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Abstract: Peripheral neuropathy (PN) is a common and often progressive condition frequently seen in primary care. The chronic pain associated with PN, or neuropathic pain, can significantly diminish patients' quality of life and be challenging to treat.
Peripheral neuropathy (PN) is a common and often progressive condition frequently seen inprimary care. It affects between 2% and 4% of the general population.1,2 In patients with causative comorbidities such as diabetes and HIV, theprevalence can be as high as 26% to 60%.1,3 PN is defined assymmetric damage to the nerves in the periphery that results in pain without external stimulation of the nerves.4 Patients describe symptoms such as tingling; numbness; andburning, shooting, or lancinating pain. In addition, the pain is not associated with a specificstimulus or nociceptive source. Often, minor injuries cause higher intensity pain that seemsdisproportionate to the injury, and extends beyond the area where the injury occurred. Thechronic pain associated with PN, or neuropathic pain, can diminish patients' quality of life significantly and can be challenging to treat.1,5
PN places a heavy burden on the healthcare system. One estimate reports that up to25% of pain clinic consultations are related to PN.6 While not well defined, those with PN incur costs ranging from $1,000 to $8,000 higher thanmatched controls, representing approximately 30% higher costs.7
PN is usually associated with an underlying disorder or treatment, including diabetes, chemotherapy, zoster infection, HIV, vitamin deficiencies (thiamine and B12), Lymedisease, hypothyroidism, and systemic lupus erythematosus.4 Each of these conditions results in further damage to the nerve endings. The exact mechanism is not well understood, but it is thought that nerve injury results in mounting inflammatory processes with therelease of proinflammatory cytokines, leading to a decrease in the large and small myelinatedfiber density.8 While this damage occurs in all neuropathy cases, the mechanismor pathway of damage varies based on the underlying etiology.
HIV-associated PN is caused by two processes and correlates with degeneration of both myelinated and unmyelinated small nerve fibers. Specific risk factors for PN are advanced disease, age, prior opiate abuse, low CD4 T-cell count, and increased HIV RNA levels. It is alsoassociated with antiretroviral medications.9 Individuals who have a particular genetic variation of mitochondrial DNA allele, specifically 4917G, found in individuals ofEuropean decent, have a significantly increased risk of developing PN.10
Because of the increased numbers of individuals affected with diabetes, diabetic PN (DPN)has become one of the most common causes of neuropathy. Patients describe allodynia,stabbing, or burning pain, or painful numbness in a stocking-glove distribution. The painusually presents in the lower extremities symmetrically and progresses proximally, stronglysuggesting DPN.4
While the exact mechanism of nerve fiber damage is not known, the duration of diabetes andsustained elevation of blood glucose and hemoglobin A1c levels have consistently demonstrated a correlation with the development of PN.11,12 Recent studies have shownthat elevated triglycerides and a lack of neurotrophic support, such as nerve growth factor,brain-derived neurotrophic factor, and neurotrophin 3, may also contribute to nerve fiberdamage and the resulting symptoms.9,13 Activation of the polyol pathway fromexcess glucose produces advanced-glycation end products, and increases oxidativestress.14 Alterations in sodium and potassium pump function in nerve fibers mayalso contribute to the symptoms of weakness and fatigue associated with PN.15
Patients undergoing chemotherapy for the treatment of cancer may develop chemotherapyinduced PN (CIPN). The risk of developing CIPN increases with the number of agents thepatient is exposed to. CIPN rates for individuals treated with a single agent range from3% to 7%, whereas those exposed to multiple agents have rates closer to40%.16 Damage to the neuron is thought to occur in the dorsal root ganglion, microtubules, Schwann cells, or excitable membrane depending on the agentused.17 As with other etiologies, damage to the mitochondria and lack of nervegrowth factor have also been seen. Beyond the classic neuropathy symptoms, patients reportfatigue myalgias, and muscle aches that are worsened with activity, suggesting damage to theautonomic fibers as well.
Postherpetic neuralgia (PHN), while not limited to the periphery, is a form of neuropathy andshares many features with other forms of neuropathy. PHN can result in a chronic pain that lingers for months to years after the acute infection has cleared.7 Estimates of lifetime prevalence have been demonstrated to be as high as 20%.18 Prevalence rates in people over 60 years old are even higher, with estimates approaching68%.19 The underlying damage to the nerve is similar to that seen in chemotherapy neuropathy. The exact mechanism of damage is related to the acute zoster infection with symptoms lingering long after the acute infection has resolved.
During the initial stages of the disease, patients may be asymptomatic.1 Most patients progress to a presentation characterized by symptoms that are unusual or exaggeratedresponses to stimuli or occur in the absence of stimuli.20 Symptoms can vary andmay be described as numbness, decrease in strength, tingling, burning, "pins andneedles" sensation, or an increased sensitivity to tactile stimulation.3,4Typically, these symptoms initially present in the toes and feet and can progress to the hands,resulting in the "stocking-glove" distribution. The pain may progress toallodynia, or a sense of pain in response to nonpainful stimuli, such as a cotton swab or bedsheets. Additionally, the patient may develop a lack of any feeling at all, and may describeheaviness or "deadness" in the affected limb.
