1. Diabetic Neuropathy : Clinical Manifestations and Management
Dr hezarkhani
Neurologist
frabi hospital

2. Diabetic Neuropathy
About 60-70% of people with diabetes have mild to severe forms of nervous system damage, including:
Impaired sensation or pain in the feet or hands
Slowed digestion of food in the stomach
Carpal tunnel syndrome
Other nerve problems
More than 60% of nontraumatic lower-limb amputations in the United States occur among people with diabetes.
Up to 70% of people with diabetes will experience nervous system damage in their lifetime. The pain and discomfort caused by diabetic neuropathy, at a minimum, contributes to a diminished quality of life. At it’s worst, diabetic neuropathy is a major contributing cause of lower-limb amputation. The next three slides will review the risk factors, pathogenesis, and diagnosis of diabetic neuropathy.

5. Diabetic Peripheral Nerve Damage

6. Myelinated Neuron

7. Incidence of Diabetic Neuropathy as a proportion of all diabetics 20 years after diagnosis

8. Risk Factors Glucose control Duration of diabetes
Damage to blood vessels
Mechanical injury to nerves
Autoimmune factors
Genetic susceptibility
Lifestyle factors
Smoking
Diet
There are several risk factors for developing diabetic neuropathy. Two of the main contributing factors are glucose control and duration of diabetes. Those who have had diabetes for at least 25 years and/or those who have had poor glucose control are at greatest risk of developing symptoms.
Mechanical injury can lead to compression of the nerves and cause disorders such as carpal tunnel syndrome and other compression neuropathies. Autoimmune dysfunction can cause inflammation of the nerves which can aggravate neuropathy. Inherited traits can increase susceptibility to nerve disease. Finally, lifestyle factors such as smoking and alcohol abise can cause blood vessel damage leading to nerve damage.

10. Underlying Mechanisms
Agreement not yet reached on exact causal relationship between insulin imbalance and nerve damage.
The relative importance and inter-relationship of the various mechanisms is the subject of ongoing research and debate.

11. Physical manifestations
Nerve fibres degenerate
Blood vessels supplying the nerves are ‘grossly diseased’
Any theory needs to account for both

12. Pathways of action Polyol pathway Triose phosphate effects
Failure of nerve growth & repair mechanism
Fatty acid metabolism

13. Polyol Pathway Polyol = Polyhydroxy alcohols High blood glucose
Nerve cell and capillary membranes have insulin-independent glucose transport.
High intra-cellular glucose levels
Conversion of glucose to sorbitol in nerve cells by aldose reductase enzyme
Sorbitol cannot cross membranes and therefore accumulates

14. Polyol Pathway Consequences of high sorbitol concentration:
Osmotic damage to nerve cells
reduction in nerve myoinositol
Inhibition of nitric oxide (NO) production
Aldose reductase competes for NADPH
NO is vasodilator
Increased production of free radicals
Superoxide, hydrogen peroxide, hydroxyl
Formed during mitochondrial respiration
Increased oxidative stress (proteins, lipids, DNA)

15. Polyol Pathway Treatment possibilities Aldose reductase inhibitors
Supplemental myoinositol
Nitric oxide stimulation/sensitisation
Vasodilators
Antioxidants

16. Triose phosphates
High intracellular glucose leads increased production of triose phosphates
Activation of protein kinase C (PKC) via DAG
Damages capillaries (permeability, contractility)
Damages nerve function
Non-enzymic reaction with proteins & DNA
Advanced Glycation End-products (AGEs)
Damage to capillaries and nerve fibres
Specific cellular AGE receptors
Protein cross-linking

17. Fatty acid metabolism Functions of DGLA and AA in nerves
Incorporated into membranes
required for normal nerve structure, which is required for normal nerve conduction
Required for regulation of nerve conduction
via inositol/calcium cycle and PGE1
Required for microvascular system
DLMG - Prostaglandin E1
AA - Prostacyclin

