In addition to the history and physical examination, ancillary studies may aid in diagnosis. These are very important for confirming or excluding the presence of underlying etiologies for neuropathic pain. Magnetic resonance imaging is used to assess the integrity of central neuroanatomic structures involved in pain signaling pathways. These include the spinal cord, brainstem, thalamus, and cortices (see Fig. 12-1). Peripheral sources for the pain can sometimes be defined by electromyography and nerve conduction studies. The latter particularly assess the function of large myelinated nerve fibers. Nonneurologic tests such as oral glucose tolerance, Tzanck prep (a rapid test previously performed to diagnose infections caused by herpes viruses) and enzyme-linked immunosorbent assay. This can be used to confirm or exclude the presence of a number of underlying diseases that may lead to sequelae of neuropathic pain. Psychiatric evaluation is also useful in evaluating possible somatization disorders in patients with multisystem complaints that may date back into early developmental stages.

Treatment

Gauging the efficacy of treatment protocols represents a significant challenge in the treatment of neuropathic pain. Severity of pain is typically assessed at the time of exam, as well as over short time intervals, and subjectively graded by the patient on the 0–10 numeric rating scale, with a score of 0 representing “no pain” and a score of 10 representing “worst possible pain.” Research suggests that clinically important pain relief is achieved with a 30% reduction in score on this scale, corresponding to a categoric rating of “moderate relief” or “much improved.” In addition, counseling patients and families about reasonable expectations for symptom improvement is crucial. Patients must understand that partial reduction in pain intensity is the norm with pharmacotherapy. Furthermore, successful treatment will require a program of adaptive coping by the patient per se. A comprehensive approach that calls on close monitoring of side effects of medications used to treat neuropathic pain is essential, as many of these drugs have significant adverse events, especially when used in older patients.

Multitiered Approach to Pain Management

The International Association for the Study of Pain has developed a multitier approach to managing neuropathic pain. This is centered around patient communication and a number of available pharmacotherapeutic agents. The first step in this system involves a thorough clinical evaluation and discussion of a patient’s underlying disease state as outlined above. The second step in the multitiered approach to managing NP is the prescription of a “first-line” pharmaceutical agent. Following prescription, the third step in treatment is reevaluation of the patient’s pain intensity and its response to therapy. Therapy is continued if the patient’s response has been complete. In contrast, if the patient has not responded to this medication, or the side effect profile is unacceptable, another first-line therapy needs to be initiated. Finally, if the patient reports a partial response, the initial therapy is continued and another first- or second-line medication is combined with this. If acceptable symptom resolution does not occur with this approach, then the physician needs to consider introducing a third-line pharmaceutical agent.

First-Line Prescription Agents

These include topical lidocaine, calcium channel α2-δ ligands (gabapentin, pregabalin), tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors.

Putative calcium channel ligands such as gabapentin inhibit presynaptic calcium channel α2-δ subunits activity in the superficial laminae of the dorsal horn of the spinal cord. Their exact site of action within the central nervous system as antiepileptic agents and for their other benefits remains unclear.

Tricyclic antidepressants historically are thought to modulate pain signaling by affecting both serotonergic and noradrenergic reuptake in descending inhibitory supraspinal pathways (Fig. 12-3). Desipramine and nortriptyline are preferred for neuropathic pain because of their favorable side-effect profiles relative to amitriptyline. Although their anticholinergic side effects demand careful consideration when these are used in patients with comorbidities, TCAs will relieve pain in PHN, postmastectomy pain syndrome, and painful diabetic neuropathy (PDN) and nondiabetic peripheral neuropathy. These agents should be tried alone initially, and then may be used in combination to pursue symptomatic improvement if necessary, provided that the clinician carefully monitors their interactions and side effects.

Figure 12-3 Serotonin Synapses of Pain Pathways.

Lidocaine preferentially inhibits voltage gated sodium channels in neuronal regions undergoing more frequent depolarization. It effectively suppresses ectopic impulses that develop following neuronal injury and the subsequent increase in sodium channel production and propagation at the affected site. This selectivity allows lidocaine to be safely used at low enough doses that avoid disrupting normal impulse conduction while still suppressing hyperexcitability. Infusion has proven an efficacious route for delivery in the treatment of both PHN and DPN (diabetic polyneuropathy), but its use is limited because of dosing and delivery issues arising with intravenous administration. Lidocaine is mainly used in the 5% patch form for the treatment of PHN and, in contrast, has a low probability for drug interactions and systemic side effects.

