Pain initiated or caused by a primary lesion or dysfunction in the nervous system. It has mechanisms and pathways for its presence

1. Neuropathic Pain
Ahmed Mohamed Ibrahim

2. Contents
• Definitions
• Classifications of Pain
• Pathway of Pain
• Pathogenesis of Neuropathic Pain
• Management
• Clinical Picture
• Assessment
• Treatment

3. Definitions
What is pain?
“An unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage.” (IASP, 1994)

4. Definitions
ALLODYNIA
• Pain due to a stimulus which does not normally provoke
pain. An example is a patient with diabetic neuropathy
whose feet are sensitive to putting on socks.
HYPERALGESIA
• An increased response to a stimulus which is normally
painful. A clinical example of hyperalgesia might be an
amputee who is unable to use a prosthesis because of
tenderness overlying the stump.
ANALGESIA
• Absence of pain in response to stimulation which would
normally be painful.

5. Definitions
HYPERALGESIA
• An increased response to a stimulus which is normally painful.
HYPERESTHESIA
• Increased sensitivity to stimulation, excluding the special senses.
HYPERPATHIA
• A painful syndrome characterized by an abnormally painful reaction to a
stimulus, especially a repetitive stimulus, as well as an increased
threshold.
HYPOALGESIA
• Diminished pain in response to a normally painful stimulus.
PARESTHESIA
• An abnormal sensation, whether spontaneous or evoked.

6. Definitions
NEURALGIA
• Pain in the distribution of a nerve or nerves.
NEURITIS
• Inflammation of a nerve or nerves.
NEUROPATHY
• A disturbance of function or pathological change in a nerve:
in one nerve, mononeuropathy; in several nerves,
mononeuropathy multiplex; if diffuse and bilateral,
polyneuropathy.
NEUROPATHIC PAIN
• Pain initiated or caused by a primary lesion or dysfunction
in the nervous system.

7. Classifications of Pain
• Neuropathic Pain & Nociceptive Pain
• Acute vs chronic pain
• Stimulus-independent vs stimulus-evoked
• Hyperalgesia vs allodynia

8. Classification of Pain
Neuropathic pain Nociceptive pain
Cause
Injury to the nervous system, often
accompanied by maladaptive changes
in the nervous system
Damage or potential damage
to tissues
Descriptors
Lancinating, shooting, electric-like,
stabbing pain
Throbbing, aching, pressure-
like pain
Sensory
deficits
Common—for example, numbness,
tingling, pricking
Uncommon; if present they
have a non-dermatomal or
non-nerve distribution
Motor
deficits
Neurological weakness may be
present if a motor nerve is affected;
dystonia or spasticity may be
associated with central nervous
system lesions and sometimes
peripheral lesions (such as complex
regional pain syndrome)
May have pain induced
weakness

9. Classification of Pain
Neuropathic pain Nociceptive pain
Hypersensi
tivity
Pain often evoked by non-painful
(allodynia) or painful (exaggerated
response) stimuli
Uncommon except for
hypersensitivity in the
immediate area of an acute
injury
Character
Distal radiation common Distal radiation less common;
proximal radiation more
common
Paroxysms
Exacerbations common and
unpredictable
Exacerbations less common
and often associated with
activity
Autonomic
signs
Color changes, temperature changes,
swelling, or sudomotor (sweating)
activity occur in a third to half of
patients
Uncommon

10. Classification of Pain
Acute Pain
Time limited, <3 months
• Results from injury to
tissue
• Resolves with healing
• Example: herpes
zoster
Chronic Pain
Persistent, ≥3 to 6 months
• Continues after initial
injury heals
• Example: postherpetic
neuralgia

11. Pathway of Pain
Transduction
1.Noxious stimuli (thermal, mechanical, and
chemical) - - - - - tissue damage
2.Traumatized tissues release inflam. mediators
(PGs, Bradykinin, 5HT, SP, Histamine).
3.Nociceptive free nerve endings sensitized by
opening Na + channels - - - - Depolarization
4.So; noxious stimuli are converted to impulse (in
milliseconds)

12. The 1st order Neuron
• Is the cell of the posterior root ganglion & its
axon.
• This axon is divided into a lateral & a medial
branch.
• The lat. branch forms the afferent sensory nerve.
• The medial branch enters the spinal cord to
ascend a few segments forming Lissauer's tract,
and relays in the cells of Substantia Gelatinosa of
Rolandi (S.G.R.) capping the post, horn of the
gray matter.

