Diabetic Neuropathy

Introduction

Background: Diabetic neuropathy is the most common complication of diabetes mellitus (DM), both types 1 and type 2. Of all complications of diabetes, neuropathy causes the greatest morbidity, and it decreases the patient's quality of life (QOL). Symptoms of neuropathy may be highly unpleasant for individuals affected, but development of secondary complications (e.g., foot ulcers, cardiac arrhythmias) leads to amputations and death in patients with DM. Diabetic neuropathy is a heterogeneous syndrome affecting different regions of the nervous system separately or in combination.

Several classifications of diabetic neuropathy are recognized. The following list offers the simplest summary of classifications (by Thomas, with slight modifications).

Symmetric polyneuropathy

… Sensory

… Sensorimotor

… Autonomic neuropathy

o Cardiovascular autonomic neuropathy

o Gastrointestinal neuropathy

o Genitourinary neuropathy

o Sudomotor neuropathy

… Symmetric lower limb polyneuropathy - Diabetic amyotrophy

… Focal and multifocal neuropathies - Ischemic (e.g., entrapment)

Understanding of the classifications becomes easier with a review of the anatomy of the peripheral nervous system. Peripheral neurons can be categorized broadly as motor, sensory, or autonomic.

… Motor neurons originate in the central nervous system (CNS) and then go to the anterior horn of the spinal cord. From the anterior horn, they exit the spinal cord (via ventral roots) and combine with other fibers to go through the brachial or lumbar plexus and innervate their target organs through peripheral nerves.

… Sensory neurons originate at the dorsal root ganglia (which lie outside the spinal cord) and follow a similar course with motor neurons. Sensory neurons are subdivided into categories according to the sensory modality they convey (see Table 1).

… Autonomic neurons consist of sympathetic and parasympathetic types. In the periphery, preganglionic fibers leave the CNS and synapse on postganglionic neurons in the sympathetic chain or in sympathetic ganglia.

Table 1.

Fiber Type	Size	Modality
A-alpha (I)	13-20 micrometers	Limb proprioception, myelinated
A-beta (II)	6-12 micrometers	Limb proprioception, myelinated, vibration, pressure
A-delta (III)	1-5 micrometers	Mechanical sharp, myelinated
C (IV)	0.2-1.5 micrometers	Thermal pain, unmyelinated, mechanical burning pain

Sensory neuropathy usually is insidious in onset and shows a stocking and glove distribution in the distal extremities. Sensorimotor neuropathy involves both sensory and motor function where pain, numbness, and paresthesias occur along with decreased strength in the lower limb muscles. The feet of patients with DM often become insensate and are highly susceptible, not only to ulcers, but to the Charcot foot (a foot that loses its structure secondary to trauma and acute arthropathy) from frequent and multiple trauma. Autonomic neuropathy involves the cardiovascular system, gastrointestinal system, and the genitourinary system.

Diabetic amyotrophy affects the proximal lower extremities and leads to muscle atrophy and weakness. The focal and multifocal neuropathies can be separated into ischemic (presumed) and entrapment neuropathies. The ischemic focal neuropathies can occur after a single acute event of ischemia to a single blood vessel or group of blood vessels that serve a single nerve or group of nerves. Cranial nerve palsies, such as oculomotor neuritis and Bell palsy, are sudden and asymmetric and generally are self-limited. Diabetic amyotrophy also can be classified under focal neuropathy because primarily the femoral nerve or upper lumbar plexus is affected. Entrapment neuropathies are more gradual in onset and usually are asymmetric. These disorders occur more frequently in the diabetic population than in the general population. Entrapment neuropathies include carpal and cubital tunnel syndromes and meralgia paresthetica. Table 1 above demonstrates that the smaller fibers are affected first in DM, and, with continued exposure to hyperglycemia, the larger fibers become affected.

Pathophysiology: The cause of diabetic neuropathy continues to be studied in both basic and clinical sciences. Thus far, it is known that diabetic neuropathy is multifactorial and that there is a large basis for prevention. Both basic science research and large prospective clinical studies, such as the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetic Study (UKPDS) have shown that tight control and euglycemia (or near euglycemia) can prevent the onset or slow progression of diabetic neuropathy.

