Neuropathic Pain

Neuropathic pain may result from efferent activity (sympathetically maintained pain) or from interruption of afferent activity (deafferentation pain).

Peripheral nerve injury or dysfunction can result in neuropathic pain. Examples are

• Mononeuropathies (involve a single nerve [eg, carpal tunnel syndrome, radiculopathy due to a herniated intervertebral disk])

• Plexopathies (involve multiple nerves within a particular neural plexus; typically caused by trauma, inflammation, or nerve compression, as by a tumor)

• Polyneuropathies (involve multiple nerves, often throughout the body; typically caused by various metabolic disorders, paraproteinemias, toxic exposures [eg, alcohol, chemotherapy]), hereditary predisposition, or, rarely, immune-mediated mechanisms—see tables Causes of Peripheral Nervous System Disorders)

Mechanisms of neuropathic pain are complex and involve changes

• At the peripheral nociceptor and nerve level

• At the dorsal root ganglion

• In central nervous system (CNS) nociceptive pathways and terminal structures

At the peripheral nerve and nociceptor level, injury results in inflammation and in activation and overrepresentation of cation channels, particularly sodium channels. These changes reduce the threshold for activation and increase the response to noxious stimuli. In chronic states, the peripheral nerve continuously triggers nociceptive ectopic signals to the CNS. This bombardment of continuous peripheral nociceptive input leads to changes in receptive nociceptors (central sensitization); they are primed, interpret pain from minor stimuli (including nonpainful stimuli [allodynia]) as substantial pain, and interpret that pain as coming from a wider area than it is. These changes can be reversed, at least for a time, if the peripheral nociceptive input can be interrupted.

Central neuropathic pain syndromes—resulting from dysfunction of somatosensory pathways in the CNS—can arise from various CNS lesions, most commonly following stroke, spinal cord injury, or multiple sclerosis–-related demyelination. To be classified as central neuropathic pain, the pain must occur within the area affected by the CNS lesion, though it does not necessarily involve the entire affected region.

A key feature of central neuropathic pain is dysfunction of the spinothalamic tract, which conveys pain, temperature, and crude touch. While spinothalamic tract damage is strongly associated with central neuropathic pain, other mechanisms may also contribute. If pinprick and temperature sensation remain intact in the painful area, clinicians should consider alternative pain sources. In patients with neurologic impairment, musculoskeletal pain is often a more common explanation (eg, shoulder pain from hemiparesis post-stroke or upper-extremity overuse syndromes in wheelchair users with spinal cord injury).

Deafferentation pain is due to partial or complete interruption of peripheral or central afferent neural activity. Examples are

• Postherpetic neuralgia

• Phantom limb pain (pain felt in the region of an amputated body part)

Mechanisms are unknown but may involve sensitization of central neurons, with lower activation thresholds and expansion of receptive fields.

Neuropathic pain syndromes are sometimes associated with overactivity of the sympathetic nervous system. The sympathetic overactivity does not cause neuropathic pain, but it can contribute to its clinical features and severity. The pain that results is called sympathetically maintained pain, which depends on efferent sympathetic activity. Complex regional pain syndrome sometimes involves sympathetically maintained pain. Other types of neuropathic pain may have a sympathetically maintained component. What triggers sympathetic overactivity in some neuropathic pain states and not others is unknown. Mechanisms probably involve abnormal sympathetic-somatic nerve connections (ephapses), local inflammatory changes, and changes in the spinal cord.

Dysesthesias (spontaneous or evoked burning pain, often with a superimposed lancinating component) are typical, but pain may also be deep and aching. Other sensations—eg, hyperesthesia, hyperalgesia, allodynia (pain due to a nonnoxious stimulus), and hyperpathia (particularly unpleasant, exaggerated pain response)—may also occur.

Patients may be reluctant to move the painful part of their body, resulting in muscle atrophy, joint ankylosis, bone loss, and limited movement.

Symptoms are long-lasting, typically persisting after resolution of the primary cause (if one was present) because the CNS has been sensitized and remodeled.

• History and physical examination

Neuropathic pain is suggested by its typical symptoms when nerve injury is known or suspected. The cause (eg, amputation, diabetes, compression) may be readily apparent. If not, the diagnosis is often assumed based on the description of the symptoms; however, those descriptors (eg, burning) are neither sensitive nor specific for neuropathic pain. Thus, additional evaluation, including neurologic examination and electrophysiologic studies, are useful to confirm the diagnosis and to identify the injured nerve. Pain that is ameliorated by sympathetic nerve block is sympathetically maintained pain.

• Multimodal therapy (eg, physical methods, antidepressants, antiseizure medications, psychotherapeutic methods, neuromodulation, sometimes surgery)

Successful neuropathic pain management starts with confirming the correct diagnosis and managing treatable causes (eg, herniated disk, carpal tunnel syndrome). In addition to medications, mobilization and physical therapy are needed to desensitize areas of allodynia and prevent trophic changes, disuse atrophy, and joint ankylosis. Psychological factors must be considered from the start of treatment. Anxiety and depression must be treated appropriately. If pain persists, neural blockade may help. When dysfunction does not respond to first-line treatments, patients may benefit from the comprehensive approach provided by a pain clinic.

Neuromodulation (spinal cord or peripheral nerve stimulation) is particularly effective for neuropathic pain.

