Tricyclic antidepressants. Of all the medications prescribed for DPNP, tricyclic antidepressants (TCAs) are 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(Drug information on 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(Drug information on 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(Drug information on norepinephrine) reuptake inhibitors. After the TCAs, the drugs that appear to be most effective for DPNP are the anticonvulsants pregabalin(Drug information on pregabalin) and gabapentin(Drug information on gabapentin), which I will later discuss in detail, and the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants duloxetine(Drug information on 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. 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 adverse-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 (SSRIs), are effective for depression but provide little relief of 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(Drug information on zolpidem), zaleplon(Drug information on 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(Drug information on oxycodone) and tramadol(Drug information on 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.
Whether oxycodone and tramadol are more effective for DPNP than other opioids is open to question; their apparent advantages may simply be related to the fact that they have 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 recent research indicates that transdermal fentanyl(Drug information on fentanyl) is beneficial for DPNP.20 Oxymorphone, which was approved by the FDA in oral short-acting and extended-release formulations in 2006, 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.
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.22 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.
Nonpharmacological therapies. The literature on nonpharmacological treatments for DPNP is limited. Of all these therapies, the one that is most supported by research is acupuncture.23,24 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(Drug information on 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).25 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.