13. The 2nd order Neuron
• Is the cell of S.G.R. & its axon.
• This axon crosses to the OPPOSITE side &
ascends in the Lateral Spinothalamic Tract of
the spinal cord then in the lateral lemniscus of
the brain stem, to relay in the thalamus.

14. • A-alpha nerve fibers carry
information related to
proprioception (muscle
sense).
• A-beta nerve fibers carry
information related to
touch.
• A-delta nerve fibers carry
information related to pain
and temperature.
• C-nerve fibers carry
information related to pain,
temperature and itch.

15. The 3rd order Neuron
• Starts in the cell of the thalamus, its axon
ascends to pass through the posterior limb of
the internal capsule conducting the impulse to
the cortical sensory area in the parietal lobe.

16. Secondary order neurons arising in the spinal cord transmit nociceptive input to the
thalamus through ascending pathways such as the spinothalamic tract, which
functions as a relay station to higher cortical centers. These centers include:
1. The anterior cingulate cortex, which is involved in anxiety, anticipation of pain,
attention to pain, and motor responses
2. The insular cortex, which may play a role in the sensory discriminative and
affective aspects of pain that contribute to the negative emotional responses
and behaviors associated with painful stimuli
3. The prefrontal cortex, which is important for sensory integration, decision
making, memory retrieval, and attention processing in relation to pain
4. The primary and secondary somatosensory cortices that localize and interpret
noxious stimuli
5. The nucleus accumbens, which is involved in placebo analgesia
6. The amygdala, hippocampus, and other parts of the limbic system, which are
involved in the formation and storage of memories associated with emotional
events, affect, arousal, and attention to pain and learning. The limbic system may
also be partially responsible for the fear that accompanies pain.

18. Disinhibition
Once a nociceptive stimulus is transmitted to
higher cortical centers, a series of events occurs
that results in the activation of inhibitory
neurons that attenuate pain.
- Spinal cord level
- Supraspinal level

20. • ↑ Release of GABA and glycine from primary
afferent terminals, and ↑ activity in inhibitory
GABAergic and glycinergic dorsal horn
interneurons. These spinal interneurons synapse
with central terminals of primary afferent
neurons, thereby reducing their activity, and also
regulate activity in ascending secondary order
neurons.
• After nerve injury, a loss of inhibitory currents
occurs as a result of dysfunctional GABA
production and release mechanisms

21. After nerve injury
• a loss of inhibitory currents occurs as a result
of dysfunctional GABA production and release
mechanisms.
• dorsal root ganglia exhibit decreased
expression of μ opioid receptors and
secondary spinal neurons become less
responsive to opioids.

22. Supraspinal level
• Descending pathways that modulate transmission
of nociceptive signals originate in the
periaqueductal gray, locus coeruleus, anterior
cingulate gyrus, amygdala, and hypothalamus,
and are relayed through brainstem nuclei in the
periaqueductal gray and medulla to the spinal
cord.
• The inhibitory transmitters involved in these
pathways include norepinephrine
(noradrenaline), 5-hydroxytryptamine, dopamine,
and endogenous opioids.

24. After nerve injury:
• diminution in tonic noradrenergic inhibition and a shift
from a predominantly inhibitory role to a facilitative
function for descending serotonergic modulation. The
manifold roles of these neurotransmitters to affect
pain, mood, and sleep may partially explain the high
comorbidity rates between pain, depression, anxiety,
and sleep disturbances.
• Monoamine reuptake inhibitors such as tricyclic
antidepressants are not only effective for neuropathic
pain and depression but also alleviate anxiety and
improve sleep

25. Pathogenesis of Neuropathic Pain
• Pain initiated or caused by a primary lesion or
dysfunction in the nervous system.
• Neuropathic pain is usually chronic, difficult to
treat, and often resistant to standard analgesic
management.

