Neuropathic Pain Management

Central Neuropathic Pain

First-Line Agents

Anticonvulsants

Example drugs: Gabapentin, Pregabalin

Anticonvulsants 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 a 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 (TCAs)

Example drugs: Amitriptyline, Desipramine, Imipramine, Nortriptyline

Tricyclic antidepressants inhibit presynaptic reuptake of serotonin and norepinephrine and block cholinergic, adrenergic, histaminergic, and Na channels. These also block hyperalgesia induced by N-methyl-D-aspartate (NMDA) agonists.

Second-Line Agents

Weak Opioids

Example drug: Tramadol

Weak opioids have low-affinity binding to μ-opioid receptors and weak inhibition of norepinephrine and serotonin reuptake. These are recommended as a second-line treatment for central neuropathic pain. These have a quick onset of pain relief and a less sedative effect. There is a lower risk of abuse than with strong opioid receptor agonists. Consider for short duration of treatment only.

Third-Line Agents

Strong Opioids

Example drugs: Levorphanol, Morphine, Oxycodone

Strong opioids are recommended as third-line treatment due to limited trials assessing long-term safety and abuse potential. These are associated with quick onset of pain relief and is therefore useful for short-term use to treat acute exacerbations or during the titration phase of first-line agents.

Other Agents

Cannabinoids¹

Example drugs: Cannabidiol, Tetrahydrocannabinol

Cannabinoids may be considered in central pain in multiple sclerosis only if all other treatments fail.

¹Refer to local guidelines on the use of cannabinoids.

Lamotrigine

Lamotrigine blocks the voltage-dependent Na channels, inhibiting presynaptic release of excitatory amino acids. This 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.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

Duloxetine has been shown to be effective in neuropathic pain due to multiple sclerosis.

Painful Diabetic Peripheral Neuropathy (DPN)

First-Line Agents

Anticonvulsants

Example drugs: Gabapentin, Pregabalin

Gabapentin has similar efficacy as Amitriptyline but with a better side effect profile. The combination of Gabapentin and Nortriptyline for diabetic peripheral neuropathy or postherpetic neuralgia can significantly lower pain scores compared to either treatment alone. Gabapentin monotherapy and Nortriptyline monotherapy have similar efficacy. Pregabalin provides significant pain relief and improved quality of sleep in diabetic peripheral neuropathy. Mirogabalin is a new α2δ ligand that is approved in Japan for the treatment of neuropathic pain.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

Example drugs: Desvenlafaxine, Duloxetine, Venlafaxine

Serotonin and norepinephrine reuptake inhibitors have highly specific inhibition of serotonin and norepinephrine reuptake, allowing the availability of these neurotransmitters in the synapse. Duloxetine is well-tolerated and not associated with anticholinergic side effects seen in tricyclic antidepressant use; however, it is more expensive than tricyclic antidepressants. Venlafaxine has shown efficacy in clinical trials involving diabetic peripheral neuropathy and mixed painful polyneuropathy.

Tricyclic Antidepressants (TCAs)

Example drugs: Amitriptyline, Desipramine, Imipramine, Nortriptyline

Tricyclic antidepressants are typically considered as first-line agents for painful neuropathies, but use may be restricted by adverse effects. The advantages are that this can address common comorbidities such as insomnia and depression. The disadvantages include the need to do a baseline echocardiogram for patients >40 years old and contraindications in patients at risk for sudden cardiac death or those with a history of cardiovascular disease.

Sodium Channel Blockers

Example drugs: Carbamazepine, Lacosamide, Lamotrigine, Oxcarbazepine, Valproic acid

Oxcarbazepine exerts a non-specific sodium channel blockade and may also have an effect on calcium and potassium channels. This may provide some pain relief in the treatment of peripheral neuropathic pain. Valproic acid can be considered if multiple other effective medications have failed, except for female patients with childbearing potential.

Second-Line Agents

Capsaicin (Topical)

Capsaicin depletes stores of substance P from sensory nerve endings, reducing or abolishing the transmission of painful stimuli from the peripheral nerve fibers to the higher centers. The patient needs to apply this 3-4 times daily and may experience initial skin irritation, which typically improves in 1-2 weeks.

Lidocaine Patches (Topical)

Lidocaine patches have a good safety profile and patient preferences. These decrease the neuronal membrane’s permeability to Na ions, thereby blocking the initiation and conduction of nerve impulses. These can provide pain relief with minimal adverse events and can improve ongoing pain, intensity of allodynia, and quality-of-life measures.

