The document discusses pain classification and mechanisms. It defines pain and different types including nociceptive, neuropathic, and chronic pain. It describes peripheral and central sensitization mechanisms. It discusses evaluation and management of neuropathic pain including first-line options like gabapentin, pregabalin, amitriptyline and second-line options like duloxetine, tramadol, opioids. Adverse effects and considerations with long term use are also summarized.

1. Dr Sankalp Mohan
Senior Resident
Neurology
Govt. Medical College
Kota

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

3. Allodynia: Painless stimuli that are experienced
as pain eg. clothing, light touch.
Dysesthesias: Unpleasant perception of sensory
stimuli to skin
Hyperalgesia: An amplified response to a
noxious stimulus
Hyperesthesia: Delayed and explosive response
to noxious stimulus applied to affected area.
Paraesthesia: Spontaneous pins and needle
sensation.

4.  The International Association for the Study of
Pain (IASP), defines chronic pain as pain
without apparent biologic value that has
persisted beyond the normal tissue healing
time (usually taken to be three months)
 The American College of Rheumatology (ACR)
defines chronic pain as widespread or
regional pain Or at least three months
 (DSM-IV) defines chronic pain as persistent
pain for six months

6.  Nociceptive pain — A nociceptor is a nerve fiber
preferentially sensitive to a noxious stimulus or
to a stimulus that would become noxious if
prolonged
 Somatic and Visceral pain
 Neuropathic Pain - arises from abnormal neural
activity secondary to disease, injury, or
dysfunction of the nervous system
 1. Sympathetically mediated pain
 2. Peripheral neuropathic pain
 3. Central Pain

7. Mixed Type
Caused by a
combination of both
primary injury and
secondary effects
Nociceptive
Pain
Caused by activity in
neural pathways in
response to potentially
tissue-damaging
stimuli
Neuropathic
Pain
Initiated or caused by
primary lesion or
dysfunction in the
nervous system
Postoperative
pain
Mechanical
low back pain
Sickle cell
crisis
Arthritis
Postherpetic
neuralgia
Neuropathic
low back pain
Sports/exercise
injuries
*Complex regional pain syndrome
Central post-
stroke pain
Trigeminal
neuralgia
DPNP

8. Four physiologic processes are associated with pain:.
 Transduction - the conversion of a noxious stimulus
(thermal, mechanical, or chemical) into electrical
activity in the peripheral terminals of nociceptor
sensory fibers.
 Transmission - passage of action potentials from the
peripheral terminal along axons to the central
terminal of nociceptors in the central nervous
system..
 Modulation - alteration (eg, augmentation or
suppression) of sensory input.
 Perception refers to interpretation of afferent input in
the brain that gives rise to the individual's specific
sensory experience.

10. CNS processing /Modulation –
- descending inhibitory and facilitatory signals
arising from the brain ie
somatosensory cortex, the hypothalamus, the
periaqueductal gray matter, and areas in the pons.
-synapse with nociceptive neurons in the dorsal horn
of the spinal cord interact with the opioid system,
noradrenergic system, and serotonergic system

11. Nociceptors –
 high-threshold mechanoreceptors (HTMs) –
myelinated A delta
 C-polymodal nociceptors (C-PMN) –
unmyelinated C fibres
 Can respond to multiple stimuli –
heat,cold,chemical

13. Peripheral sensitization -
 Tissue damage releases chemicals –
Protons,K+,Serotnin ,Histamine ,Prostaglandins
,substance P activate nociceptors
Repeated/prolonged noxious stimuli causes
changes along the neuron and DRG+
 Responds to lower threshold
 Formation of neuromas ,collaterel spruting
 Increased sodium channel expression
 Demyelination

14.  Ectopic Discharge- Increase in level of
spontaneous firing in injured neurons as well
as uninjured neighbouring neurons
 Occurs due to alteration in expression of
sodium channels
Collateral Sprouting- Primary afferent neuron
injury leads to sprouting become sensitive to
low threshold mechanoreceptors
- These mechanisms may be Important in
Hyperalgesia and Allondynia

15. Central or spinal cord level
 Increased sensitivity of spinal neurons
 Expansion of the affected area- Normally
A delta & C innervate Lamina I and II of Dorsal horn
Large myelinated neurons also project to Lamina II
 The glutamate-activated N-methyl-D-aspartic
acid (NMDA) receptor
 NMDA receptor is phosphorylated, which
increases its distribution in the synaptic
membrane and its responsiveness to glutamate

