Neuropathic pain: Etiology, pathophysiology, mechanisms, and evaluations
Introduction
Reports of more than a century of medical observation and research have demonstrated that neuropathic pain is more definitive than merely a concept or a single disorder: It is instead an evolving collection of established clinical and experimental conditions all of which share the perpetuation of manifested pain symptoms or pain-related behaviors created by neural tissue injury other than that involved with simple nociception.1, 2
While neuropathic pain has been operationally defined as an abnormal pain state that arises from a damaged peripheral nervous system (PNS) or central nervous system (CNS),3 there is supporting evidence suggesting that several disease states within this category have active residual involvement of nociceptors at the site of the original injury, creating a mixed nociceptive–neuropathic pattern. Several painful disorders categorized as neuropathic are created or maintained by aberrant neural communication involving autonomic nervous system pathways that are not considered to be purely peripheral or central. These include complex regional pain syndromes types I and II (reflex sympathetic dystrophy and causalgia, respectively) and sympathetically maintained pain (SMP).4, 5
Section snippets
Neuropathic pain syndromes
In primary care as well as many types of specialty practice, the term neuropathic pain has been most often thought of as simply meaning painful peripheral neuropathy, as commonly occurs in severe diabetes mellitus (DM). This association may have developed based upon the high incidence of diabetes, and the bilateral, distal distribution of other symptoms (sensory loss), and signs (reduced temperature and circulatory compromise) commonly revealed in this illness. In general clinical practice, the
Neuropathic pain disorders by etiology
In theory, almost any of the pathological processes known to create damage or dysfunction to neural tissue can be considered as potential causes for neuropathic pain. Viral, bacterial, aseptic inflammation, pressure due to neoplasm or other structural lesions, degenerative, ischemia, autoimmune, toxic, traumatic, and endocrine/metabolic mechanisms have all been implicated in the production of pain7, 8, 9 (Tables 1). A general lists of adjuvant analgesics for neuropathic pain can be seen in
Pathophysiologic processes subserving neuropathic pain
Predictably, there is substantial evidence that abnormal nerve activity is an important mechanism underlying the spontaneous pain typical of neuropathic pain states.10, 11, 12 It is hypothesized that sites of ectopic foci include developing on injured or regenerating nerves in the periphery, at the level of the nociceptor, neuromas, or segments of injured nerves; at the dorsal root ganglion; and in the dorsal horn laminae of the spinal cord. Indeed, after nerve transection, increased
Diabetic neuropathy
The most recent IASP definition of neuropathic pain, as noted earlier, is “pain initiated or caused by a primary lesion or dysfunction in the nervous system.”15
It is felt that there are three general phases of pain16, 17: phase 1—transient activation of the nociceptive system occurs secondary to appropriate stimuli and CNS processing of this stimulus induced information occurs appropriately; phase 2—each injury evokes mechanisms representing nociceptive system plasticity and which induces
Mechanisms of diabetic peripheral neuropathy
The theoretical constructs include metabolic, vascular, altered neurotrophic support, autoimmune, and free radicals associated with oxidative stress.
Small-fiber neuropathy
Small-fiber neuropathy (SFN) is a common peripheral nerve disease, typically idiopathic in etiology, which commonly presents in middle-aged and older people with burning pain in their feet and/or symptoms of autonomic dysfunction.77, 78, 79
The disorder selectively involves small-diameter myelinated and unmyelinated nerve fibers. Frequently, autoimmune disorders/mechanisms are suspected but rarely found. SFN can be caused by disorders of metabolism (diabetes), chronic infections (such as human
HIV-associated neuropathic pain
Distal symmetrical polyneuropathy (DSP) associated with HIV infection is the most frequent neurological complication of the disease.111 Spontaneous or evoked pain is the most common symptom of DSP.112 Aside from DSP, patients may develop mononeuritis multiplex and progressive polyradiculopathy.
The actual pathophysiology of HIV neuropathy is not known. DSP, as noted above, is associated with injury or loss of primary afferent fibers inducing distal axonal degeneration, “dying back” of the
Neuropathic low back pain
Low back pain (LBP) is one of the most common disorders, effecting about two-third of the adult population in the USA at some time in their lives. It may or may not be associated with radiculopathy or radiation to the sciatic and/or femoral nerves.123 The etiology of the pain may be secondary to a large number of possible problems, making the differential diagnosis large; however, it may be broken down to mechanical, compression, inflammatory, and neuropathic factors, which may be directly
Central poststroke pain (CPSP)
Central poststroke pain (CPSP) was originally thought to be “thalamic” pain, as described by Dejerine and Roussy,133 although it was described even earlier in 1883.134 Dejerine and Roussy133 characterized their eponymous thalamic pain syndrome as including hemiplegia; hemiataxia, and hemiastereognosis; difficulties with both superficial and deep sensation; persistent, paroxysmal, typically intolerable pain; and choreoathetoid movements.