18. Pathogenesis of Diabetic Neuropathy
Metabolic factors
High blood glucose
Advanced glycation end products
Sorbitol
Abnormal blood fat levels
Ischemia
Nerve fiber repair mechanisms
The mechanisms by which diabetic neuropathy develops are still being researched. It is thought that neuropathy can be caused or aggravated by metabolic factors, ischemia, or impaired nerve fiber repair mechanisms.
High blood glucose levels have been correlated to increase risk of diabetic neuropathy, and there are several theories as to why this occurs. Patients with diabetes have increased levels of serum advanced glycation end products (AGEs). AGEs form when excess blood glucose combines with amino acids to form, initially, early reversible glycation products. Later, irreversible advanced glycation end products are formed. AGEs are thought to contribute to blood vessel injury due to their effects on increasing vascular permeability, blood coagulation, and their effects on collagen.
Glucose entering the cells is partially metabolized into sorbitol -this occurs even more so with hyperglycemia. Excess sorbitol leads to problems with cell metabolism, and could contribute to nerve damage in this way.
Nerve ischemia, or reduced nerve blood flow, is involved in the pathogenesis of diabetic neuropathy. Evidence of vascular occlusions and thickened endoneural blood vessel walls have been found in patients with diabetic neuropathy.
Finally, the nerve fiber repair mechanisms present in persons without diabetes are impaired in those with diabetes. Nerve growth factor and other neurotrophic factors are decreased in diabetes, which leads to a decreased ability to repair damaged nerves.

19. Natural history of diabetic neuropathy and clinical signs and symptoms with pathological background.
With increasing stage of neuropathy,
there is a progressive loss of nerve fibers that convey sensation.
When the fibers undergo degeneration or impaired remyelination, they release impulse of positive symptoms.
With progression of disease, negative symptoms of sensory loss are increased

20. Multifactorial etiology of diabetic neuropathy
Multifactorial etiology of diabetic neuropathy. Hyperglycemia exerts increased polyol pathway, enhanced AGE formation, increased
oxidative stress as well as cytokine release. These factors are complicatedly interactive or independently operate for the cause and development of
diabetic neuropathy directly affecting nerve tissues or through nutrient vascular tissues

21. Mechanisms of how polyol pathway causes neuropathy.
Increased polyol pathway affects differently nerve fibers and supplying vascular tissues. In nerve tissues, polyol yperactivity causes suppression of PKC activity by the inhibition of membranous PKC-a expression while it causes increased PKC activity by elevation of membranous PKC-b expression in vascular wall.
These dichotomous processes eventually elicit decreased Na,K-ATPase activity of nerve tissues and delay of nerve conduction

22. Pathological findings of sural nerve obtained from diabetic patients with clinically overt neuropathy.
There is a marked loss of myelinated
nerve fibers of both large and small caliber. Endoneurial vessels show typical microangiopathic changes exemplified by thickened wall (arrow) (A).
There is also a marked loss of unmyelinated fibers at EM level (B).

23. Diagnostic Tests
Assess symptoms - muscle weakness, muscle cramps, prickling, numbness or pain, vomiting, diarrhea, poor bladder control and sexual dysfunction
Comprehensive foot exam
Skin sensation and skin integrity
Quantitative Sensory Testing (QST)
X-ray
Nerve conduction studies
Electromyographic examination (EMG)
Ultrasound
There are several diagnostic tests that can be used to determine the presence and type of diabetic neuropathy. Reviewing the patients’ symptoms can help determine if neuropathy is present and to what extent. It is important to remember that all other potential causes of, for example, muscle weakness and numbness, be ruled out before making a diagnosis of diabetic neuropathy.
All patients with diabetes should receive an annual foot exam in which the foot is assessed for skin sensation using a monofilament (Semmes-Weinstein 5.07 (10-g)), skin integrity (calluses and sores, especially between toes), bone deformities or deformities in the foot’s structure or biomechanics, and vibration perception. Ankle reflexes should also be tested. Quantitative sensory testing (QST) (responses to pressure, vibration, and temperature) should be used to determine loss of sensation or sensitivity of nerves. X-ray can be used to verify bone deformities.
Nerve conduction studies can detect possible nerve damage by assessing the transmission of nerve impulses. Impulses that are slower or weaker than normal may indicate damaged nerves.
EMG, in conjunction with nerve conduction studies, can help determine if there is damage to muscle or nerve by assessing how well muscles respond to nerve impulses.
When autonomic neuropathy is suspected, ultrasound of internal organs such as the bladder can assist in determining if there is any abnormal function or structure to the organ. For example, does the bladder empty completely after urination?