Currently, the factors recognized in the pathogenesis of diabetic neuropathy are metabolism, vascular insufficiency, loss of growth factor trophism, and autoimmune destruction of small unmyelinated nerves (C fibers) in a visceral and cutaneous distribution. The 2 main features that explain symptoms and complications of diabetic neuropathy are believed to be the degeneration of nerve fibers and grossly diseased blood vessels that supply those nerve fibers. Proper circulation determines whether or not nerve fibers repair themselves or proceed to total degeneration.

Metabolic failure can affect several pathways, greatly contributing to diabetic neuropathy. Hyperglycemia causes several biological changes, including an increase in the production of advanced glycosylated end products, a defect in the polyol pathway and involvement of aldose reductase enzyme, and impaired resistance to oxidative stress. All the above biological changes are closely related and work together to bring on the neuropathic complications.

Glucose is converted to sorbitol in cells by the aldose reductase enzyme. In hyperglycemia, sorbitol accumulates and results in the swelling of cells and increase activity of protein kinase C, which is implicated in the damage of blood vessels by increasing basement membrane synthesis and vascular permeability. This sorbitol accumulation also results in a decrease in the intracellular levels of myoinositol (an important membrane component) and taurine to the end point that they become rate limiting for intracellular metabolism. Nonspecific glycosylation of axon and microvessel proteins may cause reduction of endoneural blood flow and nerve ischemia, causing nerve and ganglia hypoxia and oxidative stress.

Derangement of the polyol pathway and vascular ischemia converge through oxidative stress. The conversion of glucose to sorbitol and sorbitol to fructose results in the depletion of reduced nicotinamide adenine dinucleotide (NADPH) and oxidized nicotinamide adenine dinucleotide (NAD+) stores in the cell, making the cell more vulnerable to reactive stresses. Ischemia induces reactive oxygen species, so the increase in these and the increase in vulnerability causes nerve injury. These processes are the basis of antioxidant therapy.

Another factor involved in the pathogenesis of diabetic neuropathy is the need for nerve regeneration after injury. Recent studies have suggested that loss of neurotrophic support contributes to the pathogenesis. Neurotrophic factors are proteins that promote the development, survival, and maintenance of specific neuronal populations. Sensory neuropathy involves the smallest nerve fibers (C fibers). These small nerve fibers are supported by neurotrophic factor and nerve growth factor (NGF); hence, there is active research on this factor. Several studies have demonstrated that levels of NGF are reduced significantly and its action is impaired.

Other factors implicated in diabetic neuropathy are neurotrophin-3 and insulin growth factors. Autoimmune damage has been postulated, and one study demonstrated that serum autoantibodies against sulfatide and phospholipid in patients with type 2 DM were higher in patients with documented neuropathy than in those with no neuropathy. In summary, etiology of neuropathy is multifactorial. Therapy for patients with diabetic neuropathy needs to encompass these factors to increase the yield of a successful treatment.

Frequency:

… In the US: Diabetic neuropathy occurs in 10-20% of patients newly diagnosed with DM, and its prevalence is up to 50% in elderly patients with DM. Most studies agree that the overall prevalence of symptomatic diabetic neuropathy is approximately 30% of all patients with DM. The incidence of diabetic neuropathy is 2% of the general population. Diabetic neuropathy is more common in smokers, people older than 40 years, and those who have uncontrolled diabetes.

… Internationally: Diabetic neuropathy is found around the world in 20-30% of individuals with type 2 DM. This number depends on the type of fiber that is being sensed and the sensitivity of the measure. Individuals with type 1 DM usually develop neuropathy after more than 10 years of living with DM.

Mortality/Morbidity: Mortality increases in people with cardiovascular autonomic neuropathy (CAN). The overall mortality rates over periods up to 10 years were 27% in diabetic patients with CAN detected, compared to 5% mortality in those without evidence of CAN. Morbidity results from foot ulceration and lower extremity amputation. These 2 complications are the most common causes of hospitalization among diabetics in Western countries. Severe pain, dizziness, diarrhea, and impotence are common complaints and symptoms that decrease the QOL of a patient with DM.

