Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Evaluation and Treatment of Pain in Selected Neurologic Disorders
Pain in Selected Neurologic Disorders
Although chronic pain may be the defining feature of certain neurologic disorders, physicians often focus on treatments aimed at addressing the primary neurologic condition. As most comorbidities may come from pain associated with the condition, it should be addressed early during treatment. Chronic pain is a three-dimensional process consisting of biologic, psychological, and social components. All three interact dynamically and affect the states of the others. Here, we provide a basic pathophysiologic explanation of pain that accompanies these conditions and treatment strategies to complement disease-based treatments and improve the quality of life of affected individuals. Although it is not possible to include every disorder in which pain is a feature, this chapter discusses the pertinent features of diseases that pain specialists are likely to encounter with some frequency (see the reference list for detailed reviews of each disorder in the literature, when available). We focused on the evaluation, diagnosis, and treatment of neuropathies due to peripheral nerve, spinal cord, and brain pathologies ( Table 36.1 ). Chapter 34 discusses complex regional pain syndrome (CRPS); postherpetic neuralgia and diabetic peripheral neuropathy are addressed in Chapter 33 . More details on neuroanatomy and pathophysiology can be found in Chapters 8 and 9 .
TABLE 36.1
Pain Syndromes in Neurologic Disorders
| Primary Disorder | Pain Location | Pain Classification and Descriptors | Etiologies |
| Peripheral neuropathy | Stocking-glove distribution | Neuropathic Burning, tingling, stabbing, dysesthesias |
|
| Spinal cord disorders | Radicular, transitional zone pain, deafferentation pain, musculoskeletal pain (shoulders), spasticity related pain (lower limbs), abdomen (visceral) | Neuropathic Constant burning, tingling, aching, evoked shooting pain Nociceptive Aching, dull Visceral Dull, cramping,dysreflexia, autonomic dysfunction |
|
| Brain and brainstem lesions | Contralateral extremities, ipsilateral face (brainstem) | Neuropathic Aching, burning, dysesthesias, sharp Spasticity related Musculoskeletal |
|
Peripheral Neuropathies
Most instances of painful peripheral neuropathies are acquired and can be divided into metabolic, autoimmune, infectious, traumatic, iatrogenic, and idiopathic etiologies ( Table 36.2 ). Evaluation begins with a medical history, physical and neurologic examinations, and laboratory tests. Nerve conduction studies (NCS), electromyography (EMG), autonomic function assessment, cerebrospinal fluid analysis (CSF), magnetic resonance imaging (MRI), and biopsy may be included.
TABLE 36.2
Painful Peripheral Neuropathies
| Classification by Cause | Examples |
| Metabolic disorders | Diabetes mellitus, vitamin deficiency (thiamine, vitamin B 12 ), uremia |
| Toxins | Ethanol, heavy metals (arsenic, lead), industrial solvents |
| Drug induced | Chemotherapy, isoniazid, antiretroviral therapy |
| Trauma | Complex regional pain syndrome type 2, neuromas, postamputation pain, peripheral nerve trauma |
| Entrapment | Peroneal, ulnar, median (carpal tunnel syndrome), posterior tibial (tarsal tunnel syndrome) |
| Autoimmune | Connective tissue disorders, vasculitis, paraneoplastic disorders, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy |
| Infectious | Lyme disease, spirochetal infection, herpes zoster, cytomegalovirus infection |
| Hereditary | Familial amyloid polyneuropathy, Fabry’s disease |
The Workup
To differentiate among the different types of neuropathies, a detailed history must be obtained. Specifically, the time course, presence and characteristics of sensory, motor, and autonomic symptoms, the distribution of symptoms (proximal and/or distal, hands and/or feet, symmetric/asymmetric), and intensity must be assessed. Medical history, social history, family history, medications, and exposure to toxins must be considered. The duration of symptoms is important in categorizing neuropathy into acute (<4 weeks), subacute (4–12 weeks), and chronic (>12 weeks). Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome [GBS]) peaks at four weeks of onset, and progression beyond eight weeks suggests chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Based on their distribution, neuropathies can be categorized as mononeuropathy (single peripheral nerve involvement, usually due to trauma, compression, or entrapment), mononeuropathy multiplex (multiple, separate noncontiguous peripheral nerves either simultaneously or sequentially, commonly due to systemic vasculitis), and polyneuropathy (toes and soles are affected first and hands later, usually due to metabolic, toxic, or systemic disorders).