24. Classification of Diabetic Neuropathy
Symmetric polyneuropathy
Autonomic neuropathy
Polyradiculopathy
Mononeuropathy
Most forms of diabetic neuropathy fall into one of four categories: symmetric polyneuropathy, autonomic neuropathy, polyradiculopathy, and mononeuropathy.
As their names imply, neuropathy can affect the sympathetic or autonomic nervous system, can affect one or more nerves, and can affect one or more sides of the body at one time.

26. Symmetric Polyneuropathy
Most common form of diabetic neuropathy
Affects distal lower extremities and hands (“stocking-glove” sensory loss)
Symptoms/Signs
Pain
Paresthesia/dysesthesia
Loss of vibratory sensation
Symmetric polyneuropathy is the most common form of neuropathy seen in diabetic patients. Symptoms generally begin distally in the toes and feet and move upward toward the calf. It is not uncommon for symptoms to also begin to appear in the hands, and the patient develops what is known as “stocking-glove” sensory loss.
Symptoms include pain, abnormal sensation in the affected areas, and loss of vibratory sensation. Thermal sensation is also affected.

27. Complications of Sensorimotor neuropathy
Ulceration (painless)
Neuropathic edema
Charcot arthropathy
Callosities

28. Treatment of Symmetric Polyneuropathy
Glucose control
Pain control
Tricyclic antidepressants
Topical creams
Anticonvulsants
Foot care
Symmetric polyneuropathy is treated with glycemic control, treatment of pain, and foot care.
The DCCT and other studies provide evidence that intensive glucose control is effective in both preventing the development of neuropathy and, to a lesser degree, improving neuropathic symptoms.
Pain can be treated with tricyclic antidepressants such as amitriptyline or desipramine. These drugs are contraindicated in patients with cardiac disease, and in these cases doxepin, trazodone, or paroxetine can be substituted. Nortriptyline can be substituted if cholinergic side effects are present. Topical pain relievers such as capsaicin cream can be added to the antidepressant regimen if pain persists. Anticonvulsants such as carbamazepine, gabapentin, and lamotrigine can be added to the pain relief regimen if the above remedies do not successfully alleviate pain.
Foot care is not only important in the treatment of diabetic neuropathy, it is necessary to prevent amputation. The essentials of foot care are covered in the next slide.

29. Essentials of Foot Care
Examination
Annually for all patients
Patients with neuropathy - visual inspection of feet at every visit with a health care professional
Advise patients to:
Use lotion to prevent dryness and cracking
File calluses with a pumice stone
Cut toenails weekly or as needed
Always wear socks and well-fitting shoes
Notify their health care provider immediately if any foot problems occur
Proper foot care consists of regular foot examinations by a physician to detect early neuropathy and treat existing lesions, as well as daily foot examinations by the patient. Patients should check for dry, cracking skin, calluses, and signs of infection between the toes and around the toenail.
The American Diabetes Association Clinical Practice Guidelines recommend that all individuals with diabetes receive an annual foot exam to identify high-risk foot conditions. This exam should include assessment of sensation, foot structure, vascular status, and skin integrity. Patients with neuropathy should have a visual inspection of their feet at every health care visit.

30. Autonomic Neuropathy Symptomatic Postural hypotension Gastroparesis
Diabetic diarrhea
Neuropathic bladder
Erectile dysfunction
Neuropathic edema
Charcot arthropathy
Gustatatory sweating
Subclinical abnormalities
Abnormal pupillary reflexes
Esophageal dysfunction
Abnormal cardiovascular reflexes
Blunted counter-regulatory responses to hypoglycemia
Increased peripheral blood flow

31. Autonomic neuropathy
Affects the autonomic nerves controlling internal organs
Peripheral
Genitourinary
Gastrointestinal
Cardiovascular
Is classified as clinical or subclinical based on the presence or absence of symptoms
Autonomic neuropathy can affect the limbs, the genitals and urinary tract, the gastrointestinal tract, or the heart. This form of neuropathy is classified as clinical or subclinical based on the presence or absence of symptoms.
The next five slides will review the four main categories of neuropathy affecting the autonomic nervous system.

