Key points

Introduction

Pain is classified by duration (acute vs chronic) and pathophysiology (nociceptive vs neuropathic). Chronic neuropathic pain is caused by lesions in the peripheral or central nervous system (CNS) and can occur in many forms. With neuropathic pain, nociceptive stimulation is not required, and the pain is disproportionate to the stimulation intensity. Pain signals are generated for unknown reasons and may be intensified if pain-relieving mechanisms are defective or deactivated. Furthermore, a structure–function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in both CNS and peripheral nervous system injury models of neuropathic pain.

Neuropathic pain is commonly seen in clinical practice and may be associated with a variety of peripheral nerve disorders, including neuropathy associated with diabetes, alcoholism, hypothyroidism, uremia, nutritional deficiencies, and chemotherapy, primarily treatment with vincristine, cisplatinum, zalcitabine, and paclitaxel. Other disorders that may be associated with neuropathic pain include almost all forms of hereditary and acquired neuromuscular disorders, including Charcot-Marie-Tooth disease; many forms of muscular dystrophy; Guillain-Barré Syndrome; postherpetic neuralgia; complex regional pain syndrome, type 1; and ischemic neuropathy. Neuropathic pain afflicts an estimated 1.5% of the population worldwide. In 2008, the analgesic market costs for neuropathic pain associated with diabetes alone were estimated at nearly $200 million annually and seemed to be rising.

The range of therapeutic options to treat peripheral neuropathic pain has expanded greatly in recent years. With proper treatment, most patients with neuropathic pain should experience a meaningful reduction in their pain and an improvement in quality of life. A life care plan, coordinated on behalf of patients with neuropathic pain, requires many considerations. Life care planners look to the medical community to define the nature and extent of impairment. They use their specialized knowledge and clinical judgment along with established standards of practice.

Introduction

Pain is classified by duration (acute vs chronic) and pathophysiology (nociceptive vs neuropathic). Chronic neuropathic pain is caused by lesions in the peripheral or central nervous system (CNS) and can occur in many forms. With neuropathic pain, nociceptive stimulation is not required, and the pain is disproportionate to the stimulation intensity. Pain signals are generated for unknown reasons and may be intensified if pain-relieving mechanisms are defective or deactivated. Furthermore, a structure–function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in both CNS and peripheral nervous system injury models of neuropathic pain.

Neuropathic pain is commonly seen in clinical practice and may be associated with a variety of peripheral nerve disorders, including neuropathy associated with diabetes, alcoholism, hypothyroidism, uremia, nutritional deficiencies, and chemotherapy, primarily treatment with vincristine, cisplatinum, zalcitabine, and paclitaxel. Other disorders that may be associated with neuropathic pain include almost all forms of hereditary and acquired neuromuscular disorders, including Charcot-Marie-Tooth disease; many forms of muscular dystrophy; Guillain-Barré Syndrome; postherpetic neuralgia; complex regional pain syndrome, type 1; and ischemic neuropathy. Neuropathic pain afflicts an estimated 1.5% of the population worldwide. In 2008, the analgesic market costs for neuropathic pain associated with diabetes alone were estimated at nearly $200 million annually and seemed to be rising.

The range of therapeutic options to treat peripheral neuropathic pain has expanded greatly in recent years. With proper treatment, most patients with neuropathic pain should experience a meaningful reduction in their pain and an improvement in quality of life. A life care plan, coordinated on behalf of patients with neuropathic pain, requires many considerations. Life care planners look to the medical community to define the nature and extent of impairment. They use their specialized knowledge and clinical judgment along with established standards of practice.

Gender differences

Women and men perceive neuropathic pain differently and respond to treatment differently. Women report more severe and longer-lasting neuropathic pain than men. Women and men also differ in their pharmacokinetic responses to treatments. Notable reasons for these differences include women having lower body weight and a higher percentage of body fat than men, which can affect the volume of distribution. Adults are often given the same dose of drug regardless of body weight, so women tend to have higher serum concentrations of drugs than men receiving the same treatment. Other gender differences in bioavailability, metabolism, and renal elimination also may be involved in differing medication effects. In women, fluctuating body fluid mass during the menstrual cycle can affect drug blood levels, which changes glomerular filtration rates and subsequent renal drug clearance.