Sensory symptoms include positive (burning, pain, walking on cotton wool, band-like sensation on the feet or trunk, stumbling, tingling, pins and needles) and negative symptoms (numbness, loss of sensation) in the hands and feet. Motor symptoms include weakness and fine motor difficulties (e.g. unfastening a button and opening bottles). Autonomic symptoms, such as postural hypotension, impotence, sphincter disturbance, diarrhea, constipation, dryness, and excessive sweating, point to the involvement of small myelinated or unmyelinated nerve fibers.
Medical history should look for systemic diseases that can be associated with neuropathy, such as diabetes, hypothyroidism, chronic infections, and/or autoimmune diseases. Aside from chemotherapeutic agents that may cause polyneuropathy, commonly used medications associated with polyneuropathy include pyridoxine (vitamin B6), phenytoin, linezolid, metronidazole, nitrofurantoin, isoniazid, chloramphenicol, dapsone, reverse transcriptase inhibitors, amiodarone, colchicine, and disulfiram. Family history should include ethnic background, consanguinity, and details about parents and siblings, such as the presence of high-arched feet, flatfeet, hammertoes, gait dysfunction, bilateral carpal tunnel syndrome, and other signs of possible inherited neuropathies. Social history includes the patient’s country of origin, potential occupational exposure, potential exposure to people with transmittable illness, alcohol and drug use, and travel history. Psychosocial assessment should be performed for depression, anxiety, personality disorders, substance use, and cognitive deficit comorbidities.
Neurologic examination should include examination of cranial nerves, muscle power, tone, and reflexes, detailed evaluation of all sensory modalities (pinprick, pain, temperature, vibration, and joint position), and an observation of the patient’s gait and the ability to stand up from a chair. Specific findings include anosmia (as in B12 deficiency), impaired pupillary light reflex (diabetes, GBS), ophthalmoplegia (GBS), and widespread reflex loss, including muscles that are not particularly weak or wasted, favoring demyelinating neuropathy. In contrast, selective loss of ankle reflex in the presence of distal wasting and weakness is characteristic of axonopathy. Meticulous general physical examination can identify several clues for diagnosis, nail changes (Mee’s lines) in toxin poisoning (such as arsenic and thallium), musculoskeletal abnormalities, such as pes cavus, high-arched feet, and mutilation (usually hereditary neuropathy), skin changes, or nerve thickened nerves in rare diseases.
Following history and examination, chronic, distal, slowly progressive, symmetric, predominantly sensory polyneuropathy can be diagnosed clinically without further testing. If any atypical feature is noted in the initial or subsequent evaluation, including asymmetry, severe early sensory complaints such as ataxia and loss of proprioception, early or severe pain, the predominance of or early motor involvement, proximal symptoms, and fast progression, neurophysiologic testing should be pursued. Similarly, other than a classic presentation of acute GBS, all other acute neuropathies should be further evaluated.
The clinical evaluation includes evaluation of complete blood count (CBC), erythrocyte sedimentation rate (ESR), fasting glucose or glucose tolerance test, liver and renal function tests, serum vitamin B12 and folate levels, thyroid function tests, serum protein electrophoresis, and immunofixation electrophoresis. The vasculitis profile (antinuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, extractable nuclear antigen, anti-Ro, anti-La) is added when patients suffer from related complaints, such as joint pain or Sicca syndrome. Human immunodeficiency virus (HIV), hepatitis B and C, and Lyme tests should be added based on risk factors or previous exposure. In case of alcohol abuse, malnutrition, absorption abnormalities, or vitamin toxicity, methylmalonic acid (especially when borderline B12), homocysteine (especially when borderline B12), pyridoxine (vitamin B6), thiamine (vitamin B1), and vitamin E should be evaluated. Heavy metals, including copper and zinc, can also be checked for patients with an exposure history. Sarcoidosis can be evaluated using serum or CSF angiotensin-converting enzyme, although the specificity is limited. Paraneoplastic markers, such as anti-Hu, can be added based on clinical suspicion and previous workup.