Race: Members of minority groups (e.g., Hispanics, African Americans) have more secondary complications from diabetic neuropathy, such as lower extremity amputations, than whites. They also have more hospitalizations for neuropathic complications.

Sex: DM affects men and women equally. Neuropathic pain causes more morbidity in females than in males.

Age: Diabetic neuropathy is more common in elderly patients. Up to 50% of patients with type 2 DM have peripheral neuropathy.

Clinical

History: Diabetic neuropathy is more common in patients with a longer duration of DM. Symptoms can vary significantly.

Gastrointestinal neuropathy

… Dysphagia

… Abdominal pain

… Nausea/vomiting

… Malabsorption

… Fecal incontinence

… Diarrhea

… Constipation

Cardiovascular autonomic neuropathy

… Persistent sinus tachycardia

… Orthostatic hypotension

… Sinus arrhythmia

… Decreased heart variability in response to deep breathing

… Valsalva maneuver

… Changing positions from supine to standing

Bladder

… Poor urinary stream

… Feeling of incomplete bladder emptying

… Straining to void

Sudomotor neuropathy

… Heat intolerance

… Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities

… Gustatory sweating

Mononeuropathy

… Cranial nerves III (oculomotor), VI (abducens), and IV (trochlear) cranial nerve

… Diplopia and eye pain

… In third nerve palsy secondary to diabetic neuropathy, pupil usually is spared.

… Seventh nerve palsy

… Bell palsy

Risk factors

… Advanced age

… Hypertension

… Long duration of diabetes

… Poor glycemic control

… Dyslipidemia

… Smoking

… Heavy alcohol intake

… HLA-DR æ phenotype

… Tall height

Symptoms

Peripheral neuropathy

… Dysesthetic pain (usually glove and stocking distribution)

o Burning sensation

o Skin tingling

o Allodynia - Painful sensation on contact with something that typically would not hurt (e.g., bed sheets)

o Hyperalgesia - Abnormally exaggerated response to painful stimuli

Paresthetic pain

… Sensation of pins and needles

… Electric shocklike sensation

… Numbness and aching

… Knifelike pain

… Sensation like feet have been in ice water

… Shooting and lancinating pain

Muscular pain

… Dull ache

… Night cramps

… Bandlike sensation

… Drawing sensation

… Deep aches

… Spasms

… Toothachelike pain

Physical:

Peripheral neuropathy

… Pinprick

… Proprioception

… Reflexes (ankle)

… Vibration (128 Hz tuning fork) at base of great toenail

… Monofilament (5.07) sensory; larger fibers

… Check dorsal pedal and posterior tibial pulses.

… Check for dryness, tinea pedis, cracks, onychomycoses, foot deformities, acute erythema and tenderness, and fluctuance under calluses.

The absence of perception of 128 Hz tuning fork or inability to feel a 10 g (5.07) monofilament on plantar surfaces of the foot identifies patients who are at increased risk (60% in next 3 years) of developing a foot ulcer. The 2 tests should be performed at least every year.

Cardiovascular autonomic neuropathy

… Measure blood pressure and heart rate while the patient is supine and standing.

… Have the patient breath 6x/min while monitoring heart rate in a continuous strip.

… Measure the longest R-R interval during expiration and shortest R-R interval during inspiration.

… Take the average of 6 breaths.

… The SA ratio is R-R expiration/RñR inspiration.

… The normal response is 1:2.

Differential Diagnosis

Other Problems to be Considered:

Peripheral neuropathy

Pernicious anemia
Vitamin B-6 intoxication
Isoniazid
Alcoholism
Uremia
Chemical toxins
Nerve entrapment and compression

Cardiovascular autonomic neuropathy

Myocardial infarction
Volume depletion
Drugs

Gastrointestinal neuropathy

Gastrointestinal malignancy
Peptic ulcer disease
Postsurgical vagotomy
Electrolyte imbalance

Bladder dysfunction

Bladder outlet obstruction

Mononeuropathies

Vasculitides
Acromegaly
Coagulopathies
Hypothyroidism

Workup

Lab Studies:

… Fasting plasma glucose and hemoglobin A1c represent the most important screening tool; the follow-up is glycemic control.

… Complete blood count

… Perform a hematology screen to check for anemia.