Diagnosis

Pain involves an unpleasant physical sensation within the context of an individual’s emotional, cognitive, and behavioral response to that sensation. Chronic neuropathic pain starts with pathophysiologic changes in the nerve, either from a medical condition (eg, diabetes) or direct trauma to the nerve (eg, a gunshot wound to brachial plexus), which leads to pain and inflammation. The injury heals but, if untreated, pain signals continue. Structural CNS changes alter neural transmission, resulting in chronic pain, hyperalgesia, allodynia, and occasionally the spread of pain. All of these symptoms should be considered when evaluating a patient with neuropathic pain. Despite the potentially complex cause, the diagnosis of neuropathic pain should be straightforward and is best made based on a patient’s medical history and a physical examination. Ancillary testing, including electrodiagnostic testing, nerve imaging, or serologic studies, are not generally needed. Small, unmyelinated C fibers may be involved in producing neuropathic pain, but these fibers are not assessed with traditional nerve conduction tests. Quantitative sensory testing may assess small fiber function using cold and cold/pain as well as hot and hot/pain detection threshold measurements. In addition, quantitative sensory testing may provide information on abnormal sensory processing and perception.

It is important to ask patients to describe their pain in detail, using descriptors rather than simply asking patients to rank pain intensity on a scale from 1 to 10. Patients suffering from neuropathic pain usually describe their pain as “electrical,” “squeezing,” “deep aching,” “jabbing,” “broken glass,” “cramping,” and “spasms.” The Neuropathic Pain Scale (NPS), a validated assessment tool, is easily administered and provides an accurate characterization of neuropathic pain. The NPS is easily accessed online and lists 10 pain descriptors (intense, sharp, hot, dull, cold, sensitive, itchy, unpleasant, deep, and surface) that specifically describe common neuropathic pain qualities. The NPS provides clinicians with a reproducible appraisal of the degree and quality of neuropathic pain, which can be used to measure the efficacy of therapeutic interventions.

Allodynia and hyperalgesia are 2 critical physical examination findings in patients with neuropathic pain. Allodynia is pain caused by a normally nonpainful stimulus and can be assessed by simply stroking the skin lightly. Hyperalgesia is an exaggerated pain caused by a normally painful stimulus and can be assessed by a pinprick. With hyperalgesia, patients may initially say that they cannot feel a pinprick (sensory deficit), but after several pricks the sensation becomes quite painful. This phenomenon is known as summation. Moreover, the painful sensations may linger for seconds to minutes after the stimulus has stopped. This phenomenon is known as aftersensations. Pain described using the descriptors noted in the NPS along with the presence of summation and aftersensations are the critical elements that should be present in most patients with true neuropathic pain. Some patients with neuropathic pain, however, may not have allodynia or hyperalgesia.

Mechanisms of neuropathic pain

Neuropathic pain is caused by damage to the nervous system. Unlike physiologic pain, also known as nociceptive pain, neuropathic pain is not self-limiting. The causes of neuropathic pain are many and varied and include infectious agents, metabolic disease, neurodegenerative disease, and physical trauma, among other causes. Clinically, patients vary significantly in their response to treatment. The pathophysiology of neuropathic pain syndromes is complex. Many cellular mechanisms of pain transmission have been elucidated, and the clinical correlates of these mechanisms are beginning to be recognized. A variety of pathophysiologic processes may generate and maintain the symptom of pain in peripheral nervous system disorders. Conceptually, no one mechanism may be disease-specific, and each disorder may have several mechanisms typically associated with it. Thus, accounting for the pain in any individual patient may require hypothesizing that 1 or more mechanisms are at work simultaneously. For example, a patient with a drug-induced (toxic) neuropathy may share a pain mechanism with a patient who has a metabolic (diabetes) neuropathy. This heterogeneity may explain why only a subset of patients within each diagnostic category typically responds to a particular drug. Once neuropathic pain is present, all levels of the nervous system—peripheral, central, and autonomic—may play a role in generating and maintaining pain. Therefore, independent of actual clinical diagnosis, several different pathophysiologic processes may be simultaneously present. Furthermore, some patients with neuropathic pain, especially those with mononeuropathies, may also develop secondary myofascial pain. It is imperative that clinicians realize that myofascial pain may mimic neuropathic pain and result in referred pain distant from the actual soft tissue source.

