Pharmacotherapy of Neuropathic Pain

International Association for the Study of Pain – IASP definition

Neuropathic pain à pain arising as a direct consequence of a lesion or disease affecting the somatosensory system

  • global prevalence –1.5% and 8%.
  • Causes of Neuropathic pain

Mechanism of NP

  • All the causes mentioned – can trigger the release of inflammatory mediators- alters the properties of primary afferent neuronsà
  • appearance of ectopic impulse because of increase in excitability and alterations in the properties of various types of Ca2+ channels, voltage-gated Na+ and K+ channels and function of Na+-K+ ATPases, intracellular Ca2+ handling and TRP channels
  • There are changes in synaptic transmission; excitatory synaptic processes are enhanced while inhibitory processes are attenuated.

Mechanism of NP- Allodynia

  • Aδ and C-fibers carry information of noxious stimuli which synapse primarily onto dorsal horn neurons in laminae I and II whereas
  • Aβ fibers carry tactile and innocuous (not harmful) information in laminae III and IV.
  • Normally these two are separated by GABAergic and glycinergic inhibition by suppressing the activity of pre-existing excitatory synaptic circuits
  • But post nerve injury there is attenuation of both these transmissions leading to abnormal processing of the sensory input
  • Hence, tactile information are processed as pain sensation.

Symptoms of NP

Electric shock like sensation, numbness, stabbing, pins and needles, shooting, throbbing and burning sensation

If untreated, the symptoms persist and have a propensity to become chronic.

The response to pain medications decreases in later stages.

Patients suffering from neuropathic pain frequently experience anxiety and sleep disturbances.

Untreated chronic neuropathic pain can also lead to depression in patients as the quality of life is impaired. Thus, early screening is required to diagnose it and initiate appropriate treatment for effective management of patients experiencing neuropathic pain.

Screening tool for NP

Screening tools which combine self-reporting with physical examination are more accurate than those using self-reporting alone

  • Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale
  • Douleur Neuropathique 4 (DN4) questionnaire
  • Neuropathic Pain Questionnaire
  • pain DETECT
  • ID Pain
  • Neuropathic Pain Symptom Inventory

Diagnosing neuropathic pain

  • Bedside examination – to detect the thresholds of touch, pressure, heat, cold and vibration sensation
  • Pain diagram -pinpoint location of their pain
  • Visual analogue scale

Management of NP

  • Treatment targeted to the specific diagnosis. Eg. – Control of Diabetes, removing offending drug , relieving compression
  • Pharmacotherapy- Start at lowest dose increase every 3 to 7 days to max tolerated dose
  • Behavioral Therapy, neuromodulation and psychological therapy.

NeuPSIG guidelines

1st line – Gapabentin, Gabapentin ER/enacarbil, Pregabalin, Duloxetine, Venlafaxine, TCAs

2nd line – Capsaicin patches, Lidocaine patches, Tramadol

3rd line – Botulinum toxin type A, Strong Opioids


MOA- Act on the α2δ subunit of voltage-gated calcium channels, which decrease central sensitization

Pregabalin blocks the VGCC and hence decrease glutamate and sensory neuropeptides (substance P and CGRP) release at synapse by decreasing Ca2+ influx. EAATs (excitatory amino acid transporters) activity is increased by pregabalin which caused more decrease in synaptic availability of glutamate. Decreased glutamate levels further inhibited the activation of NMDA and decreased the neuronal firing. 

Dose- started at 75-150 mg/day, titrate to 300–600 mg, in two divided doses

Side effects –

  • * Dizziness (8% to 45%), somnolence (4% to 36%), ataxia (1% to 20%), headache (5% to 14%), fatigue (5% to 11%)
  • * Angioedema, peripheral edema
  • * Suicidal Behavior and Ideation
  • * Tremor
  • * Weight gain (3.7%)
  • * Blurred vision (4.8%), diplopia
  • Precaution- Reduce dose in patients with renal insufficiency


MOA- Act on the α2δ subunit of voltage-gated calcium channels, which decrease central sensitization

  • Gabapentin 1200–3600 mg, in three divided doses.
  • Side effects- Sedation, dizziness, peripheral edema and weight gain


Mechanism of action – serotonin and norepinephrine reuptake inhibitors –  activate the descending inhibitory system

Antidepressants increase noradrenaline via blocking of noradrenaline transporters at the terminal of the descending noradrenergic fiber from the locus coeruleus.