32. Peripheral Autonomic Dysfunction
Contributes to the following symptoms/signs:
Neuropathic arthropathy (Charcot foot)
Aching, pulsation, tightness, cramping, dry skin, pruritus, edema, sweating abnormalities
Weakening of the bones in the foot leading to fractures
Testing
Direct microelectrode recording of postglanglionic C fibers
Galvanic skin responses
Measurement of vascular responses
Peripheral autonomic denervation can contribute to many different symptoms including changes in the texture of the skin, itching, edema, and sweating abnormalities in the feet. Peripheral autonomic dysfunction can also contribute to neuropathic arthropathy and fractures. Patients who already suffer from symmetric polyneuropathy are at greater risk for Charcot arthropathy. Patients should be aware of symptoms such as swelling, redness, heat, strong pulse, and insensitivity of the foot.
Peripheral autonomic dysfunction can be diagnosed using specialized techniques such as microelectrode recordings of postglanglionic C fibers. It can also be diagnosed using galvanic skin responses and quantitative sudomotor axon reflex testing (QSART) to measure the presence of sympathetic innervation in hands and feet Vascular responses can also be measured to determine peripheral sympathetic denervation. Constriction of the blood vessels in the presence of heat indicates vascular denervation

33. Peripheral Autonomic Dysfunction, cont.
Treatment
Foot care/elevate feet when sitting
Eliminate aggravating drugs
Reduce edema
midodrine
diuretics
Support stockings
Screen for CVD
Peripheral autonomic dysfunction therapy includes foot care, elimination of drugs that can aggravate symptoms (tranquilizers, antidepressants, diuretics), efforts to reduce swelling and promote blood flow. Patients with autonomic dysfunction in peripheral nerves should also be screened for cardiovascular dysfunction.
Foot care includes physician exams and patient daily examination as described in the previous slide.
Vascular denervation causes excess peripheral blood flow and edema. Diuretics, midrodrine, and ephedrine can be used to alleviate swelling, as can elevating the feet when sitting. Support stockings can promote blood flow as well.

34. Genitourinary Autonomic Neuropathy
Denervation of the genitourinary system can cause a number of symptoms, including bladder dysfunction, retrograde ejaculation, erectile dysfunction, and painful intercourse (dyspareunia) due to lack of vaginal lubrication.
Bladder dysfunction should be diagnosed with a cystometrogram. The inability to sense a full bladder can lead to bladder infections and urinary incontinence which can be treated by having the patient participate in a strict voluntary urination schedule. Catheterization can be performed in advanced cases.
Retrograde ejaculation is caused by a dysfunction in internal and external sphincter closure during ejaculation, and patients may present with cloudy urine postcoitally. This symptom can be successfully treated with antihistamines.
Erectile dysfunction can be caused by a number of factors other than diabetic neuropathy, and an attempt to discover the cause of impotence must be made prior to treatment. Sildenafil has been used successfully in treating men with impotence due to neuropathy.
Finally, painful intercourse, most common in diabetic women, is usually due to decreased libido, depression, and reduced vaginal lubrication. Treatment for sexual dysfunction in women includes use of vaginal lubricants and estrogen creams.

35. Gastrointestinal Autonomic Neuropathy
Symptoms/Signs
Gastroparesis resulting in anorexia, nausea, vomiting, and early satiety
Diabetic enteropathy resulting in diarrhea and constipation
Treatment
Other causes of gastroparesis or enteropathy should first be ruled out
Gastroparesis - Small, frequent meals, metoclopramide, erythromycin
Enteropathy - loperamide, antibiotics, stool softeners or dietary fiber
Neuropathy of the gastrointestinal tract can affect the esophagus, stomach and intestines causing pain, nausea, vomiting, diarrhea and constipation. Symptoms vary depending on which area of the digestive tract is affected.
Gastroparesis can cause anorexia, nausea, vomiting, early satiety, and postprandial fullness. Diagnosis can be confirmed by radiolabeled breath tests, radionuclide gastric emptying tests, ultrasonography or measurement of gastric impedence. Gastroparesis is treated by encouraging the patient to eat smaller, more frequent meals to prevent nausea. A dietitian should be consulted when designing a meal plan for someone with gastroparesis. Dompamine antagonists such as metoclopramide and domperidone can be used before meals to improve gastric emptying. Patients with gastroparesis and impaired absorption should be monitored for hypoglycemia.
Widespread neuropathy of the intestines can cause enteropathy, which can lead to diarrhea, constipation, or incontinence. Diarrhea can be caused by a number of factors in patients with diabetes, including bacterial overgrowth, poor intestinal motility, celiac disease, and other disorders. The cause of the diarrhea should be determined before treatment is initiated. Loperamide may be administered to treat intestinal motility disorders. Antibiotics can be used for bacterial overgrowth. Stool softeners and increased dietary fiber can be used to treat constipation.

