Non-Pharmacologic Options for the Treatment of Neuropathic Pain

Naileshni Singh, MD

Jon Zhou, MD

Samir J. Sheth, MD

FAST FACTS

Neuropathic pain (NP) has a significant impact on function and quality of life.
Owing to the multiple etiologies of NP, it often is not straightforward to diagnose and can be difficult to treat.
NP is best treated with a careful, stepwise approach that utilizes a biopsychosocial model.

INTRODUCTION

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 because of its complex pathophysiology and multidimensional nature. This chapter reviews the mechanisms, assessment, and treatment of a variety of NP pain conditions.

DEFINITIONS AND MECHANISMS

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 non-neural tissue and is due to activation of nociceptors.” The need for a “lesion” in the nervous system in the definition of neuropathic pain may be difficult to assess for, even with diagnostic studies. Many neuropathic pain conditions may not have demonstrable lesions or a known “disease” that 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

Neuropathic pain can present in a variety of different ways, and the prevalence and incidence of neuropathic pain 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 because of either direct or indirect nerve injury. See Table 29-1 for a description of the prevalence and incidence of common neuropathic pain conditions.⁶

The research literature describes a variety of mechanisms that can lead to the experience of neuropathic pain. The theories regarding causes of neuropathic pain 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 neuropathic pain 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 non-noxious 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 neuropathic pain.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.

TABLE 29-1 Prevalence and Incidence of Neuropathic Pain Conditions

NEUROPATHIC PAIN CONDITION	PREVALENCE (BEST ESTIMATE)	INCIDENCE
Painful diabetic neuropathy (DPN)	15%	15.3/100,000
Postherpetic neuralgia (PHN)	7%-27%	11-40/100,000
HIV neuropathy	35%	Unknown
AIDS neuropathy	50%	Unknown
Central poststroke pain	8%-11%	Unknown
Multiple sclerosis (MS) pain	23%	Unknown
Spinal cord injury (SCI) pain	40%-70%	Unknown
Phantom limb pain	53%-85%	Unknown
Trigeminal neuralgia	Unknown	5-8/100,000
Adapted from Sadosky A, McDermott A, Brandenberg N. A review of the epidemiology of painful diabetic peripheral neuropathy, postherpetic neuralgia, and less commonly studied neuropathic pain conditions. Pain Pract. 2008;8(1):45-56. Copyright © 2008 World Institute of Pain. With permission of John Wiley & Sons, Inc.

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 neuropathic pain 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, whereas serotonin is an inhibitory neurotransmitter involved in mood and emotion. Norepinephrine is involved in the descending inhibitory pain pathways.⁷ Owing to neurotransmitter and neuropeptide profiles, relevant drug targets may include the GABA pathways or agents that release norepinephrine and serotonin such as duloxetine. See chapter 2: Pain Anatomy and Physiology for further reference.

The phenomenon of central and peripheral sensitization as it relates to neuropathic pain 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

Neuropathic pain 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 dorsal root ganglion (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 because of 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.

CLINICAL PRESENTATION

The presentation of neuropathic pain may be variable and specific to the underlying clinical condition. Patients who experience neuropathic pain 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 3 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 neuropathic pain. The physical examination involves a detailed neurological examination with special attention paid to neurologic deficits and/or gains. Unique physical examination maneuvers include measuring the affected body part for atrophy and sensory testing for vibration/temperature, among others. Table 29-2 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 (Table 29-3). Additionally, being familiar with and referring to neuropathic pain screening and assessment tools may assist with describing the experience of pain and tracking response to treatments. See Table 29-4 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.

INTRODUCTION TO TREATMENTS

The treatment of neuropathic pain conditions can be generally described as conservative or nonconservative. Conservative measures typically include physical therapy modalities, integrative therapies, and medications. Nonconservative measures may include interventional procedures, implanted devices, and surgery. Generally, the evidence for medication treatments includes first-line, second-line, and third-line recommendations. The research and evidence-based guidelines on treatments options are usually divided by the specific pain condition.

