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12 Articles in Volume 12, Issue #3
Alternative Medicine in Chronic Migraine: What Clinicians Need to Know
Classic Central Pain Syndromes: Review of Neurologic Causes of Pain
Effective Treatments for Neuropathic Pain
Electric Current and Local Anesthetic Combination Successfully Treats Pain Associated With Diabetic Neuropathy
HCG and Diabetic Neuropathy
Migraine Treatment From A to Z
Opioid-induced Constipation: Causes and Treatments
Pain Management of Diabetic Neuropathy
Partnering With Parents
PPM Editorial Board Discusses Mental Deterioration in Pain Patients
The Critical Necessity to Diagnose Pain That Is Centralized
Unique Use of Near-Infrared Light Source to Treat Pain

Pain Management of Diabetic Neuropathy

A lack of standardization in the diagnosis of diabetic neuropathy and the challenge of symptom management contribute to the lack of a gold standard of treatment for this condition.

Diabetic neuropathy (DN) is estimated to occur in 50% of patients with long-standing type 1 and type 2 diabetes mellitus (DM).1 It is one of the major microvascular complications associated with DM that can cause considerable morbidity and mortality.2 DN presents with a heterogeneous spectrum of clinical and subclinical syndromes.3 It can manifest as mononeuropathy, polyneuropathy, and/or autonomic neuropathy.1 The major complication of somatic neuropathy is foot ulceration, which often leads to gangrene and limb loss. In fact, DN causes 50% to 75% of all ulcerations and nontrauma amputations in the United States4 and causes more hospitalizations than all other diabetic complications combined.3

High Risk of Complications
Risk for chronic complications in DM correlates with the duration of hyperglycemia. Therefore, undetected DM may cause extensive damage to the nervous system. There is a subtle distinction between the deterioration of type 1 and type 2 DM. In type 1 DM, nerve function rapidly deteriorates soon after its onset. By contrast, in type 2 DM, patients often have a long, asymptomatic period of hyperglycemia; consequently, they have subclinical or clinical neuropathic complications at the time of diagnosis.1 In fact, studies have show nerve pathology is present very early in type 2 DM, and nerve conduction velocities (NCVs) are delayed even before diagnosis.5 In addition to the duration of the disease, patient age also has a direct association with the progression of neuropathy.3 Other risk factors for DN include height, hypertension, hypercholesterolemia, cigarette smoking, and alcohol consumption.3

The epidemiology and disease course of DN remain poorly defined, in part because of variable diagnostic criteria, the failure of many physicians to identify and diagnose the disease, and a lack of standardized methodologies for the evaluation of these patients.Of the estimated 50% of patients with diabetes who have DN, 2.7 million have painful neuropathy.7 During the course of the disease, however, the pain subsides and eventually disappears, leaving behind a persistent sensory deficit.8 Because the pain of acute DN may resolve within the first year, analgesics may be discontinued as progressive neuronal damage from DM occurs. Chronic, painful DN is difficult to treat but may respond to a variety of pharmacologic agents. Referral to a pain management center may be necessary if pain is refractory to treatment.1

Diagnostic Difficulties
DN remains underdiagnosed. In the GOAL A1c (Glycemic Optimization with Algorithms and Labs at Point of Care) study, which assessed how often neuropathy is accurately diagnosed, the researchers found that the presence of mild neuropathy was accurately diagnosed in only one-third of all cases.9 Severe neuropathy was accurately diagnosed in 75% of patients evaluated. Evidently, there is a need for elucidating the science of correctly diagnosing DN in a timely manner so that physicians can employ preventive as well as therapeutic techniques.3

A thorough patient history is a prerequisite to making a diagnosis of DN.3 Conducting the assessment solely by the identification of neuropathic symptoms is not useful or accurate in the diagnosis of DN. Symptoms of painful neuropathy should be evaluated with extra caution, because they can arise from other nonspecific causes. It is essential to thoroughly examine and assess both the central and peripheral nervous systems, with emphasis on the nerves most likely to be affected by diabetes.3

The Rochester Diabetic Neuropathy Study, an assessment of tests and criteria for diagnosis and stage severity, proposed two abnormal evaluations (from among neuropathic symptoms, neuropathic deficits, nerve conduction velocity [NCV] tests, quantitative sensory tests, and quantitative autonomic function tests [QAFT]), with one of the two being abnormality of nerve conduction or QAFT. (Decreased heart rate response to deep breathing or the Valsalva maneuver was found to be the most sensitive and objective.)10

Management
Treatment of DN focuses on preventing progression of neuropathy, reducing symptoms, and preventing complications of insensate extremities.3 Successful management of these syndromes must be directed to the individual pathogenic processes.3 Treatment of DN can be broken down into protective and symptomatic.11

