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Neuropathic pain management: a reference for the clinical nurse.

Pain is a universal experience and one of the most frequent reasons for physician consultation in the United States. According to the Institute of Medicine (IOM, 2011), approximately 100 million American adults have a chronic pain condition; one in three Americans suffers from chronic pain. In America, chronic pain conditions are more prevalent than diabetes, heart disease, and cancer combined. The IOM called for improved education about pain and improved curriculum and education for health care professionals. Nurses in particular play an integral role in pain assessment and management by listening, communicating with, and educating patients and caregivers. They translate the plan of care to the patient, acting as intermediaries between the patient and health care system. Nurses are taught to practice holistically, an advantageous approach given the complexity of caring for individuals with chronic pain.

Despite improvements in pain assessment and prompt treatment, such as the adoption of the American Pain Society's "pain as the fifth vital sign" by The Joint Commission (2001), shortfalls persist in pain management education, knowledge, and attitudes. Lewthwaite and co-authors (2011) concluded nurses were least likely to answer pharmacology questions correctly and therefore recommended ongoing education in pain management, particularly pharmaceutical agents for pain management. A more recent study of graduate nursing students echoed previous research in finding nurses demonstrated insufficient knowledge on pain management (Jackson, 2011). A literature review of pain knowledge and attitudes of nursing students consistently found a knowledge deficit among nursing students (Chow & Chan, 2014). Authors advocated pain education programs as an effective tool to bridge the knowledge deficit gap. A more recent literature review (Romero-Hall, 2015) echoed the Chow and Chan findings, citing lack of knowledge as a primary barrier to proper pain management. Romero-Hall proposed computer-based simulations to improve pain management knowledge. Karahan and colleagues (2014) investigated knowledge of neuropathic pain by 60 Turkish nurses working in physical and medicine rehabilitation, neurology, and neurosurgery. Although the nurses worked with patients with neuropathic pain symptoms, none of the participants had formal training in neuropathic pain management. Based on answers to a questionnaire, 80%) (n=48) of nurses were unable to define neuropathic pain, 83.8% (n=50) were unable to cite diseases that caused neuropathic pain, and 90% (n=54) showed insufficient knowledge regarding neuropathic pain management. Authors recommended in-service training to improve nurses' knowledge of neuropathic pain management.

Definition of Pain

According to the International Association for the Study of Pain (IASP, 2013), pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (para. 4). Pain is a complex phenomenon that may function as a protective mechanism in response to an unpleasant sensory stimulus. It also may be maladaptive, such as occurs in neuropathic pain (D'Arcy, 2014). A predictable relationship between the sensation of pain and identifiable tissue injury does not exist (Rodriguez, 2015). Often a patient's report of pain intensity is inconsistent with actual tissue damage. Patients who have experienced trauma commonly present without complaints of pain even though their injuries are quite severe. In contrast, individuals may experience agonizing pain unaccompanied by noxious stimuli. For example, persons with trigeminal neuralgia commonly complain of intense burning or shooting pain independent of unpleasant stimuli. The IASP definition acknowledges pain as a personal, emotional, and subjective experience. Pain is unique to each individual, and is influenced by genetics and physiology, cognitive and emotional response, and cultural, social, and financial contexts (Briggs, 2010).

Typically, pain is classified by duration (e.g., acute or chronic), type (e.g., nociceptive, neuropathic), or etiology. Acute pain is the direct consequence of tissue damage and should subside with healing. Pain lasting longer than 6 months is considered chronic (Rodriguez, 2015). Nociceptive pain is pain that occurs from threatened or actual damage to non-neural tissue and is due to the activation of nociceptors. Neuropathic pain, on the other hand, is caused by a disease or lesion in the somatosensory nervous system (IASP, 2014). An explanation of nociceptive pain physiology is integral to understanding the pathophysiology of neuropathic pain.

Nociceptive Pain

The IASP (2014) defined nociception as, "the neural process of encoding noxious stimuli" (para. 40). Nociceptive pain results from actual or threatened tissue damage. Nociceptors in the peripheral somatosensory nervous system are high-threshold sensory receptors with the ability to transduce and encode noxious stimuli. Nociception, the neural process of encoding harmful stimuli (IASP, 2014), occurs in four phases: transduction, transmission, perception, and modulation (Briggs, 2010; Rodriguez, 2015).

Pain information is transmitted via electrical impulses and chemical messengers in the peripheral and central nervous systems. Mechanical (e.g., an incision, a broken bone), thermal (e.g., a burn), and chemical (e.g., a response to cap saicin) nociceptors located in the skin, bones, joints, and viscera convert noxious stimuli into electrical signals. These signals are transmitted from the periphery to the spinal cord (Rodriguez, 2015). Cells maybe injured due to laceration, temperature, compression, infection, dehydration, and/or inflammation. In response to direct damage and/or the inflammatory reaction to damage, cells release nociceptor-sensitizing chemicals, including potassium, hydrogen, lactate, histamine, bradykinin, prostaglandin, and serotonin. This causes an action potential, a momentary change in the cells' electrical membrane potential where potassium exits and sodium enters (Marsh, 2013a).