Opioid analgesia (Fig. 12-4) is considered by many experts to be a first-line agent as well, although considerable debate surrounds its role in management of neuropathic pain because of issues of tolerability, long-term efficacy, and the risks of misuse and abuse. Multiple trials support the use of these various pharmacologic modalities in chronic conditions such as PDN and PHN with evidence of superior efficacy and reduced side-effect burden when prescribed in combination with a calcium channel modulator. In clinical trials, opioid side effects, including nausea, sedation, and constipation, contributed to significant patient dropout, despite reported reductions in pain. Tramadol exerts its analgesic effects through both opioid and descending inhibitory pathways; it has been shown to be effective in reducing pain associated with nerve injury and improving quality of life.

Figure 12-4 Opioid Receptor-Transduction Mechanism. Inhibits adenylyl cyclase by decreasing nociceptive neurotransmitter release from presynaptic terminals. Inhibits postsynaptic hyperpolarization by increasing K+ channel conductance.

A Ten-Step Process for opioid therapy utilized over the long term has been suggested by the International Society of Interventional Pain Physicians (Box 12-1). This provides the clinician with responsible guidelines for maintaining careful control of a potentially very useful therapeutic modality.

Box 12-1

Ten-Step Process for Long-Term Opioid Therapy in Chronic Pain

Step I: Perform comprehensive initial evaluation

Step II: Establish diagnosis

X-rays, MRI, CT scan

Step III: Establish medical necessity

Physical diagnosis

Therapeutic interventional pain management

Physical modalities

Behavior therapy

Step IV: Assess risk-to-benefit ratio

Treatment is beneficial

Step V: Establish treatment goals

Step VI: Obtain informed medical consent and agreement

Step VII: Institute initial dose adjustment (up to 8–12 weeks)

Start low dose

Utilize opioids, nonsteroidal anti-inflammatory drugs, and adjuvants

Discontinue because of side effects

Lack of analgesia

Side effects

Lack of functional improvement

Step VIII: Assess stable phase

Assess for the four A’s

Step IX: Monitor adherence

Prescription monitoring program

Random drug screen

Pill counts

Step X: Assess outcomes

Successful: continue

Stable doses

Analgesia, activity

No abuse, side effects

Failed: discontinue if

Adapted from Trescot AM, Boswell MV, Atluri SL, et al: Opioid guidelines in the management of chronic non-cancer pain. Pain Physician 9:1-39, 2006.

Second-Line Pharmacotherapy

When an acceptable response to treatment is not achieved with the use of first-line agents, a number of less well substantiated second-line agents may be used. These include the anticonvulsant lamotrigine that blocks voltage-gated sodium channels implicated in hyperexcitability states, resulting in decreased net Ca⁺ influx. Lamotrigine is clinically effective in managing pain from PDN, HIV neuropathy, trigeminal neuralgia, some spinal cord injuries, and central poststroke pain, although its use is limited by the risk of severe rash and Stevens–Johnson syndrome.

Carbamazepine is the first anticonvulsant that the FDA approved for the treatment of trigeminal neuralgia. The research that supports its use for the treatment of PHN and PDN predated the era of large, multicenter clinical trials. Unfortunately, side effects and strength of evidence has relegated it to a second-line therapy. Initial trials of oxcarbazepine and other second-generation anticonvulsants for the treatment of trigeminal neuralgia and other neuropathic pain syndrome have demonstrated some favorable results, but further studies are required to establish their role, if any, in managing neuropathic pain.

Third-Line Prescription Agents

A large number of other pharmacologic agents have been or are currently under investigation for the treatment of neuropathic pain, including N-methyl-D-aspartate (NMDA) receptor blockers, selective serotonin reuptake inhibitors, bupropion, clonidine, dextromethorphan, mexiletine, capsaicin, and cannabinoids. Although clinical research has not demonstrated widespread efficacy of these agents, many have proven effective in individual cases of NP syndromes, and further research is warranted. As with any pharmacologic agent, special attention should be paid to patient education and adverse effect profile before initiating therapy with any of the third-line agents.

Painful Diabetic Neuropathy

Clinical Vignette

Julia, a 53-year-old woman, presents complaining of burning pain in her lower extremities. The pain started 18 months earlier beginning in her toes and has progressively ascended to involve her feet to the ankles bilaterally. She describes the pain as a persistent burning and tingling throughout the day, stating that her feet feel like “they’re asleep all the time,” and says the pain is worse at night. Her past medical history is significant for type 2 diabetes mellitus diagnosed 5 years prior for which she takes oral medications, including metformin and a glitazone. When questioned, she describes a pattern of poor medication compliance, erratic home blood glucose values, and denies performing regular foot inspections.

