PAIN

Pain is the human awareness of nociception and has been defined as “an unpleasant sensory and emotional experience associated with tissue damage or described in terms of such damage.” A much more complex phenomenon than simple nociception, pain may arise in 2 ways: (1) as a response to a pathophysiologic process occurring within the tissues, eg, inflammation, or (2) in response to a pathologic process occurring along and within the nervous system pain pathways.  

NOCICEPTIVE PAIN

In the first instance, the pain signal generates from intact primary afferent nerves that signal noxious events, or nociceptors. This type of pain has been called nociceptive. Nociceptors can be sensitized by release of algogenic agents (eg, protons, prostaglandins, bradykinin, serotonin, adenosine, cytokines, etc). In the second instance, the pain signal is generated ectopically and often in the absence of ongoing noxious events by pathologic processes in the peripheral or central nervous system. This pain is termed neuropathic.

During an inflammatory process, nociceptors can be sensitized by the local release of various agents, including prostaglandins, bradykinin, serotonin, adenosine, and cytokines. In addition, a proportion of afferent fibers—silent or “sleeping” nociceptors—that are normally unresponsive to noxious stimuli, are  “awakened” by inflammation and contribute to the development of nociception.

NEUROPATHIC PAIN

Neuropathic pain may result from peripheral or central nervous system pathologic events (eg, trauma, ischemia, infections) or from ongoing metabolic or toxic diseases, infections, or structural disorders (eg, diabetes mellitus, amyloidosis, HIV infection, nerve entrapment, etc).

The separation between nociceptive and neuropathic states is blurred at times. Inflammatory and neuropathic pain mechanisms may be both present during a pathologic process and in a way “feed each other.” For example, some proinflammatory cytokines (eg, tumor necrosis factor alpha) released by activated macrophages at the site of tissue trauma can damage axons and in some cases induce a neuropathic pain state. On the other hand, neuropeptides (eg, substance P, CGRP, etc) released from the firing C-fibers promote local vasodilatation, plasma extravasation, and mast cells activation with further release of inflammatory molecules, eg, histamine, serotonin, prostaglandins.

Neuropathic pain can be caused by ectopic activity with spontaneous discharge in the peripheral nervous system (PNS) pathways. Depending on the location and type of nerve injury, ectopic discharge also may originate in the dorsal-root-ganglion (DRG) cells of the damaged afferent axons. Within the same DRG, cell bodies of uninjured axons may exhibit ectopic activity too. Within the central nervous system (CNS), hyperexcitability of the pain-signaling neurons may arise, and other mechanisms that facilitate or distort afferent input are likely.

Central mechanisms underlying chronic neuropathic pain are poorly understood. Neuroanatomic, neurophysiologic, and neurochemical changes all occur as a response to PNS or CNS injury. Central sensitization at a dorsal horn level, which is mediated in part via the N-methyl-D-aspartate receptor, is the best characterized change involved in the generation of pain.

Some neuropathic pains may be sustained (in part or temporarily during the course of the painful illness) by sympathetic efferent activity.  Patients with complex regional pain syndrome (CRPS)—formerly termed reflex sympathetic dystrophy (RSD) and causalgia—have an increased likelihood of sympathetically-maintained pain (SMP). From the chemical perspective, it is important to recognize that not all CRPS is SMP, and some neuropathic pain that is not CRPS is SMP.

The interplay of PNS and CNS pain mechanisms is complex. 

The complex pathophysiology of neuropathic pain presumably relates to the diversity of syndromes. Painful mononeuropathies may involve peripheral nerve compression, transection, or inflammation. Clinically, mononeuropathies may present in syndromes as different as trigeminal neuralgia and nerve root compression for discogenic disease. CRPS features regional pain and sensory findings, and some combination of vasomotor changes, sudomotor changes, edema, motor findings, and trophic changes. Deafferentation pain is presumed to have central mechanisms. Some of these pains are induced by a peripheral injury (eg, phantom pain) and others by a CNS injury (eg, post-stroke pain).

Neuropathic pain has numerous causes, including metabolic or endocrinologic disorders, entrapment due to anatomic abnormalities, infections (eg, herpes zoster and HIV), malignancies, inflammatory conditions, autoimmune disorders, and cryptogenic causes.

Other causes of neuropathic pain include exposure to toxins or drugs, dietary or absorption abnormalities, immuno-globulinemias, demyelinating inflammatory disorders, and hereditary abnormalities.

A thorough assessment of a patient for confirmatory diagnosis of the suspected cause of neuropathic pain should consist of careful medical history-taking and physical, neurologic, regional examination. The diagnostic workup includes imaging studies, laboratory tests, electromyography/nerve-conduction velocity studies, and nerve and skin biopsies.

During the medical history-taking, physicians should focus on the onset, duration, progression, and nature of the patient’s complaints. For example, complaints of persistent numbness/weakness in an area or body part or progressive inability to do something that was once an ordinary task, such as opening jars, may be suggestive of neurologic deficits. Complaints such as pain evoked by touch, intermittent abnormal sensations, and spontaneous or shooting pains are suggestive of sensory dysfunction. Important clinical information about pain can be obtained from the presence of other concomitant systemic complaints, such as urinary frequency, fatigue, weight loss, etc. These complaints could provide clues as to the etiology of the neuropathic condition and help reach a more specific pain diagnosis.