Transduction, the first phase of nociception, occurs when the noxious stimuli is changed into a neuronal action potential. The next phase of nociception, transmission, occurs when the electrical impulse is transmitted along afferent neurons (A and C fibers) and interneurons to the spinal cord and eventually to the thalamus, a relay center where all sensory information is processed. Substance P (tachykinin), glutamate, and gamma aminobutryic acid (GABA) are neurotransmitters and neuropeptides released to help propel the signal to the brain. When sensory information arrives at the thalamus, it enters an individual's consciousness as a poorly localized sensation. Finally, the information is delivered to various parts of the brain including the somatosensory cortex, which perceives and interprets information, the reticular activating system, which produces autonomic responses, and the limbic system, which produces an emotional and behavioral response (Marsh, 2013a).

Once the information is processed and interpreted, the multidimensional conscious awareness of pain (perception) occurs. As the last phase of nociception, modulation occurs when governing structures in the dorsal horn of the spinal cord change or inhibit the pain signal (Rodriguez, 2015). Descending inhibition is achieved through release of neurotransmitters to block the pain impulse either fully or partially and produce an analgesic effect. Inhibitory neurotransmitters include endogenous opioids (enkephalins and endorphins), serotonin, and norepinephrine.

Neuropathic Pain

Nociceptive pain is protective; its aversive character motivates the individual to do something, such as quickly removing a hand when it nears an extremely hot stove or calling for help during a myocardial infarction. In contrast, neuropathic pain does not serve a protective function and is not self-limiting. Neuropathic pain denotes damage to or alteration of the usual sensing and modulating systems (Rodriguez, 2015). Any injury that occurs in the ascending and descending nerve pathways, from the peripheral nociceptors to the cortical neurons in the central nervous system (CNS), can result in neuropathic pain. Changes in nerve function are maladaptive, causing chronic and difficult-to-treat pain syndromes (D'Arcy, 2014).

Pathophysiology of neuropathic pain. Pathophysiological changes in the peripheral and central nervous systems are responsible for neuropathic pain. Mechanisms that modify the nervous system and contribute to neuropathic pain include abnormal nerve redevelopment, nerve sensitization, alterations in ion expression, loss of inhibition in modulating systems, and decreased availability of p-opioid peptide (MOP) receptors (Rodriguez, 2015).

Peripheral and central atypical nerve redevelopment occurs when nerves are damaged and normal nerve function is altered. Damaged nerves have increased excitability and fire spontaneously, creating pain signals without a stimulus. Abnormal neural activity along the afferent nerve causes sensitization and release of inflammatory substances (cytokines, bradykinin, tumor necrosis factor, substance P) in the CNS (Briggs, 2010; D'Arcy, 2014). The processes of peripheral and central sensitization are recognized as contributing to neuropathic pain. The IASP (2014, para. 54) defined sensitization as "increased responsiveness by nociceptive neurons to normal input and/or recruitment of a response to a normally sub-threshold input." Sensitized nerves have greater responsiveness and a decreased threshold. Crosstalk, new communication between nerves that previously did not synapse with one another, also occurs, amplifying electrical activity and pain signals (D'Arcy, 2014). Glutamate, the primary excitatory neurotransmitter in the brain, is released in the spinal cord during transmission and binds to Nmethyl-D-aspartate (NMDA) receptors on the postsynaptic membrane. Repetitive or excessive stimulation of C fibers by the NMDA receptors causes sensitization of the spinal cord, where mild stimulation is perceived as painful. This phenomenon, believed to play a major role in chronic pain syndromes, is termed wind-up (Marsh, 2013a).

Further atypical nerve redevelopment includes the formation of neuromas, or nerve sprouts or growths. After nerve injury, neuromas emerge and fire spontaneously to cause an increase in electrical activity. Phantom limb pain is a primary example of atypical peripheral nerve redevelopment. Approximately 42%-80% of patients who undergo amputation complain of unpleasant sensations ranging from mild to intense in the amputated limb (QuinlanCowell, 2014). According to Rodriguez (2015), the prevailing explanation is that phantom nerve pain results when irritated severed nerve endings fire spontaneously.