For acute neuropathy, laboratory work should mainly include infections (West Nile virus, Hepatitis B, C, Rabies, HIV, CMV, Lyme, ESR, and CRP), heavy metal levels (arsenic, thallium, and lead), inflammatory panel (antinuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, cryoglobulins), serum and urine paraproteins, urine porphobilinogen, and urine porphyrin excretion for porphyria evaluation.
In many cases, NCS of sensory and motor nerves, late responses (F response and H reflex), and needle EMG are performed. These tests do not provide information regarding the cause of neuropathy but enable the determination of the type (demyelinating vs. axonal) and localize the lesion more precisely than on clinical examination alone. This is valuable mainly in acute neuropathies, asymmetric neuropathies, and mononeuropathies. The classic demyelinating neuropathy findings include slowing of nerve conduction velocity, prolongation of terminal latency (F latencies), temporal dispersion, and prolonged compound muscle action potential (CMAP) or conduction block (decline in the compound muscle action potential exceeding 20% on proximal stimulation compared to that on distal stimulation). Axonal neuropathy usually shows mild slowing of nerve conduction (due to sparing of remaining axons), reduced CMAP amplitude, and fibrillations on EMG. Sensory nerve action potentials and sensory conduction velocities are reduced in both axonal and demyelinating neuropathies. However, sensory conduction studies evaluate only fast-conducting fibers, which may be normal in selective small fiber and autonomic neuropathies. Thus NCS and EMG tests are mainly useful for large fiber peripheral neuropathies rather than small fiber neuropathies.
CSF analysis is indicated in acute neuropathies for GBS evaluation, and it is useful in chronic inflammatory demyelinating polyneuropathy and chronic immune-mediated axonal neuropathies where the levels of CSF protein are elevated. Significant pleocytosis can suggest other acute inflammatory neuropathies, such as Borrelia, sarcoidosis, and HIV. Nerve biopsy, usually taken from the sural nerve, remains the primary method of establishing vasculitis neuropathy when histology is unavailable elsewhere. Combined nerve and muscle biopsies are recommended to improve the diagnostic yield. The yield of biopsy in the diagnosis of chronic axonal neuropathies is very small and not justified when vasculitis is unlikely. Skin biopsy allows for the quantification of somatic and autonomic small nerve fibers. Small fiber neuropathy is diagnosed when intraepidermal nerve fiber density falls below age- and sex-adjusted normative reference values. Fine-needle aspiration biopsy of the abdominal fat pad with Congo red staining is a minimally invasive procedure used to demonstrate tissue deposits of amyloid in patients with neuropathy related to amyloidosis.
In the case of autonomic neuropathy, bedside autonomic tests include blood pressure response to standing or vertical tilt (normal fall, <20/10 mm Hg), heart rate response to standing (increase, 11–90 beats/min), heart rate variation with respiration (normal, ≥15 beats/min, inspiratory expiratory ratio 1.2), cold pressure test (after 1 min, increase in systolic blood pressure of 15–20 mm Hg, diastolic 10–15 mm Hg). Other tests may include quantitative sudomotor axon reflex sweat test (applying electrical stimulation to introduce acetylcholine into the skin, with subsequent measurement of the volume of sweat produced), pupillary tests, Schirmer’s test, and sympathetic skin response. When hereditary etiology is suspected based on age, time course, and/or family history, genetic testing can be performed for Charcot-Marie-Tooth, amyloidosis, distal hereditary motor neuropathy, Friedrich’s ataxia, and others.
