Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:
1. Define neuropathic pain and differentiate between central and peripheral sensitization.
2. Explain how pain signals are transmitted to the brain and how neuropathic pain differs from nociceptive pain.
3. Assess common types of neuropathic pain and their treatment.
Pain serves as a protective mechanism to prevent someone who is injured from further irritating the site of injury until it heals. Chronic pain is pain that lasts longer than 12 weeks and can be broken into 3 major types: it can be pain from tissue damage, also known as nociceptive pain, or pain from somatosensory damage, also known as neuropathic pain, or a mixture of both nociceptive and somatosensory.
In patients who suffer from neuropathic pain, the nervous system inappropriately responds to pain and can cause spontaneous painful stimuli to occur via multiple mechanisms. It can affect both the central and peripheral nervous systems, and presentation can vary between patients. Statistically, neuropathic pain has an annual incidence of 1% of the general population and around 20 million people in the United States.1
The medical cost of managing neuropathic pain and its consequences is around $10.9 billion annually and is associated with a threefold increase in use of health care resources. Given its prevalence and cost, it is vital for health care providers to understand the pathophysiology and management of neuropathic pain for the provision of appropriate care to patients.
Normal Transmission of Pain Signals
Pain receptors, or nociceptors, are located in the skin and are responsible for transmitting pain signals from the periphery to the central nervous system (CNS). Pain is transmitted from the periphery to the CNS via 4 main processes: transduction, transmission, perception, and modulation.2
During the transduction phase, noxious, thermal, mechanical, and/or chemical stimuli are converted into electrical signals along slowly conducting, unmyelinated C fibers and small rapidly conducting A-[delta] fibers. Once the stimuli are converted into electrical signals, the information is then transmitted to the spinal cord and brain via the afferent nociceptor.3
The afferent nociceptor has its cell body in the dorsal root ganglion; each dorsal root ganglion has distinct sensory cell bodies that encode and then transmit information into the dorsal horn of the spinal cord.
Once in the dorsal horn, the fibers ascend approximately 2 levels before they synapse on second-order neurons. These second-order neurons then decussate across the anterior white commissure and ascend as the lateral spinothalamic tract.4
The spinothalamic tract ascends through the brainstem as the spinal lemniscus until it synapses on the ventral posterolateral nucleus of the thalamus. Axons from the thalamus then project to the somatosensory cortex of the brain. Perception of pain mainly begins at the level of the thalamus and the cortex and is the subjective appreciation of the quality, location, and intensity of pain.4
The perception of pain can be modulated by descending inhibitory input from the brain that modulates nociceptive transmission at the level of the spinal cord. Modulating nerve fibers can release inhibitory substances at the dorsal horn, such as endogenous opioids, serotonin, norepinephrine, and [gamma]-aminobutyric acid (GABA), which bind to receptors on primary afferent or dorsal horn neurons and inhibit the transmission of pain.5
Neuropathic Pain
The body is designed to safeguard itself against noxious stimuli. Normally, when a noxious stimulus, such as heat, is encountered, unmyelinated C fibers or thinly myelinated A-[delta] sensory neurons become activated, and pain signals are transmitted to the brain. This process continues only in the presence of a continuous noxious stimulus. However, if these receptors become damaged due to direct injury (lesion) or disease, then neuropathic pain can develop. The International Association for the Study of Pain (IASP) defines neuropathic pain as a pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain affects approximately 20 million people in the United States, or about 10% of the country's population.6,7
Neuropathic pain occurs after an injury or disease that affects the central or peripheral nervous system. The CNS includes the brain, brainstem, and spinal cord. The peripheral nervous system includes nerves and ganglia that are located outside the brain and the spinal cord.7 Central neuropathic pain is most commonly caused by multiple sclerosis, poststroke pain, and spinal cord injuries, whereas peripheral neuropathic pain can be caused by diabetic neuropathy, peripheral nerve injuries, nerve entrapment, postherpetic neuralgia, and phantom limb pain, among other diagnoses8 (Table 1).
Characteristics of Neuropathic Versus Nociceptive Pain
Nociceptive pain is pain that is triggered by noxious or harmful stimuli and/or inflammation of the tissues, which is considered the "normal" pain response. Many describe this type of pain as aching, throbbing, dull, or sharp. Nociceptive pain usually dissipates when the initial painful stimulus is resolved or removed.