Sodium ion channels along the nerve fiber are believed to play an integral role in neuropathic pain. When a nerve is damaged, sodium channels increase in number. Action potentials begin with the influx of sodium into a cell to cause depolarization. If damaged nerve cells contain increased sodium channels and sodium channels begin depolarization, a damaged nerve cell has increased ability to conduct action potentials. According to Rodriguez (2015), the amassing of sodium channels reduces threshold of stimulation, accelerates repetitive firing of the injured nerve cell, and thus increases pain sensations. Ectopic discharge of pain impulses is thought to result from alterations in the sodium channels.

Lost or reduced inhibitory modulation contributes to increases in neuropathic pain. When MOP receptors bind endogenous opioids (endorphins and enkephalins), an analgesic effect occurs. Researchers hypothesize either the number of MOP receptors is reduced or the endogenous opioid production pathways are altered; either way, the body becomes less capable of modulating pain impulses (Briggs, 2010; Rodriguez 2015). Additional processes that prevent inhibitory modulation include suppression of the inhibitory GABA pathway due to apoptosis in the dorsal root of the spinal cord caused by nerve injury, and increased amounts of excitatory amino acids (e.g., glutamate, substance P) (D'Arcy, 2014; Marsh, 2013a; Rodriguez, 2015). Centrally, impulses from peripheral neurons become magnified due to suppressed inhibitory and increased excitatory neurotransmitters.

Because many different processes produce neuropathic pain, it is easy to understand why patients with neuropathic pain can present with varying symptoms. In the United States, neuropathic pain affects an estimated 1%-8% of the general population (Ney, Devine, Watanabe, & Sullivan, 2013). These individuals commonly describe their pain as constant burning, shooting, or electric pain. Neuropathic pain can be stimulus-evoked by temperature or by light touch. Allodynia is defined as pain due to a stimulus that normally does not produce pain (IASP, 2014). Hyperalgesia refers to an exaggerated pain response. Abnormal sensations (paresthesia), unpleasant sensations (dysthesia), and an abnormal reaction to a repetitive stimulus in a patient who initially did not perceive the stimulus as painful (hyperpathia) are common neuropathic pain presentations. Other related symptoms include numbness and the reduction or absence of thermal, vibratory, or tactile sensation.

Classification. Typically, neuropathic pain is categorized by origin: peripheral (injury related to the peripheral nerves, plexus, root, or dorsal root ganglion) or central (injury to the spinal cord, brainstem, thalamus, or cortex) (Haanpaa & Treede, 2010). Peripherally, neuropathic pain can be subdivided further into conditions that affect a single nerve vs. those that cause widespread peripheral nerve damage. Neuropathic pain can be classified by function (sensory, motor, autonomic, or mixed) or etiology (toxic, trauma, metabolic, compressive, autoimmune, infectious, congenital/ hereditary).

Neuropathic pain has many different etiologies (see Table 1). The most common type of toxic neuropathic pain is a result of chemo-radiation for cancer treatment (Lema, 2013). Neurotoxic agents include isoniazid (Nydrazid[R]), thallium, lead, arsenic, and endogenous chemicals, such as glutamate, beta amyloid, and oxygen radicals. Diabetes mellitus is the most prominent cause of metabolic-related neuropathic pain (Pluijms et al., 2011). Alcohol-induced neuropathy results from hypothyroidism and a deficiency of thiamine (Lema, 2013).

With peripheral nerve trauma associated with phantom limb syndrome, nerve endings continue to send impulses to the brain after the limb is amputated; although the patient knows the limb is gone, he or she still feels the lost limb (Rodriguez, 2015). Following spinal cord injury, damaged nerves transmit abnormal pain impulses. The affected person may have no sensation in the area at or below the injury but may experience neuropathic pain.

Compressive neuropathic pain is the consequence of nerve entrapment and excessive pressure on axons (Lema, 2013). Typical compressive presentations include carpal tunnel syndrome, compartment syndrome, and radiculopathies. Autoimmune-related neuropathic pain is associated with multiple sclerosis, chronic inflammatory dymyelinating polyneuropathy, and vasculitic neuropathy (Lalkhen, Bedford, & Dwyer, 2012; Lema, 2013). Infections known to cause neuropathic pain include varicella zoster, human immunodeficiency virus (HIV), Guillian-Barre syndrome, Lyme disease, leprosy, and Chagas disease (Lema, 2013). Complex regional pain syndrome often is linked to trauma, although the exact mechanism is unclear (D'Arcy, 2014).

IASP Guidelines

In 2010, the IASP published a clinical update on the management of neuropathic pain that outlines first- and second-line pharmacological therapies (Attal & Finnerup, 2010). Since 2010, the IASP neuropathic pain guidelines have been divided into particular neuropathic pain presentations, including neuropathic cancer pain (Naleschinski, Baron, & Miaskowski, 2012), painful traumatic trigeminal neuropathy (Benoliel, Heir, & Eliav, 2014), herpes zoster and post-herpetic neuralgia (Haanpaa, Rice, & Rowbotham, 2015), painful diabetic neuropathy (Haanpaa & Hietaharju, 2015), and central post-stroke pain (Kitt, Finnerup, & Jensen, 2015).

