Volume 2, Number 5: May 1999

Evidence-based antiplatelet therapy: Secondary prevention of cerebral infarction with cilostazol

Nutritional Support in Hepatic Encephalopathy

Diabetic Neuropathy  - An Update

Evidence-based antiplatelet therapy: Secondary prevention of cerebral infarction with cilostazol (A multicenter, double-blind, placebo controlled, long term, randomized study: Cilostazol Stroke Prevention Study, CSPS)

Reference: Fumio Gotoh, Department of Neurology, School of Medicine, Keio University, Japan ; abstract from Satellite Symposium of "Antiplatelet Therapy Based on Evidence at International Stroke Society Regional Meeting , Yokohama, April 22, 1999

ABSTRACT:

Purpose: Cilostazol is an antiplatelet drug which increases the cyclic AMP levels in platelets via inhibition of the cyclic AMP phosphodiesterase. The purpose of the present study was to examine whether or not cilostazol can prevent the recurrence of cerebral infarction.

Subjects and Methods: In total, 1095 patients who had suffered from cerebral infarction 1 to 6 month prior to entering the trial were registered during a registration period of 4 years. Each patient was administered either 200 mg cilostazol or a placebo according to the design of double-blind randomization. The primary end point of the study was the recurrence of cerebral infarction.

Results: The recurrence of cerebral infarction was observed in 30 cases out of 526 patients with cilostazol (5.7%) and 57 cases out of 526 patients with placebo (10.8%). The recurrence rate per person-year was 0.0337 for cilostazol group and 0.0578 for placebo group. The difference between the two groups was statistically significant (p=0.0149) using Kaplan-Meier method. Further subgroup analysis showed that even in lacunar infarction group the recurrence rate was 0.0296 for the cilostazol group and 0.0525 for the placebo group and that the difference was statistically significant (p=0.0369). there was no difference in occurrence of intracranial hemorrhage or myocardial infarction between the two groups.

Conclusion: Cilostazol has preventive effect on the recurrence of cerebral infarction and is effective even in patients with lacunar infarction. There is no increase of the risk for cerebral hemorrhage by the administration of the drug.

Reference: Exp Neurol 1997 Aug;146(2):466-70

Abstract:

The preventive effects of combined or separate treatment for 10 weeks with an aldose reductase inhibitor, epalrestat (50
mg/kg/day), and a vasodilator, cilostazol (30 mg/kg/day), on nerve conduction deficits and morphometric alterations were
examined in streptozotocin-induced diabetic rats. The average motor nerve conduction velocities (MNCV) in the tail nerve of  the untreated diabetic (DM) group, the group treated with epalrestat (ES), the group treated with cilostazol (CZ), the group with both agents together (ES&CZ), and the normal control group were 34.7, 37.7, 39.3, 39.0 and 42.1 m/s, respectively. All treatments partially but significantly prevented a reduction in MNCV. The MNCV in the ES&CZ group was almost the  same as in the CZ group. In a morphometric study of the sural nerve, the DM group showed a reduction in the average  diameter of myelinated fiber and in occupancy (percentage of the fascicular area occupied by myelinated fibers), and a shift  in the diameter-frequency histogram to smaller diameters. Only the CZ group showed evidence of a partial but significant preventive effect on the decrease in occupancy. In the CS and ES&CZ groups, there was a significant tendency away from the shift of histograms to smaller diameters. The ES&CZ group did not show any fewer morphometric changes than the CZ group. Thus, there was no synergism between the effects of epalrestat and cilostazol on the development of experimental diabetic neuropathy. This finding may provide a useful clue to the mechanisms of action of ES and CZ in diabetic neuropathy

Materials and Methods:

10-week-old male Wistar rats were divided into five groups: untreated diabetic rats (DM group, n=8); diabetic rats treated with epalrestat, ( DM group, n=13) diabetic rats treated with cilostazol, (CZ group, n=13), diabetic rats treated with both ES and CZ (ES & CZ group, n=8) and a normal group (N group, n=7). Approximate daily doses of EZ and CZ were 50 and 30 mg/kg respectively. At the end of the experiment (10th week) all rats were sacrificed for nerve conduction studies of the tail nerve and morphometric studies of the sural nerve.