Inflammation is thought to play a role as a pain generator in nerves. Eliav and colleagues were able to induce an experimental neuritis in a rat by exposing the animal’s sciatic nerves to an inflammatory stimulus. In this experiment, the investigators found statistically significant heat-hyperalgesia and mechano-hyperalgesia and mechano-allodynia and cold-allodynia in the inflamed nerve for 15 days, after which responses returned to normal. Light microscopic examination of the inflamed nerves, harvested at the time of peak symptom severity, revealed that the treated region was mildly edematous and that there was an obvious endoneurial infiltration of immune cells (ie, granulocytes and lymphocytes). There was either a complete absence of degeneration or degeneration of no more than a few 10s of axons. Immunocytochemical staining for CD4 and CD8 T-lymphocyte markers revealed that both cell types were present in the epineural and endoneurial compartments. The endoneurial T cells seemed to derive from the endoneurial vasculature rather than migrating across the nerve sheath. These results provide strong evidence that focal neural inflammation potentially produce neuropathic pain, even in the absence of significant or clinically detectable structural damage to the nerve.

Furthermore, it is hypothesized and believed by most authorities that a primary neuropathic pain mechanism may be generated from ectopic impulses propagated from sites of abnormal or damaged nerve axons and the adjacent dorsal root ganglia. Ectopic impulses are associated with a general increase in the level of neuronal excitability within primary afferent fibers and their synaptic contacts within the spinal cord. Novel, voltage-activated sodium channels are expressed at these sites and are thought to play an important role in generating ectopic impulses. These channels are structurally diverse, comprised of several subunits, and may interact with extracellular matrix molecules to affect growth and myelination of axons. Differential regulation of the subunits by messenger RNA may contribute to the altered excitability of damaged neurons by influencing sodium channel function. Genetic influences may be present, because it has been shown that different strains of rats react differently to the same type of nerve injury. These differences may also been seen in the subsequently induced CNS changes.

Pharmacologic management

Despite much progress in pain research, neuropathic pain remains a formidable problem to manage. Many treatment options are available, yet less than half of patients experience clinically meaningful pain relief, which is almost always incomplete and significantly impairs their quality of life. In addition, patients frequently experience adverse effects and, as a consequence, are often unable to tolerate treatment. In some patients, combination therapies using 2 or more analgesics with different mechanisms of action may provide adequate pain relief. Although combination treatment in clinical practice may result in greater pain relief, clinical trials with analgesic combinations are lacking. Trials with multiple drug combinations pose many methodological problems, including which combination to use, occurrence of additive or supra-additive effects, and the need for sequential or concurrent treatment. Adverse-event profiles of these analgesics are scarce, whether the analgesics are used alone or in combination. If pharmacologic pain management is ineffective, invasive therapies, such as intrathecal drug administration and neurosurgical stimulation techniques (eg, spinal cord stimulation, deep brain stimulation, and motor cortex stimulation), may be considered, although these treatments have not been well studied.

Even though many options are available to treat neuropathic pain, no clear consensus has been reached on which are most appropriate. Nonetheless, recommendations can be proposed for first-line, second-line, and third-line pharmacologic treatments based on the level of evidence available for different treatment strategies. Historically, most drugs used to treat neuropathic pain are considered adjuvant analgesics (ie, medications that are, by definition, agents whose primary indication is not analgesia). For example, tricyclic antidepressants (TCAs) and antiepileptic drugs (AEDs) have been mainstay treatments for neuropathic pain and include such pharmaceuticals as amitriptyline (Elavil) and gabapentin (Neurontin), a TCA and an AED, respectively. Even today these drugs are used primarily as pain medications, although neither is approved by the Food and Drug Administration for this indication. Venlafaxine (Effexor) and other serotonin–norepinephrine reuptake inhibitors (SNRIs) may also be effective when used off-label to manage neuropathic pain, although limited data are available in humans to document their efficacy. TCAs are often the first drugs selected to alleviate neuropathic pain (ie, they are a first-line pharmacologic treatment). Although they are effective in reducing pain in several neuropathic pain disorders, treatment benefit may be compromised and outweighed by their side effects. Other options are needed in patients with a history of cardiovascular disorders, glaucoma, and urine retention. Newer drugs, for example, duloxetine (Cymbalta), also an SNRI, like venlafaxine, and pregabalin (Lyrica), an AED, may be better choices. Unlike their predecessors, these drugs are FDA approved to treat pain. Pregabalin (Lyrica) also has documented efficacy in alleviating neuropathic pain and is now a first-line treatment for neuropathic pain. Both pregabalin and gabapentin have more favorable safety profiles than older drugs, such as carbemazepine or phenytoin, with minimal concerns regarding drug interactions and showing no interference with hepatic enzymes.