On exam, her muscle strength, patellar muscle stretch reflexes, and proprioceptive sensation as well as pedal pulses are normal, but she demonstrates diminished light tough, pinprick, and vibratory sensation below the mid-calf bilaterally and absent ankle muscle stretch reflexes. She had an antalgic (painful gait) and had recently been fitted with a prosthetic boot. She also has an asymptomatic plantar ulcer surrounded by callus on the first metatarsal head of the right foot, of which she denies knowledge.

Laboratory values are significant for an HbA₁C of 8.7% and creatinine of 1.1, but are otherwise normal. Nerve conduction studies (NCS) demonstrate no abnormalities, including detailed sensory nerve testing. However, these studies did not exclude a small-fiber sensory neuropathy as these unmyelinated type C fibers cannot be separately distinguished from the large-fiber responses with standard NCS.

Overview

This is an increasingly common complication of diabetes mellitus, developing in up to 66% of insulin-dependent (type 1) and 59% of non–insulin-dependent (type 2) diabetics. Of these patients, studies suggest that up to 20% will experience symptoms of pain, loss of sensation, numbness, and tingling of at least 3 months’ duration, meeting the criteria for symptomatic peripheral neuropathy. Diabetic polyneuropathies also occur in other divisions of the nervous system and may present as autonomic neuropathies involving the gastrointestinal, cardiovascular, or genitourinary system, or as amyotrophic neuropathies with focal motor involvement especially in the thigh. Long-term complications of diabetic neuropathy include foot ulcers, which occur in 15% of diabetic patients and account for 85% of amputations in the same group (Fig. 12-5). PDN is a serious condition responsible for debilitating pain as well as serious long-term sequelae (Fig. 12-6), with early diagnosis and management crucial in preventing long-term complications and reductions in quality of life.

Figure 12-5 Diabetes Mellitus and Neuropathy.

Figure 12-6 Foot Complications in Diabetic Neuropathy.

Pathophysiology

The pathophysiology of PDN is complex, involving an imperfectly understood interaction of metabolic and vascular factors present in diabetes mellitus. Hyperglycemia and increased flux through the polyol pathway leads to intracellular accumulation of sorbitol and fructose, with reduction in Na⁺/K⁺-ATPase activity, as well as the accumulation of nonenzymatic advanced glycation end products on neural and vascular proteins. These metabolic derangements, coupled with protein kinase C activation, derangements in fatty acid metabolism, and oxidative stress driven by hyperlipidemia and hyperglycemia are responsible for gradual damage and impairment of microvascular endothelial function. Hypoperfusion follows, with hyalinization and maladaptive hyperplasia of microvascular vasa nervorum accounting for progressive dysfunction of both small and large nerve fibers. This hypoxia also damages small unmyelinated fibers innervating arterioles responsible for arteriovenous shunting in endoneurium and perineurium, further exacerbating ischemic nerve injury. Patients experiencing painful symptoms also demonstrate neovascularization on the surface of nerves in affected regions, mirroring hypoxia-induced neovascularization seen in diabetic retinopathy. This expansion of vascular territories may lead to a hyperperfusion state, with paradoxically less hypoxia in painful neuropathy and, although poorly understood, suggests a hemodynamic etiology to the development of painful symptoms in diabetic polyneuropathy.

Clinical Features and Diagnosis

Painful diabetic polyneuropathy generally occurs as a symmetrical sensory neuropathy, initially involving the distal lower extremities and spreading proximally. At the time of midcalf involvement, patients typically begin to experience symptoms in their hands as well, developing into the typical “stocking glove” sensory distribution of the disease. Although a number of systems have been proposed to screen for and diagnose diabetic neuropathy, most have proven to be poorly reproducible, and the diagnosis remains dependent on interpreting a constellation of clinical symptoms and signs. As discussed above, a thorough history and physical examination with assessment of pain characteristics as well as neurosensory testing is necessary to make the diagnosis. In the context of diabetes, the occurrence of positive symptoms overlapping regions of sensory deficit is strongly suggestive of PDN.

Nerve conduction velocity very gradually diminishes in PDN and can be used to track disease progression to some extent; however, it does not correlate with the degree of symptoms as it only evaluates large myelinated fibers. NCS are frequently normal during the early phases of the disease, owing to initial involvement of predominantly small, unmyelinated fibers. Poor glycemic control is a risk factor for developing PDN and may be reflected by high hemoglobin A₁C levels, an indication of average glucose levels over a period of 2 to 3 months.

Treatment

The mainstay of treatment in painful diabetic polyneuropathy is proper glycemic control targeting an HbA₁C at or below 6.5%. Although intense diabetes management cannot completely arrest the development of neuropathy, it has been shown to significantly delay the onset of symptoms in type 1 diabetes and may have some benefit in type 2 diabetes.

