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11 Articles in Volume 6, Issue #4
Assessing Secondary Gain In Chronic Pain Patients
Chronic Overuse Sports Injuries
Introducing Low Level Laser Therapy to Pain Management
Managing Diabetic Peripheral Neuropathic Pain (DPNP)
Moral Virtue and the Pain Physician
Non-pharmacologic Therapy for Chronic Opioid-dependent Sickle Cell Pain
Osteoarthritis of the Knee
Smoking and Low Back Pain
Temporal Tendinitis Migraine Mimic
The Underutilization of Intrathecal Treatment
Tumblin’ Dice–Why Does Random Matter?

Managing Diabetic Peripheral Neuropathic Pain (DPNP)

A review of the diagnosis, evaluation, and treatment of diabetic peripheral neuropathic pain.

Because of the prevalence of overweight (BMI 25-29.9) and obesity (30-39.9) in the United States, the incidence of diabetes is increasing.1 By the year 2010, the World Health Organization (WHO) estimates that there will be 220 million people with this disease worldwide.2 These statistics demonstrate the need to educate the physician not only about diabetes prevention and management, but also the treatment of its many complications, including peripheral neuropathy. Nearly a quarter of diabetics suffer from diabetic peripheral neuropathy now and up to 50% of all diabetics develop peripheral neuropathy after 25 years of having their disease.3 The annual incidence rate is 2%.4 Patients with diabetic peripheral neuropathy manifest painful symptoms, which are commonly characterized as burning, aching, tingling, cold, lancinating, allodynia, and/or numbness. Numerous therapeutic agents are available but there is no single therapeutic agent available that is without adverse effects and is completely effective for the general diabetic population.

Figure 1. Approach to Pain Management

Pathophysiology

There are several proposed mechanisms that alter the neural structure and predispose a patient for the development of peripheral neuropathy. These include advance glycation end products (AGEs), protein kinase C (PKC), oxidative stress, and the Polyol pathway, all of which ultimately lead to the damage of nerves. Understanding more about these individual pathophysiologic changes is important for two reasons. First, these mechanisms serve as a basis for the pharmacological action of various medications such as PKC inhibitors, which are now in clinical trials. In contrast, most of the currently recommended pharmacologic agents target the aberrant or ectopic neural signaling which are consequences of the neural damages. Second, hyperglycemia has been suggested as a catalyst for the neural tissue’s conversion from normal physiologic behavior to the pathologic state pain-producing state. Therefore, there is an emphasis on good glucose control for the prevention of pain and the progression of diabetic peripheral neuropathy.

Beyond the mechanisms of neural destruction, the types of nerves damaged translate into the pattern of clinical symptoms and signs that the patient may report and exhibit. Small nerve fiber damage produces abnormalities in the sensation of temperature, light touch, pin prick, and pain typically experienced in the early stages of DPN.5 Later, large nerve fiber damage produces diminished vibration sensation, position sense, muscle strength, sharp-dull discrimination, and two-point discrimination.5

