All patients with diabetes are at increased risk for complications affecting the cardiovascular and nervous systems, as well as the kidneys and eyes. Neuropathy is one of the most common comorbidities — affecting about 60% to 70% of patients. Managing glucose levels is the most direct way to prevent nerve damage and alleviate pain.
Diabetic neuropathy arises when glucose levels consistently remain elevated. Smokers, people aged older than 40 years and those with poorly controlled underlying diabetic disease are at highest risk.
Patients may first notice a tingling in the extremities – including the hand, arms, toes, feet, and legs— before a diabetes diagnosis is even made. This form of peripheral neuropathy may involve symptoms including numbness, weakness or pain.
Another type, autonomic neuropathies, involves the nervous system and affects the patient's cardiovascular, gastrointestinal and genitourinary systems. Patients who have an autonomic neuropathy may present with dizziness or weakness; indigestion, nausea or vomiting; diarrhea or constipation; and problems with urination.
Diabetic neuropathic pain can be focal or widespread depending on the source and requires different types of management.
Managing glucose levels
Medication, diet and exercise help keep blood glucose levels within a healthy range.
The Diabetes Control and Complications Trial found that tight glucose control reduced the risk of neuropathy by 60%1, and results from other trials, including the UK Prospective Diabetes Study and ADVANCE, show that stringent glucose control minimizes microvascular problems, including neuropathy.2,3
These studies suggest that a target HbA1C level of 6.5% or less is optimal and should be recommended to avoid neuropathic symptoms and damage. American Diabetes Association (ADA) guidelines currently recommend testing HbA1C levels twice a year. Quarterly testing is suggested for patients who have not met treatment target goals or who have changed treatment strategies.
Medications for pain management
Current first-line medications for managing peripheral neuropathic pain include tricyclic antidepressants (TCAs), selective serotonin-norepinephrin reuptake inhibitors (SNRIs) and anticonvulsants. The SNRI, duloxetine, and anticonvulsant, pregabalin, are the only medications currently approved by the FDA with an indication for diabetic neuropathic pain.
In 2004, duloxetine (Cymbalta, Yentreve) was the first FDA-approved medication for managing diabetic peripheral neuropathy. Nearly half of patients in a placebo-controlled trial that were assigned to 60 mg duloxetine twice daily, reported a 50% reduction in pain compared with about 28% of patients assigned to placebo.4
Common duloxetine adverse events include nausea, somnolence, dizziness and constipation that dissipate with use. In very rare cases the medication can cause liver damage, severe allergic reactions, pneumonia and increased risk for suicide.
Another SNRI, venlafaxine (Effexor, Pfizer), has also been shown to help manage diabetic pain, but may put patients at risk for arrhythmia.5 Dosing starts at 37.5 mg per day and can be increased by the same amount per week to a maximum of 300 mg/day. If prescribing this medication clinicians must perform ongoing cardiac monitoring.
Routine use of tricyclic antidepressants, which include amitriptyline, imipramine, nortriptyline and desipramine, are also appropriate for pain management. Results of one study showed that about 30% of patients assigned to a TCA for diabetic nephropathy experienced a 50% reduction in pain.6
For pain relief TCA doses range from 25 to 150 mg per day, lower than those typically prescribed for depression. Keep in mind that some patients are unable to tolerate TCA's anticholinergic and sedative properties. Avoid prescribing TCAs to patients who take monoamine oxidase inhibitors for depression, those with a history of CVD and patients that are younger than 65 years. Adverse events include dry mouth, constipation, dizziness, blurred vision and urinary retention.
Selective serotonin reuptake inhibitors (SSRIs) and other types of antidepressents have demonstrated varying efficacy for diabetic neuropathy, and have generally been found to be less effective than TCAs. Bupropion is an option for neuropathic pain relief. Initial doses start at 100 mg per day, and should be increased 100 mg per week, up to a maximum dose of 200 mg twice daily (400 mg per day).7
Other treatments
The FDA approved the anticonvulsant pregabalin (Lyrica, Pfizer) for diabetic neuropathic pain in 2005, after results from clinical trials indicated that 150 mg to 300 mg daily pregabalin reduced pain scores 50% compared with baseline.8 Common adverse events included dizziness, somnolence, edema and weight gain. Higher doses produced greater pain relief scores, but also carry a risk for dose-dependent adverse events.