26. Pathogenesis of Neuropathic
Pain: Peripheral Mechanisms
Peripheral sensitization
• A lowering of the stimulus (pain) threshold for
nociceptor activation and an increased frequency of
nerve impulse firing in response to stimulation
(hyperexcitability). Peripheral sensitization is often
found at the site of tissue damage or inflammation
• In most patients, this state resolves as healing occurs
and inflammation subsides
• when nociception persists because of repeated
stimulation from ongoing injury or disease (for
example, in diabetes), the changes in primary afferent
neurons may persist.

27. Pathogenesis of Neuropathic
Pain: Peripheral Mechanisms
Ectopic discharges
• Trains of ongoing electrical nerve impulses that occur spontaneously without
stimulation or originate at sites other than the normal location (or both). This
phenomenon typically occurs after nerve injury (higher number of Na+
channels )
• Ectopic discharges can give rise to spontaneous pain and may originate from
the dorsal root ganglion, other points along an injured nerve, or even
uninjured adjacent fibers

28. • Several adjuvant drugs, such as
carbamazepine, act through the blockade of
sodium channels. Yet, because none of these
drugs is selective for channel subtypes
involved in pain, all have low therapeutic
indices and many side effects.

29. Calcium channels / potassium channels
• Certain types of calcium channels (N-type, T-type, and
L-type), and to a lesser extent potassium channels
(hyperpolarization activated cyclic nucleotide gated
channels), also play a role in neuropathic pain. After
nerve injury, the expression of α2δ calcium channels
increases in and around the dorsal root ganglia,
increasing excitability
• These voltage gated calcium channels are the primary
site of action for gabapentinoids, a first-line treatment
for neuropathic pain, which have been shown in
preclinical studies to reduce hyperalgesia and
spontaneous pain.

30. Spinal mechanisms
• Synaptic plasticity: increased neuronal responses
to repeated noxious stimulation in a time and
region dependent manner
• Increased neuronal excitability of ascending
nociceptive pathways that send pain signals to
supraspinal regions
• Peripheral nerve injury increases neuronal
excitability in the spinal cord by activating
excitatory glutamate receptors (Spinal
glutamatergic regulation, wind up).

31. Windup
• Progressive increase in the frequency and
magnitude of firing of dorsal horn neurons
(DHC) produced by repetitive activation of C
fibers above a critical threshold, leading to a
perceived increase in pain intensity
• DHC continue to discharge despite cessation
of C fiber stimulation.
• Requires glutamatergic NMDA receptor
activity

32. • Similar to the role of central glutamatergic
mechanisms in the pathogenesis of other
neurological disorders such as epilepsy and
Alzheimer’s disease, glutamate receptors are
integral to the development of central
sensitization, and blockade of both NMDA and
non-NMDA receptors has been shown to
attenuate neuropathic pain in animal models.
• For TTT: NMDA receptor antagonists (such as
ketamine, dextromethorphan, memantine)

33. Sympathetically maintained pain
• Functional coupling between the
sympathetic nervous system and
somatosensory nerves after nerve
injury has been noted since the
American civil war.
• The interaction between the
anatomically distinct autonomic and
somatosensory systems is complex
but probably includes the
expression of α adrenoceptors on
primary afferent sensory fibers,
sympathetic sprouting into dorsal
root ganglia, and impaired
oxygenation and nutrition in
response to sympathetically
mediated vasoconstriction.

34. • Clinically, sympathetically maintained pain
may manifest as temperature or color changes
(or both) in an affected extremity, swelling or
atrophy, and pain worsened by cold weather
or stress, which enhances sympathetic
outflow.