Symptomatic treatment of pain is a mainstay of diabetic neuropathy management, as it has significant impact on quality-of-life issues such as sleep and daily comfort. The assessment of symptoms per se and communication regarding treatment outcome expectations is the first step in managing any chronic neuropathic pain syndrome, followed by prescription of a first-line pharmaceutical agent. Among the first-line agents previously reviewed, the serotonin–norepinephrine reuptake inhibitor duloxetine has shown particular promise in PDN, demonstrating superior efficacy compared to placebo (number needed to treat [NNT] = 4.9–5.3) and comparable safety compared to standard care (gabapentin, amitriptyline, and venlafaxine) in a number of double-blind clinical trials. Duloxetine’s frequent side effects included nausea, somnolence, dizziness, reduced appetite, and dry mouth. This is started at 30 mg/day and titrated to 60–120 mg/day after 4–5 days to minimize side effects. TCAs may also be used to treat painful diabetic polyneuropathy, with relatively lower NNTs compared to other agents (amitriptyline, 2.1; desipramine, 2.2; imipramine, 1.3; clomipramine, 2.1; and nortriptyline with fluphenazine, 1.2.)

Dosage of these agents begins at 10 mg/day and can be titrated upward to 150 mg/day as needed. Gabapentin and pregabalin may also be used at dosage ranges of 900–3600 mg/day and 300–600 mg/day, respectively, with NNTs of 3.8 and 5.9 and maximum dose. Oxycodone may also be used adjunctively in pain-resistant standard pharmacotherapy, but careful consideration of the risks and benefits should be undertaken prior to initiation because of the potential for dependence and abuse.

Complex Regional Pain

Clinical Vignette

Tracy, a 65-year-old right-hand-dominant receptionist is referred to orthopedic surgery for right carpal tunnel release following progressively worsening pain and paresthesia in her right hand. Surgery is performed under conscious sedation without complications, and the patient is discharged home that afternoon to follow up with physical therapy for rehabilitation. However, the patient fails to keep her physical therapy appointment and returns to work 4 weeks later.

Seven weeks postoperatively, the patient presents back to the orthopedic surgeon complaining of swelling, redness, and stiffness of her right hand. She also notes that her hand has become more sensitive to painful stimuli and that she experiences significant discomfort when her hand contacts virtually anything. On exam, the hand is warm, red, and swollen, with hyperhydrosis noted on the palmar surface (Fig. 12-7).

Figure 12-7 Reflex Sympathetic Dystrophy.

Despite admission to the hospital for empiric treatment of postoperative infection, the patient fails to improve and develops exquisite pain even to light touch.

Overview

Previously known as reflex sympathetic dystrophy, causalgia, and several other names, complex regional pain syndrome (CRPS) is an increasingly recognized chronic and often debilitating neuropathic pain condition characterized by autonomic and somatic neurologic dysfunction following various injuries. This often leads to chronic pain, trophic tissue changes, and motor impairment. Frequently, the clinical dysfunction often expands beyond the distribution of one peripheral nerve, and may be grossly disproportionate to the inciting event. CRPS occurs predominantly in the clinical setting of fractures and surgical trauma to the extremities, including distal radial fractures, carpal tunnel release, tibial fractures, total knee replacement, hip arthroplasty, and numerous arthroscopic procedures. It has been reported in mild trauma such as joint sprains, and nontraumatic conditions, including stroke, pregnancy, and neoplastic disease. This is occasionally documented with visceral trauma, but is much less common in this setting.

Although the epidemiology of CRPS is poorly characterized, studies closely evaluating pain symptoms suggest incidence rates of 20–25% in fractures, predominantly affecting the extremities. This occurs more frequently in females at a 2–3 : 1 ratio to males, tending to more frequently affect the upper extremities in adults and the lower extremities in children.

Pathophysiology

Although the precise pathophysiology of CRPS remains imperfectly understood, a number of studies have advanced promising and increasingly well-developed theories. Some evidence indicates that diminished sensory input, reduction of central modulation, or end organ hypersensitivity results in increased sympathetic nervous system activity following injurious stimuli. These changes may be caused by impaired transport of nerve growth factors by damaged axons or by alterations in the membrane channel populations following nerve injury. A number of studies support the assertion that catecholamine sensitivity develops in peripheral cutaneous and deep tissue nociceptors following nerve injury.