Other Agents

Alpha-lipoic acid (Thioctic acid)

Alpha-lipoic acid decreases oxygen free radicals, thereby influencing the underlying neuropathic process. This decreases pain, paresthesias, and numbness and has a favorable safety profile.

Benfotiamine 







Benfotiamine is a 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.

Botulinum toxin type A

Botulinum toxin type A is a potent neurotoxin that may have analgesic effects by acting on neurogenic inflammation. This has an off-label use for neuropathic pain and other chronic pain conditions. This is also effective in reducing pain in peripheral neuropathy.

Opioids

Opioids are recommended for avoidance of use in patients with a history of substance abuse, respiratory depression, and addiction. Taper off the medication and shift to alternative non-opioid treatment strategies as much as possible.

Tapentadol

Tapentadol is an opioid with noradrenaline reuptake inhibition with low affinity for the μ-opioid receptor. This is ideal for patients requiring continuous, around-the-clock opioid treatment.

Postherpetic Neuralgia (PHN)

First-Line Agents

Anticonvulsants

Example drugs: Gabapentin, Pregabalin

Anticonvulsants are a first-line agent for postherpetic 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 (RPCT).

Tricyclic Antidepressants (TCAs)

Amitriptyline, Desipramine, Nortriptyline and Maprotiline have been used successfully, with Amitriptyline as the most widely used tricyclic antidepressant for postherpetic 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 postherpetic neuralgia.

Second-Line Agents

Capsaicin (Topical)

Capsaicin is recommended as a second-line treatment for postherpetic neuralgia by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) due to its relatively small effective size. This provides significant pain relief, but patient response can be delayed. Discomfort and burning sensation may limit patient compliance.

Lidocaine (Topical)

Lidocaine is generally recommended as a second-line treatment for postherpetic neuralgia by the IASP NeuPSIG due to the low quality of evidence. This is recommended as first-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 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.

Tramadol

Tramadol is a weak opioid and a mixed serotonin-noradrenaline reuptake inhibitor found in studies to be an alternative if first-line oral monotherapies are ineffective. This is recommended as second-line treatment for postherpetic neuralgia by the IASP NeuPSIG due to potential safety concerns. Consider for short duration of treatment only. 







Third-Line Agents

Botulinum Toxin Type A

Botulinum toxin type A has an off-label use for neuropathic pain and other chronic pain conditions. This may be used in refractory cases.

Opioids

Example drugs: Methadone, Morphine, Oxycodone

Opioids are generally recommended as third-line treatment due to abuse potential and side effects that include endocrine effects. These have similar efficacy compared to tricyclic antidepressant but are associated with adverse events that lead to frequent discontinuation. A combination of Oxycodone and Morphine can provide a significant reduction in pain intensity, with variable improvement in sleep and disability.

Oxcarbazepine

Oxcarbazepine may be considered 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)

First-Line Agents

Carbamazepine

Carbamazepine is the drug of choice, but efficacy may be compromised by poor tolerability and pharmacokinetic interactions. This reduces the frequency and intensity of painful paroxysms and has equal efficacy for spontaneous and trigger-evoked attacks.

Oxcarbazepine

Oxcarbazepine is typically better tolerated than Carbamazepine due to decreased potential for drug interactions. This has similar efficacy to Oxcarbazepine with Carbamazepine on the number of attacks and global assessment.

If refractory to Carbamazepine and Oxcarbazepine, second-line agents may be added to the treatment regimen for trigeminal neuralgia.

Second-Line Agents

Baclofen may reduce the number of painful paroxysms in trigeminal neuralgia. Lamotrigine may be used solely or as an effective add-on therapy.

Other Agents

Other agents may be considered when treatment with all the above first- and second-line agents is unsuccessful. Other anticonvulsants (eg Clonazepam, Gabapentin, Phenytoin, Pregabalin and Valproate) may be considered. Botulinum toxin type A may be beneficial in patients with pharmacologically refractory TN, although there is limited data. These have off-label use for neuropathic pain and other chronic pain conditions. 

PATIENT EDUCATION

Central Neuropathic Pain

The patient should be given adequate information regarding central neuropathic pain, including its underlying cause. If the patient suffers from allodynia, application of a protective layer (eg cling film) between the skin and clothing may be helpful. This may be beneficial to those living in areas with cold weather; this is not recommended in hot, humid environments. Peripheral nerve desensitization technique and sensory re-education/retraining can be employed through physical therapy and occupational therapy, respectively. This can be facilitated in healthcare facilities (hospital-based or free-standing clinic) and at home.

