Diabetic Peripheral Neuropathic Pain
Authors: Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida School of Medicine, Gainesville; and George P. Samraj, MD, Associate Professor, Community Health and Family Medicine, University of Florida, Gainesville.
Peer Reviewer: Petre Udrea, MD, Board Certified Neurologist, Private Practice, Dayton, OH.
Introduction
Diabetic Peripheral Neuropathic Pain (DPNP) is an important pain syndrome that has not received attention commensurate with its clinically and epidemiologically compelling presence. Bilateral symmetrical distal polyneuropathy is the most common neuropathy seen in diabetic patients, and DPNP is the common pain syndrome associated with it.
Diabetic peripheral neuropathy (DPN) is the antecedent defect leading to DPNP in patients with long-standing diabetes. (See Table 1 below for abbreviations used in this issue.) Although DPNP can be readily seen to be consequential to quality of life, DPN and DPNP merit the energies of clinicians because diabetes remains the number one cause of atraumatic limb loss in the United States. DPN appears to be the critical element ultimately leading to this limb loss. Since limb loss in diabetics contributes to mortality, the chain of events beginning with DPN and culminating in limb loss can legitimately incriminate DPN as a culprit.
| Table 1. Abbreviations |
|
A1c = Glycosylated Hemoglobin A ALDO = Aldolase Reductase BPI = Brief Pain Inventory DCCT = Diabetes Control and Complications Trial DPN = Diabetic Peripheral Neuropathy DPNP = Diabetic Peripheral Neuropathic Pain DSP= Distal Symmetric Polyneuropathy ICDF = International Consensus of the Diabetic Foot NCV = Nerve Conduction Velocity SNRI = Serotonin and Norepinephrine Reuptake Inhibitors SSRI = Selective Serotonin Reuptake Inhibitors TCAs = Tricyclic Antidepressants UKPDS = United Kingdom Prospective Diabetes Study WNL = Within Normal Limits |
Neuropathic pain syndromes often are viewed as difficult to treat by primary care clinicians. Since 2005, pharmacotherapeutic evolution has provided the first FDA-approved tools for treatment of DPNP. Familiarity with the epidemiology, pathophysiology, diagnosis, and treatment of DPNP should be comfortably within the grasp of all primary care clinicians who deal with diabetic patients.
Epidemiology
As of 2005, 20.8 million people (7% of the U.S. population) have diabetes. As many as one-third of these are unaware they have diabetes: hence, 6.2 million have diabetes and are not diagnosed. Because age is directly related to diabetes prevalence (9.6% of adults older than 20 years and 20.9% older than 60 years have diabetes), the burgeoning population of senior citizens predicts an ever greater population of diabetics unless disease modifying interventions are identified.1
DPN: Where Are We Today?
The American Diabetes Association (ADA) initiated a telephone survey in 2005 with startling results about the state of patient knowledge and familiarity with DPN. Fewer than half of diabetics with established DPN (42%) reported that they had been informed by their physician that diabetes was the cause. Only 25% of persons with typical symptoms of DPN had a diagnosis of diabetic peripheral neuropathy, and the majority of interviewed diabetics (n = 8,119) said they had never heard of diabetic neuropathy.2 Hence, there is much groundwork to be accomplished in education of both clinicians and patients about DPN.
Consequences
DPNP has a profound impact upon quality of life.3,4 Studies of subjects with DPNP indicate that patients report poor sleep, poor physical mobility, and negative effects upon overall energy, enjoyment of life, social activities and employment.3 A study of 105 patients with DPN employed the Neuropathic Pain Score and Brief Pain Inventory (BPI) to assess impact of DPNP upon patients' lives. In addition to providing a metric for severity of pain, the BPI queries patients (by self-report) about the impact that pain had upon activities of daily living. The self-reported BPI indicated that DPNP had the greatest impact upon sleep, overall enjoyment of life, and recreational activities; it also negatively impacted general activity, mobility, work, and social activity.5
Consequences of DPN go beyond the quality-of-life category. The increased amputation rate from foot ulceration often leads to lower limb amputations, with subsequent increases in mortality.6 It generally is recognized that DPN is the most important risk factor that leads to foot ulceration and limb loss.
Treatment: How Are We Doing?
Through the year 2004, at which point there were no pharmacologic treatments specifically approved for DPNP, treatment required off-label use of agents such as anticonvulsants (e.g., valproic acid, gabapentin) and antidepressants (e.g, amitriptyline, desipramine). Opioid analgesics have been determined to be efficacious, but doses required encounter the same limitations as antidepressants and anticonvulsants: adverse effects.7
Definitions
Before going further into the scope of the problem and diagnosis, it is important to understand a few definitions.