Protective
Glycemic control is a crucial factor in the management and prevention of neuropathy. The Diabetes Control and Complications Research Group demonstrated statistically significant effects of intensive insulin therapy on the prevention of neuropathy.12 Tight control of serum glucose can improve symptoms over short time periods, although this has been seen only in uncontrolled trials.13 A simple rule demonstrated that a 1% fall in HbA1c ameliorates conduction velocity by about 1.3 m per second.14 The United Kingdom Prospective Diabetes Study showed that management of glucose levels with intensive treatment was associated with improvement in vibration perception.15 The Steno trial was a stepwise, progressive study that involved treatment of type 2 diabetic patients with angiotensin-converting enzyme inhibitors, Ca2+ channel antagonists, hypoglycemic agents, aspirin, hypolipidemic agents, and antioxidants. The evidence further substantiates the multifactorial nature of neuropathy and the significance of addressing the multiple metabolic abnormalities linked with diabetes.16

Symptomatic
The most challenging facet of DN is the treatment and management of symptoms. The pain from DN can be excruciating and debilitating. Pain typically involves the lower extremities and commonly manifests at rest and is exacerbated at night. Painful DN can occur acutely (lasting <12 months) and chronically. Diabetic polyradiculopathy is a syndrome that presents with severe disabling pain in the distribution of one or more nerve roots; it may be associated with motor weakness. Fortunately, diabetic polyradiculopathies are usually self-limited and improve over 6 to 12 months. Management of painful neuropathy usually requires treatment with antidepressants, anticonvulsants, analgesics, and other pharmacotherapy (see Table, page 20). However, before initiating pharmacotherapy, patients should be informed that 100% symptom resolution usually is not feasible regardless of the treatment plan implemented.17

Despite the effective treatments available for neuropathic pain, alarmingly, almost 25% of symptomatic patients do not receive any medical treatment at all.18 Upon initiating medications, simple measures are tried first. Generally, small-fiber (C fibers) neuropathy manifests before large fiber (A fiber); consequently, many patients complain of burning and discomfort in their feet.19 Small fibers also can be seen in peripheral sympathetic nerve fibers.3 Sympathetic blocking agents, such as clonidine, phenoxybenzamine, or regitine, may improve the pain secondary to spontaneous firing of the nerve fibers.3 However, the loss of sympathetic regulation of sweat glands and arteriovenous shunt vessels in the foot predisposes to bacterial infections, which may result in cellulitis and ulcers.3 Furthermore, these pain fibers carry the neurotransmitter substance P, which is targeted by capsaicin. Capsaicin is a powerful alkaloid that depletes substance P by local application. This diminishes the transmission of painful stimuli from the peripheral nerve fibers to higher nervous system centers.20 Of the topical therapies available, only capsaicin has been found to significantly improve function and reduce pain21; however, because of its weaker efficacy, it should be considered as ancillary therapy.22

A-fiber pain is described as a deep-seated, dull, and gnawing ache that typically does not respond to the previously mentioned therapies.3 The pain associated with this type of nerve fiber has shown response to nerve blocks, tramadol, dextromethorphan, and antidepressants.3 In addition, insulin infusion at a rate of 0.8 to 1.0 units per hour without decreasing serum glucose helps bring about pain resolution in approximately 48 hours.23 FDA-approved drugs for diabetic polyneuropathy include duloxetine (Cymbalta) and pregabalin (Lyrica).

However, because there is great variability between patients, these should not be interpreted as being superior to the other drugs available for the treatment of DN.11 One study compared the efficacy of the tricyclic antidepressants (TCAs) amitriptyline and desipramine and the selective serotonin reuptake inhibitor (SSRI) fluoxetine.24 Amitriptyline and desipramine had comparable efficacy, with the latter having fewer adverse effects. The study revealed fluoxetine to have efficacy similar to that of a placebo.24 Another study found TCAs to be more effective for short-term pain alleviation than any of the newer anticonvulsants, including pregabalin.25 Controlled-release oxycodone was illustrated in two studies as being more efficacious than placebo.26,27

Furthermore, a series of placebo-controlled studies has illustrated that α-lipoic acid, an antioxidant nutritional supplement, can alleviate pain associated with DN. A trial revealed that 600 mg per day of α-lipoic acid taken orally effectively diminished pain within 2 weeks of onset of therapy.28 This trial also demonstrated improvement in symptoms of numbness and paresthesia.28 Alpha-lipoic acid is an effective adjunctive therapy because of its ability to reduce both pain and neurologic deficits with few adverse effects.11 Other medications, herbal remedies, and additional forms of non-drug therapies have been attempted, such as transcutaneous electrical nerve stimulation (TENS), static magnetic field therapy, and acupuncture, but data on these therapies are limited.