The reported incidence of CPSP varies widely from 2%135 to
Complex regional pain syndromes as neuropathic pain
Following peripheral nerve injury, concomitant alternations may be evident in dorsal root ganglia, including transmitter changes and increased density of sympathetic nerve terminals.171 Tyrosine hydroxylase positive cell terminals that produce norepinephrine migrate from vessels supplying the dorsal root ganglion to nerve ganglion cells following sciatic nerve injury. The dorsal root ganglia then express α-adrenergic receptors. This may be a putative link between peripheral tissue injury, nerve
Postherpetic neuralgia (PHN)
PHN is a model of neuropathic pain. Its mechanisms differ from those of diabetic neuropathy as well as other models of distal symmetric neuropathy.
This disorder is secondary to a latent infection and reactivation after infection with varicella zoster virus (VZV), which typically inhabits sensory ganglion neurons. Pain is a common clinical concomitant of VZV reactivation.175
The prevalence is currently debatable. It is noted that approximately 10% of patients with VZV/herpes zoster infection will
Glial activation in neuropathic pain
In almost a counterpoint to the above-noted mechanisms of neuropathic pain, it has been reported that astrocytes and microglia in the CNS/spinal cord can be activated and induce the creation and maintenance of pain facilitation secondary to inflammation and damage to peripheral nerves, other peripheral tissues, spinal nerves, and the spinal cord. Glial cells appear to be of immune cell origin.205, 206
Glial activation can occur via a number of processes: bacteria and viruses that bind to
Diagnostic evaluation of neuropathic pain
There exist two lines of thought relative to the clinical diagnosis of pain syndromes of this type: one suggests that, since the symptom characteristics of neuropathic pain are not pathognomonic for the condition, their lack of specificity makes the diagnosis difficult to reach.215 Another provides evidence to support certain symptom characteristics as strong indicators of neuropathic pain.216 Regardless of which attitude is correct, the clinician hoping to differentiate neuropathic from
Medical pain history
The style of medical history that has been modified for the specific documentation of pain has been described in detail elsewhere.8, 217
Within that system the clinician acquires patient-specific information regarding at least eight aspects of the pain problem. A mnemonic often used to ensure that completeness of data collection regarding each characteristic is PQRST, in which P = provocative, palliative factors; Q = quality; R = region (of onset), radiation, and referred pain; S = severity; and
Physical examination of patients with neuropathic pain
In general, all major parts of the physical examination are important for adequate determination of the presence of local disease that may cause pain.4, 8 Any patient in whom the symptom characteristics suggest neurological origin may also demonstrate regional abnormalities of motor or reflex functions. However, the portions of the examination that are most relevant to the evaluation of neuropathic pain are those that are related to sensory dysfunction, such as hypoesthesia, hyperesthesia,
Integration of history/physical data for neuropathic pain evaluation
It is evident that the duration and complexity of the clinical evaluation of human neuropathic pain (NP) is highly dependent upon the patient’s ability to tolerate long and potentially uncomfortable functionality and procedures. For screening purposes, however, different methods have been developed to provide a combination of individual components of the history and physical examination. The more simple and direct methods are exemplified by Galer and Jensen221 and Krause and Backonja.216
Laboratory, radiologic, and electrodiagnostic assessment
Once the history, physical findings, and neuropathic pain questionnaire have yielded sufficient evidence to support the potential presence of NP, specific biochemical, structural, and neurophysiological tests may be applied to confirm or eliminate certain disorders from the differential diagnosis
Laboratory evaluation is necessary to determine the presence of hematologic, chemical, or pathophysiologic processes with a high potential for causing or contributing to the pain.7, 9 Such tests are
Initial symptom management
There is some disagreement as to which treatment approaches (pharmacotherapeutic or interventional) represent the best and worst chances for symptom control. Neither approach is mutually exclusive. Nevertheless, the mainstay of treatment of neuropathic pain is pharmacotherapeutic. Effective regimens often require multiple medications. The patient should be aware that pain will be less in quality and intensity and may not be ablated.227
Attempts at monotherapy with standard analgesics including
Mechanistic basis of neuropathic pain management
Management of neuropathic pain is a complicated endeavor and often is frustrating to patient and physician alike. This stems from our relatively incomplete understanding of mechanisms and the limited efficacy of currently available analgesics. Therapeutic approaches vary greatly among physicians, which reflect the paucity of randomized clinical trials, particularly those comparing different recognized drug regimens. Given our current level of understanding of neuropathic pain mechanisms and the
Adjuvant analgesics: anticonvulsants, tricyclic antidepressants and SNRIs (Tables 6–8)
It is often helpful to consider the various medications useful for neuropathic pain in terms of their traditional pharmacological indications (e.g., anticonvulsants and antidepressants). However, it is necessary to keep in mind that all these drugs have incompletely understood mechanisms of action, and the drug categories are more conventional than mechanistic.
