What Is Neuropathic Pain and How Is It Best Managed?

Introduction and Scope of the Problem

As defined by the 2011 International Association for the Study of Pain (IASP), neuropathic pain is “pain caused by a lesion or disease of the somatosensory system.” This was a new definition, distinguishing a disease of the nervous system from the neuroplastic changes that occur with persistent nociceptive input. Common disease-related neuropathic conditions are often separated into two categories: central and peripheral. Central etiologies include multiple sclerosis, spinal cord injury, and poststroke. Peripheral etiologies include diabetic and nondiabetic polyneuropathy, postherpetic neuralgia (PHN), peripheral nerve injury, cancer-related pain and radiculopathy, human immunodeficiency virus (HIV) neuropathy, postamputation pain, posttraumatic pain, and postsurgical pain. Worldwide estimates of the prevalence of neuropathic pain range from 7% to 10% in the general population. However, the prevalence of neuropathic pain among patients with cancer is much higher, with estimates ranging from 19% to 39%. Older adults are at greater risk for neuropathic pain because they have fewer inhibitory nerves, lower endorphin levels, and a slowed capacity to reverse nerve sensitization.

Pain associated with nerve injury or dysfunction is clinically characterized by negative somatosensory signs (abnormal or sensory deficits, paresthesia [e.g., tingling sensation]), positive signs (e.g., spontaneous shooting or electric shocklike symptoms), and evoked symptoms (e.g., thermal hypersensitivity to heat and cold, mechanical allodynia, and pain in response to a non-nociceptive stimulus such as light touch).

Relevant Pathophysiology

The pathophysiology of neuropathic pain differs fundamentally from that of other painful conditions. Neuropathic pain symptoms result from focal disruptions in normal afferent neuronal signaling pathways in the peripheral and central nervous systems; other painful conditions rely on these pathways being intact. The underlying causal mechanism responsible for altered somatosensory signaling can be classified as peripheral or central. Understanding these mechanisms may allow for more focused therapies and increase the likelihood of treatment success. After peripheral nerve injury, inflammatory mediators are released; these can lead to a variety of effects that can compromise transduction, conduction, or transmission of sensory information, or even cell death. First, the resultant byproducts of inflammation (e.g., prostaglandins, bradykinin, and cytokines) can both sensitize and excite nociceptors. Additionally, these mediators initiate signaling cascades that result in molecular effects such as alterations in levels of ion channel transcription and modification (primarily sodium, but also potassium, calcium, and other channels) and changes in gene expression (resulting in altered neuron phenotype) of damaged neurons. An example of aberrant receptor upregulation is the heat activation protein TRPV1. In normal nociceptors, the TRPV1 receptor is activated by noxious heat stimuli above 41°C (105 °F). In injured nociceptors, receptor activation occurs at 38°C (100.4 °F); thus spontaneous activity can occur at normal body temperature. Another hallmark of neuropathic pain is that patients experience abnormal sensation with areas of hypersensitivity adjacent to or mixed with areas of sensory deficit. These changes also lead to ephaptic conduction , in which ectopic activity is seen in adjacent, uninjured fibers resulting from cross-talk with nearby injured fibers.

Collectively, these changes result in a state of decreased threshold and increased hyperexcitability, also known as peripheral sensitization . Clinically, this aberrant activity correlates with sensations of paroxysmal shooting pain or continuous pain that occurs in the presence or absence of a stimulus. However, peripheral sensitization has not been able to fully explain the mechanisms for all the clinical findings associated with neuropathic pain, such as allodynia, increased wind-up, and hyperalgesia. Studies have indicated that central sensitization, defined as “an amplification of neural signaling within the CNS that elicits pain hypersensitivity ,” also contributes to and is triggered by nerve injury and disease. Central sensitization alters communication from peripheral afferent fibers to higher-order neurons within the dorsal root ganglion of the spinal cord and brain. Two proposed mechanisms of central sensitization are hyperexcitability and disinhibition. Hyperexcitability may cause mechanical allodynia, a common feature of neuropathic pain characterized by pain with light touch, through activation of second-order pain pathway neurons by intact non–pain-conducting peripheral afferent fibers. This activation occurs by phosphorylation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and expression of voltage-gated sodium channels within postsynaptic membranes. Disinhibition occurs at many levels within the central nervous system. Peripheral nerve lesions cause loss of inhibitory regulation through chemical cascades, resulting in apoptosis of inhibitory γ-aminobutyric acid (GABA)ergic interneurons in the spinal cord. Lesions within the central nervous system may also cause neuropathic pain symptoms via the release of chemical modulators.