This lack of feeling or numbness creates additional symptoms and risks. These risks includepostural instability, altered gait, reduced mobility, increased risk of falls, and in some cases,an increased risk of fracture.21,22 The reduced or lack of sensation may also causeinjuries to go unnoticed, increasing the risk of ulceration, infection, and necrosis. Decreasedperipheral arterial and venous circulation can cause these ulcers to heal poorly and increaseinfection rates.23 Ulcerations are a leading cause of amputation in nontraumaticinjuries.1,23
Advanced disease has been shown to cause weakness and motor wasting due to denervationof the striated muscle.9,23 Symptoms that are more extreme or beyond the periphery, such as asymmetric presentation, vision changes, or impaired bowel and bladder function, are indicative of a central nervous system (CNS) lesion and require further exam andtesting.4 Additional indications of CNS lesions include spasticity, dermatomal pattern, and associated neck and lower back pain.
In order to diagnose PN correctly, a high level of suspicion for neuropathy based on individual patient risk factors and known medical history is necessary. A variety of screening toolsare available including the painDETECT questionnaire that patients complete to rate pain andassociated symptoms (scale is freely available on the Internet). A score is then assigned, with19 or higher indicating a 90% likelihood that the individual has neuropathy. Patientscan access this questionnaire at home and bring the results to their clinic visit, or it can beadministered in the office. It is important to remember that even with diligent administration,these tools fail to identify 10% to 20% of individuals who have disease (seeScreening tools for PN).24
Differentiating nociceptive pain from neuropathic pain is important and begins with knowledge of the patient's medical history. A full description of the symptoms that thepatient is experiencing will help clarify the diagnosis. This includes differentiating numbnessversus abnormal sensation (tingling or skin crawling sensation), hypersensitivity, mechanical,or thermal stimulation.24
In addition to history, the physical exam can provide objective information about the patient's sensory status. These techniques include gait assessment, vibration, and pressure sense. An evaluation of balance includes Romberg and heel-to-toe walking. Observingthe patient ambulating a minimum of 10 feet to detect abnormal gait will help screen for fallrisk. Vibration can be tested using a 128-Hz tuning fork beginning at the distal interphalangeal joints and moving proximally until normal sensation is detected. Pressure sensation istested using a 10-g monofilament.25 This testing is done randomly at 10 specificlocations on the dorsal surface of the foot. If abnormal sensation is noted, the nurse practitioner (NP) should proceed with monofilament testing proximally until normal sensation is identified. This process allows the affected area to be mapped. It is important to note that combined use of both modalities significantly increases sensitivity and specificity, allowing NPsto be more confident with the diagnosis.25
Lab data, such as B12 levels, metabolic panel, complete blood cell count, bloodglucose level, thyroid function, and erythrocyte sedimentation rate, may be helpful in identifying potential underlying causes of the neuropathy. If the diagnosis is still uncertain, additional testing with electrodiagnostic studies such as electromyography or nerve conductionstudy, nerve biopsy, and lumbar puncture with cerebrospinal fluid analysis may help identifythe pathology.4
One of the best ways to treat pain associated with PN is to eliminate the etiology. If the painis related to DPN, correcting hyperglycemia may help reduce the pain and decrease symptomprogression. By maintaining blood glucose levels as close to normal as possible and keepingthe hemoglobin A1c below 7%, pain management will improve. Since all causes ofneuropathic pain cannot be effectively treated, pain is managed with a variety ofagents.5 However, analgesics will help provide pain relief while the underlyingcause of the pain is still being investigated.
Recently published evidence-based guidelines from the American Academy of Neurology(AAN) help NPs select the best agents to control pain.26 The guidelines were developed following a systematic review of studies conducted from 1960 to 2008, and standardcriteria for evaluation of the evidence were included. The only level A recommendation(first-line therapy) was the antiepileptic drug, pregablin. Gabapentin and sodium valproatewere rated as level B recommendations. Additional level B recommendations included usingamitriptyline, venlafaxine, duloxetine; the opioids morphine sulfate and oxycodone; and thesynthetic opioid tramadol. Alternative pharmacologic agents, capsaicin, and isosorbide dinitrate spray were also level B recommendations.27 The only nonpharmacologicagent that attained a level B recommendation was percutaneous electrical nerve stimulation.Agents that are specifically indicated for neuropathic pain management include duloxetine,gabapentin, and pregablin. Many of the others are used off-label to manage neuropathic pain(see Therapy for neuropathic pain).
PN significantly affects quality of life. The affect is multifactorial, and includes a higher rateof physical, social, and role functioning; sleep disruption; inability to participate in typicalactivities; and emotional well being.20,27 Since neuropathic pain can be moresevere during sleep, some patients will suffer from loss of sleep associated with the unrelenting pain. Often these issues result in isolative behavior that compounds the problem. Additionally, the treatment of symptoms creates an added burden on the individual due to the inconvenience of taking medication, enduring unpleasant adverse reactions of the medication,and purchasing potentially costly medication.