Table 1. Pathophysiologic Mechanisms Involved in the Development of Diabetic Peripheral Neuropathy
Advanced glycation end products (AGES) Formed during the Maillard reaction, advanced glycation end products (AGEs)6 act on specific receptors (RAGEs), inducing monocytes and endothelial cells to increase the production of cytokines and adhesion molecules.7 AGEs can form cross-links in matrix structural proteins induce mutagenesis of bacterias, physiologically increase in number as patient ages, and in pathologic states like diabetes and renal failure.6
Protein Kinase C (PKC) A family of 12 isoenzymes, PKC is activated by phosphorylation and is involved in intracellular signaling and binding to the second messenger diacylglycerol.4 Conditions with increased levels of glucose have found increased levels of PKC and diacyclglycerol in retinal, aortic, and renal tissue but decreased in neural tissues.4 However, PKC inhibitors studies suggest improvement in Na+-K+ ATPase activity, which contributes to the diminished NCV in diabetes.4
Oxidative Stress Radicals are generated from glucose metabolism to produce ATP. 4 Radicals, such as superoxide anion, are capable of profound tissue damage as well as diacyclglycerol synthesis, which activates PKC.4
Polyol Pathway This is generally a physiologic catabolic pathway supplied by intracellular glucose. It becomes pathologic when excessive glucose increases the reduction and regeneration of glutathione requiring NADPH. This results in an imbalance NADHPH/NAD ratio that causes depletion of glutathione, increases AGEs, and activates PKC and diacylglycerol4. The first redox reaction of this pathway produces sorbitol. Accumulation of this compound was once thought to be destructive to nerves; however, a study was conducted showing insignificant levels of sorbitol in diabetic patients.4
Table 2. Diagnosis of Impaired Glucose Tolerance and Diabetes Mellitus based on Fasting Plasma Glucose and Random Blood Glucose10
Diabetes Mellitus (DM)
  1. Fasting plasma glucose greater than or equal to 126 mg/dl on two occasions or
  2. Random blood glucose greater than or equal to 200 mg/dl with symptoms of diabetes
Impaired Glucose Tolerance (IGT)
  1. 1. Fasting plasma glucose greater than 140 mg/dl at 2 hours after a 75-g glucose load or
  2. 2. Plasma glucose 140-199 mg/dl with 1 intervening plasma glucose value greater than or equal to 200 mg/dl

Clinical Encounter

During the clinical encounter, there are several points that must be considered for patients with suspected diabetic peripheral neuropathy. First, some patients may not reveal symptoms immediately, but these can be detected through proper inquiry. There are also patients who are asymptomatic, but manifest signs during the physical exam. To elicit these signs, there are several tests that can be performed such as checking for pinprick sensation, temperature sensation, vibration perception with a 128-hz tuning fork, pressure sensation using a 10-g microfilament at the distal halluces, and the ankle reflexes.8 Having more than one abnormality noted gives a >87% sensitivity in detecting diabetic peripheral neuropathy.8 These simple measures are not only sensitive for the detection of diabetic peripheral neuropathy, but help to predict further complications associated with diabetes. The combined loss of the 10-g monofilament pressure sensation and reduced vibration perception predicts the real risk for developing foot ulcers.8

Second, although diabetes is the most common cause of peripheral neuropathy, there are other causes that may produce neuropathy in a diabetic patient. Therefore, this patient may have symptoms of peripheral neuropathy that are not necessarily related to his diabetes. Careful consideration of the potential differential diagnosis of lower extremity pain is warranted, and this may include easily correctable conditions such as vitamin B12 deficiency and hypothyroidism, or more ominous ones such as uremia.

Neuropathy Diagnostics. Specialized diagnostic studies such as nerve conduction velocity, nerve biopsy, and skin biopsy may be necessary to confirm the exact type of neuropathy. Nerve conduction velocity studies are commonly done to rule out other causes of neuropathy, and not just to rule in diabetes peripheral neuropathy.

Nerve biopsy is not routinely performed, but reveals the involvement of unmyelinated fibers which are often missed by commonly used electrophysiological studies.3 The nerve that is usually selected for biopsy is the sural nerve. However, there are many complications associated with this procedure such as persistent pain at the biopsy site, cold intolerance, unpleasant though mild mechanically elicited sensory symptoms, and sensory deficits in the sural distribution.7

An alternative to nerve biopsy, skin biopsy may be performed thanks to the development of a monoclonal antibody against gene product 9.5.2 This antibody acts as a panaxonal marker by allowing the visualization of small sensory fibers in the epidermis. These fibers are believed to be involved in the early stages of neuropathy.2 This procedure has advantages over nerve biopsy:, it requires less tissue to be taken (only 3mm of skin7) and appears to be a more sensitive measure of small-caliber sensory nerve fibers.2

Impaired Glucose Tolerance (IGT). Third, symptoms of peripheral neuropathic pain often manifest in patients only diagnosed with impaired glucose tolerance (IGT). Like early diabetic neuropathy, only small nerve fibers are involved in IGT compared to both small and large nerve fibers in later stages of diabetes.9 It is suggested that IGT neuropathy is a reversible precursor to diabetic neuropathy.
2 With this premise, it is advisable to perform an Oral Glucose Tolerance Test (OGTT) on patients with no prior history or family history suggestive of diabetes, but exhibiting symptoms of peripheral neuropathic pain (refer to Table 2).