35. Supraspinal mechanisms
• The brains of patients with chronic pain are different
from those without pain, with variations in metabolism
and regional concentrations of neurotransmitters
occurring in areas such as the thalamus and cingulate
cortex.
• Changes that occur in supraspinal regions may explain
the strong association between neuropathic pain and
mood disorders.
• Patients with chronic pain have also been shown to
have reduced gray matter compared with control
patients, and this can be partially reversed by
treatment.

36. • In patients with neuropathic pain, cortical reorganization
occurs after injury, and the extent of the changes seems to
correlate with the degree of pain. For example, in upper
extremity amputees with phantom limb pain, because of
the close proximity of their somatotopic representations,
the area of the brain responsible for moving the lips
transgresses into the hand movement area of the motor
cortex; this phenomenon does not occur in amputees
without phantom limb pain.
• The observation that these changes occur after injury
suggests that disinhibition may not only be a consequence
of nerve injury, but may render patients susceptible to
chronic pain

37. Central sensitization
• Refers to increased excitation and reduced inhibition of
central nervous system pathways that are associated with
neuropathic pain.
• Prolonged depolarization of dorsal horn neurons and changes
in postsynaptic membrane receptors
• Neuroglia ("glial cells") may play a role in central sensitization.
Peripheral nerve injury induces glia to release pro-
inflammatory cytokines and glutamate—which, in turn
influence neurons.

38. Clinical Picture
Positive Symptoms
• Tingling (pins and
needles)
• Prickling
• Lightning like or
lancinating
• Aching
• Knifelike
• Pulling or tightening
• Burning or searing
• Electrical
Negative Symptoms
• Numbness
• Deadness
• Feeling of wearing
socks all the time

39. Causes
• Neuropathic pain Pain initiated or caused by a
primary lesion or dysfunction in the nervous
system
A) Peripheral neuropathic pain
B) Central neuropathic pain

40. Peripheral causes of neuropathic pain
• Trauma
– e.g. surgery, nerve entrapment, amputation
• Metabolic disturbances
– e.g. diabetes mellitus
• Infections
– e.g. herpes zoster (shingles), HIV
• Toxins
– e.g. chemotherapeutic agents, alcohol
• Vascular disorders
– e.g. polyarteritis nodosa
• Nutritional deficiencies
– e.g. niacin, thyamine, pyridoxine
• Direct effects of cancer
– e.g. metastasis, infiltrative

41. Central causes of neuropathic pain
• Stroke.
• Spinal cord lesions.
• Multiple sclerosis.
• Tumors.

42. Assessment: History
• Distribution and location of pain : Dermatomal
or non- Dermatomal
• Character of complaints : e.g. burning, shock-
like, pins and needles etc.
• Duration of complaints
• Average Intensity of pain in the last day/week
(0-10)
• Extent of interference with daily activity (0-10)

43. Other in history
• Previous medical history
• Exposure to toxins or other drug treatment
e.g. radiation
• Use of pain medications
• Associated psychological and mood
disturbance

44. Assessment: Neurophysiological
EMG-NCV
• To localise pain-generator/nerve or root lesion
• To rule out :
- Axonal Vs focal segmental demyelination
- Underlying small-fiber or mixed
polyneuropathy

45. Assessment: Biopsy
Nerve ( eg, sural nerve ) :
• To diagnose vasculitis, amyloidosis,
sarcoidosis, etc.
Skin :
• To evaluate density of unmyelinated fibers
within dermis and epidermis

46. Management

47. Treatment

48. Non-pharmacological
• Cognitive-behavioral
strategies
• Meditation
• Biofeedback
• Relaxation therapy
• Physical rehabilitation
• Acupuncture
• TENS (Transcutaneous
electrical nerve
stimulation)

49. Pharmacological
Most randomized controlled drug trials in neuropathic
pain have been in painful diabetic neuropathy and post-
herpetic neuralgia, and the US Food and Drug
Administration (FDA) has approved six medications for
three neuropathic pain syndromes
Neuropathic Pain Medications Approved
by the US Food and Drug Administration (FDA)
Indication Medication
Trigeminal neuralgia Carbamazepine
Painful diabetic neuropathy Duloxetine, pregabalin, capsaicin cream
Post-herpetic neuralgia
Gabapentin, pregabalin, topical lidocaine,
capsaicin 8% patch, capsaicin cream