Expansion of neuronal fields may also occur after peripheral nerve injury, with formation of artificial synapses between somatic and sympathetic fibers, dorsal root ganglia resulting in autonomic dysfunction, and aberrant sources of pain signaling. Supporting this theory is the fact that sympathetic blockade may sometimes alleviate pain symptoms, although there is tremendous variability in clinical response to these treatments.

Loss of nociceptive small-fiber axons following nerve injury may also contribute to CRPS. Limited studies have demonstrated a 30% reduction in neurite density of skin biopsies compared to ipsilateral control sites in patients experiencing allodynia and hyperalgesia at CRPS-affected sites, strongly supporting this theory. Disproportionate inflammatory reaction following injury may occur, with free radical damage to tissues, anoxia, and subsequent dysregulation of vascular function and blood flow. Langerhans cell proliferation following denervation has also been documented, suggesting a significant inflammatory component in CRPS. Proinflammatory and chemotactic cytokines TNF-α, IL-1, and IL-6 released from these cells may play a role in the exaggerated local inflammatory response as well as the trophic changes in nails, hair, and bony tissues.

Although psychological influences in the development of CRPS have been postulated, current evidence increasingly suggests that psychological symptoms are more likely secondary to the syndrome rather than the primary cause. Overall, characterization of pathophysiological factors contributing to the development of CRPS is in its infancy, and further research is an area of high priority.

Clinical Features and Diagnosis

The major clinical features of CRPS are spontaneous pain, allodynia, hyperalgesia, edema, vasomotor instability, autonomic dysfunction, and progressive trophic changes. CRPS occurs as two subtypes, with the presence of an identifiable noxious stimulating event delineating between the two. Type I CRPS develops in the absence of an identifiable focal nerve lesion, whereas type II CRPS occurs in the presence of identifiable nerve damage. CRPS has historically been considered a multiphasic disorder, with an early “acute” phase characterized by vasomotor instability and edema, a late “atrophic” phase defined by atrophy and contracture, with an intermediate phase between the two. More recent research, however, suggests that the different symptoms of CRPS are more likely variant subtypes as opposed to stages of the disease. The vast majority of CRPS patients experience only the “acute” phase symptoms, typically with spontaneous resolution over time, and only 2% go on to develop the atrophic symptoms associated with chronic CRPS.

The predominant features of CRPS are pain symptoms such as allodynia, hyperalgesia, and spontaneous sensations of burning, shooting, aching, or other discomfort. The pain is typically experienced in a distribution beyond the initially affected nerve(s) and may spread to involve the entire affected limb and, rarely, the contralateral limb as well. These symptoms are generally constant in nature and frequently worsen over time, leading to significant impairment of quality of life and psychological distress.

Additionally, sympathetic dysfunction is present, mediating pain symptoms as well as autonomic instability (see Fig. 12-7). Patients may initially experience a warm, anhydrotic, edematous extremity with progression to a cold, hyperhidrotic limb and resolving edema. Trophic changes in the affected limb also occur, with hypertrophic or atrophic hair and nail growth and degeneration of the skin and subcutaneous fat. Connective tissues may become adherent to each other, leading to contractures and loss of function in the affected extremity. Rapid bone loss also develops, resulting in demineralization and osteoporosis. Finally, weakness, tremor, and other motor anomalies may occur in the affected extremity, with profound loss of function.

Diagnosis of CRPS is a clinical one; there are no specific diagnostic tests for CRPS. When the typical symptoms of CRPS occur in the context of surgery, fracture, or other noxious stimulus, these are very suggestive of the diagnosis. Initially one must exclude various primary neurologic, infectious, and autoimmune etiologies. Plain bony radiographic testing may help to demonstrate unilateral demineralization and cortical erosions suggestive of CRPS, and Tc 99m-labeled bisphosphonate bone scan techniques demonstrate an 80% sensitivity and specificity in detecting osseous changes typical of CRPS.

Infrared thermography demonstrating greater than 1°C difference in temperature between the affected and contralateral extremity is 93% sensitive and 89% specific in the diagnosis of CRPS, although it is rarely employed because of the specialized equipment required. In patients simultaneously experiencing severe pain and sympathetic dysfunction, stellate ganglion and lumbar paravertebral sympathetic blocks have also been used to diagnose and treat CRPS, with greater than 50% reduction in pain considered significant enough to warrant this diagnosis. However, more recent studies show that sympathetic block is neither sensitive nor specific. Nevertheless, some clinicians still perform this procedure because of the dual prospect of diagnosis and treatment coupled with low morbidity when performed by skilled professionals. Ultimately, the diagnosis of CRPS remains challenging, and further research is warranted because of its marked limitation in the patient’s ability to carry on activities of daily living (ADLs).