… Sequential multiple analysis-7 (SMA7) to check renal function and electrolyte imbalances

Imaging Studies:

… Imaging studies rarely help the physician diagnose or manage diabetic neuropathy. The following studies can be considered:

o Scintigraphic techniques to detect and quantify CAN (for research purposes)

o Radiolabeled analogs of norepinephrine, 133I - Metaiodobenzylguanidine (MIBG), and 11C hydroxyephedrine

o Adrenergic nerve terminals of the heart actively take up these compounds. Combining this technique with single photon emission computed tomography (SPECT) allows detection of decreased innervation of the heart.

… Laser Doppler: Skin blood flow is measured by continuous laser Doppler assessment in response to several stimuli.

… Microdialysis: Probes are inserted into the dermis (with an ISO-NO Mark II oxide meter, a microsensor that measures nitric oxide release from single cells).

Other Tests:

… Nerve biopsy: A biopsy can be performed to confirm and help diagnose the neuropathic stage (i.e., mild, moderate, severe).

… Nerve conduction studies (NCS) and electromyography (EMG) can document the characteristics of the neuropathy (axonal, demyelinating) and the localization (mononeuropathy versus radiculopathy or distal neuropathy).

… Electrocardiogram

o Prolongation of QT interval

ß Secondary to imbalance between right and left sympathetic innervation

ß This abnormality is thought to increase risk of arrhythmias.

… Skin biopsy - For research purposes only

o Skin biopsy is used to assess small caliber nerve fibers (C fibers). These fibers are responsible for pain and temperature sensation.

o This tool is new for clinical research, and it is used as an endpoint in diabetic neuropathy.

Procedures:

… No procedures are performed for diabetic neuropathy.

Histologic Findings: Biopsy rarely is recommended for clinical purposes. This study is performed primarily when the etiology of the neuropathy is in question or in research settings. Several studies have looked at biopsies, mainly of the sural nerve in humans. These studies basically were performed in advanced neuropathy, and vessels were found to be thickened and nerves were found to have undergone severe damage. Indications of nerve regrowth were small and weak.

Treatment

Rehabilitation Program:

…

… Physical Therapy: Physical therapy may be a useful adjunct to other therapy, especially when muscular pain and weakness are a manifestation of the patient's neuropathy. The physical therapist can instruct the patient in a general exercise program to maintain his/her mobility and strength. The patient also should be educated on independent pain management and relaxation strategies to assist with pain control. Transcutaneous electrical nerve stimulation (TENS) may be a recommended modality for patients with neuropathic pain, and the physical therapist can be helpful in teaching and monitoring the patient in its use. In a case report, DL Somers and MF Somers found that application of TENS to the skin of the lumbar region was an effective treatment for the pain of diabetic neuropathy, but there are no controlled studies to confirm this finding. In cases of foot ulcers, physical therapy may be indicated for wound care. Treatments may consist of whirlpool, Una boots (if necessary), and debridement.

…

… Occupational Therapy: Occupational therapy may be necessary in cases where a person loses a limb due to secondary complications and needs functional training to regain his/her independence.

…

… Speech Therapy: Involvement of a speech therapist rarely is indicated, but professionals from this discipline can help with patients affected by gastroparesis or dysphagia.

…

… Recreational Therapy: A recreational therapist may help the patient with performance of community activities.

Medical Issues/Complications: The main secondary complications of diabetic neuropathy are foot ulcers and leg amputations. When a foot ulcer shows signs of infection (thick yellow drainage, erythema around the wound, fever, necrotic tissue), the patient would fare much better by being admitted to a hospital, having the extent of infection assessed (e.g., with MRI), and receiving IV antibiotics and foot debridement (if necessary). Intravenous antibiotics should have broad coverage for aerobic bacteria, and, if the foot ulcer is chronic or recurrent, coverage should include anaerobes as well.

Surgical Intervention: Surgical intervention is indicated in the following cases:

… Infection is not controlled in foot ulcers. Either an aggressive debridement or an amputation may be necessary if signs of necrosis or infection do not improve with IV antibiotics.

… In cases of intractable gastroparesis (i.e., severe nausea and vomiting, severe weight loss), a jejunostomy may be performed to feed the patient nutrients, bypassing the paralytic stomach.

