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DOI: 10.1177/0145721705278800 © 2005 American Association of Diabetes Educators; Published by SAGE Publications
Practical Management of Patients With Painful Diabetic NeuropathyFrom the Intercollegiate College of Nursing, Washington State University, Spokane. Correspondence to Cynthia F. Corbett, PhD, RN, Intercollegiate College of Nursing, Washington State University, 2917 West Fort George Wright Drive, Spokane, Washington 99224 (corbett{at}wsu.edu).
Purpose Painful diabetic neuropathy (PDN) has a significant impact on patients' quality of life, affecting sleep, mood, mobility, ability to work, interpersonal relationships, overall self-worth, and independence. The purpose of this article is to provide diabetes educators with current and essential tools for PDN assessment and management. Methods Medline and CINAHL database searches identified publications on the assessment and treatment of PDN. Identified research was evaluated, and information pertinent to diabetes educators was summarized. Results Recent advancements in assessment of neuropathic pain include identifying characteristics that distinguish between neuropathic and nonneuropathic pain. In the absence of treatment, research demonstrates that nerve damage may progress while pain diminishes. Many disease-modifying and symptom-management treatment options are available. Conclusion Good glycemic control is the first priority for both prevention and management of PDN. However, even with good glycemic control, up to 20% of patients will develop PDN. PDN recognition and assessment are critical to optimize management. Although several treatment modalities are available, few patients obtain complete pain relief. Recent advances in understanding the mechanisms underlying neuropathic pain should lead to bettertreatment and patient outcomes. Combination therapy, including nonpharmacologic modalities, may be required. Research evaluating the efficacy of combination therapy is needed.
Neuropathy is the greatest source of morbidity associated with diabetes, affecting up to 50% of those with long-standing disease, and pain as a symptom of neuropathy may be seen in as many as one third of all patients with diabetes.1-6 Neuropathic pain is difficult to manage, and the available treatment options rarely provide total relief.7 Lack of definitive treatment success is related to the multifocal and poorly understood pathogenesis of painful diabetic neuropathy (PDN). Peripheral and central nervous system damage due to hyperglycemia is thought to be involved.1,8,9 PDN affects all areas of patients' lives including sleep, mood, mobility, ability to work, interpersonal relationships, overall self-worth, and independence.4,10 An understanding of PDN assessment and management strategies is therefore essential for diabetes educators.
Common pain descriptors and other symptoms of PDN are listed in Table 1.8,11 Backonja and Krause12 have identified numbness, tingling pain, and increased pain due to touch as significant indicators of neuropathic versus nonneuropathic pain. The intensity, quality, duration, and timing (eg, nocturnal) of both spontaneous and stimulus-dependent pain should be assessed.13 PDN may be bilateral or unilateral. Assessment should include monofilament, vibratory, and pinprick tests.14 Reflexes and the strength and flexibility of the toes, foot, and ankle should also be assessed.10,14 Feet should be observed and palpated for any signs of ulcer risk (eg, hammer toes, bunions, calluses, tender areas). Assessing for signs and symptoms of peripheral vascular disease, including pedal pulse quality, capillary refill, skin color and moisture, and ankle-brachial index, should be done.14
In patients with PDN, decreased sensation is nearly always present although less prominent in persons with pure small fiber neuropathy.14 Research has failed to demonstrate a definitive association between degree and chronicity of pain and nerve conduction loss.2,15 However, it is generally believed that when chronic pain subsides or resolves, the resolution is a result of worsening pathology. Research shows that nerve function continues to deteriorate, while the pain of PDN has a tendency to stabilize and sometimes improve over time.15,16 The mechanisms underlying change in pain intensity are not known. Thus, available evidence suggests that it is not unusual for symptoms reported by patients to correlate poorly with assessment findings. As a result, PDN is often confusing and frustrating for both patients and clinicians. Reported symptoms and clinical examination findings should be used to initiate management strategies and follow-up care. Referrals may be indicated for further neuropathic assessment, including nerve conduction studies (the definitive criteria for neuropathy diagnosis), for podiatric and orthotic services and for vascular consultation.17 Evaluation of glycemic control is an essential part of the assessment. In addition to hemoglobin A1C, frequent self-monitoring to identify blood glucose fluctuations is needed. Lowering blood glucose levels overall and stabilizing excursions are critical.18,19 Good glycemic control often improves symptoms and may prevent further nerve damage.9,18,20,21 It should be noted that rapid reductions in glycemic control may trigger acute PDN.8,14 Despite this phenomenon, glucose control is paramount to PDN prevention and treatment. If glycemic control is not optimal, diabetes educators should work with the client, primary care providers, and/or endocrinologist to attain improvement. Stable glycemic control is the most effective available disease-modifying treatment.19,20,22 However, this article focuses on other disease-modifying and symptom-management approaches. Disease-modifying treatments enhance nerve function and improve symptoms. Symptom-management treatments ameliorate symptoms but do not affect nerve function.