Distal Symmetric Polyneuropathy (DSP) is the most common form of neuropathy seen in diabetics, and usually manifests as burning pain, loss of proprioceptive and vibration sense, motor weakness, or autonomic dysfunction. Pain is seen most commonly in both lower extremities, although similar symptoms in the upper extremities may occur, albeit typically later in the course of neuropathy. In the primary care setting, DPN usually presents as bilateral burning pain, accompanied with paresthesias and numbness.8
Neuropathic pain is defined as symptoms resulting from insult to or dysfunction of the central and/or peripheral nervous system.
Allodynia refers to pain in response to what normally would not be perceived as a noxious stimulus.
Hyperalgesia refers to augmented pain perception of what typically would be perceived as a noxious stimulus.
Positive neuropathic symptoms: tingling, burning, or prickling sensations, sharp pains, and touch hypersensitivity.9,10
Negative neuropathic symptoms: numbness, insensitivity, loss of proprioceptive sense, loss of balance.9,10
Scope of the Problem
DPN appears to be the consistent predecessor to DPNP. The prevalence of either disorder is difficult to ascertain because of variability in diagnostic criteria8 and relative lack of large population data. DPN prevalence rates and diagnostic criteria vary widely. For instance, DPN prevalence rates in literature range from 0%-93%.8 One population study reported that some degree of neuropathy was present in 66% of diabetics.10 Because DPN may have sensory, motor, and/or autonomic components, reported prevalence rates depend upon whether investigators seek each form of neuropathy and the sensitivity of the tools chosen to detect neuropathy. Looking at the prevalence of DPN symptoms, Kastenbauer, et al found that more than half of type 2 diabetics had one or more sensorimotor or autonomic symptoms when screened with the Michigan Neuropathy Screening Instrument.12 Vinik, et al report a study in which DPN was defined as the absence of an Achilles tendon reflex in combination with signs or symptoms of polyneuropathy, in which 7% of diabetics had DPN within 1 year of receiving the diagnosis of diabetes, and half of persons with long-standing diabetes (25 years) fulfilled the diagnostic criteria.8 Suffice it to say that neuropathic symptoms are sufficiently common that all clinicians who provide care for diabetics will encounter them on a regular basis.
Only a minority of patients with DPN, perhaps 10-20%, subsequently will develop DPNP.13-16
Pathology and Pathophysiology
The etiology of DPN and DPNP remain unknown. Clinicians will recall that DPN is amongst the cluster of cardinal diabetic consequences known as microvascular disease: retinopathy, nephropathy, and neuropathy. This reflects a prevailing hypothesis that neuropathy occurs because of disease of the microvasculature supplying the nerves—the vasonervorum. There is no question that diabetics have diffuse, early dysfunction of the endothelium, resulting in exaggerated risk for macrovascular endpoints in multiple organ systems (e.g., myocardial infarction, stroke, peripheral arterial disease). This same endothelial dysfunction that is associated with macrovascular endpoints might certainly be culpable for impaired microcirculation to the nerves. Giving some support to this concept is the favorable response seen in a pilot trial of a topical nitric oxide donor in DPNP patients. (See section on Treatment.)
Another recently popular theory of etiology refers to the polyol system. Because decreased nerve conduction velocity (NCV) is seen in demyelinated nerves, and DPN usually develops decreased NCV, it has been theorized that demyelination may be a primary defect. The enzyme aldolase reductase (ALDO) plays a major role in the glucose metabolism of neuronal tissue. In the state of ambient hyperglycemia, excess glucose enters the polyol pathway and is converted to sorbitol by ALDO; sorbitol then is converted to fructose by sorbitol dehydrogenase. Accumulating sorbitol and fructose tend to collect inside the nerve cell and osmotically absorb water. Concomitant changes in NADPH and glutathione lead to accumulation of intra cellular sodium with subsequent neuronal destruction. A pharmacologic agent specifically targeting this enzyme, hoping to block diversion of the higher ambient glucose levels to the polyol pathway, failed to show a favorable impact upon DPN, despite some evidence of efficacy in animal studies.