50. Tricyclic Antidepressants
• The analgesic effect of tricyclic antidepressants is due to inhibition
of norepinephrine reuptake at the spinal dorsal synapses, with
secondary activity at sodium channels
• Amitriptyline, Nortriptyline (similar efficacy but fewer side effects
than amitryptiline)
• are effective for several different types of neuropathic pain,
mainly painful diabetic neuropathy and postherpetic neuralgia.
• initiated at low dosages (10 mg/d to 25 mg/d at bedtime), and the
dose can be increased every 3 to 7 days by 10 mg/d to 25 mg/d as
tolerated. The goal dose is 75 mg/d to 150 mg/d.
• An adequate trial of a tricyclic antidepressant should last 6 to 8
weeks with 1 to 2 weeks at the maximum tolerated dose.

52. Calcium Channel α2δ Ligands
• Gabapentin and Pregabalin: Gabapentin and
pregabalin have the most evidence-based data
for the treatment of painful diabetic neuropathy.
• Effective in treating several neuropathic pain
conditions. Generally well tolerated with few
medication interactions but can cause sedation
and dizziness.

53. Gabapentin
• Modulation of voltage-gated calcium channels to inhibit neurotransmitter
release.
• Gabapentin has also been shown to be effective in phantom limb pain,
pain in Guillain-Barre´ syndrome, and pain from spinal cord injury.
• starting dose is 100 mg to 300 mg 3 times a day, and it is titrated up every
1 to 7 days by 100 mg/d to 300 mg/d as tolerated up to a target dose of
1800 mg/d to 3600 mg/d.
• To reduce side effects, practitioners may start with a single bedtime dose,
increase to twice a day, and then increase to 3 times daily. Although 3
times a day dosing is ideal, occasionally a higher dose is given at bedtime
to limit daytime sedation. An adequate trial of gabapentin would include 3
to 8 weeks for titration and development of tolerance to adverse effects,
plus 1 to 2 weeks at the maximum tolerated dose.

54. • Pregabalin is FDA approved for the treatment of painful
diabetic neuropathy and is also effective in post-
herpetic neuralgia and spinal cord injury and other
causes of central neuropathic pain.
• Has dose dependent effects and is typically not
effective at the starting dose of 150 mg/d.
• The initial dose is either 50 mg 3 times daily or 75 mg 2
times a day, which can be increased to a total dose of
up to 300 mg/d after 1 to 2 weeks.
• Pregabalin has a similar side effect profile to
gabapentin, but patients tend to tolerate a more rapid
dose titration.

55. Serotonin Norepinephrine
Reuptake Inhibitors
• Duloxetine is a balanced inhibitor of
serotonin and norepinephrine
reuptake, while venlafaxine inhibits
serotonin reuptake at lower dosages
and inhibits the reuptake of both
neurotransmitters at higher dosages
of 150 mg/d or more.
• Starting dose is 60 mg/d, but
starting at 30 mg/d may reduce the
incidence of nausea. The usual total
daily dose is 60 mg/d to 120 mg/d,
but no additional benefit has been
found from taking dosages of more
than 60 mg/d.

56. Venlafaxine
• starting dose for immediate
release is 75 mg/d in 2 or 3
divided doses, and it can be
increased as tolerated up to
225 mg/d.
• Venlafaxine extended release
is started at 37.5 mg or 75 mg
once a day and is increased
over 2 to 4 weeks to 150 mg/d
to 225 mg/d.

57. Topical Lidocaine
• Topical lidocaine acts locally
by antagonizing sodium
channels and reducing
spontaneous ectopic nerve
discharges.
• The 5% lidocaine patch is FDA
approved for the treatment of
postherpetic neuralgia, but
the treatment effect is
moderate.

