An update on the treatment and management of diabetic peripheral neuropathy.

Learning objectives:

After reading the article, the reader will be able to:

1. Understand the prevalence and pathophysiology of diabetic peripheral neuropathy.

2. Describe the benefits and risks of the available treatment options for diabetic neuropathy.

3. Be able to apply the above concepts to dialysis patients.

Introduction

Peripheral neuropathy (PN) is a term that refers to disorders or damage of the peripheral nervous system and is a common consequence of many disease states such as diabetes, uremia, AIDS and nutritional deficiencies. Type 1 and 2 diabetes mellitus are by far the most common causes of this condition which can be grouped into three main categories as shown in Table One. Patients may experience one or all of these symptoms (McPherson, 2006).

The exact mechanism of diabetic peripheral neuropathy (DPN) is not entirely known. However, it is suspected that high glucose levels could contribute to changes in the metabolism of nerve cells.

Two main problems can result from loss or damage to the sensory nerve fibres. The first is a loss of the sensation of pain. This puts the patient at higher risk for foot infections, which can go unnoticed if proper foot care is not conducted on a regular basis. The second is the heightened sensation of pain and burning sensations that can be quite uncomfortable for the patient (ePodiatry.com, 2003).

Epidemiology of diabetic peripheral neuropathy

DPN is a very common complication of both type 1 and 2 diabetes, with greater than 40% of patients being affected within 10 years of disease onset. Though the presentation of DPN is very similar between type 1 and 2 diabetics, the onset of symptoms does not appear to be the same. Type 1 diabetics are unlikely to develop symptoms of DPN in the first five years of disease onset, whereas type 2 diabetics can develop symptoms at any time and it is not uncommon to get symptoms very early in the disease progression (Bril & Perkins, 2003).

Risk factors for the development of DPN include (Russell & Stading, 2002):

1. Poor glucose control (hyperglycemia)

2. Elevated lipid and blood pressure indexes

3. Increased duration of diabetes

4. Cigarette smoking and alcohol consumption (loose association).

The remainder of this article will focus on chronic sensorimotor DPN and its management.

Pathophysiology

The degree and duration of hyperglycemia is thought to be a contributing factor to DPN. However, it is not clear whether the association actually increases the risk or just the severity of DPN symptoms. Regardless of whether it is causative or not, it is important to maintain tight glucose control in order to prevent the development of other diabetic complications and to alleviate some of the discomfort of DPN (Boulton, Malik, Arezzo, & Sosenko, 2004).

Signs and symptoms

Sensory loss usually occurs symmetrically, first targeting the nerves with the longest axons, in a stocking-and-glove distribution (Aring, Jones, & Falko, 2005). Initially, the ankle reflexes are often reduced and, as the disease progresses, the knee reflexes are also affected. In the more severe and advanced cases, small muscle wasting can occur in the hands and feet resulting in motor weakness (Boulton et al., 2004).

The feeling of unsteadiness has more recently been associated with the development of DPN. This is thought to be due to abnormal muscle sensory function and disturbed proprioception. The presence of this symptom could lead to minor traumas and falls if the appropriate corrective measures are not taken such as using rails on stairs and in washrooms or using a walker (Boulton et al., 2004).

Patients with DPN can experience either the positive symptoms, such as pain and burning sensations or the negative symptoms, such as numbness and tingling, or both. Patients complain of the painful symptoms being more pronounced in the night, making it difficult to get a restful night's sleep. The symptoms of DPN are difficult to describe because they are very different from any other sensations of pain or numbness that the patient may have experienced before the onset of DPN (Boulton et al., 2004).

There are two major foot complications of DPN. The first is foot ulceration. All patients with DPN are at risk of developing foot ulcerations, but those with highly arched feet and clawed toes seem to be at heightened risk. The second complication is Charcot's Neuroarthropathy, which is characterized by erythema, edema and increased temperature, and can lead to foot deformity, ulceration and decreased function if not treated. Therapy often consists of immobilizing the foot with a total contact cast (Boulton et al., 2004).