Patients who suffer from neuropathic pain generally characterize their pain as a continuous, burn-like pain, or even paroxysmal. Burning pain may be reported without the presence of any noxious stimuli. Patients can also experience allodynia, which is defined by the IASP as pain due to a stimulus that does not normally provoke pain and hyperalgesia, or as increased pain from a stimulus that normally provokes pain.6 Additionally, neuropathic pain includes both negative symptoms such as sensory loss and numbness and positive symptoms such as paresthesia and spontaneous pain (Table 2).
Mechanisms of Neuropathic Pain
Nociception is a protective process that generates a withdrawal mechanism to prevent repeated contact with the area of injury. During repeated or an intense noxious stimulus, nociceptors can be sensitized. Once sensitized, nociceptors have a lower threshold for activation and pain inputs are amplified.9
Central sensitization results from changes to the properties of neurons. This change leads to patients feeling pain, sometimes without a stimulus or even an abnormal response to stimuli. Central sensitization is not due to a single event. Instead, changes in the threshold and activation kinetics of N-methyl-D-aspartate (NMDA) receptor and [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) channels, changes in the trafficking of AMPARs into the membrane, alterations in ion channels to increase inward currents and reduce outward currents, and reductions in the release activity of GABA and glycine lead to changes in cellular processes.
This cellular change includes an increase of membrane excitability, synaptic facilitation, and disinhibition. These processes then lead to central sensitization, which includes a development of or increase in spontaneous activity, a reduction in threshold for activation by peripheral stimuli, and an enlargement of receptive fields that respond to both noxious and nonnoxious stimuli.10 Release of NMDA is coupled with the release of glutamate. The influx of calcium and sodium and efflux of potassium produce larger postsynaptic potentials. In addition, damaged sensory fibers have a high concentration of sodium, which leads to spontaneous firing.11
When nerves are damaged, changes to ion channels, specifically sodium, calcium, and potassium, occur. This then leads to erroneous signaling in the brain. When there is an increase in the number and function of sodium channels at the spinal cord terminus, there is increased excitability, transduction, and neurotransmitter release.12 Increased calcium channel activity leads to increased neurotransmitter release and enhanced excitatory synaptic transmission.
Central Neuropathic Pain
Poststroke Pain
Of note, central neuropathic pain usually occurs months or even years after the CNS incident.13 Because the prevalence of strokes exceeds that of the other central neuropathic conditions, poststroke pain is the most common form of central neuropathic pain.14 The true cause of central poststroke pain is not known. However, if the stroke affects a portion of the central pain pathway, then this damage can create the sensation of pain with no minimal stimulation of the peripheral pain receptors.15 Furthermore, pain can ensue when central inhibitory pathways or sensory pathways are damaged.
Poststroke patients usually have constant, intermittent, moderate, or severe pain, which corresponds to the region of the brain that was damaged. Sensory inputs such as warmth, cold, or other stimuli are misinterpreted and can lead to pain, as well.16 Treatment for central poststroke pain is multimodal. It includes both pharmacologic and nonpharmacologic interventions. Central poststroke pain treatment usually begins with nonsteroidal anti-inflammatory drugs (NSAIDs). Health care providers can add tricyclic antidepressants and antiepileptic medications to further control pain.
Spinal Cord Injury
Central neuropathic pain is one of the most common medical complications after a spinal cord injury (SCI). After direct damage to the spinal cord, central neuropathic pain is thought to result from hyperexcitable neurons, which have an exaggerated response to stimuli at or below the level of the SCI. This hyperexcitability is thought to occur from altered expression of NMDA and glutamate receptors, sodium and calcium channels, and altered functioning of inhibitory neurons.17 SCI can also lead to glial activation and increased cytokine and prostaglandin release.
SCI neuropathic pain can be divided into 2 groups: dermatomal at-level pain of SCI or below-level neuropathic pain. Spinal cord stimulators (SCSs) have been effective with at-level neuropathic pain and incomplete lesions.18
Peripheral Neuropathic Pain
Diabetic Peripheral Neuropathy
One of the most common causes of peripheral neuropathy is diabetes mellitus.19 Consistently elevated glucose levels damage peripheral nerves, resulting in distal symmetric sensorimotor polyneuropathy. Patients typically experience the sensation of numbness, tingling, burning, and pins and needles. In diabetic patients, the painful sensation usually begins in the distal hands and feet and ascends toward the trunk. Scientists believe that damaged nerve endings contribute to the pain felt in diabetic neuropathy. The damaged nerve endings can produce disturbed action potentials, which are interpreted by the CNS as pain.19
Postherpetic Neuralgia
Postherpetic neuralgia (PHN) occurs in patients who have been exposed to chickenpox, which is caused by the varicella-zoster virus. The varicella-zoster virus infects sensory ganglia. Years later, the virus can reactivate and cause shingles. Shingles causes a painful blister rash that occurs in a dermatomal distribution that does not cross midline.
