Neuropathic pain (NP) is a difficult to diagnose and treat medical condition that affects millions of people worldwide. Adequately caring for those suffering from NP can be challenging due to its complex pathophysiology and multidimensional nature. This chapter reviews the mechanisms, assessment, and treatment of a variety of NP pain conditions.

Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as “pain caused by a lesion or disease of the somatosensory nervous system.” In contrast, nocioceptive pain is defined as “pain that arrives from actual or threatened damage to nonneural tissue and is due to activation of nociceptors.” The need for a “lesion” in the nervous system in the definition of NP may be difficult to assess for, even with diagnostic studies. Many NP conditions may not have demonstrable lesions or a known “disease” which makes the diagnosis largely determined by clinical information. The presence and level of severity of NP has significant levels of morbidity, higher depression, higher anxiety, compromised sleep, higher health care utilization, poorer quality of life, lost productivity, and increased health care costs as compared with the general population.^1,2,3,4

NP can present in a variety of different ways, and the prevalence and incidence of NP conditions vary with each syndrome. For conditions such as diabetes, painful diabetic peripheral neuropathy (DPN) can occur in up to 30% of diabetics. The prevalence of phantom limb pain ranges from 40% to 80% of amputations but is based on patient-related factors and the site of the amputation.⁵ Postsurgical pain is common after surgeries such as mastectomies and thoracotomies due to either direct or indirect nerve injury. See Table 13-1 for a description of the prevalence and incidence of common NP conditions.⁶

The research literature describes a variety of mechanisms which can lead to the experience of NP. The theories regarding causes of NP start peripherally and spread centrally in the nervous system. Specifically, mechanisms focus on abnormal firing of nerves, abnormal amplification or propagation of nerve signals, or altered inhibition of pain pathways.⁶ Spontaneous neuronal activity from an injured primary afferent neuron such as a neuroma
or lesion in the dorsal horn of the spinal cord, thalamus, or other supraspinal structures may cause pain. Upregulation of receptors such as voltage-gated sodium channels (Nav. 1.8) and transient receptor potential vanilloid (TRPV1) on nerves known to modulate NP has been demonstrated. Demyelination of nerves may cause abnormal signaling between pain fibers and other nonpain fibers. For example, ectopic discharges from damaged and demyelinated nerves may cause ephaptic crosstalk (i.e., communication) between nerves that typically propagate pain and ones that typically do not such as sympathetic fibers. Nonephaptic crosstalk through repetitive firing that releases neurotransmitters that activate nearby nonnoxious fibers may also occur.⁶ Furthermore, functional reorganization of receptive fields, known as sprouting, occurs in spinal cord dorsal horn neurons such that sensory input from surrounding intact nerves emphasizes or aggravates input from the initial area of injury. Sprouting into the dorsal horn or dorsal root ganglion (DRG) causes increased activity to both noxious and nonnoxious stimuli. Additionally, loss of segmental inhibition or descending inhibition in the spinal cord may contribute to NP.⁷ For instance, pain can occur if A beta fibers (touch, pressure, and vibration) fail to modulate input from unmyelinated C fibers and myelinated A delta fibers.

Neurotransmitters and neuropeptides have action on specific receptors that are involved in pain pathways. Understanding the interactions of these molecules in the propagation or attenuation of pain signals is important in choosing medications. Many NP medications and treatments will alter or enhance one or more neurotransmitters. For example, glutamate and aspartate along with the neuropeptide substance P are known to transmit pain. Substance P, along with other local mediators released by primary afferent neurons, may interact with C fibers to cause the perpetuation of pain chronically.⁷ Endorphins and opioids are known to target both the ascending and descending pain pathways to inhibit pain. GABA and glycine are the main inhibitory neurotransmitters in the nervous system that modulate pain while serotonin is an inhibitory neurotransmitter involved in mood and emotion. Norepinephrine is involved in the descending inhibitory pain pathways.⁷ Due to neurotransmitter and neuropeptide profiles, relevant drug targets may include the GABA pathways or agents that release norepinephrine and serotonin such as duloxetine. See Figure 13-1 for a diagram of the pain pathways and potential receptor and molecular targets of specific medication-based therapies.

