Neuropathic%20pain Treatment

• 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

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
    • Consider for short duration of treatment only

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
• Serotonin and Norepinephrine Reuptake Inhibitors (SNRI)
  • Duloxetine have been shown to be effective in neuropathic pain due to multiple sclerosis

Painful Diabetic Peripheral Neuropathy (DPN)

1st-line Agents

• Anticonvulsants
  • Gabapentin has effective pain relief for patients with DPN; similar efficacy as Amitriptyline but with a better side effect profile
  • A recent study on Gabapentin and Nortriptyline use for DPN or PHN, 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 DPN

• Tricyclic Antidepressants (TCAs)
  • Amitriptyline, Desipramine, Imipramine, Nortriptyline have been used successfully
  • Typically considered 1st-line agents for painful neuropathies, including DPN, but use may be restricted by adverse effects
  • Advantages of TCAs include their effect on insomnia and depression which are common comorbidities in neuropathic pain patients
  • Baseline echocardiogram for patients >40 years old is recommended; TCAs should not be given to patients at risk for sudden cardiac death or with history of cardiovascular disease

• Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
  • 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 TCA use; however, it is more expensive than TCAs
  • Venlafaxine has shown efficacy in clinical trials involving DPN and mixed painful polyneuropathy

2nd-line Agents

• Lidocaine (Topical)
  •  As per 2015 recommendations from the 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 DPN, 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 the IASP 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 DPN, adjunctive therapy with topical Capsaicin showed better pain relief compared to its inactive vehicle comparator

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 μ-opioid receptor
  • Approved as treatment for diabetic polyneuropathy in patients requiring continuous, around-the-clock opioid treatment
• Oxcarbazepine
  • Exerts a nonspecific sodium channel blockade and may also have an effect on calcium and potassium channels
  • Clinical trials have shown this drug to have equivocal findings in painful diabetic neuropathy while a study showed pain relief (though small but statistically significant) in treatment of peripheral neuropathic pain
• Valproic acid
  • Some studies have shown the effectiveness of Valproic acid in reducing pain in patients with DPN
  • According to the American Academy of Neurology (AAN), Valproic acid can be considered a treatment option for the management of DPN if multiple other effective medications have failed; however, it should not be offered to patients with childbearing potential
• Opioids
  • Recommended by 2010 European Federation of Neurological Societies (EFNS) and 2015 IASP NeuPSIG as one of the treatment options for DPN
  • However, 2022 AAN and 2022 American Diabetes Association (ADA) have recommended avoidance of use of opioids due to poor safety profile, increased risk of respiratory depression and addiction
  • AAN have recommended that patients who are currently on opioids for the treatment of DPN may be offered to taper off the medication and be shifted to alternative non-opioid treatment strategies

Postherpetic Neuralgia

1st-line Agents

• Anticonvulsants
  • Gabapentin and Pregabalin have established efficacy against PHN
  • 1st-line agent for PHN, especially in the elderly in whom TCAs 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 TCAs for PHN
  • Nortriptyline has been shown to be as effective as Amitriptyline but better tolerated
  • Many controlled trials have shown the efficacy of TCAs in PHN

2nd-line Agents

• Lidocaine (Topical)
  • Generally recommended as 2nd-line treatment for PHN by the IASP NeuPSIG due to low quality of evidence
    
  • Recommended as 1st-line treatment by the IASP 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 PHN supported the efficacy of Lidocaine patches with brush-induced allodynia
  • Lidocaine gel (5%) has been shown to give significant pain relief in PHN for up to 8 hours

• Capsaicin (Topical)
  • Recommended as 2nd-line treatment for PHN by the IASP 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 PHN by the IASP NeuPSIG due to potential safety concerns
    • Consider for short duration of treatment only

3rd-line Agents

• Opioids
  • Generally recommended as 3rd-line treatment for PHN by the IASP NeuPSIG due to abuse potential and side effects that include endocrine effects
  • Oxycodone, Morphine and Methadone have similar efficacy in PHN compared to TCA but these are associated with frequent discontinuation because of adverse events
  • Randomized placebo-controlled trials in PHN 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 PHN by the IASP NeuPSIG due to weak quality of evidence thus it is only used in refractory cases
• Oxcarbazepine
  • A study has shown a small but significant amount of pain relief in peripheral neuropathic pain in patients with the irritable nociceptor phenotype

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 (TN)

1st-line Agents

• Carbamazepine
  • Drug of choice for TN 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 TN

2nd-line Agents

• Baclofen has been reported in a study to be superior to placebo in reducing the number of painful paroxysms in TN
• Lamotrigine has been reported in a study to be efficacious in TN 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 TN but evidence remains insufficient to support or refute their efficacy

Other agents

• Botulinum toxin type A may be beneficial in patients with pharmacologically refractory TN, although there is limited data

Central Neuropathic Pain

Psychological Approaches

• Psychological or behavioral therapy may of benefit in some patients

Optimize Glycemic Control

• Tight glucose control in type 1 DM patients helps to delay the onset of DPN 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

• Assess and, if present, manage concurrent mood and sleep disorders
• Cognitive behavioral therapy (CBT) may be of benefit in reducing pain severity and interference in patients with painful diabetic neuropathy as per recent pilot randomized controlled study
  

• Physiotherapy has been reported to provide pain relief in some patients
• Acupuncture may relieve pain and/or reduce the need for pain medications in selected patients
  • Although rare, serious adverse effects have been reported (eg pneumothorax, hemorrhage, cardiac tamponade, life-threatening infections)

• Transcutaneous Electrical Nerve Stimulation (TENS)
  • Mild electrical stimulation through the application of surface electrodes over the painful area generates heat that relieves stiffness and improves mobility

• Interferential Therapy (IFT) uses the strong physiological effects of low frequency electrical stimulation of nerves to provide pain relief in diabetic 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
• Repetitive Magnetic Transcranial Stimulation (rTMS) uses transient magnetic field to produce electrical currents in the cortex and is currently being developed for the treatment of neuropathic pain with limited routine clinical use as further large scale studies to confirm efficacy are needed

Postherpetic Neuralgia (PHN)

Physical Methods

• If the patient suffers from allodynia, application of a protective layer (eg cling film) between the skin and clothing may be helpful
• TENS may be helpful in some PHN 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 PHN