Treatment

Because standard opioid therapy is not generally effective in managing neuropathic pain (Wynne & LaPorte, 2011), adjuvant analgesics are the foundation of neuropathic pain management (Attal & Finnerup, 2010; Vortubec & Thong, 2013). An adjuvant analgesic's primary indication is unrelated to pain management, although it does provide an analgesic effect (Prommer & Ficek, 2012). Common adjuvant analgesics include antidepressants, anti-seizure medications, muscle relaxants, sedatives, steroids, and anxiolytic medications. Most research regarding neuropathic pain has involved patients with diabetic peripheral neuropathy (DPN) and post-herpetic neuralgia (PHN) (Finnerup et al., 2015). Generally, clinicians prescribe specific medications based on neuropathic pain etiology, patient co-morbidities, drug sideeffect profile, and pain quality. Medications are started at the lowest dose and titrated to a therapeutic dose. If one medication does not work, the health care provider may add a second medication from a different class to achieve a desired analgesic effect. Treatment efficacy depends more on the underlying pathogenesis of pain than on the etiology (Vadalouca et al., 2012). Most pharmacological treatment is considered efficacious if the patient's pain is decreased by 30% (Haanpaa & Treede, 2010). A patient is unlikely to experience total pain management with any treatment; the goal of therapy is decreased pain sensations and functional rehabilitation (e.g., improved sleep and mood) (Haanpaa & Treede, 2010).

First-Line Agents

Tricyclic antidepressants. Tricyclic antidepressants (TCAs) are considered first-line therapy for neuropathic pain (Attal & Finnerup, 2010). The class includes nortriptyline (Aventyl[R]), desipramine (Norpramin[R]), amitriptyline (Elavil[R]), doxepin (Sinequin[R]), and imipramine (Tofranil[R]). Their primary mechanism is to inhibit reuptake of norepinepherine and serotonin at the presynaptic neuron. Norepinephrine and serotonin are able to inhibit pain sensations via modulation. In addition, TCAs modulate sodium channels in the peripheral nervous system and antagonize NMDA; their multimodal effects serve to augment dorsal root inhibition and reduce peripheral sensitization (Valdalouca et al., 2012).

"TCAs act on descending pathways, blocking pain messages in the spinal cord before they are recognized as pain" (Stewart, 2010, p. 36). Preliminary dosing should begin low (10-25 mg at bedtime) and be titrated upward until analgesia is reached, which may not occur for 26 weeks. The typical dose for amitriptyline is 75 mg/day (Attal & Finnerup, 2010). Side effects of TCAs include weight gain, drowsiness, dry mouth, urinary retention, sedation, cardiac arrhythmia, dizziness, orthostatic hypotension, and constipation (Trivedi, Silvestri, & Wolfe, 2013). Amitriptyline should be avoided by older adults because its anticholinergic properties can contribute to orthostatic hypotension and falls. In patients over age 40, an initial electrocardiogram and serial monitoring are recommended to assess ischemic heart conditions. Sinus tachycardia is the most common cardiovascular effect due to the increased norepinephrine and anticholinergic action (Wynne & LaPorte, 2011).

Serotonin and norepinephrine reuptake inhibitors (SNRIs). Duloxetine (Cymbalta[R]), venlafaxine (Effexor[R]), and desvenlafaxine (Pristiq[R]) are SNRIs used in neuropathic pain management. The SNRI class acts by blocking serotonin and norepinepherine transporters, thus inhibiting reuptake and increasing the amount of neurotransmitter available to interact with receptors on the postsynaptic membrane. Duloxetine is approved by the U.S. Food and Drug Administration (FDA) for management of DPN (Aurobindo Pharma Limited, 2015). Standard dosing for duloxetine is 30 mg once daily, titrated to 120 mg. Velafaxine is only therapeutic at higher doses of 150-225 mg/day (Attal & Finnerup, 2010; Votrubec & Thong, 2013).

Gabapentin. Gabapentin (Neurontin[R]) is considered first-line therapy for neuropathic pain, particularly for DPN and PF1N (Attal & Finnerup, 2010; Wynne & LaPorte, 2011). The drug is well-tolerated, has few interactions, and is inexpensive. Gabapentin increases GABA concentration in the CNS after a single dose and stimulates descending inhibition via glutamate (Vadalouca et al., 2012). Exactly how gabapentin achieves an analgesic effect is unclear; the drug's high affinity for calcium-binding is likely responsible (Trivedi et al., 2013). Dosing ranges from 100 mg three times daily to a maximum of 1,800 mg/day and titration may take weeks (Trivedi et al., 2013; Wynne & LaPorte, 2011). Side effects include cognitive and gait impairment, sedation, fatigue, confusion, tremor, weight gain, headache, and peripheral edema. Pregabalin (Lyrica[R]) is a long-acting formulation similar to gabapentin, indicated for use in both peripheral and central pain syndromes, and only requires twice daily dosing (Attal & Finnerup, 2010). Specifically, pregabalin is approved by the FDA for management of DPN, PHN, fibromyalgia, and neuropathic pain associated with spinal cord injury (Pfizer Pharmaceuticals, 2014).