Although there are a multitude of treatment options for the alleviation of DN pain, identifying a single superior approach has not been established. A general approach in the management of DN, after excluding non-diabetic etiology and stabilizing glycemic control, is to initiate therapy with either an antidepressant (eg, amitriptyline or duloxetine) or an anticonvulsant (eg, valproic acid or gabapentin). Alpha-lipoic acid should be used as an adjuvant, given its safety profile.11 If patients’ symptoms are still refractory to treatment, consideration can be given to newer medications, such as duloxetine and pregabalin. However, they are not superior to older, less costly medications.11 An opioid medication (morphine sulphate or oxycodone) also can be supplemented; however, caution of the potential for serotonin syndrome should be taken if the patient also is taking an antidepressant.29

Case Report 1
A 52-year-old woman with a history of lumbosacral disk disease presents with diabetic polyneuropathy that was diagnosed 6 years ago. The onset of symptoms began 8 years ago and initially was attributed to plantar fasciitis because of the initial presentation of unilateral foot pain. The pain later extended to the other foot, and she was worked up for neuropathy. The electrophysiologic testing revealed a mild axonal polyneuropathy. Because of her diagnosis of DM 1 year prior, the patient was given a diagnosis of diabetic polyneuropathy. Her neuropathic symptoms of numbness, tingling, pain, and bilateral burning were exacerbated. Her symptoms seemed to worsen when her diabetes was not adequately controlled. She tried a variety of medications with moderate relief. She discontinued amitriptyline because of the intolerable side effects of xerostomia (dry mouth). She tried topiramate and gabapentin, which were not found to be helpful. Her pain was treated with lidocaine patches and duloxetine 60 mg. The patient was prescribed trazodone 100 mg at bedtime and 5 mg/325 mg oxycodone/acetaminophen as needed. She also uses alternative treatment, including arnica cream. Additionally, she is taking a series of medications that treat her metabolic abnormalities. The duloxetine and lidocaine patches provide some pain relief, but she remains in considerable discomfort.11

Case Report 2
The patient is a 73-year-old woman with a history of ventricular arrhythmias, hypertension, angina pectoris, and cerebrovascular accident. She was diagnosed with painful DN in the left lower extremity 3 years prior. The patient described the pain as severe burning in the left lower extremity in a stocking-like distribution below the knee. She also complained of burning pain in the lateral aspect of the left hip and a focal aching pain in the anterior aspect of the right ankle. She attempted capsaicin cream at home to manage the pain, which she found ineffective. Therapeutic exercise and functional training were administered to the patient twice daily, 6 days per week for a total of 24 days. The pain was unchanged from the initial assessment.

Six days after referral for physical therapy, she was placed on oral acetaminophen and hydrocodone, alprazolam (benzodiazepine-class drug), and nortriptyline (TCA) given at recommended doses. Seven days after referral for physical therapy, the patient received TENS at a frequency of 80 Hz to the lumbar area of the back for 1 to 2 hours per day and during the entire night. On the first day of therapy, she reported a 38% reduction in intensity of pain following 20 minutes of TENS. After 17 days, the patient reported no pain after 20 minutes of TENS and was able to sleep through the night. Pain scales, visual diagrams, and visual analog scales were used to assess perceived pain.30

Case Report 3
The patient is a 47-year-old woman with a history of asthma, hypertension, paroxysmal atrial fibrillation, and hypercholesterolemia. She was diagnosed with type 2 DM 6 years prior. She developed severe peripheral neuropathy 2 years after the diabetes diagnosis was made. The patient initially complained of cold extremities during the summer and later developed numbness, tingling, and heaviness bilaterally with occasional burning sensations. She also complained of severe muscle cramps. An electromyogram revealed diffused peripheral neuropathy consistent with diabetes. She was placed on a trial of gabapentin 1,200 mg daily and ibuprofen 800 mg three times daily with little to no change in symptoms. She was then started on amitriptyline but was unable to tolerate the side effects of the medications. Because of her progressing neuropathy, she eventually started using a walker because of the pain and difficulty ambulating. The patient was then referred to a neurologist, who discontinued her gabapentin and ibuprofen and initiated topiramate 25 mg twice daily. The severe muscle cramps in her feet improved, after which there was gradual improvement of her other symptoms. Initially, the topiramate dose was increased to 100 mg twice daily, but she was unable to tolerate the side effects of jitteriness, nervousness, and sleep difficulties. She was tapered back down to 25 mg twice daily, and her dosage was slowly titrated up to 100 mg twice daily over several months. Her symptoms of cold sensation, shooting pains, and numbness began to improve. However, after the topiramate was started, she began to experience hypoglycemic reactions, which were controlled after the dosages of her hypoglycemic medications were altered. Other than experiencing difficulty with sleep, which occurred when she took the medication too late in the evenings, the patient has tolerated topiramate well. Her neuropathy symptoms have not exacerbated since.31

Summary
DN is a debilitating condition that affects patients’ quality of life and ability to function. It is crucial to exclude non-diabetic etiology with a thorough workup in order to administer appropriate therapy. After stabilizing glycemic control and adequately managing metabolic abnormalities, treatment can be initiated for DN pain symptoms. There are a variety of treatment options available for the alleviation of DN pain. Treatment options should be catered to the individual, given that treatment response will vary. However, physicians should keep in mind that treatment efficacy can be slight, side effects can be intolerable, regaining or improving physical function may be limited, and newer treatments can be costly.32

Last updated on: June 12, 2012
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