… When impotence is a continual problem, the patient may pursue the option of a penile prosthesis.

Consultations:

… Neurology consultation should be recommended for any neuropathy that is not managed quickly by the primary care physician.

… Cardiology should track the patient who has electrocardiogram abnormalities and/or suggestion of CAN.

… Gastroenterology can track cases of intractable GI problems, such as gastroparesis and diarrhea, as well as in the following instances:

o A question remains relative to the diagnosis.

o The patient does not tolerate first-line medications.

o Even with glycemic control, the patient continues to experience severe neuropathy.

Other Treatment (injection, manipulation, etc.): In cases of severe pain, other methods of pain control may be necessary, such as epidural catheters.

Medications

Diabetic neuropathy can be grouped into 3 specific categories (i.e., painful peripheral neuropathy, cardiovascular autonomic neuropathy, diabetic enteropathy) to simplify treatment. Based on the category, an appropriate treatment regimen can be implemented.

In painful peripheral neuropathy, the acute phase typically occurs in people with intermediate duration of diabetes. The condition has an acute onset and has a pain duration of less than 12 months. This acute phase usually is self-limited.

The first line of therapy for this type of neuropathy is tight glucose control and simple analgesics (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen). Newer NSAIDs such as the Celebrex (COX-2 inhibitor), which selectively inhibits cyclo-oxygenase-2 and reduces prostaglandin synthesis, may be tolerated better in patients who are more likely to have gastrointestinal side effects. As yet, these drugs have not been studied in diabetic peripheral neuropathy.

Chronic painful neuropathy typically occurs in people with intermediate duration of DM. This type of neuropathy usually has an insidious onset, and the pain duration is greater than 12 months. This problem may persist for years, and there may be relapses. First line of therapy can be tried initially, but it may not be enough to decrease the pain or symptoms. Treatment is often very difficult.

Grouping the type of pain can direct the course of therapy. Dysesthetic pain (refer to symptoms in Clinical section) can be relieved with capsaicin cream applied qid. The problem with this cream is that it may cause pain at the beginning of applications; patients need to be made aware of this potential effect. Additionally, very few patients comply with the frequent dosing, and the cream is messy on socks and shoes. Gabapentin also has been reported to work in the treatment of dysesthetic pain.

The next type of pain is paresthetic pain. Tricyclic antidepressants, such as imipramine and amitriptyline, have been shown to be efficacious in randomized controlled trials. Mexiletine, an orally active local anesthetic agent structurally related to lidocaine, also has been used with fair success in this kind of painful neuropathy. Carbamazepine and serotonin selective reuptake inhibitors (SSRIs) also have been used, but SSRIs seem to work only in depressed patients.

For patients with muscular pain, simple stretching exercises and proper footwear can help relieve pain. Occasionally, muscle relaxants may be of benefit in the first 2 weeks of therapy.

Each type of pain or a combination of pain types should be treated. Reevaluation of the painful neuropathy should be performed every 6 weeks. Every effort should be made to taper and eventually to stop therapies. Therapies may need to be reinstated at later dates if symptoms flare up. Most important is glucose control and a near euglycemic state; of course, this state may be difficult to achieve in the very elderly patient.

Teach patients with autonomic dysfunction of the gastrointestinal tract to eat very small meals several times a day. In severe cases, reducing the dietary fiber to near zero may improve symptoms. Medications for gastroparesis are Reglan and erythromycin.

Diabetic diarrhea is a diagnosis of exclusion and can be very difficult to control. A high fiber diet, along with diphenoxylate (Lomotil), loperamide (Imodium), or clonidine, can be helpful. Small bowel stasis contributes to bacterial overgrowth, causing diarrhea. Antibiotic treatment is recommended for a period of 2 weeks. Bacterial overgrowth does not have to be proven; it is prudent to treat the condition empirically. Doxycycline, amoxicillin, metronidazole, and ciprofloxacin are choices for the treatment of diabetic diarrhea secondary to bacterial overgrowth of the small intestine.

In cases of neurogenic bladder, voiding every 3-4 h, combined with bethanechol 10-50 mg tid/qid may relieve symptoms.