The Differential Diagnosis
Autoimmune Causes
Autoimmune neuropathies may result from connective tissue diseases, vasculitis, and autoimmune disorders of the peripheral myelin. Neuropathic pain may precede diagnosis or occur during an established disease. Mononeuropathy multiplex is characterized by pain, numbness, and weakness in the distribution of peripheral nerves, most commonly the ulnar, median, and peroneal nerves. Dysfunction typically occurs at common sites of nerve entrapment. Another presentation is distal symmetrical polyneuropathy (DSP). DSP is characterized by numbness, tingling, and pain in a characteristic symmetric stocking-glove distribution. Symptoms typically begin in the feet and include burning, aching, and dysesthesia. Asymmetry of progression is a hallmark of the disease.
Acute inflammatory demyelinating polyneuropathy, known as Guillain-Barré syndrome, occurs at an annual incidence of approximately 1.11/100,000 person-years, with a 20% increase every decade after the first decade of life. GBS may develop during the initial manifestation of HIV seroconversion. Paresthesia or dysesthesia typically precedes the development of weakness, which proceeds in an ascending pattern (distal to proximal). Clinical diagnostic criteria for GBS include relatively symmetrical weakness with decreased or absent tendon reflexes. Symptoms reach maximal intensity within four weeks of onset, and other possible causes must be excluded. A high level of protein in the CSF is suggestive.
Contemporary treatment strategies with intravenous immunoglobulins, plasmapheresis, and other agents have limited the disability associated with the disorder, but a small proportion of patients may have disability and chronic pain. Pain is often a prominent symptom during the acute phase of the illness. Deep aching and throbbing pain in the lower back region associated with radiation into the lower extremities is typically the most excruciating and disabling pain. A positive straight leg raise test may also be performed. Myofascial pain may coincide with the development of muscle spasms, cramps, and muscular tenderness. Stabbing, shock-like, or electric pain may be present in the extremities and face. Ectopic impulses caused by acute nerve root inflammation may be the pathologic mechanism associated with the acute neuropathic pain component in GBS. Chronic neuropathic pain may persist beyond treatment and recovery from paralytic disorders in a small proportion of patients. The autonomic nervous system dysfunction present in GBS may lead to the development of headaches, cardiovascular instability, visceral pain secondary to ileus, and urinary retention.
Infectious
Peripheral neuropathic pain is a common accompaniment of HIV. It is estimated that 35% of patients infected with HIV experience symptomatic DSP. Neuropathic pain may complicate any stage of the infection and result in disordered sleep and ambulation, disability, and psychosocial distress. Acute polyneuropathy associated with seroconversion typically resolves with mild, if any, residual sequelae of neuropathic pain. In the intermediate to late stages of the disease, chronic inflammatory polyneuropathy, distal symmetric HIV-induced sensory axonal polyneuropathy, and vasculitic mononeuropathy multiplex may appear. Chronic inflammatory polyneuropathy manifests as neuropathic pain associated with severe sensory loss, weakness, and gait disturbance. Distal symmetric HIV-induced sensory axonal polyneuropathy manifests as burning pain, numbness, allodynia, and evoked dysesthesia beginning in the lower extremities, with variable progression to the upper extremity. They often persist despite treatment of the primary disease.
Infections during the illness, especially if untreated or refractory to treatment, such as neurosyphilis, herpes simplex virus, and toxoplasmosis, may contribute to neurologic symptoms. Cytomegalovirus infection may give rise to progressive polyradiculopathy, mononeuropathy multiplex, or both. Polyradiculopathy is characterized by the development of pelvic and lower extremity radicular pain and urinary retention and may progress to cauda equina syndrome.
Besides the neuropathies associated with primary HIV infection, antiretroviral agents may be neurotoxic. The dideoxynucleoside family of nucleoside analog reverse transcriptase inhibitors has been shown to have specific peripheral neurotoxic effects. Antiretroviral-induced neuropathies are manifested by distal dysesthesias, burning, tingling, and shooting pains and are more rapidly progressive and more painful than HIV polyneuropathy. Antiretroviral polyneuropathy occurs in 26%–66% of patients, but the symptoms often improve with drug cessation or reduction. The antiepileptic drug lamotrigine has been shown to be beneficial in refractory cases.
