Definitions
There is a protective role in experiencing pain that warns of potential or actual tissue damage. Persistent pain, however, does not offer any such advantage. Chronic pain is a very disabling multifaceted disease that often requires multimodal treatments. Chronic pain can be classified broadly as nociceptive, neuropathic, or a mixture of the two. According to International Association for the Study of Pain (IASP), neuropathic pain is defined as pain caused by a lesion (an obvious trauma or abnormality in diagnostic testing) or disease (a known underlying cause such as stroke and diabetes mellitus) involving the somatosensory nervous system. Neuropathic pain can be further subdivided into peripheral versus central depending on the location of the damage. This chapter focuses on neuropathic pain as a result of insult to the peripheral nerves.
Not all patients with peripheral neuropathy experience pain. In a large observational study of diabetic patients, the prevalence of painful diabetic neuropathy was 21%. Whether neuropathy is affecting a single nerve, mononeuropathy, or multiple nerves, polyneuropathy, patients with neuropathy experience similar change in sensation. These changes include but are not limited to allodynia (pain after a commonly nonpainful stimulus), hyperalgesia (exaggerated pain after a commonly painful stimulus), paresthesia (abnormal nonpainful sensations that is not unpleasant), dysesthesia (abnormal painful sensation that is unpleasant), and hyperpathia (prolonged persistent painful sensation after repetitive stimulation). A type of neuropathy involving inflammation of the nerve is termed neuritis. This is often related to a viral or bacterial infection. A classic example is acute inflammatory demyelinating polyneuropathy (AIDP).
Epidemiology
Given the lack of validated clinical diagnostic tools to identify neuropathic pain, the incidence and prevalence of neuropathic pain has been challenging to estimate. The recent development of simple symptom-based screening tools has helped provide such information on the general population. One study demonstrated that the best estimate of prevalence of neuropathic pain ranges from 7% to 10%. Neuropathic pain is also more frequently seen in women and in patients older than 50 years of age with the peak age between 50 and 64 years of age.
Mechanisms
Multiple mechanisms have been proposed for the development of neuropathic pain. Having a better understanding of the pathophysiology of neuropathic pain can in turn assist in finding better treatment options for patients. The pathological changes that cause neuropathic pain predominantly involve small sensory fibers, including unmyelinated C fibers and myelinated Aβ and Aδ fiber. After nerve injury, voltage-gated sodium channels accumulate around the injured site and along the length of the axon, which results in hyperexcitability and ectopic action potential discharges. Sodium channel blockers and membrane stabilizers specifically target this mechanism to ease neuropathic pain. Transient receptor potential vanilloid type 1 (TRPV1) channels have been suggested to play a role in neuropathic pain. TRPV1 receptors are activated by heat (>42°C), low pH (pH < 6), and endogenous lipid molecules. Nerve injury results in downregulation of TRPV1 receptors on the injured nerve and upregulation of uninjured C fibers resulting in spontaneous nerve activity, which in turn may be experienced as heat hyperalgesia along with burning pain. Capsaicin is a naturally occurring vanilloid that activates TRPV1 receptors stimulating influx of cations that result in desensitization.
Nerve injury can also induce sprouting of sympathetic fibers into the dorsal root ganglion (DRG), which presents as another mechanism for neuropathic pain and more specifically sympathetically mediated pain. After partial nerve injury, both damaged and undamaged axons begin expressing α-adrenoreceptors making them sensitive to various neurotransmitters from postganglionic sympathetic terminals. In both circumstances, the sympathetically mediated pain can theoretically be treated with sympathetic blocks or α1 antagonists.
Changes in the central nervous system can occur after a peripheral nerve injury. Such change includes alteration of inhibitory control in the spinal cord. The disinhibition is orchestrated by multiple mechanisms. Opioid and gamma-aminobutyric acid (GABA) receptors have been found to be downregulated. The amount of GABA, an inhibitory transmitter, is reduced in the dorsal horn while the expression of cholecystokinin, an opiate receptor inhibitor, is upregulated. In addition, the death of inhibitory interneurons in lamina II is thought to be through an excitatory mechanism. The culmination of these disinhibitory changes leads to spontaneous activation and an exaggerated painful response. As such, drugs targeting GABA receptors or drugs that mimic descending inhibition such as clonidine can have therapeutic value in treating neuropathic pain.