Results:

Eparestat and cilostazol had no effects on blood glucose levels. Motor nerve conduction velocity (MNCV) in treated groups (Es, CZ, ES& CZ) were significantly higher than in the untreated DM group 10 weeks after the study. Average diameter of myelinated fibers and the myelinated fiber occupancy for the sural nerve in DM group was significantly lower than those in the N group; those in the ES, CZ, and ES&CZ groups were intermediate between those in the DM and N groups.

Discussion:

In the nerve conduction study, treatment with ES and CZ had partial but significant preventive effects on the slowing of nerve conduction. The effects of CZ alone and ES+CZ were almost identical, and the effects seemed to be greater than that of ES alone.

CZ alone did significantly limit the decrease in occupancy, and CZ alone and ES +CZ significantly prevented the shift of histograms to smaller diameters.

No synergistic or additive effect was observed for epalrestat and cilostazol and this may explain the action via a common mechanism to exert an ameliorative effect on experimental diabetic neuropathy (EDN).

Many agents have been reported to have an ameliorative effect on the reduced nerve blood flow in EDN. These observations suggest that endoneural ischemia might be the most basic etiologic factor in the development of EDN.

It is important to clarify the pathogenesis of EDN to develop a successful therapy for human diabetic neuropathy. Experimental studies involving the combined administration of several agents with different pharmacologic actions should provide useful clues to the pathogenesis of diabetic neuropathy.

Nutritional Support in Hepatic Encephalopathy

Reference: Nutrition 1999;15:220-228.

Abstract:Hepatic encephalopathy (HE) is a syndrome of global cerebral dysfunction resulting from underlying liver disease or portal-systemic shunting. HE can present as one of four syndromes, depending on the rapidity of onset of hepatic failure and the presence or absence of preexisting liver disease. The precise pathogenesis is unknown but likely involves impaired hepatic detoxification of ammonia as well as alterations in brain transport and metabolism of amino acids and amines. The etiology of malnutrition in hepatic failure is multifactorial. nutritional deficits may be clinically manifest as marasmus or kwashiorkor, or both. Nutritional support in HE is directed towards reducing morbidity related to underlying malnutrition and concurrent disease. However, reaching nutritional goals is often complicated by protein and carbohydrate intolerance. The use of protein restriction who exhibit protein intolerance with standard feeding solutions or in patients who present with advanced degrees of encephalopathy.

HE typically presents as one of four major syndromes;acute hepatic encephalopathy, acute episodic hepatic encephalopathy, chronic portosystemic encephalopathy and subclinical or latent hepatic encephalopathy. Pathogenesis of HE is unknown but is likely to be multifactorial.

Alterations in substrate metabolism in liver failure
Carbohydrate
1. Decreased hepatic and skeletal muscle glycogen synthesis
2. Increased gluconeogenesis
3. Glucose intolerance and insulin resistance
Fat
1. Increased lipolysis
2. Enhanced turnover and oxidation of non-esterified fatty acids
3. Normal or increased ketogenesis
Protein
1. Increased catabolism
2. Enhanced peripheral utilization of BCAA
3. Decreased ureagenesis

Malnutrition is common in patients with cirrhosis.In alcoholic liver disease, malnutrition may approach 100% (33% severe) and in non-alcoholic cirrhosis ranges from 12 to 40%. Whether or not malnourished patients are more prone to develop HE has not been clearly established, but could be expected based on several factors.
1. Malnutrition tends to be more common in patients with advanced liver disease and HE is more likely in this group
2. Nutritional deficits such as decreased lean body mass and hypoalbuminemia could theoretically promote HE.

Approach to nutritional support of HE

1. Enteral feeding is preferred whenever possible due to significant risks of TPN
2. Vegetable protein diets containing more than 50g/d are poorly tolerated (flatulence, bloating, early satiety)
3. BCAA-supplemented solutions are anticatabolic and have a stimulatory effect on hepatic protein synthesis.

Specific recommendations

1. Patients with Grade 1-2 HE can initially receive general ( or vegetable protein) diets or tube feeding using standard enteral formulas.
2. Central or peripheral parenteral can be used to support patients in whom enteral feeding is contraindicated. or to supplement enteral nutrition in those with mild to moderate gastrointestinal dysfunction. Protein may be initiated at 0.5-0.6 g/kg/day and then advanced by 0.25-0.5 g/kg/day until the target level is reached or progression to grade 2 HE occurs. Target doses of 1.0-1.5 g/kg/day are reasonable.
3. Zinc supplementation with 600 mg/day (as zince acetate or zinc sulfate).