Symptomatic orthostatic hypotension can be very troubling in patients with diabetic neuropathy. Increasing the patient's salt intake, along with use of compression stockings, may help. If these modalities do not improve symptoms, then fludrocortisone may help.

For diabetic impotence, several modalities may be used for treatment. Despite the choices, it is a very difficult condition to treat. All other causes of impotence must be excluded. Once the diagnosis has been confirmed, then drugs such sildenafil (Viagra) can be used (if not contraindicated in the patient) or older methods such as vacuum devices or intracavernosal papaverine injections. Referral to a urologist is suggested.

A promising near-future treatment for diabetic peripheral neuropathy is the antioxidant alpha-lipoic acid. Trials are ongoing now and results are expected to come out at the end of 2001.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) -- For use in the acute phase of painful neuropathy, along with glucose control, or for use as first-line therapy of painful peripheral neuropathy.

Drug Name	Ibuprofen (Motrin, Ibuprin) -- NSAIDs may help decrease inflammation caused with diabetic neuropathy. They also decrease pain.
Adult Dose	400-800 mg PO q6-8h prn with meals
Pediatric Dose	5-10 mg/kg PO q6-8h prn
Contraindications	Documented hypersensitivity; GI bleed, especially peptic ulcer disease; advanced renal disease
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in patients who potentially are dehydrated; long-term effects may lead to papillary necrosis of kidney, interstitial nephritis, proteinuria, and, occasionally, nephrotic syndrome

Drug Name	Naproxen (Naprosyn, Anaprox, Naprelan) -- For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which results in a decrease of prostaglandin synthesis.
Adult Dose	250-500 mg PO bid prn
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity, peptic ulcer disease, recent GI bleeding or perforation, and renal insufficiency
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Drug Category: Tricyclic antidepressants (TCAs) -- Tricyclic antidepressants are good for paresthetic pain, such as the feeling of pins and needles, electricity, numbness, and achy knifelike shooting pains.

Drug Name	Imipramine (Tofranil) -- This is the original TCA used for depression. These agents have been suggested to act by inhibiting reuptake of noradrenaline at synapses in central descending pain modulating pathways located in the brainstem and spinal cord.
Adult Dose	Start at 25 mg PO qhs; can increase up to 150 mg PO qhs
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; concurrent use of MAOIs; during acute recovery period of myocardial infarction
Interactions	Increases toxicity of sympathomimetic agents such as isoproterenol and epinephrine by potentiating effects and inhibiting antihypertensive effects of clonidine
Pregnancy	D - Unsafe in pregnancy
Precautions	May impair mental or physical abilities required for performance of potentially hazardous tasks; caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, or receiving thyroid replacement

Drug Name	Amitriptyline (Elavil) -- Analgesic for certain chronic and neuropathic pain.
Adult Dose	25 mg PO qhs initially; increase slowly to 100 mg PO qhs
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; patient has taken MAOIs in past 14 d; has history of seizures, cardiac arrhythmias, glaucoma, and urinary retention
Interactions	Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (e.g., cimetidine, quinidine) may increase levels; inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in cardiac conduction disturbances and history of hyperthyroidism, and renal or hepatic impairment; avoid using in elderly patients

Drug Category: Antiepileptic drugs (AEDs) -- The use of AEDs for the control of painful peripheral neuropathy has taken on great interest as a potential therapy. These drugs have been found to have analgesic effects to neuropathic pain. The pharmacology of these drugs involves blocking channels and inhibiting specific neuronic components.

Drug Name	Gabapentin (Neurontin) -- Excellent in treating pain described as dysesthetic, such as burning or pins and needles. Gabapentin should be used after all other first-line measures have been used without relief. This drug is a second-generation anticonvulsant. Gabapentin increases brain GABA levels, binds to alpha-2-delta subunit of voltage-gated Ca2 channel, and inhibits branched chain amino acid transferase.
Adult Dose	Administer gradually; not to exceed 3600 mg/d (in divided doses)
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity
Interactions	Antacids may reduce bioavailability of gabapentin significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe renal disease; patients should be advised that the drug may cause dizziness; driving is not recommended until patients become used to the effects of gabapentin