Another promising etiologic theory involves toxicity of what are known as advanced glycation endproducts. (AGE). Clinicians are quite familiar with the advanced glycation endproduct of hemoglobin known as hemoglobin A1c. Other proteins like lipoproteins, fibrin, collagen, and albumin also undergo glycation. In the presence of elevated intracellular glucose levels, glucose can integrate by covalent bonding into diverse proteins by the non-enzymatic method known as glycation. Some proteins that are glycated have altered natural function. Additionally, glycated proteins may cross-link and produce advanced glycation endproducts, which cause tissue damage, including nerve damage.17 In consonance with the microvascular aspects of nerve damage, when AGEs accumulate, they bind with endothelial cells resulting in increased vascular permeability, enhanced endothelium-dependent coagulation activity, and interference with production of endothelial nitric oxide (NO). Impaired endothelial function compromises blood flow.
In theory, pharmacologic agents that block activity of Protein Kinase C (PKC) might favorably affect production of AGE. Figure 1 shows some of the potential pathologic roles of AGE that might be obviated by an effective PKC blocker.18
| Figure 1. AGE and Metabolic Alterations that May Lead to DPNP |
|
Although the defects that lead to DPN and DPNP remain to be confirmed, the pathology of the progressive disorder is well described. The nerve damage usually is insidious, and slowly progressive. DPN has a predilection for the longest axons, which explains why symptoms in the feet generally are seen first, but the hands may be involved later in the disease. Similarly, the vagus nerve, which is the longest autonomic nerve, is affected prior to shorter nerves,8 hence the commonplace experience of diabetic gastroparesis.
Nerves undergo damage to both small fiber and large fiber systems, but usually small fiber dysfunction precedes that of the large fibers, and sensory loss occurs prior to motor loss. This progression becomes important when nerve conduction testing is considered, since pain symptoms are primarily modulated through the small fiber nerves, but nerve conduction testing monitors large fiber nerve function. Accordingly, patients may be burdened with significant DPNP but not yet have attained any meaningful decrement in large fiber function, resulting in an uninformative nerve conduction study. It also follows that normal nerve conduction studies in a patient with symptoms typical of painful neuropathy are not inconsistent with the diagnosis of DPNP.
In most patients with small fiber damage from DPN, there is a predictable progression of symptoms, beginning with pain and progressing to reduced pinprick sensation. (See Figure 2.)
| Figure 2. Small Fiber Damage |
|
Large fiber damage results in reduction of vibration sense, loss of proprioception, weakness, muscle wasting, and reduction or loss of deep tendon reflexes.8
For the autonomic component of neuropathy, the parasympathetic system usually manifests dysfunction prior to the sympathetic system. Autonomic dysfunction is seen in the majority of patients at the time the diagnosis of diabetes is made, if sufficiently sophisticated neurometric tools, such as infra-red pupillometry, are applied.8
Diagnosis
A provisional diagnosis of DPNP may be made when a patient has typical symptoms of diabetic neuropathy (positive or negative), accompanied by neuropathic pain symptoms (e.g., burning, stinging, lancinating, hypersensitivity) distributed symmetrically in a stocking-glove distribution, in the presence of confirmed abnormal nerve function, without other identifiable etiology for neuropathy.
There are numerous correct objective ways to confirm neuropathy, including nerve conduction studies, biothesiometry, monofilament testing, deep tendon reflex assessment, and vibration testing. Although each of these methods, alone or in combination, is appropriate to diagnose DPN, a recent comparison trial has indicated that vibration testing has the greatest positive predictive value for the presence of neuropathy in diabetics.19 In this trial, several national and international scoring systems for diabetic peripheral neuropathy were compared with Semmes-Weiss monofilament testing and vibration testing in diabetics with and without foot ulcers, and in nondiabetics. Scoring systems included the International Consensus of the Diabetic Foot (ICDF) Score, the Dutch Netherlands Diabetes Federation Score, the San Antonio Consensus Sum Score, and others. The predictive values in this trial were good for all scoring systems, but the use of the tuning fork provided the best predictive values, and hence was recommended by the authors.
Use of the tuning fork to diagnose vibration impairment is straightforward, but has been recommended in various methods by several resources. The authors recommend the following steps to assure successful identification of impaired vibration sense:
- Select a 128-Hz tuning fork (others either do not work, have not been validated, or both).
- Show the patient the device and explain that you will first be checking the vibration at their wrist to make sure they recognize the stimulus.
- Percuss tuning fork to initiate vibration and place against patient's wrist bony prominence to ascertain that patient can recognize vibration and its extinction.
- If patient does not perceive vibration, select another more proximal bony prominence; even a elbow, clavicle or skull bony prominence (e.g., mastoid) will suffice if vibration impairment exists at the wrist.