Prevention

There is no definite method of preventing DPN, however, The Diabetes Control and Complication Trial (DCCT) (DCCT Research Group, 1989) did show that maintaining tight glucose control in patients with type 1 diabetes reduced the risk of both DPN and autonomic neuropathy (Boulton et al., 2005). A study looking at the development of peripheral neuropathy in patients with type 2 diabetes (Partanen et al., 1995) also noticed a correlation between the prevalence of DPN and degree of hyperglycemia. Based on this evidence, the Canadian Diabetes Association recommends tight glycemic control for prevention and secondary intervention of DPN.

Though the development of DPN may be inevitable, there are ways that patients can protect themselves from the complications. Proper foot care is extremely important in this population and a list of essential steps can be found in Table Two. Good blood pressure control and lipid management, reducing alcohol and cigarette smoking may also help to prevent or delay the progression of DPN (Boulton et al., 2005).

Treatment alternatives

Introduction

Good glucose control is the only currently known therapy to delay the development and progression of DPN. Once a patient has been diagnosed with DPN, treatment options focus on symptom control.

Antidepressants

Antidepressants are a common group of drugs used for neuropathic pain. Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have been tested for off-label uses in pain management.

TCAs

Amitriptyline was the first and most frequently studied TCA to show a significant improvement in pain scores. Later, other TCAs, such as desipramine and nortriptyline were proven to have beneficial effects. The most common and least tolerated adverse effects with tricyclic antidepressant use are the anticolinergic effects, which include dry mouth, blurred vision, constipation, urinary retention and cognitive impairment. Of the available agents, desipramine and nortriptyline appear to be better tolerated with less anticolinergic effects (McPherson, 2006). Other serious side effects associated with these agents relate to cardiovascular toxicity and include orthostatic hypotension, tachycardia and changes in AV conduction (Lacy, Armstrong, Goldman, & Lance, 2002).

Dosing of these agents should start low and titrate up to the desired effect. Patients should also be advised to take these agents before bed due to their sedating properties.

Selective seritonin reuptake inhibitors (SSRIs) and seritonin/norepinephrine reuptake inhibitors (SNRIs)

In a recent Cochrane review (Saarto & Wiffen, 2006) of antidepressant use in the management of neuropathic pain, the SSRIs, such as citalopram, paroxetine, sertraline and fluoxetine, were shown to have little benefit. The SNRI, venlafaxine, is so new to the market that there has been insufficient research published to assess its efficacy in pain management.

Anticonvulsants

Anticonvulsants were introduced to the market for the treatment of seizures in the 1950s. Very soon after this introduction, it was noticed that these medications are also effective in the management of pain.

Alpha2-Delta Ligands

Gabapentin is commonly used for the treatment of chronic pain, especially those with neuropathic origin, although it has never been approved for this indication (McPherson, 2006). To date, there have been seven randomized controlled trials of gabapentin in diabetic neuropathy. Four were placebo-controlled and three had active comparators. Three of the four placebo-controlled trials showed a statistically significant difference in pain, which was generally defined as at least a 50% reduction in pain. The fourth trial showed no benefit, but used the lowest dose of all the trials at 900 mg per day. Two studies compared gabapentin to amitriptyline, showing that gabapentin is at least as effective as amitriptyline if not slightly more effective. One study attempted to compare gabapentin plus venlafaxine to gabapentin alone, however not enough patients finished the study to enable an evaluation. Based on these studies, the target dose for neuropathic pain is 1800 mg to 3600 mg per day, in three divided doses (Wiffen, McQuay, Edwards, & Moore, 2006).

The most common adverse effects noted to be associated with gabapentin use are related to the central nervous system. These include somnolence, ataxia and dizziness. Patients may also notice problems with gait or balance and experience gastrointestinal upset (Lacy et al., 2002). To minimize the impact of these adverse effects on the patient, it is important to start patients on a low dose, preferably at bedtime, and titrate the dose and frequency into the target range. Gabapentin is mainly cleared by renal excretion and it requires significant dosage adjustment in renal insufficiency (Wong et al., 1995).