PHN occurs in the same dermatomal distribution as shingles. The herpes zoster virus damages peripheral and central nerve fibers from inflammation/immune reaction that occurred as a reactivation of the varicella virus. When the nerves become damaged, their threshold for activation is lower and these nerves may then discharge spontaneously.
Patients with PHN may experience allodynia and 3 major types of pain: They may experience constant pain without a stimulus (which patients describe as burning or throbbing), intermittent pain without a stimulus (which they describe as shooting or stabbing), or pain that is provoked by a stimulus but disproportionate to the stimulus.20
First-line treatments for PHN are tricyclic antidepressants, gabapentin, and pregabalin. Topical lidocaine and capsaicin creams may also be useful adjunctive therapies for PHN.
Trigeminal Neuralgia
Trigeminal neuralgia (TN) is a chronic pain condition that affects the fifth cranial nerve (trigeminal nerve). People who suffer with this chronic pain condition experience sudden-onset, extreme burning or shock-like facial pain that lasts seconds or even hours. The pain can be triggered by contact with the cheek; even the slightest touch can trigger it.
TN can be caused by a blood vessel pressing on the trigeminal nerve as it exits the brainstem. When the nerve is compressed, the blood vessel can damage the myelin sheath surrounding the nerve, which leads to erroneous impulses. TN usually affects people 50 years and older and is more common in women than in men.
Phantom Limb Pain
Phantom limb pain affects 60% to 85% of patients with amputations.21 When patients receive surgical amputations, significant damage is done to the peripheral nerves. The damaged peripheral nerves can then create neuromas, which can become hyperexcitable due to an increase in sodium channels, which leads to spontaneous discharges.22
Chemotherapy-Induced Peripheral Neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is common among patients who are treated with certain chemotherapy drugs. Chemotherapy medications can cause multiple types of neuropathies, including large and small fiber, sensory and/or motor, demyelinating and axonal, cranial and autonomic.23
Sensory symptoms are the first to develop. Patients will typically begin to first notice deficits in their hands and feet. Patients can experience spontaneous burning, shooting, or electric shock-like pain.24 The 6 main types of chemotherapy agents associated with the development of CIPN include platinum-based medications, vinca alkaloids, epothilones, taxanes, protease inhibitors, and immunomodulatory drugs such as thalidomide.
The main mechanisms of the CIPN pain are microtubule disruption, oxidative stress, mitochondrial damage, altered ion activity, myelin sheath damage, DNA damage, and neuroinflammation.25
Diagnosis
Diagnosing peripheral neuropathy can be an arduous task. The health care provider must differentiate between nociceptive pain and neuropathic pain. As always, it is imperative to begin with a detailed history and physical examination, which can then enable the practitioner to rule out treatable causes of pain.
The physical examination should include evaluation of tone, strength, reflexes, sensation, and vasomotor/sudomotor activity.26 Screening tools exist, such as painDETECT, Neuropathic Pain Questionnaire, ID Pain, and Standardized Evaluation of Pain, to help providers determine which patients may have neuropathic pain. If neuropathic pain is suspected, then different treatments exist to help them manage the pain.
To diagnose neuropathic pain, the practitioner must find that the following 2 factors are present:
1. The continuing pain is disproportionate to any inciting event.
2. The patient must report at least 1 symptom in 3 of the 4 following categories and must display at least 1 symptom in 2 of the 4 following categories:
A. Sensory
B. Vasomotor
C. Sudomotor/edema
D. Motor/trophic
Management
Neuropathic pain is difficult to treat; many patients do not find that their pain is sufficiently controlled with NSAIDs and/or opioids alone. This is because NSAIDs and opioids do not target the underlying cause of neuropathic pain. When interviewing patients, it is important to determine the site, intensity, course, nature, occurrence pattern, triggers, and what worsens or relieves that pain.27 Asking these questions can then help to guide treatment.