36. Cardiovascular Autonomic Neuropathy
Symptoms/Signs
Exercise intolerance
Postural hypotension
Treatment
Discontinue aggravating drugs
Change posture (make postural changes slowly, elevate bed)
Increase plasma volume
Subclinically, cardiovascular autonomic neuropathy is diagnosed by cardiovascular reflex testing. Clinically, the disorder manifests itself in the form of an inability to exercise and postural or orthostatic hypotension. Exercise intolerance can be caused by impaired modulation of the sympathetic nerves leading to irregular heartbeat. Denervation of the heart muscle can also occur in advanced cases and is characterized by a fixed heart rate of beats per minute. In such cases, myocardial infarction can occur.
Postural hypotension is defined as a fall in systolic blood pressure in excess of 20mmHg when in an upright position.This condition is caused by a combination of central and peripheral cardiovascular sympathetic denervation. Hypertension can also occur at night when the patient is supine. Postprandial hypotension is not uncommon, and could be caused by a pooling of bloodin the abdomen.
Postural symptoms can be treated by discontinuing drugs which may aggravate the disorder, and by making slow rather than sudden changes in posture. Elevating the head of the bed at night can prevent hypertension. Another method of treatment is to cross the legs while standing, and “tense” the leg muscles to increase cardiac output.
Increasing the plasma volume of the blood with mineralocorticoid fludrocortisone and a high salt diet can be helpful in severe cases.

37. Polyradiculopathy Lumbar polyradiculopathy (diabetic amyotrophy)
Thigh pain followed by muscle weakness and atrophy
Thoracic polyradiculopathy
Severe pain on one or both sides of the abdomen, possibly in a band-like pattern
Diabetic neuropathic cachexia
Polyradiculopathy + peripheral neuropathy
Associated with weight loss and depression
Polyradiculopathy is a term used to describe nerve damage to nerve roots, normally lumbar and thoracic.
Lumbar polyradiculopathy is the most common type of polyradiculopathy. Damage to the L2, L3, and L4 nerve roots causes pain in the thigh followed by muscle weakness and wasting of the thigh muscle (hence this disorder is also called diabetic amyotrophy). The symptoms generally resolve themselves within six months to two years.
Thoracic polyradiculopathy is caused by damage to the T4 through T12 nerve roots, and results in abdominal pain which can occur in a band-like pattern around the abdomen. Both lumbar and thoracid polyradiculopathies can occur at the same time.
Diabetic neuropathic cachexia is a syndrome which results when polyradiculopathy and peripheral neuropathy occur simultaneously. Severe weight loss, wasting and muscle weakness result.

38. Polyradiculopathy, cont.
Polyradiculopathies are diagnosed by electromyographic (EMG) studies
Treatment
Foot care
Glucose control
Pain control
Patients should be diagnosed based on history, clinical examination, and electromyographic (EMG) studies.
Foot care, intensive glucose control, and treatment for pain are the three main elements of treatment for polyradiculopathy, similar to peripheral neuropathy.

39. Mononeuropathy Peripheral mononeuropathy
Single nerve damage due to compression or ischemia
Occurs in wrist (carpal tunnel syndrome), elbow, or foot (unilateral foot drop)
Symptoms/Signs
numbness
edema
pain
prickling
The two main types of mononeuropathy caused by diabetes are peripheral mononeuropathy and cranial mononeuropathy.
Mononeuropathies are caused by damage to a single nerve due to compression or vessel disease. Peripheral mononeuropathy occurs with damage to the peroneal nerve of the leg or damage to nerves affecting the wrist or elbow. Symptoms of both include numbness, swelling, pain and prickling sensations.

40. Mononeuropathy, cont. Cranial mononeuropathy Mononeuropathy multiplex
Affects the 12 pairs of nerves that are connected with the brain and control sight, eye movement, hearing, and taste
Symptoms/Signs
unilateral pain near the affected eye
paralysis of the eye muscle
double vision
Mononeuropathy multiplex
Cranial mononeuropathy affects the cranial nerves and most commonly affects those that supply the extraocular muscles. Symptoms include pain on one side of the face and near the affected eye, ptosis (drooping eyelid), double vision and paralysis of the eye muscle. Symptoms normally resolve within 2-3 months.
The occurrence of multiple mononeuropathies is known as mononeuropathy multiplex.