Diabetic Neuropathy  - An Update

Source: http://www.joslin.org/education/library/neuropathy.html

 Nerve damage resulting from chronically high blood sugars can be one of the most frustrating and debilitating complications of diabetes because of the pain, discomfort and disability it can cause, and because available treatments are not uniformly successful.

 Some patients find some relief from this nerve damage or neuropathy by keeping blood sugars as closely controlled as possible, getting regular exercise and keeping their weight under control. Using non-narcotic pain relievers consistently throughout the day - rather than waiting until nighttime when symptoms can become more severe - also seems to help if pain is the major symptom. Surprisingly, clinicians have found that certain antidepressants may be helpful and can take the edge off the pain of neuropathy as well.

 While pain or numbness in the legs or feet may be the most common complaint from people diagnosed with neuropathy, it is not the only symptom of this complication. Neuropathy can cause a host of different types of symptoms, depending on whether nerves in the legs, the gastrointestinal tract, or elsewhere in the body are affected. If you have any of these symptoms, neuropathy may be the culprit:
 

1.       inability to adequately empty the bladder of its contents, resulting in frequent infections;
2.       nausea, vomiting, abdominal fullness or bloating, diarrhea, or constipation;
3.       low blood pressure upon standing that causes fainting or dizziness;
4.       inability to lift the foot or new deformities of the foot, or foot ulcers;
5.       trouble achieving or maintaining an erection.

 While physicians have found some medications and other treatments that help ease these symptoms in some people, prevention continues to be the key. "Hemoglobin A1c readings that are above 8 percent cause concern that any diabetes complication, including neuropathy, may develop," says John Hare, M.D., medical director of Joslin's Affiliated Center's program. "The good news is that the Diabetes Control and Complications Trial shows that people who keep their blood sugars consistently in this healthful range can decrease their risk of nerve damage by over 50 percent. Getting diabetes under better control also may help limit the amount of damage caused by neuropathy once it's developed."

 If your doctor has told you that symptoms you have been experiencing are a result of neuropathy, you certainly have many questions. Here are some answers that may be helpful to you as you battle this complication.

 What are the different types of neuropathy?

 There are three broad types of neuropathy: sensory, autonomic and motor:

Sensory neuropathy (or peripheral neuropathy, usually just called neuropathy) affects the nerves that carry information to the brain about sensations from various parts of the body -  how hot or cold something is, what the texture of something feels like, the pain caused by a  sharp object or heat, etc. This is the most common form of diabetic neuropathy.

Autonomic neuropathy affects the nerves that control involuntary activities of the body, such as the action of the stomach, intestine, bladder and even the heart.
 
Motor neuropathy affects the nerves that carry signals to muscles to allow motions like walking and moving fingers. This form of neuropathy is very rare in diabetes.

 Sensory neuropathy can lead to pain, numbness or tingling in the extremities and, ultimately, an inability to feel heat, cold, pain or any other sensation in affected areas. Autonomic neuropathy can lead to impotence in men, bladder neuropathy (which means the bladder is unable to empty completely), diabetic diarrhea, or bloated stomach. Motor neuropathy can lead to muscle weakness.

 If you are diagnosed with neuropathy, your physician may use terms to describe the type that you have based on whether only one side of your body is affected (asymmetric) or both sides (symmetric). If only one kind of nerve is affected, your doctor may say you have mononeuropathy. If several nerves are affected, the term polyneuropathy may be used.

 Other terms may be used based on what parts of the body are affected:

      Distal Neuropathy - is a form of sensory neuropathy that affects the hands or feet. It can be asymmetric but is usually symmetric, and is the most frequently diagnosed type of neuropathy
      Femoral neuropathy -- is painful sensory neuropathy that centers in the thigh muscles. It can be asymmetric or symmetric.
      Diabetic amyotrophy - is motor neuropathy that affects the thigh nerves, with resulting  weakness often in addition to or instead of pain. It can be symmetric or asymmetric.
      Gastroparesis -- is autonomic neuropathy that affects the stomach, preventing it from  emptying normally. It can result in ulcer-like symptoms, vomiting, bloating, and poor absorption of food resulting in malnutrition and hypoglycemic episodes as food fails to be absorbed at the anticipated rate. High blood sugars can later result when the meal finally makes its way through the system.
      Diabetic diarrhea - is autonomic neuropathy that results in an erratic functioning of the small intestine. This can cause unformed stools to be passed. If the nerves which communicate with the sphincter muscles (which control passing a bowel movement) are not working properly, stool can pass without warning, and/or without being able to control when it comes out, resulting in fecal incontinence. Constipation also can result when the large  intestine is involved and the stool remains in the large intestine too long. Bladder neuropathy - occurs when the bladder nerves no longer respond normally to pressure as the bladder fills with urine, and do not enable the bladder to empty completely.  Some urine continually stays in the bladder, leading to urinary tract infections. Symptoms of this problem include cloudy urine, painful urination, low back pain and fever.
      Postural hypotension - is autonomic neuropathy that results in low blood pressure when standing. In people with postural hypotension, the pulse does not go up to compensate for the change in blood pressure, so fainting and dizziness can result.
      Charcot joint- is also called neuropathic arthropathy and occurs when the bones in the feet fracture or "powder" and the foot becomes misaligned. The foot becomes deformed as a result of the lack of nerve stimulation, which causes the muscles to lose the ability to support the foot properly. Walking makes it worse. People who already have neuropathy in their feet and have lost sensation are at a greater risk of developing this.
      Unilateral foot drop - occurs when the foot can't be picked up because a nerve in the leg has been damaged either by blood vessel disease or compression.
      Impotence - is caused by autonomic neuropathy and/or sensory neuropathy, and/or blood vessel disease that leads to an inability to have and maintain an erection in men.

 What is peripheral neuropathy and what causes it?
 Peripheral neuropathy (more commonly called neuropathy) is a general term for diseases that cause damage to the nerves outside of the brain and spinal cord. While diabetes is a frequent cause of neuropathy, it is not the only cause. Nutritional deficiencies (B-12 and folate), chemical exposures, pressure on nerves, or medications (such as some of those used for chemotherapy or to treat AIDS), can also cause neuropathy.

Theories abound as to why exactly neuropathy occurs in people with diabetes. In general, diabetic neuropathy is thought to be a result of chronic nerve damage caused by high blood sugars. "There are many possible ways this might happen," says Dr. Hare. "Nerves are surrounded by a covering of cells, just like an electric wire is surrounded by insulation. The cells surrounding a nerve are called Schwann cells. One theory suggests that excess sugar circulating throughout the body
 interacts with an enzyme in the Schwann cells, called aldose reductase. Aldose reductase transforms the sugar into sorbitol, which in turn draws water into the Schwann cells, causing them to swell. This in turn pinches the nerves themselves, causing damage and in many cases pain. Unless the process is stopped and reversed, both the Schwann cells and the nerves they surround die."

 Another theory is that certain intracellular metabolites, such as myoinositol, become depleted, leading to nerve damage. Still other theories hold that pathways such as the protein kinase C pathway, being studied by George King, M.D., and his colleagues at Joslin, are triggered by chronic high blood sugars, resulting in several diabetes complications, perhaps including neuropathy.

 "Recent studies have suggested that decreased blood flow to the nerves can also contribute to the development of diabetic nerve disease," says Dr. King. There are multiple studies ongoing which are designed to improve blood flow to the nerves in diabetic animals and in patients. Two new categories of drugs being examined are called antioxidants and PKC inhibitors. Preliminary studies using these drugs have shown encouraging results in animal models of diabetes. Clinical trials are being planned and some are already in progress.

 How is neuropathy diagnosed?
 People may seek their doctor's help for treatment of pain, not knowing exactly what causes it. Men may come to the doctor concerned about a decreasing ability to have and maintain an erection. Increasingly frequent urinary tract infections may be another clue, as may be recurring diarrhea or constipation, or vomiting or symptoms resembling an ulcer. Fainting spells upon standing may indicate postural hypotension.

 A physician may detect early signs of neuropathy. He or she may notice that knee jerk and ankle jerk reflex tests show nerves aren't as responsive as normal, or may observe a dip in blood pressure when you go from a reclining to a sitting position. These are signs that increased attention to blood sugars are warranted to try and limit further problems.

 A variety of tests, including electromyography (a test that measures the response of muscles to electrical impulses) and nerve conduction studies (a study of the flow of electrical current through the nerves) combined with clinical observations may help a physician rule out other possible causes of pain, and diagnose neuropathy. To diagnose Charcot foot fracture, the doctor may take an x-ray and possibly do a bone scan.