Pharmacology of neuropathic pain
From a practical standpoint, pharmacotherapy remains the pillar of pain management strategies, despite their limitations. From a conceptual standpoint, adjuvant analgesic drugs may be categorized into two broad classes, membrane-stabilizing agents (AEDs and anesthetics) and medications that enhance inhibitory mechanisms in the dorsal horn. This classification system may provide a simple framework with which to approach therapy; however, it should be kept in mind that most of these agents have
Mechanisms of action237–239
Membrane-stabilizing agents include local anesthetics, such as lidocaine and some anticonvulsant drugs, including topiramate (TPM), carbamazepine (CBZ), phenytoin (PHT), and valproic acid (VPA).12 Their molecular mechanism of action involves blockade of frequency and voltage-dependent sodium channels on damaged or regenerating neuronal membranes.10, 11 It appears that minimal doses of suppressive drugs may inhibit ectopic discharges without interfering with normal neuronal function. It is also
The treatment of comorbid depression and anxiety
It is crucial that psychosocial and emotional factors be anticipated and clinically explored, because there is a high comorbidity of depression and anxiety disorders in patients with chronic pain. Moreover, given the similarities between the pharmacology of mood and depression and pain transmission (e.g., serotonin and norepinephrine), patients with concomitant systemic illness and stress may be at risk for depression and development of an abnormal chronic pain state. Pharmacotherapeutic
Ablative procedures
After multiple therapeutic medication trials in which there has been minimal patient-perceived therapeutic benefit and perhaps significant drug-related side effects, patients may believe that they have little recourse but to undergo invasive, ablative procedures in attempts to relieve their pain. Specific treatment modalities aimed at the underlying pathophysiology are usually not possible in most neuropathies, particularly with chronic sensory polyneuropathies. In general, ablative procedures
Mechanistic approach to the selection of treatment
When standard therapies are found to be only partially effective in controlling symptoms it is often helpful to select other medications or interventions based upon the compatibility of the mechanisms of the patient-specific illness and the treatment being considered260 (Boswell et al., 1991).
For example, it has become popular to contrast neuropathic pain with typical postinjury, nociceptive pain. Nociceptive pain, typically thought to indicate a properly functioning nervous system, is
Stimulus-evoked neuropathic pain and opioid analgesics
Various studies suggest that stimulus-evoked neuropathic pain is more sensitive to selected opioids than stimulus-independent pain.229 Opioid responsiveness may be maintained in some forms of stimulus-evoked pain, because opioid receptors in the substantia gelatinosa are preserved. On the other hand, segmental loss of presynaptic central opioid receptors occurs following injury or loss of C fibers, typically seen after deafferentation injury. However, the magnitude of receptor loss is minimal
Anticonvulsants237–239 (Table 7)
Anticonvulsants are useful for trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy, and central pain.233, 235 Although anticonvulsants have traditionally been thought of as most useful for lancinating pain, they may also relieve burning dysesthesias. Chemically, anticonvulsants are a diverse group of drugs, are typically highly protein bound, and undergo extensive hepatic metabolism. Carbamazepine (CBZ) has a long history of use for neuropathic pain, particularly trigeminal
Antidepressants235,236,237 (Table 8)
Tricyclic antidepressants have been used for years for the management of neuropathic pain syndromes, including diabetic neuropathy, postherpetic neuralgia, and migraine headache.234, 295, 296 However, pain relief is often modest and accompanied by side effects. Controlled studies indicate that approximately one-third of patients will obtain more than 50% pain relief, one-third will have minor adverse reactions, and 4% will discontinue the antidepressant because of major side effects.234
Tramadol230–232,248
Tramadol appears to be a global utilized analgesic for chronic non-cancer pain of all types available in multiple dosage forums.
Tramadol is a centrally acting opioid analgesic that is related structurally to codeine and morphine. It consists of two enantiomers, both of which are important in the drugs’ analgesic mechanisms. The (+)-tramadol and the metabolite (+)-O-desmethyl-tramadol (also called M1) are μ opioid receptor agonists. (+)-Tramadol also inhibits serotonin reuptake, while the
Summary and recommendations
Neuropathic pain is a common cause of chronic pain and tends to be resistant to usual doses of traditional analgesic medications. Three classic examples of neuropathic pain include trigeminal neuralgia, postherpetic neuralgia, and diabetic neuropathy. Neuropathic pain is often described as lancinating or burning in nature. Both types of pain may be present at the same time, often accompanied by allodynia.
Neuropathic pain may be manageable with one monotherapy or more adjuvant analgesic drugs
Discussion
The goals of providing medical care for patients with neuropathic pain are often directed by changes in the quality, intensity, timing, and regional distribution of the patients’ symptoms, rather than objective signs or test results of the underlying etiology.
When considering those limitations, it is helpful to target specific symptoms, e.g., burning pain with tricyclic antidepressants and sharp, shooting pain with anticonvulsants. However, from a practical standpoint, pharmacological choices
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