Evaluation
Patients with neuropathic pain have distinctive symptoms that differ from patients with nociceptive pain. The patient can present with positive symptoms including paresthesia, dysesthesia, allodynia, hyperalgesia, and hyperpathia. Negative symptoms may also be present, such as reduced sensory perception to light touch, pinprick, vibration, or temperature. The most common symptoms a patient may describe are tingling, pins and needles, burning, and shooting sensations. Screening tools have been developed to identify patients with neuropathic pain in the form of questionnaires. These questionnaires focus on patient-reported verbal descriptors of their symptoms. Some of the most common scales are the Neuropathic Pain Questionnaire (NPQ), painDETECT, ID-Pain, and DouleurNeuropathique 4 (DN4). These screening tools are useful first-line instruments to identify patients with neuropathic pain; however, their efficacy of accurately identifying these patients is unknown.
Physical examination should include a thorough sensory examination including testing of light touch, vibration, pinprick, temperature, and temporal summation. Light touch can be assessed by application of cotton wool to skin, vibration by utilizing a tuning fork, pinprick by a sharp object such as body pin, temperature with cold and heat stimuli such as a metal object. Temporal summation can be tested with repetitive stimulation. Peripheral neuropathy is often described as a stocking glove distribution of altered sensory perception during testing.
Diagnostic testing may be helpful in patients with suspected neuropathic pain. Electrodiagnostic testing (EDX) is one of the more common studies performed that involves two separate portions. The nerve conduction study measures electrical impulses by stimulating the nerves with electric current, whereas electromyography detects electrical activity of a muscle utilizing a fine needle. EDX may provide confirmation of neuropathy and differentiate whether the process is demyelinating or axonal as well as if the patient has mononeuropathy or polyneuropathy. However, EDX can be normal if the painful peripheral neuropathy (PPN) only involves small fibers as EDX only tests damage in large fibers. Skin biopsy is an option to test for abnormality in small-fiber neuropathy; however, its utility is controversial and there is poor correlation between abnormal biopsy findings and pain.
In addition, quantitative sensory testing (QST) is occasionally used to assess small and large fiber neuropathies as well as monitor somatosensory deficits and painful neuropathies. QST is not meant to be used in isolation to determine neuropathic pain, but to provide complementary information. It is also important to note that the treatment of neuropathic pain does not change with these confirmatory testing. Laboratory testing is another important tool to help identify potentially treatable causes of pain such as diabetes mellitus and other causes of peripheral polyneuropathy including metabolic, toxic, genetic, or infectious/inflammatory etiologies.
The IASP has developed a grading system intended to determine the likelihood that the patient’s pain is neuropathic. “Possible” neuropathic pain is defined as symptoms consistent with neuropathic pain features as well as the pain distribution are anatomically consistent with the suspected lesion. “Probable” neuropathic pain requires additional clinical evidence on physical examination such as sensory changes. “Definite” neuropathic pain involves further objective diagnostic confirmatory tests, such as an electrodiagnostic study or advanced imaging study.
Painful Neuropathies
Again, this section will focus on neuropathies whose symptoms are peripheral. The etiology of neuropathies with painful peripheral symptoms can further be categorized as injury/acquired, genetic, autoimmune/infectious, or as a result of systemic disease (i.e., diabetes mellitus). PPNs vary widely in their origin; therefore, a thorough medical history and physical exam should guide further diagnostic evaluation and treatment considerations. Reviewing all PPNs is outside the scope of this text, and therefore the focus will be on clinically relevant topics and special cases.
Injury/Acquired Painful Peripheral Neuropathies
Acquired peripheral neuropathies can be caused by injury or through iatrogenesis. They often become chronic, lasting longer than the inciting injury. Treatment is tailored to the specific injury and often requires a multimodal approach.