 How is it treated?
 Unfortunately, there are no miracle cures or treatments for neuropathy, although a variety of treatments are often helpful. There is no way to heal or replace nerves that have been damaged.

The most important thing someone who has neuropathy can do is keep their blood sugar levels as close to normal as possible, exercise regularly, and make sure their weight is as close to what it should be as possible. This will help keep blood sugars closer to normal and limit the damage high blood sugars can cause to nerves. Exercise will have the added benefit of keeping muscles that may be weakened by decreasing nerve activity to remain strong and toned. Dr. Hare says he finds that patients with painful neuropathy say the pain seems less severe if they get some simple exercise regularly.

 Patients with painful neuropathy will try almost any kind of pain reliever their physicians will give them. "One can try a variety of non-narcotic pain killers," says Dr. Hare. "But one should stay away from the more powerful narcotics, which do not work very well for neuropathy, but will lead to addiction."

 Dr. Hare recommends acetaminophen (Tylenol®), aspirin and ibuprofen (Motrin ®, Advil ®, etc.) first. Pain medicines are best used regularly throughout the day, rather than waiting for pain to become severe. At that point, pain medicines are less able to stem the tide, says Dr. Hare. Some physicians recommend creams that contain capsaicin, an extract of the hot capsicum pepper (which includes red, cayenne and tabasco peppers) and can be rubbed on the skin over the pain. It is believed in some circumstances that these creams block pain signals, although they do not work for everyone - occasionally, they may even worsen the pain in some patients or cause other adverse effects, like eye or skin irritation. Be sure to check with your doctor before trying such products and follow application instructions carefully. Capsaicin, which has been approved by the Food and Drug Administration for treating pain, is available in over the counter topical salves that include
 ArthiCare® and Zostrix®.

 Certain antidepressants also seem to be particularly helpful for pain, says Dr. Hare. Elavil ® (amitriptyline), Norpramin® (desipramine) or Imipramine® are members of the tricyclic antidepressant category of drugs. These medications are not prescribed because the patient is depressed - "although having constant pain for months can be depressing," notes Dr. Hare. "Rather, it seems that the medications block the pain. Patients take them at night, and they have the effect of helping patients tune the pain out. When I prescribe them to patients, I explain that it's kind of like having a full bladder. If you aren't doing anything, you notice the full bladder and you feel the need to go to the bathroom right away. But if you're engrossed in a TV show, you don't notice it as much and can go for quite a while before going to the bathroom. These anti-depressants have largely the same effect on pain, helping patients notice it less. Because the pain is usually worse at night, patients take the medication at night and it seems to help them sleep. It also helps them with the depression and insomnia they may be experiencing as a result of the neuropathy."

 "Antidepressants can take several weeks to become effective, so I tell patients to give it a month before deciding whether it is helpful or not," says Dr. Hare. "These drugs can also cause dry mouth, which most patients find not to be much of a problem."

 Other types of drugs that sometimes help are anti-convulsants such as phenytoin (Dilantin®), carbamazepine (Tegretol®) or gabapentin (Neurontin®). Drugs such as mexiletine (Mexitil®) normally used to treat irregular heart rhythm, sometimes relieve neuropathy pain. Drugs like metaxalone (Skelaxin®) that generally depress the central nervous system can help reduce muscle pain. All of these drugs, however, can have such unpleasant side effects as dizziness or confusion when taken in large doses, especially by elderly patients.

 Many patients will ask their physician about the value of nutritional supplements or vitamins to ease pain. "If the neuropathy is caused by a vitamin deficiency, such as a B vitamin deficiency, taking B6 or B12 will help," notes Dr. Hare. "But if you're body is not deficient in these B vitamins, the vitamins will just go down the drain in your urine. You'll notice that your urine is a very bright yellow - but the treatment probably won't do you any harm. As for other nutritional supplements or
 vitamin treatments, there isn't anything that is widely accepted as being useful-unfortunately. But other vitamins that are not so easily passed through the urine can lead to vitamin toxicity. So you need to be careful that you aren't taking too much of any vitamin supplement in the distant hope of easing the pain."

 Some patients have experienced success will other forms of pain management - biofeedback, meditation, acupuncture, etc. "I don't discourage a person from trying any safe, non-drug approach to pain relief," says Dr. Hare. "What may not work for one person may work really well for someone else."