Summary of Evidence Regarding Treatment Recommendations

Neuropathic pain treatment begins with an initial pain assessment. Differentiating neuropathic from nociceptive pain will guide appropriate treatment. Nociceptive pain is caused by acute illness (from injury or inflammatory processes) that results in actual or potential tissue damage which activates pain receptors to warn or protect individuals. Neuropathic pain results from lesions or malfunction of the nervous system and serves no protective purpose. Clinical examination of patients with chronic neuropathic pain may reveal autonomic abnormalities such as trophic skin changes (e.g., alopecia or changes in pigmentation), motor weakness, tremors, and dystonia. More commonly, however, the clinical examination is completely normal. Unfortunately, there is often overlap of neuropathic and nociceptive pain mechanisms (mixed pain). Neurophysiological testing for peripheral nerve conduction disorders is not as effective for small Aδ and C pain fibers; thus these tests are of limited utility. Some value has been found in autonomic function testing using the quantitative sudomotor axon reflex test (QSART) and nerve biopsies to determine the extent of neuropathy. Many of these tests, however, are not specific for neuropathic pain and are also abnormal in peripheral neuropathies not associated with pain. QSART has been predominately useful in pharmacological studies, providing data for treatment effects of various drugs.

Because the physical exam can be variable and diagnostic testing does not directly confirm causal relationships between identified lesions and pain, a variety of screening tools have been developed. These tools have been validated by several studies, shown to have high sensitivity and specificity to differentiate neuropathic from nociceptive pain, and have been shown to have an impact on treatment. They generally consist of a combination of self-report and physical findings that can be conducted at the bedside. The Neuropathic Pain Diagnostic Questionnaire (DN4) has high sensitivity and specificity and is easy to use.

It is widely accepted that a multidisciplinary approach, including both nonpharmacological as well as pharmacological interventions, is appropriate when managing neuropathic pain. However, compared to other types of chronic pain, there are relatively few studies examining the efficacy of this approach for neuropathic pain specifically. Rather, the understanding that pain and disability are also affected by social and psychological factors (including depression and pain catastrophizing , which refers to the tendency to focus on and potentially magnify pain sensations along with feeling helpless in such pain) allows this method to be extrapolated to neuropathic pain as well. There are only a few trials to date examining the effects of psychological treatments in neuropathic pain, and they provide insufficient evidence.

There has been a growing interest in the potential benefits of exercise in neuropathic pain. As with the evidence for a multidisciplinary approach, there has been some extrapolation of the known benefits of exercise in attenuating pain and improving function. There is a growing body of literature suggesting that for peripheral neuropathy, certain exercises such as balance training can potentially attenuate symptoms of neuropathy and potentially slow the progression of neuropathic pain, along with improving function and managing psychosocial factors of pain such as mood. There has even been some evidence to suggest the utility in ameliorating neuropathic pain related to spinal cord injury as well. Though further research is needed in order to determine types and intensity of exercise, it can be a useful adjunct for some patients in the treatment of their neuropathic pain.

With regard to pharmacological management of neuropathic pain, effective strategies incorporate both the tailored implementation of agents across different classes of medications and a multidisciplinary team approach. Management of neuropathic pain should be pursued using a stepwise approach. First-line treatment medications include tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentinoids, and topical agents for focal pain. Second-line treatments should include a combination of first-line treatments and the possible addition of tramadol. When a patient has reached third-line treatments, agents such as selective serotonin reuptake inhibitors (SSRIs), anticonvulsants, NMDA antagonists, and interventional therapies should be considered along with referral to a pain specialist. Fourth-line treatments include options for surgical management with neuromodulation. It isn’t until fifth-line treatments that low-dose opioids should be considered. Sixth-line treatment has reached the point where targeted drug delivery is a last-line option. At every step of management, adverse effects to the population being treated must be considered, especially in older adults with multiple comorbidities. Given that there are multiple neuropathic causes for pain, combination therapies generally produce greater pain relief and fewer side effects than an escalating monotherapeutic approach. For a summary of these agents and their mode of action and duration of treatment, see Table 6.1 .