neuropathic%20pain
NEUROPATHIC PAIN
Neuropathic pain is the sensation of pain due to abnormal discharges of impaired or injured neural structures in the peripheral &/or central nervous system.
It is characterized by hyperesthesia, hyperalgesia and allodynia.
Common neuropathic pain syndromes are central neuropathic pain, painful diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, postsurgical neuropathic pain, HIV-related neuropathy, lumbosacral radiculopathy and complex regional pain syndrome.

Principles of Therapy

  • Selection of a particular drug will depend on the experience of the clinician and patient, along with the expected adverse reactions
  • Combination therapy may be necessary to optimize pain control
    • Medications should be chosen based on their additional potential therapeutic effects

Pharmacotherapy

Central Neuropathic Pain

1st-line Agents

  • Anticonvulsants
    • Eg Gabapentin, Pregabalin
    • Bind to presynaptic voltage-gated Ca channels in the dorsal horn, resulting in a decrease in the release of excitatory neurotransmitters such as glutamate and substance P
      • Pregabalin has higher affinity for the presynaptic Ca channel and has been shown to provide significant pain relief in chronic central neuropathic pain following spinal cord injury
  • Tricyclic Antidepressants
    • Eg Amitriptyline, Desipramine, Imipramine, Nortriptyline
    • Inhibit presynaptic reuptake of serotonin and norepinephrine, and block cholinergic, adrenergic, histaminergic and Na channels; block hyperalgesia induced by N-methyl-D-aspartate (NMDA) agonists

2nd-line Agent

  • Weak Opioid
    • Eg Tramadol
    • Low-affinity binding to µ-opioid receptors and weak inhibition of norepinephrine and serotonin reuptake
    • Recommended as a 2nd-line treatment for central neuropathic pain
    • Has quick onset of pain relief and less sedative effect
    • Lower risk of abuse than strong opioid receptor agonists

3rd-line Agent 

  • Strong Opioids
    • Eg Oxycodone, Morphine, Levorphanol
    • Recommended as 3rd-line treatment due to limited trials assessing long term safety and abuse potential
    • Associated with quick onset of pain relief and is therefore useful for short-term use to treat acute exacerbations or during titration phase of 1st-line agents

 Other Agents

  • Lamotrigine
    • Blocks voltage-dependent Na channels inhibiting presynaptic release of excitatory amino acids
    • May be considered in central post-stroke pain or spinal cord injury with incomplete cord lesion and brush-induced allodynia only if all other treatments fail
  • Cannabinoids
    • Eg Tetrahydrocannabinol, Cannabidiol
    • May be considered in central pain in multiple sclerosis only if all other treatments fail

Painful Diabetic Peripheral Neuropathy

1st-Line Agents

  • Anticonvulsants
    • Gabapentin has effective pain relief for patients with diabetic peripheral neuropathy; similar efficacy as Amitriptyline but with a better side effect profile
    • A recent study on Gabapentin and Nortriptyline use for diabetic peripheral neuropathy or postherpetic neuralgia, showed significantly lower pain scores in the combination phase than for either treatment alone; Gabapentin monotherapy and Nortriptyline monotherapy were similar in efficacy
    • Pregabalin provides significant pain relief and improved quality of sleep in diabetic peripheral neuropathy
  • Tricyclic Antidepressants
    • Amitriptyline, Desipramine, Imipramine, Nortriptyline have been used successfully
    • Typically considered 1st-line agents for painful neuropathies, including diabetic peripheral neuropathy, but use may be restricted by adverse effects
    • Advantages of tricyclic antidepressants include their effect on insomnia and depression which are common comorbidities in neuropathic pain patients
    • Baseline echocardiogram for patients >40 years old is recommended; tricyclic antidepressants should not be given to patients at risk for sudden cardiac death or with history of cardiovascular disease
  • Serotonin-Norepinephrine Reuptake Inhibitors
    • Eg Duloxetine, Venlafaxine
    • Highly specific inhibition of serotonin and norepinephrine reuptake allows the availability of these neurotransmitters in the synapse
    • Duloxetine is well-tolerated and not associated with anticholinergic side effects seen in tricyclic antidepressants use; however, it is more expensive than tricyclic antidepressants
    • Venlafaxine has shown efficacy in clinical trials involving diabetic peripheral neuropathy and mixed painful polyneuropathy