Complex regional pain syndrome
Complex regional pain syndrome (CRPS) is a potentially devastating painful condition that typically occurs following trauma such as wrist or ankle fracture or surgical procedure. CRPS has an approximate overall diagnosis rate of 0.07%, is more common in females, and peaks between ages 45–55. It is important to identify CRPS early to improve outcomes and reduce disability.
Currently, CRPS is diagnosed clinically by criteria accepted by the IASP called the Budapest Criteria. It has been validated to have a sensitivity of 99% and a specificity of 68%. , The clinical criteria consist of four categories, both in patient-reported symptoms and signs examined by a physician as outlined by Harden et al. in Table 5.1 . The first category is sensory. The hallmark of CRPS is allodynia, which is defined as pain to a nonpainful stimulus. Patients with CRPS may report that the affected extremity is subject to severe pain with nonnoxious stimuli, such as wind, clothing, bedsheets, or shoes.
| Appendix II Budapest Clinical Diagnostic Criteria for CPRS |
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The second category is vasomotor. This consists of skin temperature changes, skin color changes, or asymmetry in these findings. Sudomotor change is the third category and consists of edema, changes in sweating, or sweating asymmetry. The last category is motor or trophic changes. This could be weakness, dystonia, tremor, decreased range of motion, or hair, nail, or skin changes. The patient must exhibit a symptom in each of the four categories and at least two signs in separate categories at the time of diagnosis. Importantly a final criterion is that no other condition or disease can better explain the signs and symptoms exhibited by the patient.
Prompt treatment is important as CRPS can spread to different limbs and centrally as it affects the spinal cord and brain. Treatment should be guided by a pain specialist who has experience in treating this disorder to prevent disability and further impairment. Treatment is typically based upon symptom severity and may include a host of treatments. Neuropathic medications such as anticonvulsants and antidepressants, sympathetic nerve blocks, physical therapy, psychological therapy, spinal cord stimulation (SCS), DRG stimulation, ketamine infusions, and intrathecal drug pumps are all treatment modalities used in CRPS.
Chemotherapy-induced peripheral neuropathies
Chemotherapy-induced peripheral neuropathy (CIPN) is a common problem occurring in approximately 30%–40% of those treated with neurotoxic chemotherapy. Traditional chemotherapeutic agents causing CIPN are the platinum, taxanes, and vinca alkaloid medications. These drug classes cause CIPN by direct neuronal toxicity. Factors affecting the development of CIPN include route of medication delivery and dosing.
The platinum-based chemotherapies, such as cisplatin, are believed to exert their CIPN producing action by attacking the DRG sensory neurons. They also have a unique characteristic of “coasting” wherein despite cessation of the drug, symptoms continue to worsen for months. Taxanes cause an axonopathy of sensory neurons that is both length and dose dependent. Vinca alkaloids also cause a length-dependent sensory neuropathy but may affect motor neurons as well. They are common in the treatment of hematological malignancies.
Prevention of CIPN is difficult and there are currently no specific treatments except symptom management. Despite their lifesaving effects, these medications can lead to significant adverse effects. Multiple studies have investigated the treatment of CIPN with neuropathic pain medications with duloxetine showing some benefit.
Nutritional deficiencies causing peripheral neuropathy
Nutritional deficiencies can lead to PPNs. Pain is typically not the only symptom but can be the most concerning for patients. Thiamine deficiency (vitamin B1) is common in chronic alcoholics, dialysis patients, and patients on specific diets that avoid thiamine. Thiamine deficiency leads to beriberi, which is a clinical syndrome consisting of cardiovascular effects and heart failure along with PPN. Thiamine deficiency caused by chronic alcoholism can cause a similar syndrome, Wernicke-Korsakoff.
Vitamin B12 deficiency can also lead to a PPN. Vitamin B12 is absorbed in the gastrointestinal tract. Diseases, such as chronic gastritis or pernicious anemia, that affect absorption can lead to deficiency of vitamin B12. This leads to altered metabolism of homocysteine causing a peripheral neuropathy. The mainstay of treatment is B12 replacement therapy.