For refractory pain, opioids may alleviate nociceptive and neuropathic pain. The effectiveness of opioids in relieving acute pain has been well studied and established. The use of opioids to treat any type of chronic pain, however, including neuropathic, remains controversial and is attributable in part to a lack of understanding of neuropathic pain and its mechanisms. Despite this contention, several randomized controlled clinical trials with opioids—morphine, oxycodone, and tramadol—were successful in helping alleviate neuropathic pain. Tramadol is unique among opioids because of the additional serotonergic and noradrenergic signaling it stimulates. Tapentadol (Nucynta), a newer drug, has both opioid and noradrenergic-stimulating components and is FDA approved for neuropathic pain. Individual titration of opioid dosing and long-term follow-up studies are needed to measure long-term pain relief and to assess quality of life. Until that occurs, long-acting opioids, such as methadone, long-acting oxycodone (OxyContin), or morphine sulfate (MS-Contin), should be considered in patients whose pain is refractory to adjunctive agents.

Topical agents, including formulations of lidocaine, clonidine, capsaicin, and ketamine, are effective in treating localized neuropathic pain. The efficacy of topical lidocaine patches (Lidoderm), and capsaicin ointment (Zostrix) is well documented in alleviating postherpetic neuralgia. Topical application is a novel approach to treating neuropathic pain and has the advantage of minimizing systemic side effects. If specific topicals are to be trialed for a patient, a compounding pharmacist can create customized formulations.

Recently included among these pharmacologic options is the use of cannabinoids, a class of drugs that take their name from Cannabis sativa , the botanic from which they were first isolated and which includes herbal preparations of cannabis as well as synthetic, semisynthetic, and extracted cannabinoid preparations. Cannabis is administered mainly by 3 routes: via the lungs by inhalation of vaporized or smoked organic plant material; via the gut with ingestion of lipophilic, alcoholic, or supercritical fluidic extracts of plant material; or via the skin by topical application of plant extracts. Cannabinoids produce analgesia via supraspinal, spinal, and peripheral modes of action, acting on both ascending and descending pain pathways. Cannabinoids are most commonly researched clinically for their role in managing neuropathic pain, but cannabinoids have also been used to treat malignant pain and other chronic pain syndromes, especially those involving hyperalgesia and allodynia, as well as acute pain applications.

Complementary and alternative medicine approaches

Adding complementary and alternative therapies to conventional medicine may enhance treatment of neuropathic pain. To date, only preliminary data support combining alternative therapy with selected conventional medications for patients with neuropathic pain. Randomized, controlled trials with appropriate control groups are needed to validate the effectiveness of this therapeutic approach. If Western medicine pharmacologic approaches are unsuccessful, however, then complementary and alternative medicine approaches, such as acupuncture, Chinese herbs, craniosacral therapy, and others, should be considered for individual patients as long as patients and clinicians are aware that the efficacy of this approach has not been systematically studied.

Rehabilitation medicine approaches

Patients with neuropathic pain may benefit from physical and occupational therapy modalities, including ultrasound, exercise, massage, orthotics, and bracing. A recent study showed that osteopathic manipulative treatment significantly alleviated chronic neuropathic pain associated with spinal cord injury over several weeks, coming remarkably close to the level of pain relief provided by standard pharmacotherapy. At times, functional orthotics and bracing may also be helpful. A long-range management regimen should be oriented toward maximizing quality of life and minimizing comorbidity. For patients who have been deconditioned by immobility and lack flexibility, strength, or endurance, treatment often includes exercise. Physical therapy encourages patients to use their own muscles to further increase flexibility and range of motion before advancing to other exercises that improve strength, balance, coordination, and endurance. To relieve pain, a physical therapist may use electrical stimulation, hot packs or cold compresses, ultrasound, traction, or deep tissue massage. Physical therapists may also teach patients to use assistive and adaptive devices, such as canes or braces, and instruct exercises for patients to do at home.

Occupational therapists help patients perform their activities of daily living independently and they may recommend using adaptive equipment to replace lost function.

Rehabilitation psychologists help patients relieve stress, cope with chronic neuropathic pain, and treat depression, all of which are common in patients suffering from chronic neuropathic pain.