Topical lidocaine. Topical lidocaine patches recommended for treatment of PHN produce a local analgesic effect by blocking voltagegated sodium channels and reducing pain impulses (Dworkin et al., 2010). Patches are applied directly over the painful area. No more than four patches should be used per day and each patch should be removed after 12 hours. Topical lidocaine patches are considered first-line for older adults with central side effects to other medications (Attal & Finnerup, 2010).

TCAs, pregabalin, gabapentin, and SNRIs are recommended as first-line treatments by the Neuropathic Pain Special Interest Group of the IASP because of their proven efficacy (Attal & Finnerup, 2010). Second-line therapy for neuropathic pain consists of tramadol (Ultram[R]), strong opioids, capsaicin, cannabinoids, and botulinum toxin A (Attal & Finnerup, 2010; Feinberg et al., 2015). These pharmacological agents have been studied less than the first-line medications but have shown efficacy in neuropathic pain management. The IASP recommended tramadol and strong opioids as first-line agents in patients with episodic exacerbations of pain (Attal & Finnerup, 2010). Multidimensional therapy (mixing agents from different drug classes) is indicated when a medication partially manages pain but produces troublesome side effects when titrated to a higher dose (Trivedi et al., 2013). Pharmacists can help the health care provider select a combination of analgesics based on complementary mechanisms of action.

Second-Line Agents

Strong opioids. Research has supported the use of strong opioids in peripheral neuropathic pain (Attal & Finnerup, 2010). Opioids exert their influence centrally by binding to mu receptors embedded in the neuronal cell membrane and diminishing neuronal excitability (Wynne & LaPorte, 2011). Opioids commonly used for neuropathic pain include oxycodone, morphine, and methadone. Oxycodone is the moststudied opioid for neuropathic pain, with a dosing range of 10-20 mg (Attal & Finnerup, 2010). Class-wide side effects are respiratory depression, somnolence, nausea, vomiting, and addiction (Trivedi et al., 2013). Long-term opioid use is controversial because of its association with hyperalgesia, hypogonadism (decreased testosterone hormone, diminished sex drive, irregular menses), impaired sleep, depression, and immunosuppression (Attal & Finnerup, 2010).

Tramadol. Tramadol is a nonopioid centrally acting analgesic with opioid-like effects (Trivedi et al., 2013). It has a weak affinity for mu opioid receptors, and mildly inhibits the reuptake of serotonin and norepinephrine. Tramadol is considered first-line therapy for DPN (Attal & Finnerup, 2010; Trivedi et al., 2013). Standard dosing begins at 50 mg once a day and can be titrated to 400 mg/day. Common side effects are dizziness, dry mouth, constipation, nausea, somnolence, and cognitive impairment, especially in older adults. Taking tramadol may increase the risk of seizures in patients with a history of epilepsy or in patients taking another medication that decreases the seizure threshold (e.g., TCAs) (Attal & Finnerup, 2010).

Capsaicin. Capsaicin, the active ingredient in chili peppers used in topical creams, is indicated for treatment of peripheral neuropathy. Capsaicin causes depletion of substance P and over time results in epidermal nerve fiber degeneration, subsequently causing an analgesic effect (Trivedi et al., 2013). According to Attal and Finnerup (2010), capsaicin causes axonal desensitization and thus inhibits pain transmission. Capsaicin cream 0.075% is available over-the-counter. A highdose transdermal patch (Qutenza[R]) is approved for treatment of PHN by the FDA (Acorda Therapeutics, 2013). The patch deliverers a therapeutic dose with each application. Per manufacturer's guidelines, it should be used only once every 3 months. Side effects include local burning, tingling, and erythema.

Cannabinoids. This series of compounds acts on cannabinoid receptors to suppress neurotransmitter release in the brain. They are recommended for neuropathic pain management in multiple sclerosis (MS) and refractory peripheral neuropathic pain with allodynia. Cannabinoids are the psychoactive ingredients found in the cannabis plant.

Synthetic cannabinoids include dronabinol (Marinol[R]) and nabilone (Cesamet[R]). Possible adverse effects include sedation, dizziness, fatigue, dry mouth, oral discomfort, and gastrointestinal effects. Cannabinoids are contraindicated in patients with a history of mental illness because they have precipitated psychotic incidents (Attal & Finnerup, 2010). Cannabinoids are effective in treating spasticity and chronic pain associated with MS (Ware & Desroches, 2014).