2nd-line Agents

  • Weak Opiod
    • Tramadol
    • Recommended by European Federation of Neurological Societies (EFNS) and International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) as 2nd-line treatment except for those with acute exacerbation of diabetic peripheral neuropathy, in which case it can be considered as 1st-line option
    • Tramadol and Tramadol/Paracetamol combination are effective in reducing pain due to diabetes
    • Use with caution in the elderly because of risk of confusion; it is also associated with increased risk of serotonin syndrome when used together with serotonergic drugs
  • Lidocaine (Topical)
    •  As per 2015 recommendations from International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG), Lidocaine patches can be a 2nd-line treatment due to its safety profile and patient preferences
    • Decreases neuronal membrane’s permeability to Na ions, thereby blocking the initiation and conduction of nerve impulses
    • Small randomized or open-label trials have shown the efficacy of topical 5% Lidocaine transdermal patches for pain relief in patients with diabetic peripheral neuropathy, with minimal adverse events; significant improvement in ongoing pain, intensity of allodynia and quality-of-life measures have also been noted
  • Capsaicin (Topical)
    •  It has been proposed by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) that Capsaicin patches can be a 2nd-line treatment for peripheral neuropathy
    • Depletes stores of substance P from sensory nerve endings, reducing or abolishing transmission of painful stimuli from the peripheral nerve fibers to the higher centers
    • Patient needs to be willing to apply 3-4 times daily and may experience initial skin irritation which typically improves in 1-2 weeks
    • In studies of patients with diabetic peripheral neuropathy, adjunctive therapy with topical Capsaicin showed better pain relief compared to its inactive vehicle comparator

3rd-line Agents

  • Strong Opioids 
    • Eg Oxycodone, Morphine 
    • Effective in reducing pain in diabetic peripheral neuropathy
    • Recommended as 3rd-line therapy because of concerns regarding long-term safety including potential for addiction and misuse

Other Agents

  • Botulinum toxin type A
    • A potent neurotoxin that may have analgesic effects by acting on neurogenic inflammation
    • Randomized controlled-trials have shown that Botulinum toxin type A was effective in reducing pain in peripheral neuropathy versus placebo
  • Alpha-lipoic acid (Thioctic acid)
    • Decreases oxygen free radicals thereby influencing the underlying neuropathic process
    • Studies have shown that it decreases pain, paresthesias and numbness, and has a favorable safety profile
  • Benfotiamine
    • Lipid-soluble thiamine derivative that studies show to have improved neuropathic pain in patients with diabetic neuropathy as being a transketolase activator and inhibitor of alternative metabolic pathways implicated in the pathogenesis of hyperglycemia-induced vascular damage
  • Tapentadol
    • An opioid with noradrenaline reuptake inhibition with low affinity for the mu opioid receptor
    • Approved as treatment for diabetic polyneuropathy in patients requiring continuous, around-the-clock opioid treatment

Postherpetic Neuralgia

1st-line Agents

  • Anticonvulsants
    • Gabapentin and Pregabalin have established efficacy against post herpetic neuralgia
    • 1st-line agent for post herpetic neuralgia, especially in the elderly in whom tricyclic antidepressants are not well-tolerated
    • Gabapentin produces significant pain relief and improvement in measures of quality of life and mood
    • Pregabalin has been shown to significantly decrease pain and improve sleep in randomized placebo-controlled trials 
  • Tricyclic Antidepressants
    • Amitriptyline, Desipramine, Nortriptyline and Maprotiline have been used successfully with Amitriptyline as the most widely used tricyclic antidepressants for post herpetic neuralgia
    • Nortriptyline has been shown to be as effective as Amitriptyline but better tolerated
    • Many controlled trials have shown the efficacy of tricyclic antidepressants in post herpetic neuralgia

2nd-line Agents

  • Lidocaine (Topical)
    • Generally recommended as 2nd-line treatment for postherpetic neuralgia by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) due to low quality of evidence
    • Recommended as 1st-line treatment by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) for the elderly frail patients, in whom there are concerns for central nervous system adverse reactions from oral medications
    • Five randomized placebo-controlled trials in postherpetic neuralgia supported the efficacy of Lidocaine patches with brush-induced allodynia
    • Lidocaine gel (5%) has been shown to give significant pain relief in postherpetic neuralgia for up to 8 hours
  • Capsaicin (Topical)
    • Recommended as 2nd-line treatment for postherpetic neuralgia by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) due to relatively small effective size 
    • Provides significant pain relief but patient response can be delayed
    • Discomfort and burning sensation may limit patient compliance
  • Tramadol
    • A weak opioid and a mixed serotonin-noradrenaline reuptake inhibitor found in studies to be an alternative if first-line oral monotherapies are ineffective
    • Recommended as 2nd-line treatment for postherpetic neuralgia by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) due to potential safety concerns