Pregabalin is a new alpha2-delta ligand on the market and is the first agent to have been approved for the primary indication of neuropathic pain.

A study comparing both fixed-dose (600 mg/day) and flexible-dose (150 to 600 mg/day) pregabalin to placebo, showed a significant difference in pain and sleep scores in favour of pregabalin at 12 weeks. There was no significant difference between the two pregabalin regimens (Freyhagen, Strojek, Griesing, Whalen, & Balkenohl, 2005). Based on this study, starting with a low dose of pregabalin, 150 mg/day, and titrating up by 150 mg/week to a maximum of 600 mg/day, is shown to be both safe and effective. As with gabapentin, pregabalin requires dosage adjustment in renal insufficiency (Product Information Lyrica[R], 2005).

This agent is very similar to gabapentin with the same mechanism of action and, therefore, you can expect this agent to carry the same toxicity profile. Due to these similarities, it is unlikely that this agent would be of benefit if gabapentin has proven ineffective or intolerable in a particular patient. The only benefit this agent has over gabapentin is the fact that it is more potent and, thus, you will achieve similar efficacy at lower doses (Prod. Info. Lyrica[R], 2005).

Other anticonvulsants

Other anticonvulsants such as carbamazepine, phenytoin, sodium valproate and clonazapam are also commonly prescribed for diabetic neuropathy, though very few placebo-controlled trials have been published. This leaves very little evidence to support their use for this indication.

Carbamazepine and phenytoin are the only of these anticonvulsants specifically tested in the treatment of diabetic neuropathy. One study comparing carbamazepine (Rull, Quibrera, Gonzalez-Millan, & Lozano Castenada, 1969) and another comparing phenytoin (Chadda & Mathur, 1978) to placebo found that 30% to 50% more patients improved on the active agent compared to placebo. An additional study comparing phenytoin to placebo (Saudek, Werns, & Reidenberg, 1977) found no benefit with the active treatment.

Side effects to consider when using these agents include, but are not limited to, blood dycrasias, hypotension, bradycardia, hyponatremia, and urinary retention for carbamazepine and blood dycrasias, gingival hypertrophy, osteomalacia and hyperglycemia for phenytoin (Lacy et al., 2002).

Neither of these agents should be considered as first-line agents in the management of DPN. If other agents are ineffective or contraindicated, then anticonvulsants could be tried.

Opioids

The opioid analgesic agents are often left as a last resort to treat neuropathic pain and are thought by many practitioners to be of little benefit in this type of chronic pain management. However, there have been several studies published in recent years on oxycodone that may indicate a potential place for it in the treatment of neuropathic pain.

There have been two randomized, placebo-controlled trials (Gimbel, Richards, & Portenoy, 2003; Watson, Moulin, Watt-Watson, Gordon, & Eisenhoffer, 2003) looking at the safety and efficacy of controlled-release oxycodone for this indication. Based on these trials, daily doses ranging from 10 to 60 mg would be a safe and effective regimen.

Opioids, as we know, do not come without their share of adverse effects. Constipation, nausea, vomiting and sedation are the most common and can greatly impact a patient's productivity throughout the day. Physical dependence will also develop with chronic use and, therefore, it is important to reduce the dose of the agent slowly, if discontinuation is necessary, to avoid any symptoms of withdrawal.

When a patient is started on an opioid for chronic pain, it is important to start the dose low and titrate up. This allows the lowest possible dose to be used to maintain the desired effect and minimize adverse effects. Combinations of long-and short-acting agents are commonly used to achieve pain control when initiating therapy, until the ideal long-acting maintenance dose can be determined (McPherson, 2006).