Genetic Painful Peripheral Neuropathies
Charcot-Marie-Tooth disease
Charcot-Marie-Tooth disease (CMT) is the most commonly inherited PPN with a prevalence between 1 in 1213 and 1 in 2500. It is a group of differentially inherited diseases (CMT1-4 and CMT1X) that can cause a PPN. Most are inherited in an autosomal dominant pattern, but CMT4 is autosomal recessive and CMT1X follows X-linked inheritance. This means that the majority of CMTs will have a 50% chance of transmission to future generations by the affected parent. Clinical manifestations beyond PPN include distal symmetric leg weakness, decreased or absent reflexes, and significant foot deformities (pescavus and equinus protonation).
Hereditary sensory and autonomic neuropathies
The hereditary and sensory autonomic neuropathies (HSAN) are another group of genetically acquired diseases. They primarily affect the myelinated and unmyelinated sensory nerves. HSAN I is the most common pattern of inheritance and is autosomal dominant. The typical clinical presentation includes sensory loss and neuropathic pain. Onset of HSAN I commonly occurs in the early twenties. HSAN II–III are inherited in an autosomal recessive pattern and along with HSAN IV and V do not typically cause painful neuropathy. In fact, they often cause a degree of insensitivity to pain with type IV causing a profound lack of pain sensation with onset in infancy.
Painful channelopathies
Channelopathies are a group of disorders resulting in an identified genetic mutation affecting pain receptors. The two most commonly affected receptors are voltage-gated sodium ion channels (Na1.7, Na1.8, and Na1.9) caused by mutations in the SCN genes ( SCN9A , SCN10A , and SCN11A ) and TRP channels. Conditions resulting from these genetic alterations include inherited erythromelalgia, paroxysmal extreme pain disorder, small-fiber neuropathy, and familial episodic pain syndromes. Onset of these conditions varies but can occur as early as birth or later in adulthood. There are no genetic treatments currently available for these conditions, so treatment focuses on symptom management with strategies described later in this chapter. Interestingly, genetic mutations in the SCN9A and SCN11A can also cause insensitivity to pain. ,
Autoimmune/Infectious Painful Peripheral Neuropathies
Postherpetic neuralgia
Postherpetic neuralgia (PHN) is the persistence of dermatomal pain 90 days after acute herpes zoster manifestation. It is the most common sequelae of herpes zoster infection. Herpes zoster is caused by reactivation of the varicella zoster virus that causes chicken pox. There is an annual incidence of one million cases in the United States, and the condition affects roughly 20% of patients with herpes zoster. The pain may be described as burning and electric-like and is caused by damage to the nerve and secondary inflammation caused by the replicating virus. The American Academy of Neurology suggests initial treatment should focus on neuropathic pain medications and lidocaine patch 5%, which is FDA approved for PHN. The varicella zoster vaccine is suggested in patients over 60 years old and may prevent herpes zoster infection and presumably PHN. Interventional procedures for treatment-resistant cases can include nerve blocks at the nerve innervating the affected dermatome and neuromodulation.
HIV/AIDS-associated peripheral neuropathy
HIV-associated peripheral neuropathy is the most common neurological complication of HIV/AIDS. The most prevalent clinical manifestation is a distal symmetric polyneuropathy that can be burning in nature. Symptoms are not believed to be correlated with lower CD4 counts or higher viral load, but may be related to longer lifespans in HIV/AIDS- affected patients and increase in comorbid diseases with age. The specific pathophysiology of HIV-associated peripheral neuropathy is unknown, but it is not believed to occur through direct damage of neurons from the virus itself. Studies have shown limited efficacy for most oral medications traditionally used for PPNs. Treatments that have shown improvement compared with placebo include capsaicin 8% and smoked cannabis. ,
AIDP/CIDP
AIDP and chronic inflammatory demyelinating polyneuropathy (CIDP) are autoimmune disorders. PPN can be part of a patient’s symptomatology, but the hallmark of these diseases is significant muscle weakness resulting from axonal damage. AIDP is thought to be initiated most frequently by infections of campylobacter jejuni leading to anti-ganglioside antibodies and complement attacking the nodes of Ranvier at nerves.