- Percuss tuning fork to initiate vibration and place against patient's bony prominence of great toe.
- If vibration is not perceived, the provisional diagnosis of DPN may be made.
- If vibration is perceived, ask patient to report when the vibration ceases.
- At the point the patient perceives that vibration has ceased, place tuning fork on your own wrist bony prominence.
- If you still feel vibration when the patient does not, this is consistent with impaired vibration sense, or early DPN.
Because vibration testing is now the preferred method, and because obtaining a tuning fork is of minimal expense, and these devices are essentially lifetime-durable, other methodologies for nerve function testing will not be detailed further here.
Clinical Presentation
Of all the neuropathies associated with diabetes, DPN is the most common. DPNP typically presents with pain that is described similarly to other neuropathic pain complaints. Pain is characterized as shooting, stabbing, or burning, and may be accompanied by paresthesias or frank numbness.20 The unusual combination of absence of sensation or altered sensation with pain may be one of the factors that leads to delay in presentation: patients may find it difficult to reconcile that they are experiencing two "opposite" feelings at the same time, and simply dismiss symptoms or not relate them to the clinician. Patients also may report allodynia and/or hyperalgesia. Cold, hot, or touch sensation may each be perceived as noxious, unpleasant, or exaggerated. Several techniques for assessing different forms of allodynia include lightly rubbing or brushing the skin with a cotton swab (dynamic mechanical allodynia, finger pressure on the skin (static mechanical allodynia), and using the tuning fork applied to the skin after placing it in warm or cold water (thermal allodynia).21
Proprioceptive loss may manifest as loss of balance, which could lead to falls or hesitancy to engage in life activities. Additionally, intact proprioception is necessary to have proper bony and cartilaginous apposition for functional joint activity. Proprioceptive loss, if rapid, may lead to joint deformation and destruction, the ultimate example of which is the Charcot joint (neuropathic joint).
Two additional characteristics of DPNP are worth noting. First, it is typically worse at night.20 Although the reasons why DPNP worsens at night are unclear, data are consistent that patients with DPNP report interrupted sleep. Indeed, because this is so problematic, clinical trials often include impact upon sleep as a specific endpoint. The degree to which excessive daytime sleepiness secondary to nighttime sleep problems is responsible for such incidents as motor vehicle accidents has not yet been clearly discerned.
Finally, DPNP typically is worsened by activity. This may result in restricted social engagement by the patient, and equally important, my reduce their ability to engage in exercise, which is critical to optimum diabetic control.20
Treatment
Goals of treatment for patients suffering DPNP are several:
- Prompt, effective, tolerable pain modulation;
- Patient education on the etiology, management, and prevention of progression of DPNP;
- Restoration of function; and
- Optimized diabetic control.
Step 1 is pain modulation. The term "modulation" rather than "remission" has been chosen because the authors recognize that although currently available pharmacotherapeutic tools offer important steps forward in pain management, few patients ultimately enjoy total resolution of pain. It is wise for the clinician to advise the patient that current FDA-approved therapies offer at least a 50% reduction in pain from baseline for most subjects, but that this degree of improvement may not be seen for 4-6 weeks or longer. No currently available therapy has been found to be satisfactory in all patients,22 and all available therapeutic choices have adverse effects limiting applicability for some persons.
The other concomitant priority for patients with DPN or DPNP should be enhanced glucose control. In both the United Kingdom Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT), hyperglycemia is the primary correlate of diabetic neuropathy.23 There was a curvilinear relationship between achieved A1c and microvascular endpoints, documenting the value in tight control of glucose in diabetes. Recently, the group that originally was randomized into the DCCT was followed 8 years post-trial, and it was discerned that early tight control resulted in sustained risk reduction at that late date.24 Intense diabetic management improved diabetic neuropathy at least 8 years beyond the end of the DCCT similar to the improvement experienced with diabetic retinopathy and nephropathy.24
Once the issue of glucose optimization has been refocused, pain control should be a priority that is addressed promptly. The authors are in agreement with the recent commentary of Dworkin, et al, about the relative lack of sophistication of neuropathic pain management, "Our ability to translate pain complaints and sensory findings into specific pathophysiologic mechanisms that have treatment implications is in its infancy."21
Specific Pharmacotherapy
There are now two FDA-approved agents for treatment of DPNP, which will be discussed first, followed by inclusion of other agents that have shown some efficacy and are in common usage, despite that their use is off-label.