Painful Diabetic Peripheral Neuropathy (DPN)

The patient should be educated about the following: Mechanisms of diabetic peripheral neuropathy and what is currently known and unknown; importance of optimal glycemic control; available management; regular checkups and laboratory follow-up; and expected outcomes.

Patient Counselling

Patients should be counseled on how to optimize their glycemic control through: Well-balanced diet; reduced physical inactivity; regular exercise on most days of the week; glucose monitoring; and adherence to maintenance medication (eg oral antidiabetics and/or insulin use) and pain medication. Help the patient understand that complete pain relief may not be achieved despite the best efforts of the patient or physician. Inform patients of possible adverse effects from medications and any potential for abuse or development of tolerance.

Postherpetic Neuralgia (PHN)

Explain the current pathophysiology, locally available management, and possible prognosis of postherpetic neuralgia to help alleviate anxiety about the disorder. Educate about the effects of treatment and its side effects, and if there is a need for laboratory monitoring. Encourage social and physical activities.

Trigeminal Neuralgia (TN)

Explain the current pathophysiology, locally available management, and possible prognosis of trigeminal neuralgia to help alleviate anxiety about the disorder. Educate about the effects of treatment and its side effects and if there is a need for laboratory monitoring. Encourage social and physical activities.

LIFESTYLE MODIFICATION AND OTHER THERAPIES

Central Neuropathic Pain

Psychological Approaches

Psychological or behavioral therapy may be of benefit in some patients with central neuropathic pain.

Painful Diabetic Peripheral Neuropathy (DPN)

Optimize Glycemic Control

Tight glucose control in patients with diabetes mellitus is beneficial because it can delay the onset of diabetic polyneuropathy and help to slow its progression. The benefits of intensive insulin therapy usually outweigh the risks. Observe caution in the elderly because they are more susceptible to hypoglycemia.

Proper Foot Care 







Daily foot inspection with the use of a handheld mirror or the help of a family member or carer. Acceptable foot hygiene should be done. Appropriate footwear with seamless-fitting socks or hosiery that is changed daily is recommended, such as prefabricated well-fitted walking shoes or athletic shoes or custom-made shoes. Footwear should cushion and distribute pressure evenly on foot surfaces.

Referral to Healthcare Professionals

Primary care physician (PCP) (eg family medicine, internist, endocrinologist, neurologist, pain medicine specialist, and/or vascular medicine specialist) referral may be done for optimization of medical and pain management and tetanus prophylaxis in case of the presence of diabetic foot ulcer. Referral to a surgeon (eg general surgeon, orthopedic surgeon, and/or thoracic and cardiovascular surgeon) may be done whether revascularization or amputation is necessary or not; refer if with trauma, cellulitis, or acute ischemia of the foot.

A Physical Medicine and Rehabilitation (PMR) doctor, or physiatrist, may assess the body impairments, activity, and community participation; identify facilitators or barriers of PMR management; and coordinate medical, surgical, and PMR services. Physiatrists may prescribe the following: Assistive rehabilitation technology (ART) such as mobility aids, adaptive devices, and/or orthotic devices; therapeutic exercises and activities through physical therapy and occupational therapy, respectively; and physical modalities, both the conventional and innovative technologies.

Psychological Approaches

Assess and, if present, manage concurrent mood and sleep disorders. Cognitive behavioral therapy (CBT) may be of benefit in reducing pain severity.

Alternative and Experimental Therapies

Acupuncture may relieve pain and/or reduce the need for pain medications in selected patients. This should be done by a trained and competent health professional due to possible serious adverse effects (eg pneumothorax, hemorrhage, cardiac tamponade, life-threatening infections). Transcutaneous electrical nerve stimulation (TENS) is a mild electrical stimulation through the application of surface electrodes over the painful area that 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. Frequency-modulated electromagnetic neural stimulation may be helpful but with limited evidence of efficacy. Repetitive magnetic transcranial stimulation (rTMS) uses transient magnetic fields to produce electrical currents in the cortex; this is not widely available for clinical use.

Postherpetic Neuralgia (PHN)

Referral

Consult a primary care physician if the zoster vaccine is needed to prevent recurrence.

Physical Medicine and Rehabilitation

The management may be considered similar to diabetic peripheral neuropathy.

Psychological Approaches

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