The phenomenon of central and peripheral sensitization, as it relates to NP is of interest when considering the chronicity of many pain conditions which often exceeds the initial injury. Neuroinflammatory mediators such as substance P, cytokines, prostaglandins, and histamine can stimulate or sensitize pain fibers to cause peripheral sensitization of the nervous system. Through repetitive stimulation of pain fibers, molecular and anatomical changes occur in the central nervous system called central sensitization. Central sensitization occurs through multiple mechanisms that include abnormal signaling or altered inhibition from the peripheral nervous system.⁶

NP conditions such as postherpetic neuralgia (PHN) or painful. DPN have mechanisms that are complicated and specific to the condition. PHN is caused by reactivation of the Varicella zoster virus latent in the dorsal columns of spinal cord sensory neurons after an initial infection. The virus causes focal necrosis of neuronal cell bodies, decrease in epidermal nerve fiber density, neurogenic inflammation, and demyelination of neurons in the DRG and peripheral nervous system.⁸ The virus may be reactivated in the elderly or immunocompromised leading to a severe pain condition. DPN has a mechanism of pain related to hyperglycemia causing nerve damage, sprouting and hyperexcitability of nerves, and the release of inflammatory mediators. Neurovascular changes causing hypoxia or sympathetic nervous system sprouting in the DRG are also thought to contribute to the pain experience in diabetics.⁹ Mechanical pain associated with chronic nerve compression such as in trigeminal neuralgia (TN) or carpal tunnel syndrome may be relieved by decompression. Direct nerve injury and sensitization may occur during common surgical procedures such as mastectomy, inguinal herniorrhaphy, or thoracotomy.¹⁰ Patients who undergo chemotherapy may experience pain due to neurotoxic therapeutic agents,
such as platinum agents, vinca alkaloids, and taxanes. Radiation induced nerve injury is believed to be related to fibrotic compression of nerves, injury to the vascular supply, and direct axonal injury and demyelination from X-rays.¹¹ Sympathetically maintained pain in causalgia or complex regional pain syndrome (CRPS) is hypothesized to be related to dysfunction of the sympathetic nervous system along with neurogenic inflammation and sensitization of nociceptors; however, neuroplastic changes and autoimmune mechanisms have not been ruled out.¹² The myriad of conditions along with the differing pain mechanisms makes the treatment and diagnosis of NP challenging for clinicians and frustrating to patients.

The presentation of NP may be variable and specific to the underlying clinical condition. Patients who experience NP may describe the pain as “burning,” “numbness,” “itchy,” “sharp,” and “shooting” or “electric.” The pain may be evoked or spontaneous. In DPN, the pain occurs in a “stocking glove pattern” sensitive to touch and typically in the lower extremities. Patients with radiculitis may report pain radiating to the extremities from the lumbar or cervical spine in a dermatomal pattern. Patients who suffer from TN may experience pain along any of the three dermatomal regions innervated by cranial nerve V, which is the trigeminal nerve. A thorough history may reveal a recent surgery, procedure, stroke, injury, worsening diabetes or other metabolic disorder, new medications, or use of chemotherapy agents. However, in many cases, it may be idiopathic.

Physical examination and diagnostic testing may assist with the diagnosis of NP. Table 13-2 details physical examination maneuvers and diagnostic testing that may provide evidence for many common and uncommon NP conditions. Responses to physical examination may be illustrated through pain descriptors such as allodynia, hyperalgesia, or paresthesia, which are common in NP disorders. Additionally, NP screening and assessment tools may assist with describing the experience of pain and tracking response to treatments. See Table 13-3 for a list of NP clinical screening and assessment tools.¹³ Validated tool and surveys can assess the quality of pain, severity of symptoms, exacerbating and alleviating factors, affective manifestations, and physical examination signs and other factors that may assist patients and clinicians in recognizing and treating NP (Table 13-4).