Several classes of medications are effective (see table Medications for Neuropathic Pain), but complete relief is unlikely, and setting realistic expectations is important. The goal of pharmacologic management is to lessen neuropathic pain so that it is less debilitating.

Per recommendations based on a systematic review and meta-analysis from an international group with expertise in neuropathic pain (1), medications for neuropathic pain are best introduced stepwise, with treatment individualized based on patient response and adverse effects.

• First-line medications: Tricyclic antidepressants (TCAs), antiseizure medications, and serotonin- norepinephrine reuptake inhibitors (SNRIs)

• Second-line treatment options: Topical medications, including lidocaine and capsaicinSecond-line treatment options: Topical medications, including lidocaine and capsaicin

• Third-line treatment option: Opioid analgesics, but they are generally less effective for neuropathic pain than for nociceptive pain and are associated with risk of dependence and other adverse effects

For tricyclic antidepressants (amitriptyline, nortriptyline, desipramine), the primary mechanism of action is thought to be from blocking the reuptake of (amitriptyline, nortriptyline, desipramine), the primary mechanism of action is thought to be from blocking the reuptake ofnorepinephrine and serotonin though selective serotonin reuptake inhibitors (SSRIs) have not been found to be effective for the treatment of neuropathic pain. Analgesic doses are usually lower than those used to treat depression or anxiety. Anticholinergic and adrenergic adverse effects often limit effective dosing. Secondary amine tricyclic antidepressants (nortriptyline and desipramine) have a more favorable adverse effect profile than tertiary amine tricyclic antidepressants (amitriptyline).reuptake inhibitors (SSRIs) have not been found to be effective for the treatment of neuropathic pain. Analgesic doses are usually lower than those used to treat depression or anxiety. Anticholinergic and adrenergic adverse effects often limit effective dosing. Secondary amine tricyclic antidepressants (nortriptyline and desipramine) have a more favorable adverse effect profile than tertiary amine tricyclic antidepressants (amitriptyline).

Antiseizure medications most commonly used for neuropathic pain include gabapentin and pregabalin, which is similar in mechanism of action to most commonly used for neuropathic pain include gabapentin and pregabalin, which is similar in mechanism of action togabapentin but has more stable pharmacokinetics and a higher affinity for the calcium channel subunit thought to be responsible for their mechanism of action. Some patients who do not respond well to or who do not tolerate gabapentin do respond to or tolerate pregabalin and vice versa. Gabapentin and pregabalin bind with high affinity to the alpha-2-delta subunit of voltage-gated calcium channels on presynaptic neurons. This reduces calcium influx during depolarization, leading to decreased release of excitatory neurotransmitters such as glutamate, substance P, and norepinephrine. The net effect is reduced synaptic transmission in pain pathways and modulation of nociceptive signaling.

DuloxetineDuloxetine is a serotonin and norepinephrine reuptake inhibitor, which has been found to be effective for diabetic neuropathic pain, fibromyalgia, chronic musculoskeletal pain (including low back pain), and chemotherapy-induced neuropathy.

Venlafaxine'sVenlafaxine's effects and mechanism of action are similar to those of duloxetine, and studies have shown efficacy for neuropathic pain.effects and mechanism of action are similar to those of duloxetine, and studies have shown efficacy for neuropathic pain.

Topical medications and lidocaine-containing patches may be effective for peripheral pain syndromes. Capsaicin exerts its analgesic effect by binding TRPV1 receptors on nociceptive C-fiber terminals, causing an initial burning sensation followed by desensitization and functional impairment of these fibers, partly through depletion of substance P and other neuropeptides. Low-dose topical creams (0.025 to 0.075%) require multiple daily applications and provide modest, short-term relief but are limited by poor adherence and local irritation. In contrast, high-dose 8% capsaicin induces a more profound, long-lasting nociceptor defunctionalization after a single supervised application, with pain relief lasting up to 3 months in focal neuropathic pain conditions such as postherpetic neuralgia and diabetic neuropathy.Topical medications and lidocaine-containing patches may be effective for peripheral pain syndromes. Capsaicin exerts its analgesic effect by binding TRPV1 receptors on nociceptive C-fiber terminals, causing an initial burning sensation followed by desensitization and functional impairment of these fibers, partly through depletion of substance P and other neuropeptides. Low-dose topical creams (0.025 to 0.075%) require multiple daily applications and provide modest, short-term relief but are limited by poor adherence and local irritation. In contrast, high-dose 8% capsaicin induces a more profound, long-lasting nociceptor defunctionalization after a single supervised application, with pain relief lasting up to 3 months in focal neuropathic pain conditions such as postherpetic neuralgia and diabetic neuropathy.

Other potentially effective treatments include

• Dorsal column cord stimulation (electrode placed epidurally) for certain types of neuropathic pain (eg, diabetic neuropathy, complex regional pain syndrome)

• Electrodes implanted along peripheral nerves and ganglia for certain chronic neuralgias (peripheral nerve stimulation, dorsal root ganglion stimulation)

• Sympathetic blockade, which is found to be effective in patients demonstrating sympathetically mediated symptoms as found in complex regional pain syndrome

• Neural blockade or ablation (radiofrequency ablation, cryoablation, chemoneurolysis)

• Transcutaneous electrical nerve stimulation (TENS)