Pharmacologic treatment may be used initially to manage symptoms of neuropathic pain and improve function. First-line treatments include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentinoids, and topical medications. These medications are trialed for 4 to 6 weeks. If there is an exacerbation or inadequate response to first-line agents, then second-line tramadol or a combination of first-line agents is trialed for 4 to 6 weeks (Table 3).26
Tricyclic antidepressants have been used to treat neuropathic pain for about 25 years. They are thought to alleviate neuropathic pain by inhibiting the reuptake of serotonin and norepinephrine in the spinal dorsal horn. Tricyclic antidepressants are thought to work by activating a descending inhibitory response. Research has shown that these drugs exert an analgesia effect when taken at lower doses than those prescribed for depression.27
International guidelines of neuropathic pain have made the use of SNRIs a first-line treatment, especially duloxetine and venlafaxine. These drugs enable descending inhibition by blocking serotonin and norepinephrine reuptake.26 These medications have shown to be helpful in peripheral diabetic neuropathy and in central neuropathic pain due to multiple sclerosis.
Additionally, anticonvulsant medications, such as gabapentin and carbamazepine, are believed to treat neuropathic pain by stabilizing membranes and also by depressing segmental and descending excitatory pathways. Gabapentin binds to the [alpha]-2-[delta] calcium channel subunit and exerts an analgesic effect by suppressing the presynaptic calcium influx and inhibiting the release of excitatory neurotransmitters.27
A multimodal approach to treat neuropathic pain has been shown to be effective, so topical agents can especially help when combined with other therapies. Topical agents such as lidocaine and capsaicin have been shown to be effective in some types of neuropathic pain. Topical lidocaine decreases ectopic firing of peripheral nerves by blocking sodium. Capsaicin 8% (high concentration) patches can be applied to the affected area. Capsaicin 8% is administered in carefully controlled conditions within a clinic or hospital, usually after a local anesthetic-because it can initially exacerbate pain. Studies have shown that about 10% more participants report much or very much reduction in pain at 8 and 12 weeks after a 1-time application of high-dose capsaicin, compared with participants who received low-dose capsaicin (0.04%).28
Second-line treatments include tramadol and tapentadol. Tramadol is a weak opioid receptor agonist and inhibitor of serotonin and norepinephrine reuptake. Tapentadol is a weak [mu]-receptor agonist and norepinephrine inhibitor.
Neurostimulation is considered the fourth-line treatment. A nonpharmacologic approach to neuropathic pain involves neuromodulation. Nerve stimulation involves the electrical stimulation of the nervous system to modify a person's perception of pain and has interestingly been used since ancient times.29 In 1965, Melzack and Wall introduced gate theory, which involves a "gate" that can be opened or closed depending on the balance between the firing of small and large neural fibers. They believed that, if rubbing the area of pain stimulated large fibers, then the gate would close and the pain would decrease.29 Wall and Sweet tested the concept of gate theory in 1967 and made an implantable stimulator, which was used to treat chronic pain by peripheral nerve stimulation, and the field of neuromodulation began.29
Nerve stimulation uses electrical current to treat chronic pain. SCSs, which are implanted into the patient's back, have 3 main parts: a pulse generator that creates electrical pulses, a lead wire that transmits the electrical pulses to the spinal cord, and a hand-held remote control that can adjust the stimulator settings and turn it on and off. The SCS, through electrical pulses, activates nerves where a patient's pain is felt. This activation changes the way the brain perceives pain. By effectively interrupting the afferent pain signals, the patient should feel less pain; rather he or she will have a tingling or paresthesia feeling where he or she once felt pain.30
Conclusion
Neuropathic pain, which is caused by a lesion or dysfunction of the peripheral or CNS, is a chronic condition that affects not only people in the United States but people globally, as well. Therefore, it is imperative for clinicians to be able to diagnose and then treat neuropathic pain. There are multiple causes of both central and peripheral neuropathic pain. A proper history, physical examination, and even questionnaire can help elucidate whether a patient's pain is neuropathic in origin. First-line agents include tricyclic antidepressants, gabapentinoids, SNRIs, and topical medications. Second-line agents include the weak opioids, and neurostimulation is considered a fourth-line treatment option for patients who fail medical management.
References