulation that employ specialized TENS units
7. On broken skin areas or wounds,
8. Over a tumour/malignancy
9. Directly over the spinal column

68. • Exert pulsed electrical signals to the spinal
cord to control chronic pain
• consists of a pulse generator with its remote
controls, implanted stimulating electrodes and
conducting wires
• temporary screening trial with an external
pulse generator
SPINAL CORD STIMULATION

70. The most common use of SCS is failed back surgery syndrome
(FBSS)
• treatment of inoperable ischemic limb pain
Complications include
• lead migration,
• lead breakage,
• infection.
• Other complications include haematomas (subcutaneous
or epidural),cerebrospinal fluid (CSF) leak, post dural
puncture headache, discomfort at pulse generator
site, seroma and transient paraplegia.

72. • Cognitive behavioral therapy
• Biofeedback
• Relaxation therapy
• Psychotherapy and individual or group
counseling
• Aerobic exercise
• Acupuncture
• Physical and occupational therapy
Behavioural Therapy

73. Burning Tingling Shooting Electric shock-like Numbness
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