Tramadol

Tramadol is categorized as a "non-opioid analgesic". It is a non-selective serotonin and norepinephrine reuptake inhibitor and, thus, is very similar to the SSRIs and SNRIs. Tramadol also has an active metabolite that acts as a weak mu opioid agonist, which also contributes to its analgesic properties (McPherson, 2006). Despite its agonistic properties with the mu receptor, it is thought to have very little addiction potential. The only formulation available in Canada is a combination product with acetaminophen 325 mg and tramadol 37.5 mg under the brand name of Tramacet[R] Thus, patients should be cautious of taking other products that contain acetaminophen to ensure that they do not exceed the maximum daily dose of 4.0 g.

There have been three randomized controlled trials comparing tramadol to placebo (Erdine, 1997; Harati et al., 1998; Sindrup, Madsen, Brosen, & Jensen, 1999), each showing significant improvement in pain scores, though none of these trials were specifically done in patients with diabetes. It should be noted, however, that the maximum length of treatment used in either of these studies is six weeks and, thus, long-term safety cannot be assessed. Two additional studies were conducted comparing tramadol to clomipramine and morphine, however, due to insufficient data, no conclusions can be drawn from these trials.

Patients should be started on 37.5 mg of tramadol once or twice a day, and this can be titrated up to 300 to 400 mg per day. Dose adjustments for renal impairment are recommended. For patients with a creatinine clearance of less than 30 mL/min, the daily dose should not exceed 200 mg (Product Information Ultram[R] 2004). For patients with a creatinine clearance of less than 10 mL/min, the daily dose should not exceed 100 mg (Izzedine et al., 2002).

Side effects that are common with tramadol include nausea, somnolence, constipation, dizziness and orthostatic hypotension. Caution should be used in patients with seizure disorders because tramadol has been shown to decrease seizure threshold. Patients who take other medications that increase serotonin levels, such as the SSRIs, should be careful as this combination will increase their risk of serotonin syndrome (Duhmke, Cornblath, & Hollingshead, 2006).

Mexiletine

Mexiletine is a local anesthetic, taken by mouth, which is similar to lidocaine and has been studied in symptomatic management of neuropathic pain of various ideologies. There have been a few studies (Dejgard, Petersen, & Kastrup, 1988; Stracke, Meyer, Schumacher & Federlin, 1992) looking at this agent, specifically in patients with diabetic neuropathy, however results are somewhat conflicting. This agent cannot be recommended as a first-line agent, though it may be considered in a patient with refractory pain. The dose that was successful in the study by Dejgard et al. was 10 mg/kg daily. Side effects to consider when using mexiletine consist of gastrointestinal upset, sleep disturbance, headache, shakiness, dizziness, tiredness and, in rare cases, tachycardia.

Diabetic neuropathy in dialysis patients

There are no studies specifically in dialysis patients on the treatment or prevention of DPN. Tight blood glucose control to prevent and delay DPN in diabetic dialysis patients should be encouraged. Proper foot care should also be recommended for these patients.

For dialysis patients who already have DPN and are experiencing pain, symptom relief with either tricyclic antidepressants (TCAs) or anticonvulsants can be trialed. Dose reductions and special considerations are required for some of the agents.

Tricyclic antidepressants (TCAs)

These agents should be administered at bedtime to avoid daytime sedation and used with caution in patients with cardiovascular disease due to the anticholinergic effects. In addition, these agents can cause dry mouth and, in patients who are already fluid-restricted, particularly hemodialysis patients, it may increase their desire to drink.

Anticonvulsants

Gabapentin is mainly renally cleared and it requires a significant dosage adjustment in renal insufficiency. Gabapentin is also cleared by hemodialysis and should be dosed after dialysis at bedtime (Wong et al., 1995).

As with gabapentin, pregabalin requires dosage adjustment in renal insufficiency. The pregabalin dose should be adjusted based on creatinine clearance and dosed after hemodialysis at bedtime (Prod. Info. Lyrica, 2005):

Summary

It is clear that the majority of the evidence for symptomatic management of DPN is for either TCAs or anticonvulsants. The Canadian Diabetes Association recommends agents from these classes as first-line therapy. Though these agents appear to be effective, the management of neuropathic pain is still quite difficult and many patients only achieve partial relief from therapy while others find no relief. It is important to focus on the prevention of onset and progression of diabetic neuropathy by dealing with the root of the problem, glycemic control. Patients should be educated on the importance of intensive glycemic control for the prevention of all diabetes complications, including peripheral neuropathy (Bril & Perkins, 2003).