Botulinum toxin A. Botulinum toxin A (BTX-A), a powerful neurotoxin injected subcutaneously, has been effective in decreasing neurogenic inflammation involved in peripheral neuropathic pain. One benefit of BTX-A is the lack of systemic side effects. Botulinum toxin A is believed to work by decreasing neurogenic inflammation (Attal & Finnerup, 2010).

Common Neuropathic Pain Presentations

Trigeminal Neuralgia

Each year, 12 people per 100,000 are diagnosed with trigeminal neuralgia (TN, tic douloureux) (National Institute of Neurological Disorders and Stroke, 2013). The precise etiology of TN is unclear but it is linked to vascular compression (Warren, 2010). Chronic compression of the trigeminal nerve by a vessel causing breakdown of the myelin sheath is the predominant accepted explanation for TN (Marsh, 2013a). Alternate explanations for TN include MS or compression by a tumor (Warren, 2010). TN is characterized by facial tics and short attacks of paroxysmal excruciating pain described as stabbing or burning. Pain is triggered by non-noxious stimuli (e.g., wind on the cheek). TN may progress, causing extended, more frequent periods of intense pain. Although the condition can occur at any age, including infancy, the typical patient with TN is a woman over age 50. Painful traumatic trigeminal neuralgia (PTTN) usually occurs as a result of damage to afferent sensory nerves after den tal extractions (Benoliel et al., 2014). Recommended first-line pharmacological management of TN (Attal & Finnerup, 2010) and PTTN (Benoliel et al.., 2014) includes TCAs, SNRIs, gabapentin, and pregabalin.

Post-Herpetic Neuralgia

Post-herpetic neuralgia, a condition induced by herpes zoster (shingles), is caused by the same vims responsible for chickenpox (varicella zoster virus [VZV]). After the initial infection, VZV lays dormant in the dorsal root ganglia. Resurgence of VZV is associated with diminished cellular immunity, as occurs with aging. The reactivated vims moves down the peripheral nerve from the ganglia to the skin of the corresponding dermatome, erupting as a unilateral, localized, painful rash on the tmnk, forehead, or face. Similar to varicella, the zoster rash progresses from vesicles to pustules to scabs; however, in zoster, the principal presentation is pain rather than itching. Zoster generally clears in a few weeks. However, if the pain persists for more than 4 months after the initial zoster attack, the person is diagnosed with PHN (Marsh, 2013a). Pain associated with PHN can be continuous, intermittent, or stimulus-evoked (allodynia), and is described as throbbing, piercing, or stabbing. An estimated 10%25% of adults will have herpes zoster and, of that group, 9%-15% will suffer from PHN (Litchfield, 2010). Recommended first-line therapy for treatment of PHN includes TCAs, gabapentin, opioids, and topical capsaicin (Haanpaa et al., 2015).

Diabetic Neuropathic Pain

Pluijms and colleagues (2011) classified DNP as the most prevalent type of neuropathy. The condition results from the toxic effect of glucose on the nerve cells. Hyperglycemia causes injury to small blood vessels that supply the nerves (vasa nervomm), in turn causing neuronal ischemia. The most prevalent presentation is distal-symmetric peripheral neuropathy that affects the feet and knees. Decreased sensation occurs first in the toes and moves upward; the distal region of the longest nerve fibers is affected first. Damage to the small Type C fiber is associated with DNP. Initially, the presentation is decreased sensation accompanied by tingling and burning in the feet. Foot pain is more remarkable at night and is aggravated by touch; paroxysmal attacks of shooting pain are common. The World Health Organization (2015) estimated 9% of all people age 18 or older will have diabetes. Diabetic neuropathy affects approximately 60%-70% of all persons with diabetes (Marsh, 2013a). Symptoms of DPN generally increase with disease duration and poor glycemic control (Smith & Argoff, 2011). Recommended firstline treatment for DNP includes TCAs, SNRIs, and gabapentin (Haanpaa & Hietaharju, 2015).

Central Post-Stroke Pain Syndrome

Central post-stroke pain syndrome (CPSP) can occur following a cerebrovascular attack (CVA). Generally, CPSP presents days to weeks after the stroke with chronic disabling pain, dysesthesia, allodynia, and hyperpathia. CPSP is a principal obstacle to rehabilitation following stroke. Approximately 8% of all persons who experience a CVA experience CPSP (Flaster, Meresh, Rao, & Biller, 2013). Few double-blinded, placebo-controlled studies have been conducted on its treatment. Similar to other neuropathic pain conditions, CPSP responds to pregabalin and amitriptyline (Kitt et al., 2015).