58. Topical Capsaicin
• Capsaicin is a hot chili
pepper extract, and its
mechanism of action in
treating neuropathic pain
is not well understood,
but it is thought to result
in desensitization of
sensory axons and
epidermal denervation

59. Tramadol and Opioid Analgesics
• Tramadol and opioid analgesics are effective in
different types of neuropathic pain but are generally
not recommended as first-line treatments because of
concerns about long-term safety.
• Recommended as first-line treatments in acute
neuropathic pain, neuropathic pain due to cancer, and
episodic exacerbations of severe neuropathic pain.
• They are also used while a first-line medication is being
titrated when immediate pain relief is needed.

60. • Tramadol has a dual mechanism of action: as a central
opioid agonist at the mu receptor and as an inhibitor of
norepinephrine and serotonin reuptake.
• Tramadol has been shown to be effective in several
neuropathic pain conditions should be avoided in
patients with a history of substance abuse. started at a
low dose, 50 mg once or twice a day, and titrated every
3 to 7 days by 50 mg/d to 100 mg/d in divided doses as
tolerated. The maximum dose is 100 mg 4 times a day
(maximum total daily dose 300 mg/d in patients older
than 75 years)

61. Carbamazepine
• Carbamazepine is
FDA approved for the
treatment of
trigeminal neuralgia
and is the first-line
medication for
treatment in this
neuropathic pain
condition.

62. • Divalproex sodium has been found to have a
beneficial effect in treating painful diabetic
neuropathy and trigeminal neuralgia but lacks
efficacy in reducing overall pain or improving
quality of life

63. • Lamotrigine is the only drug that has been
found to be moderately effective in patients
with HIV-associated neuropathy who were
receiving antiretroviral treatment.

64. • Lacosamide, topiramate, zonisamide, and
phenytoin have also been studied in painful
diabetic neuropathy, but only inconclusive
evidence exists for their use in the treatment
of neuropathic pain.

65. • SSRIs have been shown to have efficacy in the
treatment of neuropathic pain in small studies,
but pooled data failed to show a significant
difference in pain relief compared to placebo.
• A weak analgesic effect has been found for
citalopram, paroxetine, and escitalopram, but not
fluoxetine.
• SSRIs must be used with caution alongside
tricyclic antidepressants because of an increased
risk for serotonin syndrome.

66. Cannabinoids
• have been found to be effective in treating
neuropathic pain associated with multiple
sclerosis and in neuropathic pain with
allodynia, but overall the results of clinical
trials have been inconsistent, and legal and
regulatory issues surround its use.
• They are recommended as third-line
analgesics for the treatment of neuropathic
pain by the Canadian Pain Society

67. NMDA receptor antagonists
(such as ketamine, dextromethorphan,
memantine)
• The long-term use of these drugs to
treat chronic neuropathic pain has
also had mixed results, and their use
may be limited by side effects.
• The use of ketamine infusions as a
treatment for refractory neuropathic
pain has generated intense interest,
although studies are limited by
methodological flaws and lack of long
term follow-up

68. Combination Therapy
• Few studies have examined the efficacy of this
strategy.
• Compared to monotherapy, the combination
of gabapentin and morphine or gabapentin
and nortriptyline was found to provide better
pain relief at lower dosages in patients with
painful diabetic neuropathy and postherpetic
neuralgia.

69. Repetitive transcranial magnetic
stimulation (rTMS)
Transcranial magnetic stimulation appears poised for the larger
trials necessary for regulatory approval of a NP indication
• Repetitive TMS in treatment of resistant diabetic neuropathic
pain. rTMS significantly reduced painful diabetic neuropathy.
rTMS may produce its analgesic effects, inducing motor cortex
plasticity and activating descending inhibitory pain control
systems. (Ann et al., 2019)
• High-frequency rTMS applied over the M1 for 10 consecutive
days can provide long-term pain relief in patients with thalamic
pain without causing severe adverse effects. (Lin et al., 2018)
• The results demonstrate that 10 rTMS sessions over the M1 can
induce short-term pain relief in malignant neuropathic pain.
(Khedr et al., 2015)