41. Mononeuropathy, cont. Treatment Foot care Glucose control Pain control
Treatment for mononeuropathy includes the three main elements previously described: foot care in the case of peripheral mononeuropathy, intensive glucose control, and treatment for pain.

42. Other Treatment Options
Aldose reductase inhibitors
ACE inhibitors
Weight control
Exercise
In addition to the treatment methods already discussed, there are some other forms of treatment that can assist in reversing or slowing the development of diabetic neuropathy.
In addition to lowering blood glucose, hyperglycemia can be minimized by administering an aldose reductase inhibitor to prevent sorbitol formation (which may play a role in diabetic neuropathy).
ACE inhibitors, which are known to improve symptoms of hypertension and intraglomerular pressure in patients with diabetes, have also been somewhat successful in treating peroneal and sural neuropathies in the leg.
The Steno type 2 trial showed that behavioral changes such as weight control, exercise, and smoking cessation along with pharmacological intervention can slow the rate of progression of autonomic neuropathy.

45. Anticonvulsant Drugs for Neuropathic Pain Disorders
Postherpetic neuralgia
gabapentin*
pregabalin *
Diabetic neuropathy
carbamazepine
phenytoin
gabapentin
lamotrigine
HIV-associated neuropathy
lamotrigine
Trigeminal neuralgia
carbamazepine*
oxcarbazepine
Central poststroke pain
Anticonvulsant medications have been used in the treatment of neuropathic pain for many years without FDA approval (except for carbamazepine’s indication for trigeminal neuralgia). Pregabalin, however, as of September 2004 has received approvable letters from the FDA for neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. The slide provides a summary of many of the controlled trials that have been conducted examining the efficacy of anticonvulsant drugs in the treatment of various neuropathic pain syndromes.1-7
The studies of carbamazepine and phenytoin conducted in the 1960s and 1970s do not meet today’s standards of methodological rigor.8 The phenytoin studies have produced both successful and unsuccessful results.9
The two studies of gabapentin are among the largest clinical trials of the treatment of neuropathic pain ever conducted.8,10 These studies have stimulated a great deal of clinical and research interest in the efficacy and mechanisms of action of anticonvulsant drugs in treating patients with neuropathic pain.
First-generation anticonvulsant drugs, which include carbamazepine and phenytoin, sometimes provoke serious side effects and drug-drug interactions that do not occur with second-generation anticonvulsants.11 We will be focusing on gabapentin because it is the anticonvulsive most commonly used for neuropathic pain and for which there is the most clinical data.
1. Rowbotham M et al. JAMA. 1998;280:
2. Eisenberg E et al. Neurology. 2001;57:
3. Simpson DM et al. Neurology. 2000;54:
4. Campbell FG et al. J Neurol Neurosurg Psychiatry. 1966;29:
5. Zakrzewska JM et al. Pain. 1997;73:
6. Zakrzewska JM et al. J Neurol Neurosurg Psychiatry. 1989;52:
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8. Rull J et al. Diabetologia. 1969;5:
9. Chadda VS et al. J Assoc Physicians India. 1978;26:
10. Backonja M et al. JAMA. 1998;280:
11. Ross EL. Neurology. 2000;55:S41-S46.
*Approved by FDA for this use.
HIV = human immunodeficiency virus.