Acknowledgement

The authors wish to thank Lori Harwood, Nurse Practitioner/Clinical Nurse Specialist at London Health Sciences Centre, London, Ontario, and Jennifer Dykeman, Renal Pharmacist, Clinical Coordinator Pharmacy Services, Atlantic Health Sciences Corporation, Saint John, New Brunswick, for their help in reviewing the final draft of this article.

References

Aring, A.M., Jones, D.E., & Falko, J.M. (2005). Evaluation and prevention of diabetic neuropathy. American Family Physician, 71(11), 2123-2128.

Boulton, A.J.M., Malik, R.A., Arezzo, J.C., & Sosenko, J.M. (2004). Diabetic somatic neuropathies. Diabetes Care, 27(6), 1458-1478.

Boulton, A.J.M., Vinik, A.I., Arezzo, J.C., Bril, V., Feldman, E.L., Freeman, R., et al. (2005). Diabetic neuropathies, A statement from the American Diabetes Association. Diabetes Care, 28(4), 956-952.

Bril, V., & Perkins, B. (2003). Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 27(Suppl. 2), 57-80.

Canadian Diabetes Association 2003 Clinical Practice Guidelines Expert Committee. (2003). Neuropathy. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 27(Suppl. 2), S72-73.

Chadda, V.S., & Mathur, M.S. (1978). Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy. Journal of the Association of Physicians of India, 26, 403-406.

DCCT Research Group. (1989). Implementation of a multicomponent process to obtain informed consent in the Diabetes Control and Complications Trial. Control Clinical Trials, 10(1), 83-96.

Dejgard, A., Petersen, P., & Kastrup, J. (1988). Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet, 1(8575-8576), 9-11.

Duhmke, R.M., Cornblath, D.D., & Hollingshead, J.R.F. (2006). Tramadol for neuropathic pain (Review). The Cochrane Library, Issue 2, 1-13.

ePodiatry.com (2003). Peripheral neuropathy. Retrieved May 19, 2006, from: http://www.epodiatry.com/neuropathy.htm

Erdine, S. (1997). Efficacy of tramadol hydrochloride in chronic painful diabetic neuropathy: A double-blind placebo controlled study. Proceedings of the 8th World Congress on Pain, 371. Seattle: IASP Press.

Freyhagen, R., Strojek, K., Griesing, T., Whalen, E., & Balkenohl, M. (2005). Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomized, double-blind, multicentre, placebo-controlled trial of flexible and fixed dose regimens. Pain, 115, 254-263.

Gimbel, J.S., Richards, P., & Portenoy, R.K. (2003) Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial. Neurology, 60, 927-934.

Harati, Y., Gooch, C., Swenson, M., Edelman, S., Greene, D., Raskin P., et al. (1998). Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology, 50(6), 1842-1846.

Hays, L., Reid, C., Doran, M., & Geary, K. (2005). Use of methadone for the treatment of diabetic neuropathy. Diabetes Care, 28, 485-487.

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Sindrup, S.H., Madsen, C., Brosen, K., & Jensen, T.S. (1999). The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels. Clinical Pharmacology and Therapeutics 66(6), 636-641.

Stracke, H., Meyer, U.E., Schumacher, H.E., & Federlin, K. (1992). Mexiletine in the treatment of diabetic neuropathy. Diabetes Care, 15(11), 1550-1555.

Watson, C.P., Moulin, D., Watt-Watson, J., Gordon, A., & Eisenhoffer, J. (2003). Controlled-release oxycodone relieves neuropathic pain: A randomized controlled trial in painful diabetic neuropathy. Pain, 105, 71-78.