AIDP, also called Guillain-Barre syndrome (GBS) after the clinician who first described it, is the most common cause of adult onset acute flaccid paralysis in the United States, but can also cause painful neuropathy. Approximately one-third of patients diagnosed with AIDP complain of pain during the initial presentation. The yearly incidence of GBS is one per 100,000. Pain is common in GBS with approximately 89% of patients affected. Suggested mechanisms leading to pain in GBS are inflammation and compression of the nerve roots. Aside from treating the underlying cause of GBS, pain arising from GBS is typically treated with neuropathic pain medications, specifically gabapentin and carbamazepine. Epidural steroids have also shown efficacy.
CIDP is rare and affects approximately 40,000 people in the United States. Of those, 13%–17% have symptoms of severe pain. CIDP is characterized by relapsing and remitting symptoms, unlike AIDP. Although, individuals who initially present with AIDP may be later diagnosed with CIDP if their symptoms reoccur. The most commonly used diagnostic criteria are published by the European Federation of Neurological Societies (EFNS). Initial treatment of CIDP consists of immunoglobulin, corticosteroids, and/or plasma exchange.
Painful Peripheral Neuropathies Resulting from Systemic Diseases
Diabetic painful peripheral neuropathy
Diabetic PPN is the most common peripheral painful neuropathy with a known etiology. Recent studies suggest a prevalence of approximately 18% of type 2 diabetics is affected. According to the World Health Organization, diabetes occurs in 8.5% of the worldwide population over the age of 18 and continues to increase. Although the exact mechanism of hyperglycemic-induced PPN is yet to be elucidated, both nerve injury and neurovascular alterations are likely to blame. Axonal atrophy, degeneration or regeneration, altered peripheral vascular flow, and peripheral sensitization all lead to neuropathic pain experienced by these patients. Typical pain is in the classic “stocking and glove” distribution although it can vary and be manifested as radiculopathy, mononeuritis multiplex, and mononeuropathies. The quality of pain is usually described in terms of burning, electric, and stabbing sensations.
Treatment of diabetic PPN is multimodal. Hyperglycemic control is pivotal in preventing neuropathy in type 1 diabetics but plays a much smaller roll in reducing PPN in type 2 diabetics. Numerous studies have been performed and show level A evidence for first-line medications gabapentin, tricyclic antidepressants (TCAs), and duloxetine including the European Federation of Neurological Society guidelines.
Treatment of Painful Peripheral Neuropathies
Treatment of PPNs should follow a multimodal approach maximizing efficacy and reducing side effects. Ideally, less invasive techniques are preferred, but treatment should be tailored to each individual’s symptoms. General treatment considerations include medications (enteral, parenteral, and topical), modalities, interventional techniques, and psychological intervention.
Medications
Oral medications are often first-line treatment for neuropathic pain conditions with common ones being outlined in Table 5.2 . Recommendations for treatment by the European Federation of Neurological Societies Task Force (EFNS) were developed by reviewing the Cochrane Database and Medline for class 1 and 2 randomized control trials. These guidelines continue to recommend TCAs, gabapentin, and pregabalin as first-line, tramadol as second-line, and stronger opioids as third-line treatments. This may vary among specific neuropathic conditions (i.e., HIV-induced neuropathy or trigeminal neuralgia) and many investigational studies have reviewed the use of these medications.
| Chemical Modulator | Pharmacologic Option |
|---|---|
| Alpha 2 agonists | Clonidine |
| AMPA (Na + channel) antagonist | Gabapentin, carbamazepine, valproic acid, phenytoin |
| GABA B agonists | Baclofen |
| Glutamate antagonist | Gabapentin |
| NE reuptake inhibitors | TCAs |
| NMDA Ca 2+ channel antagonist | Ketamine, amantadine, dextromethorphan, haloperidol |
| Non-NMDA Ca 2+ channel blocker | Nifedipine |
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