During physical examination, inspection of the symptomatic region is essential, with focus on the anatomic pattern and localization of the abnormal sensory symptoms and neurologic deficits.

Neuropathic pain often is described as burning, shooting, stabbing, paroxysmal, or electrical. Also, it often is associated with sensory changes such as dysesthesias (abnormal pain perception) or paresthesias (abnormal perception of a nonpainful nature).

Paresthesias are abnormal, intermittent but nonpainful sensations, perceived spontaneously or evoked by a stimulus. Dysesthesias also may be spontaneous or evoked; however, they are characterized as abnormal noxious sensations.

Patients with acquired neuropathies more often complain of paresthesias and dysesthesias than do those with inherited PNS diseases.



Allodynia, which may be mechanical or thermal, is the painful response to an ordinarily non-noxious stimulus, such as one’s clothing, the mere movement of air, touch, or the nonpainful application of a cold or warm stimulus.

Hyperalgesias are exaggerated pain responses to a mildly noxious mechanical or thermal stimulus.

Hyperpathia may be characterized as a delayed and explosive pain response to a noxious, or at times, non-noxious stimulus.

Allodynia, hyperalgesia, and hyperpathia are positive sensory phenomena as opposed to the negative sensory phenomena defined by anesthesia and hypoesthesia.

The positive and negative sensory findings follow neuroanatomic patterns of distribution, and, therefore, can provide important information on the diagnosis and nature of the condition.

Primary hyperalgesia results from sensory modulation at the peripheral level and is related to a local inflammatory—nociceptive or neuropathic—state.

Static mechanical allodynia (tenderness), pinprick hyperalgesia, warm allodynia, and heat hyperalgesia commonly are present in the primary zone at the epicenter of the pain generator, and all together these sensory findings are consistent with the phenomenon of primary hyperalgesia.

Both dynamic mechanical allodynia and cold allodynia/hyperalgesia commonly are present in the zone surrounding cutaneous injury. Secondary hyperalgesia results from sensory modulation at a spinal level (central sensitization).

When evaluating a patient for neuropathic pain, a thorough diagnostic workup is essential to delineate its cause and the potential mechanisms involved in generating the pain. Laboratory studies, samples from skin and nerve tissue, and anatomic and neurophysiologic studies have a role in the evaluation of chronic neuropathic pain.

Necessary are a complete blood cell count (CBC), an erythrocyte sedimentation rate (ESR), a general chemistry profile, thyroid-function tests, vitamin B12 and folate serum levels, fasting blood glucose (FBG), and glycosylated hemoglobin (HbA1c). Also important (according to the clinical presentation) are serum protein electrophoresis with immunofixation, Lyme disease antibody titers, hepatitis B and C screening titers, HIV screening, antinuclear antibodies (ANA), rheumatoid factor, Sjögren’s syndrome titers (SS-A, SS-B), and antineutrophil cytoplasmic antibody.

In addition to the aforementioned laboratory tests, the complete diagnostic workup also should include cryoglobulins, antisulfatide IgM antibody titer, anti-HU titers, serum and urine screening for heavy metals, and cerebrospinal fluid (CSF) to rule out the demyelinating neuropathies (eg, Guillain-Barré syndrome) and polyradiculopathies related to meningeal carcinomatosis.

Besides the many laboratory tests necessary to a thorough workup, the EMG-NCV studies and quantitative sensory testing (QST) may identify or localize a lesion. Also, they may indicate an axonal versus a focal segmental demyelinating process, or they may help detect diffuse abnormalities, indicating a polyneuropathy.

For nerve biopsy, usually the sural nerve is selected because the sensory deficit following the procedure is limited to the dorsolateral aspect of the ankle and foot. The biopsy is useful for the diagnosis of vasculitis, amyloidosis, tumor infiltration, IgM monoclonal gammopathies, chronic inflammatory demyelinating polyradiculopathies, and small-fiber neuropathies, among others.

Skin biopsy is considered promising for evaluating the density of unmyelinated fibers within the dermis and epidermis. Immunostaining with a panaxonal marker has been used to demonstrate the intraepidermal network of C-fibers.

Based on a comprehensive assessment, a multimodality approach can be devised for the treatment of neuropathic pain. The most important treatments in most cases are pharmacologic. Some patients benefit from interventional strategies that may involve neural blockade or sophisticated neuraxial stimulation or infusion.

Pharmacologic therapies for neuropathic pain include antiepileptic drugs (AEDs), antidepressants, local anesthetics, and other adjuvant analgesics. Opioid analgesics have shown efficacy against neuropathic pain.

Clinicians must keep in mind that patients experiencing neuropathic pain need treatment plans tailored to their individual needs. A trial of single medication can be initiated and titrated in a patient who continues to function at an overall high level. However, as a patient becomes more incapacitated by pain, a more aggressive plan that includes combination therapy is necessary. The majority of such patients can be helped with various combination regimens of AEDs, opioids, antidepressants, and topical analgesics.

To address pain and functional impairments, pharmacotherapy often is combined with rehabilitative and psychologic approaches in the comprehensive management of patients with chronic neuropathic pain.

More effective novel pharmacologic agents are becoming available and will expand the treatment armamentarium in the field of pain management. It is incumbent upon physicians to evaluate the efficacy and side-effect profile of these new agents entering the market and to strive for the maximal amount of pain relief for their patients. The ultimate goal of therapy for patients with neuropathic pain is to improve their quality of life.