The effect on a person's daily routine can be quite significant. Often it is the nonpainful symptoms that can be the most problematic. These include loss of balance, muscleweakness, clumsiness, loss of depth perception, lack of coordination, dizziness, and generalized weakness.28 These nonpainful symptoms can also result in injury. One studyfound that approximately 50% of the patients with PN experienced near or actual injury as a direct result of these symptoms.20 These symptoms and risk of injuryresult in individuals having a significant fear of falling, contributing to decreased mobility,isolative behaviors, and additional negative impact on quality of life.
Mr. J, 58, has a 10-year history of type 2 diabetes and complains of intractable burning inhis feet, especially at night. Describing the pain as "walking across hotcoals," he finds that the pain is waking him up at night, and getting back to sleep isnearly impossible. He is also experiencing daytime drowsiness. Other pertinent details of hismedical history include hypertension, obesity, and mild renal insufficiency. Because he isbetween jobs, he does not have insurance coverage and is extremely concerned about thecost of medications.
Pregabalin, a level A recommendation from the AAN (2011), would be considered a first-lineapproach for JB, but it is expensive. Duloxetine is used with extreme caution in the arena ofrenal impairment, and it is also expensive. For those reasons, the tricyclic antidepressantamitriptyline (a level B recommendation per AAN guidelines and FDA off-label use for PN)was considered. It has the added benefit of being used at the hour of sleep as it causes drowsiness. A baseline ECG should be done to rule out recent myocardial infarction, dysrhythmia,heart block, or prolonged QT interval. A starting dose of amitriptyline 25 mg at bedtime wasrecommended. The dose can be increased by 10 mg weekly as needed to reach pain control orat a maximum of 100 mg daily. At follow-up, Mr. J reported great relief in pain with amitriptyline 100 mg taken at bedtime.
Ms. E, 46, has been experiencing increasingly painful numbness and burning in her feet for atleast 4 months. After being treated for colon cancer, she developed PN and was initiallytreated with gabapentin 300 mg daily (FDA off-label use for PN). While this has previouslyrelieved her pain, it is not helping now. Ms. E feels depressed and is having trouble sleepingthrough the night.
Before changing medications, it is worth exploring a higher dose of gabapentin since it didhelp initially and Ms. E's dose is relatively low. Gabapentin can be titrated upwardto 1,200 mg taken three times a day (total dose 3,600 mg daily, according to AAN guidelines), but should be increased gradually.26 Dosage adjustments are needed forpatients with impaired renal function.
If symptoms resolve as gabapentin is increased, Ms. E's depression symptoms mayalso resolve since pain induced insomnia may be related to her neuropathy. If she is still experiencing depression, it is recommended to stop gabapentin and consider duloxetine for both thepain and depression. Duloxetine should be used cautiously with renal impairment; glomerularfiltration rate should be assessed first.
Ms. M, 84, who is living in an assisted living setting, presents with a burning sensationacross her left flank for the past 48 hours. She noticed a blistering rash along a dermatomalline on her left flank. On exam, the NP diagnoses new-onset shingles and starts her on the antiviral, acyclovir, to address the acute infection. Initiating therapy within the first 24 to 72hours of rash development will significantly reduce the destruction of nerves, pain during theacute phase, and speed healing.29
While medications such as tricyclic antidepressants and some anticonvulsants are first-linetherapy and can be very cost effective, they present a challenge in the elderly due to adverse reaction profile. Drowsiness, nausea, constipation, and weakness make these medications potentially harmful. Pain during the acute phase of the illness, while the rash is still anissue, can be managed with low-dose opioid therapy or tramadol. Once the rash has healed,treatment of pain can be transitioned to a lidocaine or capsaicin patch. Both should be usedonly after the initial rash has healed; they need to be applied and monitored by nursing staffat the assisted living facility. A topical treatment for Ms. M is advantageous, as it does nothave systemic adverse reactions.14
As the case studies illustrate, management of pain associated with PN is complex when considering the many patient-related variables that influence the choice of agents. There aremany agents to treat neuropathic pain, and it is worth the time and effort to find a regimen forpatients to help improve quality of life and restore functional ability. NPs must be knowledgeable with the many choices available and need to understand the adverse reaction profiles and contraindications before using them.
It is equally important for NPs to examine the etiology of pain associated with PN since paincan sometimes be controlled with aggressive treatment of the cause. Examples include maintaining glycemic control for diabetes in an effort to limit pain related to diabetic PN, and using antivirals within 72 hours of an outbreak of herpes zoster to help mitigate potential PHN.
There are several new treatments under review to treat pain associated with PN. Benfotiaminehas shown some promise with relieving pain associated with diabetic PN, but more investigation is needed.30 Other agents that have demonstrated some pain relief include alpha-lipoic acid as well as folate and B vitamins. Local pain relief has been provided withbotulinum toxin injections intradermally in the feet, but large-scale studies are needed beforeit is recognized as mainstream therapy.30
As new therapies are developed, NPs need to keep current of innovations to continue to offerevidence-based management for patients. This is especially relevant as prevalence rates ofPN rise as a result of the ever-increasing rate of diabetes. NPs will need to continue to provide early screening and detection in an effort to prevent further vascular and nerve damage.Prevention is preferable to managing this complex disorder.
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