Neuropathic Cancer Pain

Roughly one-third of patients with cancer experience neuropathic pain (Vadalouca et al., 2012). Neuropathic cancer pain (NCP) results from mixed mechanisms of nociceptive pain and neuropathic pain with inflammatory and ischemic components. NCP can be induced by the disease itself or by cancer treatments, such as radiation, chemotherapy, or surgical resection. The incidence and presentation of NCP are complex, depending on the person's age, health state prior to cancer diagnosis, specific type of cancer, and type of treatment. Tumor expansion can result in compression, infiltration, and/or entrapment. According to Smith and colleagues (2014), the highest rate of NCP occurs due to nerve injury or scar formation secondary to surgical management of thoracic, breast, head and neck, and bone and soft tissue malignancies. Radiation therapy also can cause nerve inflammation and scarring. The use of chemotherapeutic agents often leads to peripheral nerve damage. Particular neurotoxic agents associated with NCP include bortezomib, platinum compounds, taxanes, thalidomides, lenalidomide, and vinca alkaloids. See Table 2 for a complete list of neurotoxic agents by class. NCP severity varies with the specific agent used, treatment duration, and cumulative dose. It is described as spontaneous burning with periodic sharp, stabbing sensations occurring with allodynia and hyperalgesia. Pharmacological recommendations for NCP include gabapentin, opioids, TCAs, SNRIs, and topical lidocaine and capsaicin (Naleschinski et al., 2012).

Nursing Implications

Neuropathic pain can be a chronic, debilitating illness that requires long-term care. When a patient first presents with neuropathic pain symptoms, he or she should have a thorough history and physical examination. To provide better patient care, nurses should be familiar with neuropathic pain clinical assessment tools. The IASP recognized five assessment tools: the Douleur Neuropathique 4 questions (DN4), the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), painDETECT, the Neuropathic Pain Questionnaire (NPQ), and ID Pain (Haanpaa & Treede, 2010). The NPQ, painDETECT, and ID pain tools question patients about their symptoms. The surveys ask if and how often a patient experiences tingling, pins and needles, a burning sensation, electric shocks, numbness, or pain evoked by light touch or freezing pain. The LANSS and the DN4 tools, along with the questionnaire portion, include a clinical examination for brush allodynia and raised pinprick threshold. Once a diagnosis is made, a patient begins treatment with first-line medications to help alleviate neuropathic symptoms. The clinical nurse plays an integral role in patient education and is able to assess treatment side effects. When administering medications, the nurse must know the rationale for each drug's use. For example, patients with neuropathic pain commonly receive antidepressants and antiseizure medications but may have no history of epilepsy or depression. Table 3 may be a tool for the clinical nurse for patient education during medication administration.

Conclusion

Although neuropathic pain may be difficult to treat, advances in its management have been made. Nurses should understand goals of neuropathic pain management are different from nociceptive pain management. Patients with neuropathic pain generally require more drugs and report less-effective pain management than patients with nociceptive pain (Marginelli, Zanette, & Tamburin, 2013). Furthermore, because most medications used in the treatment of neuropathic pain are adjuvants, nurses must delineate the rationale for the medications they administer (Attal & Finnerup, 2010). Nurses should be familiar with indications, contraindications, and possible adverse effects of medications for neuropathic pain in order to educate patients and monitor their response. Without this knowledge, nurses will have difficulty advocating for a patient with neuropathic pain. E03

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ADDITIONAL READING

Marsh, J.D. (2013b). Chronic disorders of neurological function. In LE.C. Copstead & J.L. Banesik (Eds.), Pathophysiology (5th ed.) (pp. 922-941). St. Louis, MO: Saunders.

Bree Blumstein, MSN, RN, AGACNP-BC, is Registered Nurse, Medical Intensive Care Unit, Ronald Reagan University of California Los Angeles Medical Center, Los Angeles, CA.

Thomas W. Barkley, Jr., PhD, ACNP-BC, FAANP, is Professor of Nursing, Coordinator of the Adult-Gerontology Acute Care Nurse Practitioner Option, and Director of Nurse Practitioner Programs, California State University, Los Angeles, CA.