Lyme disease is a multisystem disorder caused by several Borrelia subspecies bacteria that are transmitted by infected ticks. A history of a tick bite, especially when the patient has been in the northern, mid-Atlantic, and north-central regions of the United States, is common. Patients may also show a ring-like skin lesion at the site of the bite and flu-like symptoms. Within days to weeks, a disseminated infection may affect the skin, nervous system (neuropathy, headaches, cognitive deficits, sleep disorder, fatigue), heart (conduction blocks), or joints. Diagnosis is confirmed by serology or polymerase chain reaction on suspected lesion skin biopsy. It is distinguished from other neurologic disorders as it is transferred focally, and there is no evidence of multiple sclerosis or demyelinating disease.
Appropriate antibiotics are mandated. However, more than 16%–18% of antibiotic-treated Lyme patients continue to suffer from chronic pain years after diagnosis. Chronic neuropathic pain may be radicular and associated with sensory abnormalities, such as paresthesias. Additionally, in 10% of patients with antibiotic-treated Lyme-arthritis, chronic arthritis develops and is unresponsive to additional antibiotic courses. Nonsteroidal medications are the mainstay of treatment.
Metabolic
Nutritional deficiencies can cause peripheral neuropathies and chronic pain. Thiamine or vitamin B1, vitamin B12, and vitamin B9 (folate) are used for myelination of the central and peripheral nervous system and are necessary for function. Thiamine is responsible for the use of glucose and energy in the central nervous system. B12 and B9 work together to produce methionine from homocysteine. The deficiencies should not be considered independently of one another. Deficiencies of these vitamins lead to demyelination of the spinal cord, cranial nerves, and peripheral nerves, and loss and swelling of the myelin sheath. The prevalence of B12 deficiency varies by age group and affects 3% of young adults and up to 6% of the elderly, whereas folic acid deficiency has been estimated to have a prevalence of 2%. In elderly patients, B1 deficiency is about 5%.
Although the symptoms are largely overlapping, there are more spinal cord and peripheral nerve disorders caused by B12 deficiency, more affective disorders caused by folate deficiency, and additional cardiovascular disorders caused by B1 deficiency. , Typical symptoms progress symmetrically, including pain, paresthesia, ataxia, spasticity, paraplegia, impaired sense of vibration and proprioception, and progressive weakness. , In addition, cognitive deficits, hearing loss, macular degeneration, and affective changes including depression can be prominent.
The main source of B9 and B12 intake comes from the consumption of animal products, whereas that of B1 intake comes from meat, whole grain, and fish. Therefore it is important to examine the patient’s diet and any digestive issues they may have. Malnutrition, alcoholism, gastric surgery, anemia, malabsorption disorders, pernicious anemia, and gastric acid reduction therapy can all contribute to B12 and B9 deficiencies. Elderly patients are also at a higher risk of developing B12 deficiency. Alcoholism, dialysis, chronic diarrhea, and high doses of diuretics are risk factors for B1 deficiency.
Initial laboratory assessments include CBC, which can show megaloblastic anemia and macrocytosis (mean cell volume greater than 100 femtoliters), serum/plasma folate levels, and B978-0-323-71101-2. For folate deficiency, additional assessments include red cell folate concentrations, whereas B12 deficiency should be confirmed with elevated plasma methylmalonic acid levels. Total plasma homocysteine levels are also indicative of both folate and B12 deficiency. Cervical and thoracic spinal cord MRI T2-weighted sequence may show bilateral posterior column hyperintensities indicating severe myelopathy. , B1 levels can be measured by thiamine diphosphate using chromatography. Oral or injected administration of the missing factor is recommended as a treatment. Patients with anemia or digestive issues are recommended life-long therapy.