3rd-Line Agents

  • Opioids
    • Generally recommended as 3rd-line treatment for postherpetic neuralgia by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) due to abuse potential and side effects that include endocrine effects
    • Oxycodone, Morphine and Methadone have similar efficacy in postherpetic neuralgia compared to tricyclic antidepressants but these are associated with frequent discontinuation because of adverse events
    • Randomized placebo-controlled trials in postherpetic neuralgia showed that Oxycodone and Morphine provide significant reduction in pain intensity, with variable improvement in sleep and disability
  • Botulinum toxin type A
    • It showed positive results in 2 randomized controlled trials
    • It has been recommended as 3rd-line treatment for postherpetic neuralgia by International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) due to weak quality of evidence thus it is only used in refractory cases

If adequate pain control is not achieved using pharmacological agents discussed above, consider expert referral to a pain medicine specialist for alternative therapy

  • Alternative therapy includes NMDA-receptor antagonists, intrathecal steroids, IV adenosine 5’-triphosphate, or combination therapy

Trigeminal Neuralgia

1st-line Agents

  • Carbamazepine
    • Drug of choice for trigeminal neuralgia but efficacy may be compromised by poor tolerability and pharmacokinetic interactions
    • Randomized placebo-controlled trials have shown reduction in frequency and intensity of painful paroxysms and equal efficacy for spontaneous and trigger-evoked attacks
  • Oxcarbazepine
    • Typically better tolerated than Carbamazepine due to decreased potential for drug interactions
    • Two randomized placebo-controlled trials found similar efficacy of Oxcarbazepine with Carbamazepine on number of attacks and global assessment

If refractory to Carbamazepine and Oxcarbazepine, 2nd-line agents may be added to treatment regimen for trigeminal neuralgia

2nd-line Agents

  • Baclofen has been reported in a study to be superior to placebo in reducing the number of painful paroxysms in trigeminal neuralgia
  • Lamotrigine has been reported in a study to be efficacious in trigeminal neuralgia and may also be effective as add-on therapy
  • Other anticonvulsants (eg Clonazepam, Gabapentin, Phenytoin and Valproate) have been suggested in small open-label studies to have therapeutic benefit for trigeminal neuralgia but evidence remains insufficient to support or refute their efficacy

Non-Pharmacological Therapy

Central Neuropathic Pain

Psychological Approaches

  • Psychological or behavioral therapy may of benefit in some patients
Painful Diabetic Peripheral Neuropathy (DPN)

Optimize Glycemic Control

  • Tight glucose control in type 1 diabetes mellitus patients helps to delay the onset of diabetic polyneuropathy and helps to slow the progression of the disease
    • The benefits of intensive insulin therapy usually outweigh the risks
  • It is generally agreed that any improvement in glycemic control in type 2 diabetes mellitus patients is beneficial
    • Use tight glucose control in the elderly with caution as they are more susceptible to the effects of hypoglycemia

Proper Foot Care

  • Patients should inspect their feet daily, use proper foot hygiene and wear proper fitting socks/hosiery that is changed daily
  • Footwear
    • Patients with neuropathy may benefit from well-fitted walking shoes or athletic shoes
    • If patient has evidence of increased plantar pressure then their footwear should cushion and redistribute pressure
  • Expert referral if patient suffers trauma, cellulitis or acute ischemia of the foot

Psychological Approaches

  • Cognitive behavioral therapy may of benefit in reducing pain severity and interference in patients with painful diabetic neuropathy as per recent pilot randomized controlled study
Alternative Therapies
  • Physiotherapy has been reported to provide pain relief in some patients
  • Acupuncture has minimal but not insignificant risks
    • May relieve pain and/or reduce the need for pain medications in selected patients
  • Transcutaneous Electrical Nerve Stimulation
    • Mild electrical stimulation through the application of surface electrodes over the painful area generates heat that relieves stiffness and improves mobility
  • Interferential Therapy uses the strong physiological effects of low frequency electrical stimulation of nerves to provide pain relief indiabetic peripheral neuropathy
  • Spinal Cord Stimulation has high costs and risks but with limited evidence of efficacy
  • Frequency-Modulated Electromagnetic Neural Stimulation may be helpful but with limited evidence of efficacy

Postherpetic Neuralgia

Physical Methods

  • If the patient suffers from allodynia, application of a protective layer (eg cling film) between the skin and clothing may be helpful
  • Transcutaneous electrical nerve stimulation may be helpful in some postherpetic neuralgia patients
  • Acupuncture has limited success
  • Physical and occupational therapy may also have a role in treating patients with chronic pain

Psychological Approaches

  • Cognitive-behavioral therapy, relaxation training, biofeedback and self-hypnosis techniques may help in managing intractable postherpetic neuralgia
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