Capsaicin, a topical treatment without systemic side effects, has been shown to be effective, but clinicians must spend time educating patients about application techniques. The drug must be applied three to four times per day for six to eight weeks to achieve symptom improvement. Adverse events include a temporary burning sensation that diminishes with prolonged use but is often intolerable for patients with diabetic neuropathy.9
IV α-lipoic acid infusions at 600 mg per day may also reduce neuropathic symptoms after about three weeks. Results from the SYNDEY 2 trial indicated that an 600 mg daily oral formulation administered in four doses also produced good results among patients with distal symmetric polyneuropathy after five weeks.10
Acetaminophen and ibuprofen do not effectively manage nerve pain in most cases. Because of their risk of promoting gastrointestinal bleeding, clinicians should limit use to short-term adjuvant therapy in patients with a reduced risk of kidney and GI dysfunction.
Because of the risks of dependency and constipation, clinicians should reserve opioids such as oxycodone and tramadol for controlling diabetic neuropathic pain only in the most severe cases.
Electrical nerve stimulation
Transcutaneous electrical nerve stimulation (TENS), a widely used pain therapy that consists of applying mild electrical currents to painful areas using surface electrodes, may have a limited role in managing diabetic neuropathy, according to a recent guideline from the American Academy of Neurology.
A study of 15 trials investigating TENS in diabetic neuropathy control found that the treatment relieves painful symptoms after daily application. Another study found superior results with combining TENS and TCA drug therapy. However, the lack of studies involving larger patient populations precludes a conclusive recommendation.
Other types of muscle and nerve stimulation techniques may potentially play a role in neuropathy treatment, but also lack a consensus finding.
Care of the extremities
Since peripheral neuropathy is one of the most common forms of diabetic neuropathy and pain, caring for the extremities – especially the feet and toes – can provide symptom relief and prevent further damage. A lack of sensation in the feet may lead to unnoticed injuries, wounds or ulcerations that can become infected due to poor circulation.
To avoid these problems, including risk for toe, foot or lower leg amputation, clinicians should conduct annual foot examinations to assess foot pulses and determine ankle reflexes, as well as vibration and pinprick sensations.
Also, be sure to educate patients, so they can perform self-examination and adhere to good hygiene protocols for the feet. Feet should be carefully dried after exercise or bathing to prevent skin breakdown.
For those patients who are unable to bend over or otherwise see the bottoms of their feet, clinicians can suggest the use of wall-mounted mirror or handheld mirror. If a patient's vision is poor, recommend that a close relative or other loved one perform the inspection. Specifically instruct the examiner to look for cuts, scratches, cracks or other areas of the foot that do not appear normal. If any of these symptoms are noticed, the patient or loved one should seek a health professional's opinion immediately to avoid complications.
More than 60% of lower-limb amputations that are not caused by trauma occur in people with diabetes. Breaks in the skin that are left unchecked can lead to infection caused by poor circulation and possibly the risk of toe, foot, or leg amputation. Recommending a podiatrist for toenail care can also be beneficial.
Alice McCarthy is a freelance medical writer.
References
1. UK Prospective Diabetes Study Group. Lancet. 1998;352:854-865.
2. ADVANCE Collaborative Group. Lancet. 2007;370:829-40.
3. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993; 329:977-986.
4. Goldstein DJ. Pain. 2005;116:109–118.
5. Rowbotham M. Pain. 2004;110:697–706.
6. McQuay H. Pain. 1996;68:217–27.
7. Shah TH. Am J Hosp Palliat Care. 2010;27: 333–336.
8. Dworkin RH. Nature Reviews Drug Discovery. 2005;4:455–56.
9. Norrie P. Int J Evid Based Healthc. 2010;8:147-8.
