ABSTRACT: A variety of effective treatments are available for diabetic peripheral neuropathic pain (DPNP), including topical agents, oral medications, and nondrug approaches. The lidocaine patch 5% is recommended for relatively localized pain. If the pain is widespread or is not alleviated by topical therapy, consider a tricyclic antidepressant (TCA). For patients who are unable to tolerate the TCAs or who obtain insufficient relief from these agents, other options are the anticonvulsants pregabalin and gabapentin and the serotonin norepinephrine reuptake inhibitor antidepressants duloxetine and venlafaxine. If these agents fail to provide sufficient analgesia, consider an opioid (oxycodone or tramadol). Of the nonpharmacological therapies for DPNP, the use of acupuncture is best supported by the literature; transcutaneous electrical nerve stimulation is another option.
Key words: neuropathic pain, diabetic neuropathy, peripheral neuropathy, diabetes mellitus
Diabetic peripheral neuropathic pain (DPNP) affects an estimated 10% to 20% of the more than 20 million people in the United States who have diabetes mellitus.1,2 The pain can be severe and can markedly interfere with functioning. Although there is no cure for DPNP, for many patients the pain can be controlled to a degree sufficient to improve their quality of life. In this article, I outline a variety of effective management strategies, including topical agents; oral medications; and nonpharmacological therapies, such as acupuncture and transcutaneous nerve stimulation.
As with most types of neuropathic pain, the cause of DPNP is unknown. Although DPNP appears to be related to pathological changes in the peripheral nerves, why pain develops in some patients with demonstrable peripheral neuropathy but not in others remains unclear. This disparity has resulted in more attention being paid to the role of the brain and the rest of the CNS in the development and perpetuation of pain.3
Improved glucose control seems to reduce the overall risk of diabetic peripheral neuropathy, but whether it specifically decreases the incidence of DPNP has yet to be determined.4
Symptoms. DPNP is most commonly described as a burning or electric shock sensation and is usually located in the feet and lower limbs, although the hands may be affected as well.5 Patients may also experience allodynia, in which ordinarily nonpainful stimuli induce pain, or hyperalgesia, in which the response to painful stimuli is increased. Even when patients are experiencing pain, they may also feel numbness over the affected area.
Although patients with lower extremity pain usually report that placing weight on their feet exacerbates the pain, DPNP frequently worsens at night. This can cause or exacerbate sleep disorders. Insomnia has been associated with abnormal glucose tolerance test results and may precipitate diabetes mellitus.6
Evaluation. DPNP is the most likely diagnosis in a patient with diabetes mellitus who has foot or lower limb pain. A 2-hour oral glucose tolerance test is recommended for patients who have this type of pain but who have not yet been evaluated for diabetes mellitus.7 However, there are other potential causes of peripheral pain that should be considered, including pain related to vitamin B12 deficiency, claudication, and osteoarthritis. These causes can usually be differentiated from DPNP by appropriate testing.8
Neurological studies, such as nerve conduction velocity and quantitative sensory tests, usually demonstrate a reduction in functioning of the peripheral nerves in patients with DPNP. However, there is minimal correlation between the results of these tests and the presence or severity of DPNP; thus, they provide limited assistance in making the diagnosis. These tests should not routinely be ordered for patients who are believed to have DPNP.
There are now several published guidelines on neuropathic pain in general and more specifically on DPNP.5,9-11 These guidelines provide extensive references to support their recommendations. For the most part, the guidelines are in agreement about which therapies appear to be most effective. Treatment recommendations based on these guidelines are provided in the Table. Note that only 2 medications have an FDA-approved indication for the treatment of DPNP: pregabalin and duloxetine.
Although a number of the medications discussed here are categorized as antidepressants or anticonvulsants because of their nonanalgesic effects, the pain relief they provide is unrelated to these effects. They should be considered primary analgesics in the same way that opioids are.
Topical analgesics. If the pain is relatively localized, I recommend beginning treatment with the lidocaine patch 5%. Although it has an FDA-approved indication only for the treatment of postherpetic neuralgia, it is also effective for DPNP.12 Furthermore, as I explain to patients, it is a topical medication with localized action and therefore is very unlikely to cause systemic adverse effects or to interact with other medications. This is a significant advantage for many persons with diabetes, who often have comorbid conditions.