Duloxetine was the first FDA-approved agent for treatment of DPNP. Its mechanism of action capitalizes upon the knowledge that one of the endogenous pain-damping systems involves the combined modulation of serotonin and norepinephrine. Hence, dual serotonin-norepinephrine reuptake inhibitors (SNRI) fill an intellectually sensible position. Several published trials show that duloxetine provides prompt effective reductions in pain. Clinicians also may be aware the duloxetine is approved for use in depression. DPNP clinical trials specifically excluded patients with depression, to ensure that therapeutic effects were clearly related to direct pain reduction, rather than mood impact. Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine and sertraline have not shown remarkable beneficial effects in DPNP, and hence are not recommended.
Both duloxetine 60 mg and 120 mg are approved for treatment of DPNP. In one study, within one week there was a statistically significant reduction in pain compared to placebo; by 2 weeks a 30% mean reduction in pain had been achieved, and this was sustained throughout the 12-week trial.25 By the end of the trial, the majority of patients enjoyed a greater than 50% reduction in pain (baseline pain = 6.5 on a scale of 0-10). Clinical trials of duloxetine also show prompt improvements in sleep, another primary complaint of DPNP sufferers.
The most common side effects of duloxetine are nausea and somnolence.26 Fortunately, both usually are transient. For instance, in clinical trials submitted for FDA registration, when nausea occurs, it is mild to moderate in most patients, occurs early in treatment, and the mean duration is approximately 6 days. These data are accrued utilizing doses of 60-120 mg/d. From prior experience with the SNRI venlafaxine, clinicians have learned that gentle titration during the initial dosing administration enhances tolerability. Similarly, the authors suggest initiating duloxetine at a dose of 20-30 mg/d for one week, after which transition to the therapeutic dose of 60 mg/d should be simpler. Because the adverse effect profile of 30 mg is essentially indistinguishable from placebo, the first week of acclimatization to the SNRI should be very well tolerated.
Duloxetine is a moderate inhibitor of the P450 CYP II26 enzyme. Hence, medications that are metabolized by this pathway merit clinician vigilance lest these drugs accumulate.
Pregabalin is the only other FDA-approved agent for the specific indication of DPNP. Clinicians who are familiar with gabapentin may expect a similar efficacy and tolerability profile to that agent. The mechanism of action of pregabalin is complex: it is listed as an alpha-2-delta ligand, which binds with the neuronal alpha-2 subunit to modulate voltage-gated calcium channels. Ultimately, pregabalin affects a diversity of neurotransmitters, including norepinephrine, serotonin, dopamine, glutamate, and substance P.27
Like duloxetine, pregabalin at doses of 100 mg tid provides a prompt and effective reduction in DPNP within 2 weeks' time, and some trial data indicate efficacy at the one-week mark. The most common adverse effects of pregabalin are sedation, weight gain, and edema.
Opioid treatment has sometimes been described as ineffective for neuropathic pain, whereas recent data have confirmed that neuropathic pain simply may require higher doses of opioids to attain satisfactory pain reduction. Since 1998, there have been five double-blind, randomized controlled trials of opioids which show a statistically significant reduction in pain and improvements in sleep.21 As in all other clinical trials of chronic opioid therapy, constipation, nausea, sedation, and pruritus were commonplace adverse effects (the latter three of which usually are transient). A recent small trial of controlled release oxycodone versus placebo determined that high-dose (i.e., 80 mg/d) provided a statistically significant and clinically meaningful pain reduction in DPNP; the adverse effects profile, however, was problematic.28
Tramadol often is grouped among opioids because it does have some mu-receptor activity, however it also modulates serotonin and norepinephrine. Two trials have shown significant pain relief at doses up to 400 mg/d.21 The most common adverse effects were dizziness, nausea, constipation, and somnolence. Clinicians who choose to utilize tramadol must recognize that this agent reduces seizure threshold.
Gabapentin, in doses ranging from 300-1200 mg tid (total daily doses up to 3600 mg) has been shown to favorably impact DPNP. In a trial of 165 DPNP patients, gabapentin treatment was statistically superior to placebo in reducing mean pain score, sleep interference, and quality of life.29
Venlafaxine has shown efficacy in pain reduction for DPNP patients, but generally at higher doses.30 Because higher doses of venlafaxine also are associated with increases in pulse and blood pressure, the latter of which is particularly consequential to diabetics, its use should be reserved for the situation in which an SNRI is preferred but duloxetine is not available or not tolerated.