Traumatic
Injuries from motor vehicle accidents, falls, sports, and medical procedures can stretch, crush, or compress nerves or detach them from the spinal cord. Furthermore, less severe traumas, such as broken or dislocated bones, can also cause serious nerve damage. Prolonged pressure on a nerve (such as a cast) or repetitive, forceful activities can cause ligaments or tendons to swell, which narrows the slender nerve pathways. The incidence of traumatic peripheral nerve injury varies from 2.8% to 5% in the population. Chronic postsurgical pain is experienced by 10%–50% of individuals, depending on the type of surgery and surgical technique. It is experienced by 50%–85% of patients after limb amputation, 30%–50% of patients after thoracotomy, and 20%–50% of patients after mastectomy. Medical history, trauma details, and physical examination are usually enough for clinical diagnosis. In cases of peripheral neuroma formation following trauma, classic surgeries including neuroma resection, neurorrhaphy, and nerve stump repositioning can be considered. Peripheral nerve stimulation or spinal cord neurostimulation (SCS) may be options in cases with severe pain or when drug adverse events prevent the continuity of pharmacologic therapies.
Iatrogenic
Neurotoxic cancer treatments, such as platinum compounds, taxanes, vinca alkaloids, thalidomide, and bortezomib, can damage the organization of microtubules in neuronal axons and sensory axons, resulting in neuropathic pain. Moreover, 30%–40% of patients treated with neurotoxic chemotherapy develop neuropathic pain. Most chemotherapy-induced neuropathic pain is dose-dependent, and neuropathy develops about two months after the start of treatment. However, with some medications, neuropathy can worsen even with the cessation of chemotherapy. In one study, 30% of 114 lymphoma patients continued to present new symptoms after discontinuation of vincristine administration. Patients developed paresthesia, burning sensations, numbness, autonomic dysfunction in the cardiovascular and digestive systems, and tactile hypersensitivities. , Some patients also experienced urinary retention, sexual dysfunction, and constipation. Symptoms are typically symmetric and occur in the hands and feet in a stocking-glove distribution.
Although chemotherapy-induced neuropathy is common in oncologic patients, it is important to rule out other causes of neuropathy. Direct neoplastic infiltration can mimic CIDP and can occur in leukemia, neurolymphomatosis, and carcinoma. Graft-versus-host disease from bone marrow transplantation can also cause neuropathy. Certain comorbidities can present a higher risk of chemotherapy-induced neuropathy, such as diabetes. For diagnostic testing, NCS are the best as reduced compound sensory action potentials are associated with chemotherapy-induced neuropathy.
Small Fiber Neuropathy
Small fiber neuropathy results from dysfunction of small diameter peripheral nerve fibers, such as C fibers and Aδ fibers. Worldwide, 53 out of 100,000 people suffer from small fiber neuropathy. , About 50% of all small fiber neuropathy cases are idiopathic. Symptoms of small fiber neuropathy include pain, paresthesia, allodynia, hyperesthesia, and autonomic and enteric dysfunction such as dry eyes, dry mouth, abnormal sweating, syncope, and gastrointestinal issues. , The pain is described as burning, shooting, and electric shock-like. , Patients often have multifocal and widespread pain. However, fibromyalgia patients tend to lack pinpoint tenderness on physical examinations.
Several conditions are associated with small fiber neuropathy, such as diabetes, HIV and hepatitis C infections, B12 deficiency, thyroid dysfunction, chronic inflammatory demyelinating polyneuropathy, Sjogren’s syndrome, and GBS. , Recent studies also show that there may be a relationship between complex chronic pelvic pain, as 64% of patients with complex chronic pelvic pain from referral clinics also tested positive for small fiber neuropathy. Exposure to toxins such as alcohol, thallium, neurotoxic antibiotics, and chemotherapy medications are also associated with the development of small fiber neuropathy. ,
Diagnostic criteria include signs of small fiber damage (pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia) and/or length-dependent symptoms along with low intraepidermal nerve fiber density on skin biopsy from the thigh or distal calf and/or abnormal quantitative sensory testing thermal thresholds in the ankle and foot. Autonomic function tests, such as a quantitative sudomotor axon reflex test, can also be a helpful diagnostic test when combined with other tests. A sural nerve conduction study or electromyography may be used to reject large fiber neuropathy.