The lidocaine patch is recommended for localized pain because only up to 3 patches can be applied at a time. The patches are worn for 12 hours and then removed. Since the analgesia continues for 12 hours after they are removed, it usually does not matter when they are applied; for ease of use, most patients put them on in the evening and then remove them the next morning.
The patch also provides a physical barrier between the outside environment and the painful area. This is an added benefit for patients with DPNP who have allodynia or hyperalgesia, in which external stimuli may exacerbate the pain. However, it is important to caution patients that the lidocaine patch should be placed only over intact skin; therefore, the patches should not be applied to the painful ulcers that many patients with diabetes experience.
The other topical analgesic that is commonly used for DPNP is capsaicin. Before the lidocaine patch 5% was introduced, I frequently prescribed this medication, but I have found the lidocaine patch to be more effective. Also, many patients with DPNP are unable to tolerate the sensation of heat that occurs at the site where capsaicin (which is made from chili peppers) is applied, especially if allodynia is present.13
Tricyclic antidepressants. Of all the medications prescribed for DPNP, the use of the tricyclic antidepressants (TCAs) is most strongly supported by research. Certainly, if patients are able to tolerate TCAs and there are no contraindications to their use, these should be the first oral medications tried. However, many patients, especially those who are older, are unable to tolerate the anticholinergic and antihistaminic effects of these agents. TCAs are contraindicated in patients with preexisting cardiac conduction defects. Because DPNP is more likely to occur as patients age, these issues often arise when TCAs are being considered for the treatment of this problem. I usually do not prescribe TCAs for patients older than 50 years even if there are no apparent contraindications.
One myth that is still widely propagated is that amitriptyline possesses the most potent analgesic properties of the TCAs. In fact, all the TCAs appear to be equally analgesic. Thus, consider other TCAs, such as desipramine and nortriptyline, that have fewer anticholinergic and antihistamic effects than amitriptyline. Although many patients who take TCAs feel oversedated because of the antihistaminic effect, some may find this beneficial because it helps them sleep during the night, when DPNP is often most severe.
Other serotonin norepinephrine reuptake inhibitors. After the TCAs, the drugs that appear to be most effective for DPNP are the anticonvulsants pregabalin and gabapentin, which I will later discuss in detail, and the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants duloxetine and venlafaxine. Few studies have compared these medications, and no factors have been identified that can predict which one is most likely to be effective for an individual patient. However, there are several factors to consider when deciding the order in which they are to be tried.
If TCAs provide insufficient analgesia and depression is not present, it would make sense to try one of the anticonvulsants first because they seem to provide analgesia by a different mechanism than the SNRIs, which have effects similar to those of the TCAs but with more benign side-effect profiles.
Because they are both antidepressants, duloxetine and venlafaxine should be chosen ahead of the anticonvulsants if the patient has comorbid depression. Depression is common among patients with diabetes mellitus, and it may precipitate and exacerbate this disease.14,15 Like the TCAs, duloxetine and venlafaxine possess excellent antidepressant properties. The other classes of antidepressants, such as selective serotonin reuptake inhibitors, are effective for depression but provide little relief for pain.
Duloxetine has an FDA-approved indication for DPNP; thus, some physicians may feel more comfortable prescribing it rather than venlafaxine. However, duloxetine may cause more drug-drug interactions because it has a stronger inhibitory effect on the hepatic cytochrome P-450 2D6 enzyme system, which is involved in the metabolism of multiple medications.16
I usually start duloxetine at 30 mg/d for 1 week and then increase the dosage to 60 mg/d. By starting at the lower dosage, the nausea associated with this medication can usually be avoided. For most patients, 60 mg/d is usually sufficient, but some patients find 90 or even 120 mg/d to be markedly more effective.17
If venlafaxine is used, I recommend the extended-release formulation. Patients only need to take this once a day, and it is much less likely to cause nausea than the immediate-release formulation. I usually start the medication at 75 mg/d (37.5 mg/d for elderly patients) and then increase it at 3- to 4-day intervals to 150 mg/d. I maintain patients at this dosage for 2 to 3 weeks. If at that time the response is insufficient, I again gradually begin to increase the dose by 37.5 mg on a weekly basis. The highest dosage I usually prescribe is 450 mg/d; some physicians use even higher dosages, but there is no evidence to suggest that a higher dosage will provide substantially greater relief of pain.