 -Lipoic AcidOne putative mechanism of PDN is nerve damage related to an imbalance of oxidative stress and antioxidant defenses.23 -Lipoic acid is a powerful antioxidant found in mitochondria and
approved for PDN treatment in
Germany.24 Several
double-blind studies have demonstrated improved nerve function following oral
or parenteral treatment with at least 600 mg/d of -lipoic
acid.23,25-27
Improvements in PDN symptoms were also reported. In the SYDNEY
Trial,27 after 14
daily infusions (5 d/wk) of 600 mg of -lipoic acid, the
active-treatment group had a mean reduction of 5.7 in the overall symptom
score compared with 1.8 in the placebo group. Adverse effects appear to be
mild and include headache, skin rash, gastrointestinal upset (at dosages
>600 mg/d), and
hypotension.24
Since -lipoic acid can chelate metals such as iron and copper,
monitoring for mineral imbalances is necessary during
treatment.24
Evening Primrose Oil Jamal and Carmichael28 studied 22 patients with distal diabetic polyneuropathy who received either 360 mg/d of GLA (via evening primrose oil) or placebo for 6 months. The GLA group had significant improvement on all 6 nerve function tests that were measured and in overall symptom scores as compared with the placebo group. Keen et al29 enrolled 111 patients with mild diabetic neuropathy, of whom 84 (76%) completed the 12-month trial. Those who received evening primrose oil with 480 mg/d of GLA had significant improvements on 13 of 16 nerve function tests as compared with placebo recipients. Symptomatic response was not measured. In a similarly designed study with 55 participants who received either 480 mg/d of GLA via evening primrose oil or a placebo for 12 months, no improvement in vibratory sensation threshold was realized.30 Participants taking evening primrose oil reported side effects similar to those of placebo recipients in all 3 studies. However, GLA can inhibit platelet aggregation and has been associated with sporadic reports of seizure activity; it must be used with caution in persons taking antiplatelet or anticoagulant medications and is contraindicated for those with a history of seizure disorder.24
Near-Infrared Treatment
Isosorbide Dinitrate Spray
Analgesics Very little research exists about the effectiveness of over-the-counter analgesics for PDN treatment. The lack of evidence is likely based on the fact that patients and practitioners generally report poor efficacy of nonsteroidal anti-inflammatory medications (NSAIDs) and acetaminophen when used to alleviate PDN. One study compared ibuprofen (600 mg 4 times per day) and sulindac (200 mg twice per day) and a placebo for PDN treatment.34 A single-blind design in which each participant (N = 18) sequentially used each of the 2 active treatments and the placebo for 8 weeks was used with participants serving as their own controls. Compared to baseline, suldinac and ibuprofen significantly reduced pain. In contrast, there was no difference in baseline pain and pain reported after 4 or 8 weeks during placebo use. No changes in creatinine or protein levels occurred. However, research on the potential relationship between long-term use of NSAIDs and renal function must be further studied. In addition, the potential for gastrointestinal hemorrhage associated with NSAIDs must be considered, particularly in older adults.1,5 Two recent double-blind studies reported that controlled-release (CR) oxycodone reduced pain and improved sleep and other quality-of-life measures as compared with placebo in patients with PDN.35,36 Gimbel et al35 conducted a 6-week multicenter, randomized, double-blind trial of CR oxycodone (n = 82) compared with placebo (n = 77). The starting dosage was 10 mg every 12 hours and could be increased to a maximum of 60 mg every 12 hours. Oxycodone provided significantly more analgesia than placebo did, but adverse effects were significantly more frequent with oxycodone (96%) than with placebo (68%). The most common side effects were constipation, drowsiness, nausea, and dizziness. In a crossover trial of 4 weeks' duration for each treatment period (N = 36), Watson et al36 compared CR oxycodone (maximum dosage 40 mg every 12 hours) with an active control benztropine (maximum 1 mg every 12 hours). Pain scores and measures of health-related quality of life improved with oxycodone compared with benztropine. Adverse reactions were similar between the 2 groups. Harati et al37 and Sindrup et al38 evaluated tramadol for treatment of PDN symptoms. Tramadol exhibits low-affinity binding to selected opioid receptors and weak inhibition of norepinephrine and serotonin reuptake.37 Thus, its mechanism of action is similar to those of narcotic analgesics and antidepressants, which have been effective in treating PDN symptoms. In each of these randomized trials, participants receiving tramadol reported significantly greater benefits than the placebo groups, including reduced pain and enhanced physical and social functioning. The tramadol groups reported more side effects, most commonly constipation, headache, and drowsiness. Harati et al39 evaluated the longer-term effectiveness of tramadol in an open-label study with 117 participants from their initial trial. Nearly 10% (n = 13) discontinued because of side effects, while 3% (n = 4) stopped because of ineffective pain relief. In the 85 participants (73%) completing the study, tramadol significantly reduced pain and maintained pain relief as compared with pretramadol ratings. Further trials are needed to discern the long-term risk-benefit of narcotic analgesics for PDN treatment. Initial results indicate that tramadol is effective for many patients without severe side effects. Careful follow-up for adverse effects is warranted in older adults.