Tricyclic antidepressants (TCAs) have been a mainstay of neuropathic pain treatment for more than three decades, and likely will continue to comprise a significant portion of DPNP pain modulation. Because most of the patients with DPNP are at mid-life and beyond, potential cardiovascular toxicity, as well as other alpha-adrenergic, histaminergic, and anticholinergic adverse effects, must be considered before their utilization. Nonetheless, because a large number of clinical trials confirm their efficacy in various neuropathic pain syndromes,21 and because they are fairly well tolerated at low doses and are quite inexpensive, they may be considered a foundation therapy.
Topical lidocaine 5% is one of two agents that show promise as a treatment for DPNP.31 In an open-label trial (n = 56), patients received up to four lidocaine 5% patches for up to 18 hours per day (product labeling indicates three patches for up to 12 hours/day usage, but additional literature exists that longer duration use is effective and well-tolerated). In this three-week trial, patients achieved a statistically significant reduction in pain by trial end (three weeks). Interestingly, there was a differential effect among those with allodynia vs. those without. Patients with allodynia did not respond as well as those without.
A final treatment option that has only undergone a pilot trial evokes interest because of its physiologic underpinnings. Because DPNP is considered a microvascular disorder with endothelial dysfunction, the authors of this small DPNP trial theorized that local application of nitroglycerin, a nitric oxide donor, might remedy some of the pathophysiologic defects attendant to DPNP. In a small trial of patients with enduring DPNP (2.6 years mean), without discontinuing background medications (acetaminophen, amitriptyline, and gabapentin), patients were advised to spray a single spray of nitroglycerin to the affected area at night.32 The study was performed in a double-blind, placebo controlled manner with two cross-over periods. At trial end, nitroglycerin spray had produced a statistically significant and clinically meaningful reduction in pain score greater than 30%. The authors report that despite a single nocturnal spray, pain relief persisted until the following night when reapplied. Some patients reported an increased exercise threshold and improved sleep. Nitroglycerin spray, as studied, is indicated for absorption through the buccal mucosa. The skin of the lower extremities is much less absorptive, hence that adverse effect profile is superior to what is reported with traditional oral spray administration.
Once again, it is important to note that only duloxetine and pregabalin are approved by the FDA specifically for treating DPNP.
Putting it all Together
Successfully managing DPNP is challenging, and may require a number of therapeutic steps, including consultation. Polypharmacy has been and likely will continue to be the rule for patients with DPNP, despite the fact that no FDA-approved agent has been studied as part of combination therapy.
A patient who presents with symptoms suggestive of DPNP should have the neurologic status of their lower extremities confirmed. Vibration sense is the preferred screen (see section on Diagnosis), but monofilament testing and ankle jerk testing are further confirmation of neurologic integrity. If one or more of these neurologic tests indicate neuropathy, in the absence of other explanations of peripheral neuropathy, a provisional diagnosis of DPNP may be made.
At this point, the patient should be encouraged to optimize glucose control. Initial choices of therapy for pain include duloxetine, topical nitroglycerin spray, pregabalin, and TCAs.
Because topical nitroglycerin is inexpensive and non-toxic, it is a reasonable first choice. For patients with significant economic constraints, the cost issues of TCAs make them a viable initial option. For persons without burden of economic restrictions, duloxetine and pregabalin are two other reasonable initial choices. Advantages of duloxetine include its once-daily administration, lesser expense than pregabalin, and non-scheduled status. Advantages of pregabalin include its freedom from drug-drug interactions and prompt reduction in pain. Disadvantages of duloxetine include its initial nausea, and interactions with the CYP IID6 system. Disadvantages of pregabalin include its thrice daily administration, its greater expense (about 150% the price of duloxetine, retail), its scheduled status, and its problems with weight gain, sedation, and edema.
Lidocaine 5% patch is a reasonable second-tier treatment. Gabapentin is only a reasonable second-line agent if pregabalin would be a good choice but is unavailable to the patient. Opioids are listed as a reasonable second-tier choice because at therapeutic doses, the adverse effect profile is difficult, not to mention the necessary consideration of abuse and diversion issues. In the event that neither first- nor second-line agents are effective, consultation certainly is appropriate. (See Figure 3.)
Conclusion
DPNP is an important disorder experienced by a substantial population of diabetics. It has received insufficient attention in the past. DPN is readily diagnosed with the tools available to primary care clinicians, and numerous therapeutic options should provide a hopeful attitude toward this otherwise potentially disabling malady.
References
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Diabetic Peripheral Neuropathic Pain (DPNP) is an important pain syndrome that has not received attention commensurate with its clinically and epidemiologically compelling presence.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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