46. Tricyclic Antidepressants: Adverse Effects
Commonly reported AEs (generally anticholinergic):
blurred vision
cognitive changes
constipation
dry mouth
orthostatic hypotension
sedation
sexual dysfunction
tachycardia
urinary retention
Fewest AEs
Desipramine
Nortriptyline
Imipramine
Doxepin
Amitriptyline
Adverse effects commonly reported with TCAs are anticholinergic effects, which are listed on the left side of the slide. The adverse effects include blurred vision, cognitive changes (such as concentration, memory loss, and confusion), constipation, dry mouth, orthostatic hypotension, sedation, tachycardia, and urinary retention. All TCAs are reported to cause these adverse events in varying degrees of frequency and severity.1,2
The TCA agents listed on the right side of the slide are organized in descending order of adverse effects, starting with desipramine (fewest adverse effects), nortriptyline, imipramine, doxepin, and amitriptyline (most adverse effects).2,3
Because of the potential for adverse events and outcomes, amitriptyline should not be prescribed for people older than 65 years. Desipramine would be more appropriate for this population. Of all the drugs that are inappropriate for the elderly, amitriptyline is one of most frequently prescribed.4
Because the TCAs appear to be almost equally efficacious, a rational approach for clinical practice is to start with the agents with the fewest adverse effects, unless a specific “side effect,” such as nighttime sedation, is desired.
1. Rowbotham MC, Petersen KL, Davies PS, et al. Recent developments in the treatment of neuropathic pain. Proceedings of the 9th World Congress on Pain. Seattle, Wash: IASP Press; 2000:
2. Mackin GA. Medical and pharmacologic management of upper extremity neuropathic pain syndromes. J Hand Ther. 1997;10:
3. Tunali D, Jefferson JW, Greist JH. Depression and Antidepressants: A Guide. Madison, Wis: Information Centers, Madison Institute of Medicine; 1999.
4. Piecoro LT, Browning SR, Prince TS, et al. Database analysis of potentially inappropriate drug use in an elderly Medicaid population. Pharmacotherapy. 2000;20:
Most AEs
AEs = adverse effects.

47. Principles of Opioid Therapy for Neuropathic Pain
Opioids should be titrated for therapeutic efficacy versus AEs
Fixed-dose regimens generally preferred over prn regimens
Document treatment plan and outcomes
Consider use of opioid written care agreement
Opioids can be effective in neuropathic pain
Most opioid AEs controlled with appropriate specific management (eg, prophylactic bowel regimen, use of stimulants)
Understand distinction between addiction, tolerance, physical dependence, and pseudoaddiction
Opioid therapy entails a number of risks for patients, but these potential problems can be prevented or circumvented.
Titration of opioid analgesics should be based on optimizing therapeutic efficacy while minimizing side effects. Regimens of fixed doses are generally preferred over prn regimens.1
Documentation is critical and should include the initial evaluation, substance abuse history, psychosocial issues, pain/pain relief, side effects, functional outcomes, and continuing monitoring. Regular discussions with family members about the patient’s condition and use of opioids can improve the accuracy of monitoring.1
The laws on patient monitoring vary from state to state, but the federal government regulates and legislates the use of controlled substances and drugs. Generally, federal laws have priority over state laws.2
Most opioid side effects can be controlled with appropriate specific management (eg, prophylactic bowel regimen, use of stimulants).3
Patients on opioids or those who appear to require them also have significant psychosocial rehabilitative issues and are generally best referred to a multidisciplinary center with experience managing chronic pain with opioids.1
Addiction is referred to by many as psychological dependence.
1. Pappagallo M. Aggressive pharmacologic treatment of pain. Rheum Dis Clin N Am ;25:
2. Clark HW. Policy and medical-legal issues in the prescribing of controlled substances. J Psychoactive Drugs. 1991;23:
3. Zenz M. Morphine myths: sedation, tolerance, addiction. Postgrad Med J. 1991;67:S100-S102.

48. References
American Diabetes Association: Preventive Foot Care in Diabetes
(Position Statement). Diabetes Care 27 (Suppl.1): S63-S64, 2004
Feldman, EL: Classification of diabetic neuropathy. In UpToDate.
Wellesley, MA, UpToDate, 2003
National Diabetes Information Clearinghouse. Diabetic Neuropathies:
The Nerve Damage of Diabetes. Bethesda, MD: National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health (NIH), DHHS; 2002
National Diabetes Information Clearinghouse. Prevent Diabetes
Problems: Keep Your Feet and Skin Healthy. Bethesda, MD: National
Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health (NIH), DHHS; 2003

49. References, cont. Feldman, EL: Pathogenesis and prevention of diabetic
polyneuropathy. In UpToDate. Wellesley, MA, UpToDate, 2003.
Feldman, EL, McCulloch, DK: Treatment of diabetic neuropathy. In
UpToDate. Wellesley, MA, UpToDate, 2003.
Stevens, MJ: Diabetic autonomic neuropathy. In UpToDate.
Wellesley, MA, UpToDate, 2003.
Feldman, EL: Clinical manifestations and diagnosis of diabetic