Table 3. Pharmacologic Agents for Glucose Control
Drug Mechanism of Action Side Effects
Sulfonylureas Stimulate insulin release from the pancreas Hypoglycemia, disulfiram-like reactions
Biguanide(Metformin) Inhibit gluconeogenesis and increases glycolysis Gastrointestinal disturbances, lactic acidosis, weight loss
Glitazones Increase peripheral sensitivity to insulin Weight gain, hepatotoxic
Alpha-glucosidase inhibitors Inhibit intestinal Alpha-glucosidases, therefore decreasing glucose absorption from intestines Gastrointestinal disturbances
Insulin In liver - increase conversion of glucose to glycogenIn adipose tissue - increase triglyceridesIn muscle – participates in the synthesis of glycogen and protein Hypoglycemia, hypersensitivity reaction, preliminary injection may induce transient neuritis
Table 4. First Line Medications
Name Precautions Contraindications Side Effects
Tricyclic Antidepressants Monitor EKG before starting TCA for patients greater than 40 years old3 Significant cardiac conduction disease, Long QT syndrome, MI within 6 months, ventricular arrhythmias, frequent premature contractions,3 glaucoma, suicidal ideation Anticholinergic effects, convulsions, coma, arrhythmias
Oxycodone High addictive potential Pseudomembranous colitis, respiratory depression Constipation, respiratory depression, pinpoint pupils
Duloxetine Avoid using with MAO inhibitors Narrow angle glaucoma,13 renal clearance <30 ml/min13 Anorexia, constipation, insomnia, GI disturbances
Pregabalin Rhabdomyolysis Edema, dizziness
Table 5. Second Line Medications
Drug Type Adverse Effects
Gabapentin Anticonvulsant Sedation, ataxia, confusion, diarrhea, headache, nausea
Carbamezapine Anticonvulsant Elevated LFT, agranulocytosis, aplastic anemia, diplopia, ataxia
Lamotrigine Anticonvulsant Steven-Johnson syndrome, toxic epidermal necrolysis
Tramadol Opioid Seizures
Venlafaxine Serotonin and norepinephrine reuptake inhibitor Anxiety, headache, insomnia

Preventive Pain Management

Controlling hyperglycemia not only helps prevent the development of DPNP, but it also delays its progression (refer to Figure 1). Observational studies suggest that good glucose control and avoidance of extreme blood glucose fluctuations improve neuropathic symptoms.8 In fact, the United Kingdom Prospective Diabetes Study (UKPDS) showed that progression of disease depends on management of glucose in both type I and type II diabetes.4

Lifestyle Modifications. The initial approach to glucose control is with lifestyle modifications. One lifestyle modification is weight loss. In the geriatric population, a 7% reduction in weight and 150 minutes of moderate exercise weekly is recommended.11 Others, such as improvement of lipid and blood pressure indexes, smoking cessation, and alcohol drinking reduction are recommended even if there are no definitively positive preventive studies.8

Pharmacologic Intervention. Pharmacologic intervention is encouraged only after the lifestyle modifications have failed (refer to Table 3 and Figure 2). These are dependent on several factors such as: 1) the type of diabetes; 2) body mass index (BMI); and 3) any associated comorbidities. The first factor to be determined is the type of diabetes the patient suffers from. Type I diabetics usually have decreased production of insulin whereas Type II diabetics have peripheral resistance to insulin action. Distinguishing features of Type I diabetes include an insulin and/or C-peptide level below 5 mU/mL, and glutamic acid decarboxylase antibodies.10 However, type II diabetics may have insulin or C-peptide levels below 5 mU/mL when glucose levels exceed 300.10 The next factor is Body Mass Index, which is (weight [kg])/(height [m]).2 A BMI of 25-29.9 is considered overweight, a BMI of 30-39.9 is considered obese, and a BMI>40 is considered morbidly obese. The final factor is the presence of associated comorbidities that may influence which pharmacologic agents are ultimately selected. These comorbidities include gastrointestinal, renal, and hepatic pathologies.