Drug Name	Carbamazepine (Tegretol) -- AED used mainly in partial seizures. Can be used in peripheral neuropathy as a third-line agent if all other agents fail to reduce or improve symptoms of diabetic neuropathy. First generation anticonvulsant. Slows the recovery rate of voltage-gated Na channels, minor Ca2+ channel antagonist effect, and it is related chemically to tricyclic antidepressants.
Adult Dose	100 mg PO bid initially; increase to 400 mg PO bid
Pediatric Dose	Not established; used in children with seizure disorders safely but has not been looked at for peripheral neuropathy treatment in children
Contraindications	Documented hypersensitivity; should not be used in patients with a history of previous bone marrow depression
Interactions	The simultaneous administration of phenobarbital, phenytoin, or primidone, or a combination of any 2, produces marked lowering of serum levels; the half-lives of phenytoin, warfarin, doxycycline, and theophylline are shortened significantly; concomitant use of erythromycin, cimetidine, propoxyphene, isoniazid, or calcium channel blockers has been reported to result in elevated plasma levels, resulting in toxicity in some cases; reliability of oral contraceptives in preventing pregnancy may be affected
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Warn patient about dizziness and hazards of driving or operating heavy machinery; patients should be made aware of potential hematologic problems; any fever, sore throat, ulcers in mouth, easy bruising, or petechial or purpuric hemorrhage should be reported immediately to a physician or patient should go to an emergency room for further evaluation; physicians should obtain complete blood counts prior to administration of the drug

Drug Category: Selective serotonin reuptake inhibitors (SSRIs) -- Serotoninergic antidepressants have had mixed reviews in the literature. Paroxetine and citalopram are reported to relieve painful sensory symptoms. Fluoxetine was found to relieve symptoms only in depressed patients.

Drug Name	Paroxetine (Paxil) -- SSRI that can be used in second-line or third-line treatment of painful diabetic neuropathy; good for patients who already are depressed.
Adult Dose	Initial dose is 20 mg PO qd; can increase to doses used for depression, if necessary
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; concurrent administration with MAOIs or administration within 14 d of discontinuing an MAOI
Interactions	Documented hypersensitivity; concurrent administration with MAOIs or administration within 14 d of discontinuing an MAOI
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Exacerbations of mania may occur; hyponatremia has been reported but improves once drug is discontinued; abnormal bleeding also has been reported, such as ecchymoses and purpura

Drug Name	Citalopram (Celexa) -- One of the newest antidepressants can be used as a second-line or third-line therapy in neuropathy resulting from paresthesia.
Adult Dose	20-40 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; concomitant use in patients taking MAOIs
Interactions	May be potentiated by azole antifungals, omeprazole, and macrolides; serotonin syndrome may be induced by buspirone, tramadol, MAOI, and nefazodone
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in DM and breastfeeding; cirrhosis, suicidal tendencies, and SIADH; common adverse effects include fatigue and sexual dysfunction

Drug Name	Fluoxetine (Prozac) -- One of the older SSRIs; found to relieve symptoms of painful diabetic neuropathy in depressed patients.
Adult Dose	20-40 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; concurrently taking MAOIs or took them in the last 2 wk
Interactions	Increases toxicity of diazepam and trazodone by decreasing clearance; also increases toxicity of MAOIs and highly protein-bound drugs
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in hepatic impairment and history of seizures; MAOIs should be discontinued at least 14 d before initiating fluoxetine therapy

Drug Category: Antiarrhythmic agents -- Mexiletine and lidocaine have been used in this drug class. Some intractable neuropathic pain states have been shown to improve with administration of these agents.