Idiopathic Sensory Polyneuropathy
A significant number of patients exhibit symptoms of peripheral neuropathic pain in a characteristic stocking-glove distribution without a definable causative agent. This diagnosis is one of exclusion following a comprehensive evaluation, including history, physical and laboratory tests, NCS/EMG studies, and biopsy. The disorder is estimated to occur in approximately 25% of those aged 65 years and older and in as many as 50% of those aged 85 years and older. In many cases, the disorder is characterized by the loss of peripheral pain and temperature sensation. In a significant proportion of cases, complaints of burning, tingling, and symptoms of restless legs syndrome may be predominant. This syndrome may be associated with difficulty ambulating, falls, and a reduction in quality of life. The symptoms are typically worse at night, leading to disrupted sleep, with therapy aimed at minimizing insomnia.
Pain in Neuromuscular Disorders
Neuromuscular disorders describe a heterogeneous group of neurologic conditions associated with diseases of the peripheral motor nerves, neuromuscular junction, muscles (muscular dystrophies, myopathies), and anterior horn cells. In a large series of patients with post-polio syndrome, a large proportion of patients (80%) reported muscular and joint pain. The common feature in these conditions is the notable loss of muscle power and tone and the presence of muscular atrophy. Syndromes with slow progression over time are characterized by disorders of ambulation, which may lead to chronic disability and incapacitation. With disease progression, concomitant musculoskeletal pain may be associated with the loss of neuromuscular support of the axial spine, pelvic, and shoulder girdles. As is common in other chronic pain syndromes, pain may be associated with significant psychosocial distress, mood, and sleep disorders.
The Treatment of Peripheral Neuropathies
This section will focus on the treatment of pain related to peripheral neuropathies. Attention must be paid to treating the underlying causes. Infectious pathogens should be treated with antibiotics or antiviral agents, as appropriate for specific conditions. Nutritional deficiencies should also be addressed. Systemic autoimmune disorders and specific demyelinating disorders (such as GBS/CIDP) can be treated with steroids and other immunosuppressants, and in some instances, IVIG or plasmapheresis. Neuromodulatory medications may also be utilized. Gabapentinoids, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-depressants (TCAs), and capsaicin are the most effective options. Most of these first- and second-line options come with considerable potential for side effects. If the patient does not gain significant relief or has adverse effects from a medication, then dosing should be adjusted and/or alternative therapy may be used or added. The treatment of autonomic neuropathies should not be overlooked. Most cases of orthostatic hypotension can be initially managed with non-pharmacologic treatments, including avoidance of triggers, a head-up tilt of the bed at night, and adequate hydration and compression stockings. Gastroparesis, which can be a significant pain generator, should be managed with supportive measures including small regular meals 4–5 times a day, low-fat and low-residue meals, avoidance of carbonation, alcohol, and tobacco, and optimization of liquid nutrition ( Table 36.3 ).
TABLE 36.3
Therapeutic Considerations
| Neuropathic Pain | ||
| First line |
|
|
| Second line |
|
|
| Third line |
|
|
| Nociceptive pain | ||
| First line |
|
|
| Second line |
|
|
| Spasticity related pain | ||
| First line |
|
|
| Second line |
|
|
| Headaches | ||
| Acute measures |
|
|
| Preventive measures |
|
First Line Agents
Gabapentinoids are traditionally the first agents trialed and include gabapentin and pregabalin. They work by blocking presynaptic α-2-δ calcium channels in the dorsal horn, thereby inhibiting neurotransmitter release. Gabapentin and pregabalin both have been shown to be effective with numbers needed to treat (NNT) of 50% pain reduction of 3.9 (3.3–4.7) in painful polyneuropathy, 4.6 (4.3–5.4) in postherpetic neuralgia, and 4.0 (3.6–5.4) in combined etiologies of peripheral neuropathy pain. Gabapentanoids should be trialed for four to six weeks with two weeks at the maximum tolerated dose. Effects are typically not seen in practice for three to four weeks.