16. Central
sensitization
Peripheral
sensitization
CNS
PNS
CNS
central
nervous
system
“Healthy”
nociceptor
s
Normal
transmission
Central
reorganization
Abnormal
nociceptors
Physiologi
c state
Nociceptive Pain Neuropathic Pain
PNS
peripheral
nervous
system
Pathologic
state

19.  Pharmacological
 Physical Therapy
 Behavioural Therapy
 Neuromodulation
 Interventional Approaches

20. 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

21. I. Most studies have been performed in postherpetic
neuralgia (PHN) and painful diabetic neuropathy (PDN)
II. Specific drug recommendations for the pharmacologic
treatment of neuropathic pain vary between these
multiple guidelines- IASP,EFNS,AAN ,NICE
III. First line agents include either calcium channel alpha
2-delta ligands (gabapentin or pregabalin ) or tricyclic
IV. Opioids should be considered a second or third-line
option.
V. Cause specific – Carbamzepine for trigeminal
neuralgia

22. TOPICAL ANALGESICS (capsaicin,
lidocaine patch 5%)
ANTICONVULSANTS (gabapentin,
lamotrigine, pregabalin)
ANTIDEPRESSANTS (nortriptyline,
desipramine)
OPIOIDS (oxycodone, tramadol)

23. Gabapentin and pregabalin bind to the voltage-gated
calcium channels at the alpha 2-delta subunit
PREGABALIN
 Started at 50-75 mg/day increased till 150-600mg /day
 Pregabalin may provide analgesia more quickly
than gabapentin
 pregabalin has the limitation having a short half-life (5–
6.5 hours), which necessitates frequent administration
 FDA approved in - Neuropathic pain – diabetic,post
herpetic neurlagia,Fibromyalgia
 European Union appoved for Central Neuropathic pain –
Spinal Cord injuries ,Multiple sclerosis

24.  American Academy of Physical Medicine and
Rehabilitation, in their joint evidence-based
guideline (2010), reported that pregabalin was
established to be effective and recommended that
it be offered for relief of painful diabetic
neuropathy (Level A recommendation)
 AAN guidelines for painful diabetic
neuropathy(Level A) Pregabalin should be offered
"if clinically appropriate.“

25. Cardiovascular: Peripheral edema (≤16%)
Central nervous system: Dizziness (8% to 45%),
somnolence (4% to 36%), ataxia (1% to 20%),
headache (5% to 14%), fatigue (5% to 11%)
Gastrointestinal: Weight gain (≤16%), xerostomia
(1% to 15%)
Neuromuscular & skeletal: Tremor (≤11%)
Ocular: Blurred vision (1% to 12%), diplopia
(≤12%)
Miscellaneous: Infection (3% to 14%), accidental
injury (2% to 11%)

26.  FDA approved for postherpetic neuralgia
 Anticonvulsant: uncertain mechanism
 Limited intestinal absorption
 Usually well tolerated; serious adverse effects
rare
◦ dizziness and sedation can occur
 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)*
*

27.  Mechanism of action – unknown
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 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
- AAN guidelines in diabetic neuropathy – insufficient
evidence .
- IASP recommendation +

28.  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.

29.  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,

30.  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

31.  The effi cacy of tramadol, including the combination
with acetaminophen, has been established mainly in
PDN
 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

32.  now established that strong opioids
(oxycodone, methadone, and morphine) have
effi cacy 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 -2.6 %

33.  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

34. 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)

39. 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 - PHN (60
minutes) and HIV neuropathy (30 minutes).

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

41.  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

42.  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

43.  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

44.  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

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

46.  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

47. 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

48.  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

50. 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.

52.  Cognitive behavioral therapy
 Biofeedback
 Relaxation therapy
 Psychotherapy and individual or group
counseling
 Aerobic exercise
 Acupuncture
 Physical and occupational therapy

54.  1.International Association for the Study of Pain.
Classification of chronic pain. Pain; 24:S1.Guidelines for
Management .NOV 2010
 2 .Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the
pharmacological treatment of neuropathic pain: 2010
revision. Eur J Neurol 2010; 17:1113.
 .3. . AAN Guidelines on Painful Diabetic Neuropathy
Susan Jeffrey – April 2011
 4. NICE clinical guidelines – April 2013

55. - 5.. Bradley s Neurology – 6th Edition
- 6. www.uptodate .com
- 7.The neurologic Basis of Pain – Marco Pappagalo
2005
- 8. Nature Clinical Practice Neurology (2006) 2, 95-
106
doi:10.1038/ncpneuro0113 .Mechanisms of
neuropathic pain