Wiffen, P.J., McQuay, H.J., Edwards, J.E., & Moore, R.A. (2006). Gabapentin for acute and chronic pain (Review). The Cochrane Library, Issue 2, 1-18.

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Contact hours: 2.0 hrs

By Jennifer Donnan, BscPharm, and Seadna Ledger, BscPharm

Jennifer Donnan, BscPharm, is a Clinical Pharmacist I, Eastern Health, St. John's, Newfoundland.

Seadna Ledger, BscPharm, is a Renal Pharmacist, London Health Sciences Centre, London, Ontario.

Address correspondence to Jennifer Donnan, e-mail: [e-mail]

Submitted for publication: September 5,2006.

Accepted for publication in revised form: November 9,2006.

Table One: Categories of diabetic peripheral neuropathy

Category   Characteristics
Sensory    Inability to feel temperature, pressure or pain
           Feeling of numbness, tingling or burning
           Heightened sensation of pain
Motor      Loss of strength and inability
           to control movement
Autonomic  Inability to control heart rate or digestion

Modified from ePodiatry.com (2003).
Peripheral neuropathy. Retrieved May 19,2006, from:
http://www.epodiatry.com/neuropatby.htm

Table Two: Tips for maintaining healthy feet

1. Make a habit of checking your feet daily for any abnormal markings or
signs of wounds, cracks, blisters or bruises.
2. If you cannot easily see the bottoms of your feet, use a mirror.
3. A change in colour, swelling or warm legs and feet can be a sign for
infection. See your doctor if this occurs.
4. If you happen to cut or scratch your feet, clean it with soap and
water and cover it with a dressing to prevent infection. If the wound
turns red, becomes sore or feels warm, bring it to the attention of
your doctor.
5. Toenails should be trimmed straight across.
6. Feet should be washed on a daily basis.
7. Proper drying of the feet is just as important as washing. Complete
drying, especially in between the toes is essential.
8. Moisturize your feet daily with skin lotion, rubbing until all of the
lotion is absorbed or removing the excess with a cloth. This will
prevent cracks from forming and infection from starting.
9. Change your socks daily.
10. When selecting shoes, ensure they have good support and low heels
(less than 5 cm). Having your shoes professionally fitted will help to
find the right support.
11. It is important to have properly fitted shoes for both inside and
outside the house. Walking barefoot will put you at risk for cuts and
picking up infections.
12. When selecting socks, ensure they are loose fitting. Avoid wearing
anything with elastics on your legs, as this will decrease the blood
flow to your feet.
13. Avoid extreme temperatures. For example, wear warm shoes in the
winter and stay away from the hot sun in the summer months. Also, avoid
taking hot baths, using electric blankets or hot water bottles. With
decreased feeling in your feet, you could easily burn them.
14. Maintain a good exercise schedule.
15. If you do notice infection, sores, blisters, corns, calluses or
ingrown toenails on your feet, it is important to get professional
assistance from you doctor to treat them. Some over-the-counter remedies
may not be appropriate for people with diabetes.

Modified from the Canadian Diabetes Association 2003
Clinical Practice Guidelines Expert Committee. (2003).
Neuropathy. In Canadian Diabetes Association 2003
Clinical Practice Guidelines for the Prevention and Management of
Diabetes in Canada. Canadian Journal of Diabetes, 27(Suppl. 2).

Table Three: Dosing recommendations for gabapentin

Creatinine Clearance (mL/min)  Dose per day

>60                            900-3600 mg
30-59                          400-1400 mg
15-29                          200-700 mg
<15                            100-300 mg

Modified from Product Information (2003). Neurontin[R], gabapentin.
Pfizer Inc., New York, NY.

Table Four: Dosing recommendations for pregabalin

Creatinine Clearance (mL/min)  Dose per day

>60                            150-600mg
30-60                           75-300mg
15-30                           25-150mg
<15                             25-75mg

Modified from Product Information (2005). Lyrica[R],
pregabalin. Pfizer, New York, NY, USA.