 For gastroparesis, in which the stomach is not emptying properly, physicians at Joslin may prescribe Reglan ® (metoclopramide) or Propulsid ® (cisapride), which will help the stomach push food and get it through the rest of the digestive process. These may be used in conjunction with Carafate ® (sucralfate) which "helps to sop up extra acid that may be sitting in the stomach," Dr. Hare says.

 A new drug to treat gastroparesis, or even to slow the development of gastroparesis in people who are beginning to have symptoms is now in clinical trials, notes Dr. Hare. This drug, called domperidone, seems to stimulate normal contraction of the stomach with fewer side effects than other agents and may be particularly beneficial to patients with diabetes, says Joslin Senior Physician James Rosenzweig, M.D. A large trial of domperidone in patients with diabetes, under Dr. Rosenzweig's direction, is currently under way at Joslin in Boston and at a number of affiliates for people with very mild symptoms of "diabetic stomach."

 For those experiencing bladder neuropathy, which results in the bladder never completely emptying, Urecholine ® may be prescribed. "This is a urine propellant that helps to keep the bladder clear," says Dr. Hare. "Because patients with this problem will be more likely to develop frequent urinary tract infections, the physician may also prescribe chronic antibiotic therapy to try and keep the bacterial count in the bladder and urinary tract at a manageable level."

 Impotence in men that is a result neuropathy or blood vessel damage (versus psychological causes or due to medications such as anti-depressants or blood pressure medication) can be treated using certain drugs that are either inserted into the end of the penis or injected to cause an erection before intercourse. Vacuum devices that enable an erection to be achieved, or a surgically implanted prosthesis are also options to be explored with a physician.

 The new drug Viagra is also an option, although patients should be sure to check closely with their physician before taking the drug. People with diabetes are more prone to heart and blood vessel disease than non-diabetics, and the use of Viagra leading to the resumption of sexual activity in individuals with underlying cardiovascular disease (diagnosed or undiagnosed) should be reviewed with a physician. Also, the use of Viagra with nitroglycerine tablets (a treatment for acute heart
problems such as angina or heart attack) has led to several reported deaths. Finally, there is an unproven suspicion that usage may affect retinal circulation (in addition to its known side effects).

 Patients with postural hypotension may be prescribed certain blood pressure raising medications or may benefit from support stockings to prevent pooling of blood in the legs. For patients with diabetes who also have high blood pressure, the process of balancing blood pressure lowering medications with medications that will keep blood pressure from dipping too low while reclining and then sitting up can be particularly tricky, and may require several adjustments to fine-tune.

 Charcot damage is addressed by avoiding putting any weight on the foot while it heals. The foot is usually put into a cast for a period of weeks to limit damage. Later, the patient wears special shoes. Surgery may be needed to restore a more normal shape to the foot.

 Some patients may remember a lot of talk in the late 1980s and early 1990s about a new class of drugs called aldose reductase inhibitors, which it was thought might be a significant breakthrough in treating some types of neuropathy. "Unfortunately, to date none of these drugs has proven to be sufficiently effective and side-effects have been a concern. As a result none have come to market to treat neuropathy yet, although companies are still working to develop them," says Dr. Hare.

 How can further problems be avoided?
 One of the major issues with neuropathy, particularly sensory neuropathy, is that eventually the affected nerves die, and the patient experiences a complete loss of sensation in the area. For this reason, if you have developed neuropathy in your feet and legs, you need to check your feet every day for cuts and other problems that you may no longer feel. You need to make sure your shoes are in excellent condition and don't have pebbles or rough spots in them that could damage feet without your knowing about it. If you have neuropathy, you should not use heating pads or electric blankets - you could be seriously burned without knowing it. You should be especially careful when taking baths to ensure that the water is not too hot, as it would be relatively easy to scald your feet or legs if they have become desensitized to pain.

 When will the pain end?
 "There's no easy answer to the question, 'when will the pain end?'," notes Dr. Hare. "Maybe if a patient gets their blood sugars under good control, that will be enough to ease the pain. If it doesn't, perhaps a daily regimen of Tylenol every few hours plus an anti-depressant at night and regular exercise every day will make the pain manageable. It can take up to two years for the pain of neuropathy - which is caused by ongoing damage to the nerve - to be replaced by the numbness that occurs when the nerve cells are more severely damaged. Our goal in the meantime is to identify ways to help patients manage the pain and discomfort of neuropathy, and to help patients lead as normal a life as possible despite the pain or other side-effects caused by this complication."