Unlike the TCAs, duloxetine and venlafaxine have limited antihistaminic effects and therefore are not usually very sedating. For those patients who have difficulty in sleeping, consider prescribing one of the nonbenzodiazepine sedative-hypnotics, such as zolpidem, zaleplon, eszopiclone, or ramelteon, in addition to the antidepressant.18
Anticonvulsants. Pregabalin and gabapentin appear to have very similar analgesic effects, but I prefer trying the former first. Gabapentin can be effective, but it is frequently difficult to reach a therapeutic dosage because it is often too sedating. For most patients, a dosage of at least 1600 mg/d is required, and many need an even higher dosage. However, even when the dose is divided so that most is given at night, many patients still complain of feeling sedated during the day when they take this medication.
Although pregabalin is also sedating, it appears to be much less likely to affect daytime functioning. Also, as with duloxetine, some practitioners may feel more comfortable prescribing it because it has an FDA-approved indication for the management of DPNP.
Opioids. Oxycodone and tramadol are the 2 opioids whose use in treating DPNP is most supported by the literature. Because DPNP is usually a consistent, unrelenting pain, consider prescribing the extended-release formulations of these drugs after the optimal dose has been determined by use of the immediate-release formulation first. DPNP tends to be a chronic condition that requires long-term treatment; therefore, potential problems associated with extended use of opioids, including impairment of the immune system and hypogonadism as well as the risk of abuse, must be carefully weighed against potential benefits.
It is questionable whether oxycodone is more effective for DPNP than other opioids; its apparent advantage may simply be related to the fact that it has been the subject of more research for the treatment of DPNP than have the other opioids. A number of other opioids also appear to be effective for the treatment of neuropathic pain in general,19 and there is research indicating that transdermal fentanyl is beneficial for DPNP.20 Oxymorphone is a metabolite of oxycodone and therefore is likely to provide similar analgesia.
Tramadol is a combination drug that contains a weak opioid and a weak SNRI. Studies of opioid antagonists have shown that most of the analgesia provided by tramadol is related to its SNRI properties.21
I have never been very enthusiastic about the use of tramadol. Because it contains an opioid, it poses a risk of abuse and psychological dependence (ie, addiction). I prefer to use drugs with more substantial SNRI effects, such as the TCAs, duloxetine, or venlafaxine.
Botulinum toxin A. At least one study has demonstrated potential benefits for DPNP with injection of botulinum toxin A, indicating that this may become an additional option.22 This study was relatively small and it is still unclear how long the therapeutic effects of this medication last; therefore, additional research will be needed before it can be recommended as a standard treatment. However, it might be worthwhile to consider it for patients whose DPNP does not respond to the other therapies.
Combination analgesic therapy. Combination therapy with 2 or more of the medications described here is often prescribed for patients with DPNP. However, there are few formal studies on the efficacy of combination therapy or which combinations are most effective.23 If combination therapy is being considered, it makes sense to choose drugs from different classes, such as an antidepressant coupled with an anticonvulsant or an opioid other than tramadol.
The literature on nonpharmacological treatments for DPNP is limited. Of all these therapies, the one that is most supported by research is acupuncture.24,25 As an acupuncturist, I definitely believe this therapy is worth considering. The only major risk factor associated with it is infection, and this is eliminated by the use of disposable needles. As with the lidocaine patch, I tell patients that while I cannot guarantee acupuncture will be beneficial, it will not exacerbate comorbid disorders or affect medications they are taking. Even if acupuncture simply allows patients to reduce their need for oral analgesics, this can be a marked benefit.
Another nonpharmacological treatment that may be beneficial for DPNP is transcutaneous electrical nerve stimulation (TENS).26 TENS provides a mild electrical stimulation through the application of surface electrodes over the painful area. There is essentially no downside to TENS other than that it must be used cautiously in patients with pacemakers. Because the electrodes and connecting wires are worn under clothing, TENS can be used throughout the course of the day while the patient performs activities.
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