CURRENT CONCEPT OF NEUROPATHIC PAIN

Dr Sankalp MohanSenior Resident

NeurologyGovt. Medical College

Kota

“Pain is an unpleasant sensory and emotional experience

associated with actual or potential tissue damage or described in

terms of such damage.”

IASP Definition of Pain

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

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 

ACUTE AND CHRONIC PAIN

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

Mixed TypeCaused by a

combination of both primary injury and secondary effects

Nociceptive vs Neuropathic PainNociceptive

PainCaused 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

Postoperativepain

Mechanicallow back pain

Sickle cellcrisis

ArthritisPostherpetic

neuralgia

Neuropathic low back pain

Sports/exerciseinjuries

*Complex regional pain syndrome

Central post-stroke pain

Trigeminalneuralgia

DPNP

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.

PATHOPHYSIOLOGY OF PAIN

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

Nociceptors – high-threshold mechanoreceptors (HTMs) –

myelinated A delta   C-polymodal nociceptors (C-PMN) –

unmyelinated C fibres

Can respond to multiple stimuli – heat,cold,chemical

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

MECHANISMS FOR PERSISTENT PAIN 

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

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

Central sensitization

Central sensitization

Peripheral sensitization

CNS

PNS

CNScentralnervous system

“Healthy” nociceptor

sNormaltransmission

Central reorganization

Abnormalnociceptors

Physiologic state

Nociceptive Pain Neuropathic PainPNS

peripheral nervous system

Pathologic state

Pharmacological Physical Therapy Behavioural Therapy Neuromodulation Interventional Approaches

Approach to treatment

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 dose5. Physical, psychological, environmental and

behavioural factors

IMPORTANT CONSIDERATIONS

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

TOPICAL ANALGESICS (capsaicin, lidocaine patch 5%)

ANTICONVULSANTS (gabapentin, lamotrigine, pregabalin)

ANTIDEPRESSANTS (nortriptyline, desipramine)

OPIOIDS (oxycodone, tramadol)

Classes of Drugs

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

Pregabalin and Gabapentin

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.“

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%)

Side effects

Gabapentin in Neuropathic Pain Disorders 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)*

*

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 +

Tricyclic antidepressants

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

FewestAEs

Most AEs

AEs = adverse effects.

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

topiramate , lamotrigine , levetiracetam ,phenytoin ,  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

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

OPIODS

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 %

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

Topical vs Transdermal Drug Delivery Systems

Systemic activityApplied away from painful site

Serum levels necessarySystemic side effects

Peripheral tissue activityApplied directly over painful site

Insignificant serum levelsSystemic side effects unlikely

Topical (lidocaine patch 5%)

Transdermal(fentanyl patch)

IASP RECOMMENDATIONS

AAN GUIDELINES

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).

Emerging Drug Treatments

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

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

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

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

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

Interventional treatments

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

TENS

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

TENS electrodes are contraindicated:1. Over the eyes due to the risk of increasing intraocular pressure2. Transcerebrally3. 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 present6. Internally, except for specific applications of dental, vaginal,

and anal stimulation that employ specialized TENS units7. On broken skin areas or wounds, 8. Over a tumour/malignancy9. Directly over the spinal column

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

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.

Cognitive behavioral therapy Biofeedback Relaxation therapy Psychotherapy and individual or group

counseling Aerobic exercise Acupuncture Physical and occupational therapy

Behavioural Therapy

THANK YOU

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

REFERENCES

- 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,

95-106doi:10.1038/ncpneuro0113  .Mechanisms of neuropathic pain