The most commonly used anti-depressants for the treatment of chronic pain today are serotonin and norepinephrine reuptake inhibitors, such as duloxetine and venlafaxine. They facilitate descending inhibition by blocking serotonin and noradrenaline reuptake and have been shown to be effective in peripheral diabetic neuropathy, painful peripheral neuropathy, and multiple sclerosis. , The NNT for 50% degree of pain relief in peripheral neuropathy is 5.1 (3.9–7.4). The period of the trial should be limited to four to six weeks. Patients with comorbid depression may benefit from duloxetine, which can be used to treat both depression and neuropathic pain with similar higher dosing. ,
TCAs, such as amitriptyline, nortriptyline, and desipramine, are less commonly used today because of their side effects. TCAs have multiple modes of action, with the most important pain-relieving effect likely due to the inhibition of serotonin and noradrenaline reuptake. , However, they also block histamine, adrenalin, acetylcholine, and sodium channels, accounting for their broad side effect profile. Their pain-relieving effect occurs in 20%–30% of the effective anti-depressant dose. Caution is required in the use of TCAs in the elderly and frail to avoid potential adverse effects, such as falls, cardiac arrhythmias, orthostasis, urinary retention, and dry mouth. Based on a meta-analysis of randomized controlled trials, the NNT to obtain one patient with a 50% degree of pain relief is 2.8 (2.2–3.8) for painful polyneuropathy, 2.3 (2.1–2.7) for postherpetic neuralgia, 2.5 (1.4–11) for peripheral nerve injury, and 2.3 (2.1–2.7) for combined etiologies of peripheral neuropathy pain. When trialing TCAs, it is recommended that it be done over four to eight weeks.
Second Line Agents
Combination therapy is acknowledged as a significant part of the management. The combination of anti-depressants and pregabalin has shown efficacy in diabetic neuropathy. Combination therapy should be trialed for several weeks (determined by the specific added drug) and ceased if ineffective or if there are significant side effects. Topical agents may also be employed.
Topical lidocaine works by decreasing ectopic firing of peripheral nerves, and both topical application and patch have shown efficacy for postherpetic neuralgia and mixed neuropathic pain with an NNT of 50% pain relief of 4.4 (2.5–17). Topical lidocaine has been shown to be less effective in postsurgical neuropathic pain and diabetic peripheral neuropathy with allodynia or hyperalgesia. The main advantage is the lack of significant side effects and safety profile in the elderly compared to the previous options. Capsaicin is another topical choice. It binds to the TRPV1 receptor located on the Aδ and C-nerve fibers and results in the release of substance P and depolarization of the nerve. Capsaicin has an NNT of 30%–50% pain relief of 11 (5.5–317) for painful polyneuropathy, 10–12 for postherpetic neuropathy, 6.5 (3.4–69) for peripheral nerve injury, and 11 for HIV-related peripheral neuropathy. Despite their analgesic effect, the use of opioids is controversial, and they should be used as an adjunct second or third therapy, if at all. Several reviews have shown no evidence for using hydromorphone, fentanyl, morphine, or buprenorphine. , , , Combination therapy with gabapentin and opioids may provide better pain relief than gabapentin or opioids alone but is associated with higher rates of side effects.
Tramadol has been shown to be effective in the treatment of painful polyneuropathy with an NNT of 3.5 (2.4–6.4) and in the treatment of postherpetic neuropathy with an NNT of 4.8 (2.6–27), with a combined etiologies NNT of 3.9 (2.7–6.7). , , Tapentadol is a newer weak µ-receptor agonist and norepinephrine reuptake inhibitor. Its mechanism of action is slightly different from that of tramadol, with stronger noradrenaline reuptake inhibition and nearly no effect on serotonin reuptake. It is the first opioid that is FDA-approved for painful diabetic peripheral neuropathy. However, tapentadol efficacy remains inconclusive. Anti-convulsants, such as lamotrigine, carbamazepine, topiramate, and sodium valproate, and N-Methyl-d-aspartate antagonists have been suggested. Nevertheless, no clear benefit was demonstrated, with a relatively higher number of side effects.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here