Antidepressants In 2004, duloxetine became the first medication to receive a Food and Drug Administration (FDA) indication for PDN treatment. Duloxetine inhibits both serotonin and norepinephrine transportors.46 In a 12-week, double-blind, placebo-controlled study (N = 112), non-depressed participants with PDN demonstrated significant reduction in 24-hour average pain when given 60 mg of duloxetine as compared to those receiving placebo.47 A separate 12-week, double-blind, placebocontrolled study (N = 109) tested the effectiveness of a 120-mg per day dosage of duloxetine. Participants receiving the duloxetine significantly improved overall pain, but the 120-mg dose resulted in more side effects than were realized in the study testing 60-mg dosing.47 Common side effects for 60 mg or 120 mg dosing were nausea, tiredness, dizziness, constipation, dry mouth, increased sweating, and muscle weakness (asthenia).47 Duloxetine appears to be a promising PDN therapy. It may prove especially useful for persons suffering from PDN and depression.48,49 Uncontrolled studies of other antidepressants for PDN demonstrate the need for further research using stronger study designs. Trazodone was evaluated in an open-label study of 31 patients with PDN.50 After 2 weeks of therapy (50-100 mg/d), 23% experienced complete, 13% considerable, 26% some, and 13% no relief; 26% discontinued therapy because of side effects, primarily dizziness. Venlafaxine was also evaluated in a small open-label study (N = 11).51 Participants demonstrated 75% to 100% pain reduction within 14 days of initiating venlafaxine (37.5-75 mg/d). The results of these studies must be interpreted cautiously because of the small sample sizes and lack of randomized controlled designs.
Anticonvulsants Findings from several studies using gabapentin dosages ranging from 900 to 3600 mg/d suggest that gabapentin is superior to placebo52 and equivalent to amitriptyline53,54 in reducing PDN and improving quality of life for some patients; 1 placebo-controlled trial that found it probably ineffective or only minimally effective used a fixed low dosage of 900 mg/d.55 Side effects reported with gabapentin include somnolence, dizziness, confusion, headache, and gastrointestinal complaints. Lamotrigine has recently been investigated as a treatment for PDN. In a small (N = 13 completing study), 6-week, open-label study, lamotrigine was initiated at 25 mg/d and titrated to 400 mg/d.56 By week 2, mean reduction of each of 5 pain measures was statistically significant. The investigators noted a pattern of clear response to lamotrigine in 9 participants and a lack of response in 3. A randomized, placebo-controlled, double-blind, 8-week trial was subsequently conducted in 59 patients with PDN.57 Lamotrigine dosing began at 25 mg/d and was titrated gradually (to 50 mg/d for weeks 2-4 and by 100 mg/d weekly thereafter) to 400 mg/d. Patients recorded pain intensity twice daily using a 0 to 10 scale. Significant reductions in pain intensity scores were realized with lamotrigine (baseline 6.4, treatment 4.2) and placebo (baseline 6.5, treatment 5.3); however, there were statistically significant differences in favor of lamotrigine at dosages of 200 mg/d and higher (P < .001). The reported incidence of adverse reactions in each group was similar. Pregabalin is the most recent anticonvulsant medication approved by the FDA for PDN treatment. In a randomized, controlled trial, 337 participants with PDN compared 3 different doses of pregabalin (75, 300, 600 mg/d orally) with placebo.58 For participants receiving 300 and 600 mg per day, significant improvements in pain and sleep were realized. Dizziness, sleepiness, and peripheral edema were the main side effects.58
Capsaicin Topical Cream Topical capsaicin and TCAs were compared in a double-blind parallel study with 250 participants.60 Statistically significant improvements in pain and activities of daily living were realized in both groups after 8 weeks of therapy, and the treatments appeared to be equally effective. No drug-drug interactions have been reported with capsaicin.24 Burning sensations and skin irritation have been the main reported side effects.
Mexiletine Symptom relief improved with increasing doses (up to 675 mg/d). Despite the seeming dose-dependent effect, no significant correlation was found between mexiletine plasma concentration and therapeutic or adverse effects. Side effects were more prominent with higher doses and were primarily gastrointestinal. Because of the anticipated potential cardiac effects (mexiletine is used to treat arrhythmias), Oskarsson et al63 performed 24-hour electrocardiography on participants in their study. No significant cardiac events occurred.