Drug Name	Mexiletine (Mexitil) -- An orally active local anesthetic drug structurally related to lidocaine. May operate by reducing spontaneous discharges from damaged primary small nerve fibers; recommended only in intractable cases; can be used for both dysesthetic and paresthetic pain.
Adult Dose	225-675 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; mexiletine is contraindicated in cardiogenic shock or in patients who have second-degree or third-degree AV block (without a pacemaker)
Interactions	Medications that decrease mexiletine levels include aluminum-magnesium hydroxide compounds, atropine, narcotics, hydantoin, rifampin, and urinary acidifiers; metoclopramide and urinary alkalinizers may increase mexiletine levels; cimetidine can either increase or decrease mexiletine levels; medications whose levels are increased by mexiletine include caffeine and theophylline
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	As previously noted, second-degree or third-degree AV block (without a pacemaker) is a contraindication; can be cautiously used in patients who have pacemakers and second-degree or third-degree block, in those with first-degree AV blocks, sinus node dysfunction, intraventricular conduction abnormalities, hypotension, or congestive heart failure (cardiology consultation is recommended before using this medication in any of these medical conditions); liver injury reported, particularly in conjunction with congestive heart failure or cardiac ischemia; monitor liver enzymes; rarely leukopenia or agranulocytosis has been seen; CBC should be monitored; convulsions have occurred in about 0.2% of patients on this medication, thus, caution is indicated if there is history of seizures; avoid other drugs, which significantly modify the pH of urine

Drug Category: Synthetic adrenocortical steroids -- Florinef is used in severely symptomatic orthostatic hypotension. Use if salt tablets and pressure stockings fail to alleviate hypotension.

Drug Name	Fludrocortisone Acetate (Florinef) -- Used to increase standing blood pressure. Acts to increase sodium retention and expand plasma volume.
Adult Dose	0.05 mg PO bid initially; increase to 0.1 mg PO bid
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity and systemic fungal infections
Interactions	Antagonizes effects of anticholinergics; rifampin, hydantoin, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Taper dose gradually when therapy is discontinued; caution in Addison disease, potassium loss, and sodium retention

Drug Category: Prokinetic agents -- Erythromycin, Cisapride, and Reglan are used to treat diabetic gastroparesis.

Drug Name	Erythromycin (E-Mycin, Erythrocin, Ery-Tab, EES) -- Macrolide antibiotic that duplicates the action of motilin and is responsible for the migrating motor complex activity, by binding to and activating motilin receptors. Intravenous administration of this drug enhances the emptying rate of both liquids and solids. Effect can be seen with oral erythromycin. Substitution of the enteric-coated form may be tolerated better by the patient.
Adult Dose	Initial: 250 mg PO 30 min ac
Pediatric Dose	Not established; weight-based dosing recommended; consult a gastroenterologist
Contraindications	Documented hypersensitivity and hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI side effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name	Cisapride (Propulsid) -- Widely used for gastroparesis. Facilitates release of acetylcholine from the myenteric plexus. Increases postprandial/postantral motility and appears to normalize fasting and fed gastric motor patterns.
Adult Dose	10-20 mg PO 30 min ac and hs
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; not to be used in patients with renal failure; may induce arrhythmias
Interactions	Ketoconazole inhibits metabolism of cisapride; can result in prolongation of QT interval on ECG; can accelerate gastric emptying and, therefore, reduce the absorption of certain drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Potential benefits should be weighed against risks prior to administration of cisapride to patients with conditions associated with QT prolongation and uncorrected electrolyte disturbances; gastroparesis may be responsible for poor diabetic control in some patients; exogenously administered insulin may begin to act before food has left the stomach and can lead to hypoglycemia because the action of the prokinetic influences the delivery of food to the intestines and, thus, the rate of absorption, insulin dosage or timing of dosage may require adjustment

Drug Name	Metoclopramide (Reglan, Maxolon, Clopra) -- Dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. Acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, which provides important antiemetic activity; side effects and tachyphylaxis are problems.
Adult Dose	10-30 mg PO 1 h ac and hs
Pediatric Dose	>6 years: 0.1 mg/kg 1h ac 6-14 years: 2.5 to 5 mg 1h ac
Contraindications	Documented hypersensitivity; should not be used in cases of gastric hemorrhage, mechanical obstruction, or perforation; contraindicated in patients with pheochromocytoma may cause hypertensive crisis; should not be used in epileptics or patients receiving other drugs that are likely to cause extrapyramidal reactions
Interactions	Antagonized by narcotics and by anticholinergic drugs; absorption of drugs may be diminished, whereas the rate and/or extent of absorption of drugs from small bowel may be increased
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Gastroparesis may be responsible for poor diabetic control in some patients; exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia; because the action of prokinetic effects influences the delivery of food to intestines and, thus, the rate of absorption, insulin dosage or timing of dosage may require adjustment