To ensure that these therapies reduce hyperglycemia, it is necessary to monitor blood glucose levels regularly, and Hemoglobin A1c levels every three months. The goal for Hemoglobin A1c is generally

It is important for diabetic patients to have good foot care. This involves the wearing of comfortable, well fitting shoes, and the daily inspection of the feet for dry or cracking skin, fissures, planter callus formation, and signs of infection.

Pain Management Options for DPNP

There are numerous agents, both nonpharmacologic and pharmacologic, available for DPNP and each has some risk of adverse side effects. Careful selection of the appropriate agent depends upon a thorough understanding of the patient’s history, such as past medical history and current medications taken, and the findings from the physical examination. It is also important to educate the patient about the agent chosen and note any precautions or adverse side effects it might cause. With the current therapies available, there is no guarantee that the patient will receive 100% relief from any of these interventions.13

There have been investigations into nonpharmacologic agents such as acupuncture, magnets, and transcutaneous electrical nerve stimulation. Only acupuncture has some evidence that it may be effective for the control of DPNP.13

As stated earlier, the pharmacologic agents recommended for diabetic peripheral neuropathic pain do not reverse or inhibit the pathological mechanisms leading to neural damage, but modify the transmission of neural signals interpreted as pain. These agents have been investigated in clinical trials to determine their efficacy in diabetic peripheral neuropathic pain. A common index used was “numbers needed to treat/numbers needed to harm" (NNT/NNH) ratio, where a value of 1 suggested a relatively ineffective and potentially more toxic medication.3 The extent of pain relief was also evaluated where there was a change in pain intensity score of 30-50%, signifying that the change was clinically meaningful.14

According Argoff et al, the first-line or first-tier medications for DPNP include duloxetine, pregabalin, oxycodone CR, and the class of tricyclic antidepressants.13 Each of these were chosen to be included in this criteria by reviewing the evidence from randomized placebo controlled clinical trials and their application in clinical practice.13 Only duloxetine and pregabalin are FDA approved for the treatment of DPNP. However, tricyclic antidepressants are still the most commonly prescribed agents despite their significant toxicity and potential for lethality13 (refer to Table 4: First Line Medications).

Tricyclic antidepressants (TCAs). Tricyclic antidepressants (TCAs) inhibit reuptake of serotonin and/or norepinephrine in the presynaptic membrane, and modulate sodium channels and NMDA receptors.15 TCAs include amitriptyline, imipramine, desipramine, nortriptyline, clomipramine, and other agents. Amitriptyline has been the most studied of the TCAs and has been found to be effective for pain, independent of its effect on depression.13 Desipramine was compared to amitriptyline and was found to be better tolerated by patients despite no significant difference in pain reduction.13 Nortriptyline with fluphenazine has been compared with the anticonvulsant carbamezapine and found to be equal in pain relief.13 TCAs are not without adverse effects. They are associated with anticholinergic effects (dry mouth [xerostomia], constipation, dizziness, blurred vision, and urinary retention), cardiac arrhythmias, and coma. Tertiary TCAs such as amitriptyline have more pronounced anticholinergic effects than secondary TCAs such as nortriptyline.

Pregabalin. Pregabalin is a selective high affinity ligand for alpha2-delta protein subunit of voltage-gated calcium channels, which play a role in the development of pathologic changes believed to be associated with neuropathic pain in humans.16 These agents reduce calcium influx and, subsequently, the release of several neurotransmitters associated with analgesia such as glutamate, substance P, and calcitonin gene-related peptide (CGRP).17 Compared to gabapentin, pregabalin exhibits linear pharmacokinetics across its therapeutic dose range, with low inter-subject variability, unlike the less-than-proportional pharmacokinetics observed with increasing doses of gabapentin.17 Pregabalin has no known drug-drug interactions, but requires titration to higher doses for effect, and dosage adjustments for renal insufficiency.13

Duloxetine. Duloxetine, serotonin-norepinephrine reuptake inhibitor, has shown promise as an effective initial agent for DPNP. The trials used to investigate its potential to relieve DPNP took into consideration its effect as an anti-depressant by excluding candidates with any history suggestive of depression. This has minimized the possibility that pain relief was secondary to the treatment of depression.18 However, this does not exclude the possibility of subclinical depression. At a dose of 120 mg/d duloxetine has shown improvement in shooting, stabbing, hot-burning, and splitting pain sensations and at 60mg/d patients it has shown improvement in stabbing and sharp sensations.19 One limitation of clinical trials for duloxetine is that candidates were not representative of the general population due to the study designs. Therefore, further investigations of duloxetine with patients having comorbidities may be necessary. This is true for all newly launched medications in the past decade.