Electrical Stimulation Various forms of electrostimulation have been shown to improve PDN. The hypothesized mechanism of action is pain pathway alteration. Transcutaneous electrical nerve stimulation (TENS) using a portable, rechargeable H-wave machine significantly reduced pain in treatment versus control (sham-treated) participants with PDN.64 Results indicated both a treatment and a placebo effect, but the treatment effect was significantly greater (P = .03). TENS was administered for 30 minutes daily with 4 self-adhesive electrodes placed on specified areas of each lower extremity. The long-term effectiveness of TENS for PDN was evaluated in a study with 54 patients treated twice a day for an average of 35 minutes each treatment for a mean of 1.7 years.65 More than 75% of participants reported significantly reduced pain. Pretreatment pain reoccurred approximately 1 month after TENS therapy was discontinued.64 Monthly treatments have been suggested for maintenance, but further research is needed to evaluate this recommendation. Percutaneous electrical nerve stimulation (PENS) uses disposable acupuncture-like needles connected to electrodes to stimulate peripheral nerves affected by PDN. In a randomized placebo-controlled study (N = 50), Hamza and colleagues66 reported that the technique, delivered 3 times a week for 30 minutes at each session, significantly reduced pain and nonopioid analagesic use and improved sleep quality and mood compared with sham treatment. More than 90% of participants reported significant benefits of active treatment during the crossover study. PENS had residual effectiveness for only about 1 week. Electrical spinal cord stimulation has also been shown to be effective for PDN relief. Tesfaye and colleagues67 reported on a sham-controlled study involving 10 patients with PDN of more than 1-year duration that had not been responsive to traditional pharmacotherapy. Treatment consisted of electrical stimulation via a lead placed midline on the dorsal aspect of the spinal cord. Symptom relief was significantly greater in the activetreatment group. Because of the invasiveness of this therapy, it is considered only as a last-resort treatment option.
Acupuncture Walker11 reported similar results among 40 PDN patients treated with acupuncture. Retrospective medical record evaluation showed that nearly 90% of those treated for 20 minutes once a week for 2 to 3 months reported improvements in pain, sleep, mobility, and mood. The first benefit reported by most participants was improved sleep. Walker also reported lasting benefits, with only "a few" patients requesting an extra treatment for recurring pain; in those cases, 1 treatment was generally sufficient to reduce recurrent symptoms.
Magnet Therapy
Polyurethane Film
Patients with diabetes should be informed regarding PDN, including (1) the risk for development of neuropathies, (2) signs and symptoms of PDN, (3) the possible relationship between poor glycemic control and diabetic neuropathy, (4) the lack of a cure for neuropathic pain, and (5) the availability of treatment for neuropathic pain. The distinction between neuropathic and nonneuropathic pain is important for the patient to understand because the most common medications for treating PDN are not traditional pain medications. Medicines known to help relieve PDN are also used to treat depression and seizures. Patients should be told that antidepressants help relieve pain associated with diabetic neuropathies even though the person is not depressed. Encouraging patients to keep diaries using a visual analog scale to record response to therapy may improve clinical decisions. Because most patients will not achieve complete relief with a single type of therapy, treatment options should be discussed, including the advantages and disadvantages of each. Patients should be reassured that treatment can help and advised that medications need to be taken routinely and at regular times throughout the day. Medication taken only when the pain becomes severe is not as effective as regularly scheduled doses. For each type of therapy, patients need to be aware of possible side effects. For drugs with potential for serious adverse effects, patients should know when to seek medical assistance.
All patients with diabetes are at risk for PDN and should be assessed for adequate glucose control as it has been shown to slow progression of nerve damage. Good glycemic control is essential for prevention and management of PDN, often reducing pain in those with PDN. Neuropathic pain differs from nonneuropathic pain, and patients should be evaluated for characteristics of neuropathic pain (Table 1). Treatment to alleviate symptoms includes pharmacologic and nonpharmacologic therapies (Table 2). TCAs have been widely studied but provide complete pain relief in only a small number of patients, are ineffective for many, and have the potential to cause serious adverse reactions. Anticonvulsants are an alternative to antidepressants, but the older drugs can cause serious or intolerable adverse effects and interact with numerous medications. The newer anticonvulsants (eg, pregabalin; lamotrigine) appear to be the best alternatives to antidepressants. The most promising nonpharmacologic treatment is MIRE. For optimal outcomes, combination therapy with 2 or more treatment options may be considered, as many patients with PDN continue to experience pain with a single treatment. Long-term efficacy needs to be studied for all therapies. Many newer therapies require further research with stronger study designs before they can be definitively recommended. Finally, the potential effectiveness of combination therapies requires investigation.
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Abstract
Assessment
-linolenic acid (GLA), which is essential for healthy nerve
tissue and
myelin.