TABLE 29-2 Physical Examination and Diagnostic Testing for Neuropathic Pain

PHYSICAL EXAMINATION	DIAGNOSTIC TESTING
Touch	Comprehensive metabolic panel
Pinprick	Complete blood count
Pressure	Sedimentation rate
Cold	Folic acid
Heat	Thyroid function test
Vibration	Hgb A1c and fasting glucose
Temporal summation	Infectious Disease Panel including HIV, hepatitis, and Lyme disease titer
Measure affected areas for loss of mass	MRI
Motor strength	CT
Cranial nerves	EMG/NCS
Gait	Skin biopsy
Reflexes	Vitamin B₁₂ level
Skin changes	Heavy metal serum
Atrophy	Serum electrophoresis and immunofixation
Rash	Antinuclear antibody
Temperature	Rheumatoid factor
Upper motor neuron signs	Sjogren titers
Palpation of masses or lymph nodes	Cryoglobulins
	CSF study
	Orthostatic vital signs
	Urine or serum toxicology
Adapted from Kerstman E, Ahn A, Battu S, et al. Neuropathic pain. Handb Clin Neurol. 2013;110:175-187. Copyright © 2013 Elsevier. With permission.

CONSERVATIVE, INTEGRATIVE, AND ALTERNATIVE MODALITIES

Physical therapy (PT) modalities are often the first-line conservative treatment for most painful conditions. Exercise reduces neuropathic pain symptoms in both experimental studies and clinical studies of DPN. Balance, mobility, strength, decreased inflammation, decreased allodynia, and increased hypoalgesia are some of the improvements seen with exercise therapy in peripheral neuropathic conditions such as DPN.¹⁴ In
CRPS, range of motion exercises are thought be a cornerstone of treatment that prevents loss in bone density and muscle atrophy and can reduce the symptoms of chronic pain. If PT and other movement-based or active therapies fail, other modalities can be considered.

TABLE 29-3 Screening and Assessment Tools for Neuropathic Pain.

SCREENING TOOLS

ASSESSMENT TOOLS

Leeds Assessment of Neuropathic Symptoms and Signs (LANSS)

Neuropathic Pain Questionnaire (NPQ)

Douleur Neuropathique 4

Questions (DN4)

painDETECT

ID Pain

Standardized Evaluation of Pain

Neuropathic Pain Scale (NPS)

Neuropathic Pain Symptom Invent

Short-Form McGill Pain

Questionnaire 2 (SF-MPQ-2)

Adapted by permission from Springer Jones RC 3rd, Backonja MM. Review of neuropathic pain screening and assessment tools. Curr Pain Headache Rep. 2013;17(9):363. Copyright © 2013 Springer Science+Business Media New York.

TABLE 29-4 Pain Nomenclature and Definitions.

PAIN NOMENCLATURE	DEFINITION
Allodynia	Pain due to a stimulus that does not normally provoke pain, lowered threshold stimulus and response differ
Anesthesia dolorosa	Pain in an area or region that is anesthetic
Dysesthesia	An unpleasant abnormal sensation, whether spontaneous or evoked
Hyperalgesia	Increased pain to a normally painful stimulus
Hyperesthesia	Increased sensitivity to stimulation, excluding the special senses
Hyperpathia	Abnormally painful reaction to a stimulus, especially a repetitive stimulus
Hypoalgesia	Decreased pain in response to a normally painful stimulus
Neuralgia	Pain in the distribution of a nerve or nerves
Neuritis	Inflammation of a nerve or nerves
Neuropathy	A disturbance of function or pathological change in a nerve(s)
Paresthesia	An abnormal sensation, whether spontaneous or evoked
This table has been reproduced with permission of the International Association for the Study of Pain^® (IASP). The table may not be reproduced for any other purpose without permission.

Passive modalities for patients with NP may include transcutaneous electrical nerve stimulation (TENS), devices that are applied externally to painful areas that reduce action potentials and increase pain thresholds in the peripheral nervous system. TENS can be used for neuropathic pain including DPN, TN, stump pain, phantom limb pain, radiculopathy, HIV neuropathy, CRPS, entrapment neuropathy, spinal cord injury, postlaminectomy, cancer-related neuropathic pain, poststoke, and central pain where efficacy has been demonstrated.¹⁵ Along with TENS, ultrasound and manual therapy may also be prescribed.

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