Oxycodone CR. Oxycodone CR is an opioid agonist designed to slowly release oxycodone over many hours. Just like all of the other opioids analgesics, oxycodone has historically been considered after other pharmacologic agents have failed for the treatment of DPNP.14 Oxycodone is often initially given in one of its short-acting forms, slowly titrated to an effective dose with minimal adverse effects, and then converted to the long-acting form once the effective dose has been determined.11 One of the concerns associated with opioid use in general is the addictive potential; but for patients with no substance abuse history, this potential is low.14

If the first-line medication is not effective or the patient suffers from significant side effects, the physician may chose to replace the medication with another first-line agent or a second-line agent. According to Argoff et. al, second-line or second-tier medications include carbamezapine, gabapentin, tramadol, lamotrigine, and venlafaxine ER13 (refer to Table 5: Second Line Medications).

Gabapentin. Gabapentin is an alpha2-delta ligand anticonvulsant much like pregabalin. Its effect on pain is related to its interaction with the L-amino acid transporter, alteration of the release of GABA, high affinity for alpha2-delta subunit of voltage-activated calcium channels, inhibition of voltage-activated sodium channels, and alteration of monoamine neurotransmitter release, and blood serotonin levels.20 It is renally excreted and crosses the blood brain barrier. In trials comparing its effect with TCAs such as amitriptyline, the pain relief was equal, but the onset was more rapid.20 It also markedly improves sleep.3

Although it has been suggested it is preferable to select medications that modify sodium and calcium ion channels and neurotransmitter release, the exact mechanism of action for carbamezapine is unknown. A trial comparing carbamezapine with nortriptyline-fluphenazine found it to be equally in degree of pain relief with less adverse effects.13

Tramadol. Tramadol is a “central acting analgesic with unique properties as a weak inhibitor of norepinephrine and serotonin and low affinity binding to mu receptors."13 Several trials have found it to provide pain relief. However, this agent has not been shown to improve sleep in patients with pain, is associated with adverse effects such as seizures at higher doses, requires that 4 doses per day be given in order to be most effective, and has an abuse potential.13

Lamotrigine. Lamotrigine is an anticonvulsant believed to inhibit glutamate release by stabilizing neural membranes through blocking of the sodium channels.21 It has been found to produce pain relief in both AIDS-related neuropathy and DPN. However, it is associated with adverse cutaneous effects which may limit its use in the general population.

Venlafaxine. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor. Two trials have been conducted suggesting its effectiveness in DPNP. It has an advantage of once daily dosing with the ER formulation.13

Figure 2. Approach to Glucose Control

Conclusion

The increased incidence of diabetes, secondary to the prevalence of overweight and obesity1 demands proper education for the diagnosis and management of diabetes, including its complications, such as diabetic peripheral neuropathy (DPN). Numerous studies have investigated the possibility of a monotherapeutic approach for DPNP management. Results are promising, but many have adverse effects and the candidates in these studies are not generally representative of the general population who are typically afflicted with comorbidities or have social/personal considerations such as issues of compliance and medication cost. DPN’s management has prompted numerous trials involving pain medications. Finding the right pharmacologic agent is as challenging as diagnosing the patient, since there are several variables to consider, from comorbidities to drug-drug interactions. Even when the right agent is determined, it does not necessarily relieve the pain 100%. Physicians should not just treat the pain, but also treat the underlying cause—hyperglycemia. Physicians must manage patients on multiple levels and using both nonpharmacologic and pharmacologic methods in a multi-disciplinary, multi-functional strategy to mitigate initial pain onset and manage progression to other complications. n

Last updated on: May 16, 2011
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