Noradrenaline inhibits acute pain through α2-adrenergic receptors by pre-synaptic (inhibit neurotransmitters release) and post-synaptic (hyperpolarize cell membranes) mechanisms.

  • exert an analgesic action at doses lower than that required for antidepressant action, independently of their antidepressant action 
  • Amitriptyline most widely used – doxepin , imipramine , nortriptyline , and desipramine also have been used.
  • Amitriptyline /nortriptyline may be started at 10 mg/d bedtime and slowly titrated up to an effective analgesic dose (eg, 75 mg/d).
  • Side effects- Commonly reported AEs (generally anticholinergic): ◦ blurred vision ◦ cognitive changes ◦ constipation ◦ dry mouth ◦ orthostatic hypotension ◦ sedation ◦ sexual dysfunction ◦ tachycardia ◦ urinary retention


  • Analgesic effect- attributed to activation of the descending pain inhibitory system by serotonin and noradrenalin.
  • Fewer side effects than TCAs
  • venlafaxine , duloxetine
  • Venlafaxine- 150-225mg/day
  • Duloxetine – 60 -120 mg /day . Started at 30 mg/day
  • ADR – nausea, somnolence, dry mouth, constipation, reduced appetite, diarrhea, hyperhidrosis, and dizziness,


Due to potential risk of abuse and concern about a recent increase in prescription opioid-associated overdose mortality, strong opioids are now recommended as third line of therapy.

  • Tramadol- μ-Receptor agonist and monoamine reuptake inhibition
  • Morphine- μ-Receptor agonist
  • Tramadol àStarted at 50 mg once daily, and then titrated as tolerated. The effective dosage range is 200–400 mg/day.
  • Morphine àIndividual titration
  • Side effects- Induces dizziness, dry mouth, nausea, constipation, and somnolence

NICE guidelines recommend tramadol only for use in rescue therapy on the basis that it was generally associated with higher rates of withdrawal due to adverse events compared with other treatments options

Lidocaine patch

  • Lidocaine 5% – Sodium channel blockade
  • Up to 3 patches applied once daily directly over painful site for 12 h
  • Most appropriate for patients with well localized neuropathic pain and Allodynia
  • most common side effect: application-site sensitivity

Capsaicin patch 8%

  • Capsaicin is an irritating chemical found in chili peppers that causes burning pain upon contact with skin.
  • Immediately after topical application, it induces the release of substance P, which causes vasodilation and local irritation.
  • Upon chronic application, the nociceptive threshold is increased by depletion of substance P.
  • Agonist of the transient receptor potential vanilloid receptor (TRPV1) and activates TRPV1 ligand-gated channels on nociceptive fibers
  • One to four patches to the painful area for 30-60 min every 3 months
  • 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

Botulinum toxin

  • Botulinum toxin (BoNT) inhibits the release of pain mediators in peripheral nerve terminal, DRG, and spinal cord neuron, thereby reducing the inflammatory response and preventing the development of peripheral and central sensitization.
  • deactivates the sodium channel
  • Acetylcholine release inhibitor and neuromuscular-blocking agent.
  • 50–200 units to the painful area every 3 months
  • Side effects- Pain at injection site

Behavioral therapy

  • Cognitive behavioral therapy
  • Relaxation therapy
  • Psychotherapy and individual or group counseling
  • Acupuncture
  • Physical and occupational therapy

How to Select First-Line Treatment

  • Although pregabalin and gabapentin have the same mechanism of action on the alfa2delta  subunit of the presynaptic calcium channel, and randomized controlled trials showed that the two drugs have the same efficacy,
  • pregabalin has a linear pharmacokinetic profile, more favorable than gabapentin.
  • The  pregabalin absorption after oral intake is not saturable and the bioavailability is virtually complete.
  • Therefore, in daily clinical practice, pregabalin is a better option than gabapentin.

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