Note: The off-label usage of some medications for neuropathic pain management is discussed in this article.
TABLE 1.
Classifications of Neuropathic Pain

Neuropathic Pain
Presentations by
Etiology                               Examples

Toxic              Chemo-radiation, isoniazid, thallium, lead,
                   arsenic, glutamate, free oxygen radicals

Metabolic          Diabetic neuropathy, thiamine deficiency,
                   hypothyroidism

Trauma             Phantom limb, spinal cord injury

Compressive        Carpal tunnel syndrome, compartment syndrome,
                   radiculopathy

Autoimmune         Multiple sclerosis, chronic inflammatory
                   dymyelinating polyneuropathy, and vasculitic
                   neuropathy

Viral              Varicella zoster virus, HIV, Guillain-Barre
                   syndrome, Lyme disease, leprosy, Chagas' disease

Mixed              Chronic regional pain syndrome

Source: Lema, 2013

TABLE 2.
Neurotoxic Agents by Class

Class                                   Medications

Bortezomib                  Cytomib[R], Velcade[R]

Platinum compounds          Cisplatin (Platinol[R])
                            Carboplatin (Paraplatin[R])
                            Oxaliplatin (Eloxatin[R])

Taxanes                     Paclitaxel (Abraxane[R], Taxol[R])
                            Docetaxel (Taxotere[R])

Thalidomide, lenalidomide   Thalomid[R], REVLIMID[R]

Vinca alkaloids             Vincristine (Oncovin[R])
                            Vnblastine
                            Vindesine
                            Vinorelbine (Navelbine[R])

Source: Naleschinski et al., 2012

TABLE 3.
Medications by Class for Neuropathic Pain

Medication         Primary Mechanism
by Class               of Action                   Explanation

TCA            Inhibits reuptake of NE      Pain transmission is
               and serotonin, increasing    decreased via NTs and
               the levels at the            sodium channels, causing
               postsynaptic membrane        inhibition in the CNS.

SNRI           Inhibits reuptake of NE      Interferes with pain
               and serotonin at             transmission using NT or
               presynaptic neuron in the    chemicals in the CNS
               CNS

Gabapentin     Inhibits voltage-gated       Decreases
               calcium channels at the      hyperexcitability of
               synaptic knob in the CNS     neurons in the CNS
               and increases amount of
               GABA in CNS

Topical        Inhibits voltage-gated       Localized nerve fiber
lidocaine      sodium channels in the       desensitization
               PNS

Capsaicin      Depletes substance P,        Localized nerve fiber
               resulting in epidermal       desensitization
               nerve fiber degeneration

Tramadol       Bind to mu receptors,        Centrally acting
               inhibits NE and serotonin    analgesic inhibits pain
                                            transmission.

Strong         Bind to mu receptors in      Centrally acting
opioids        the CNS                      analgesic inhibits pain
                                            transmission.

Cannabinoids   Bind to cannabinoid          Provide analgesia through
               receptors                    activation of cannabinoid
                                            receptors

Botulinum      Decreases neurogenic         Provides localized
toxin A        inflammation                 analgesia

Medication
by Class             Side Effects          Indications

TCA            Weight gain, drowsiness,    DNP   CPSP
               dry mouth, constipation,    PHN   NCP
               urinary retention,          TN
               orthostatic hypotension

SNRI           Nausea, sedation,           DNP   CPSP
               dizziness, fatigue,         PHN   NCP
               decreased sexual libido     TN

Gabapentin     Sedation, cognitive and     DNP   CPSP
               gait impairment, fatigue,   PHN   NCP
               weight gain                 TN

Topical        No systemic side effects    PHN
lidocaine                                  NCP

Capsaicin      Localized burning,          PHN
               tingling, erythema          NCP

Tramadol       Dizziness, dry mouth,       DNP
               constipation, nausea,
               sedation, cognitive
               impairment

Strong         Hypotension, respiratory    DNP
opioids        depression, dry mouth,      PHN
               constipation, nausea,       NCP
               sedation, cognitive
               impairment

Cannabinoids   Sedation, dizziness,        MS
               fatigue, dry mouth, oral
               discomfort,
               gastrointestinal effects

Botulinum      No systemic side effects    DNP
toxin A

TCA--tricyclic antidepressant; CNS--central nervous system;
CPSP--central poststroke pain; DNP--diabetic neuropathic pain;
GABA--gamma-aminobutyric acid; MS--multiple sclerosis;
NCP--neuropathic cancer pain; NE--norepinephrine; PHN--postherpetic
neuralgia; SNRI--serotonin norepinephine reuptake inhibitor;
TN--trigeminal neuralgia

Sources: Acorda Therapeutics, 2013; Attal & Finnerup, 2010; Aurobindo
Pharma Limited, 2015; Benoliel et al., 2014; Dworkin et al., 2010;
Haanpaa & Hietahraju, 2015; Haanpaa, Rice, & Rowbotham, 2015; Kitt,
Finnerup, & Jensen 2015; Naleschinski et al., 2012; Pfizer
Pharmaceuticals, 2014; Trivedi, Silvertri, & Gil, 2013; Vadalouca et
al., 2012; Vortubec & Thong, 2013; Ware & Desroches, 2014; Wynne &
LaPorte, 2011
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Title Annotation:CNE SERIES
Author:Blumstein, Bree; Barkley, Thomas W., Jr.
Publication:MedSurg Nursing
Date:Nov 1, 2015
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