Diagnosis and Treatment of Pain in Small Fiber Neuropathy
There are several different classes of medications commonly used to treat neuropathic pain. These include antidepressants, anticonvulsants, opioids, and topical treatments. Tricyclic antidepressants (TCAs) consistently are recommended as first tier drugs across all guidelines [43, 44, 45•, 46–48]. The criterion for study inclusion varies amongst the guidelines; however, the number of studies for neuropathic pain reviewed ranged from 2 to 17. The NNT was 2.1 to 2.5 based on the type of TCA. None of the studies specifically treated patients with small fiber neuropathy. TCAs consistently were selected as first-tier choices based on their efficacy and other factors such as cost and availability. Their mechanism of action is inhibition of serotonin and norepinephrine reuptake. TCAs also have anticholinergic effects that can cause significant side effects for some patients, and specifically should be avoided in elderly adults. They are contraindicated in patients with a significant cardiac history, glaucoma, or recent monoamine oxidase–inhibitor (MAOI) use. Guidelines note that safety and tolerability factors may limit the use of TCAs.
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are another class of antidepressants commonly used for the treatment of neuropathic pain. Both duloxetine and venlafaxine are recommended as second-line agents in most guidelines. For duloxetine, most guidelines reviewed two to three studies [43, 44, 45•, 46, 47, 48••]. It has been found to be effective in painful diabetic neuropathy and the NNT was 5.2. It has not been studied for other forms of neuropathic pain; therefore, it is frequently recommended as second- or third-line treatment. It has a rapid onset of action and is generally well tolerated. It should be avoided in patients with uncontrolled narrow-angle glaucoma or those being treated with MAOIs. In rare cases it has been associated with abnormal bleeding, hepatotoxicity, and serotonin syndrome.
Venlafaxine is another SNRI that typically is recommended as a second-line agent. Two studies have found it to be effective for painful diabetic neuropathy and for mixed neuropathy with a NNT of 4.6 [43, 44, 45•, 46, 47, 48•]. In a study that compared imipramine and venlafaxine head to head, the imipramine group had a higher proportion of responders . Generally, venlafaxine is well tolerated, but should be avoided in patients being treated with MAOIs. In some cases, it has been noted to increase blood pressure and cause ECG changes. Rare adverse events including bleeding, hyperlipidemia, and pulmonary complications (interstitial lung disease and eosinophilic pneumonia) have been reported. Due to differences in the NNT, TCAs are recommended over SNRIs in most guidelines except in elderly patients or others at risk for adverse events.
In addition to antidepressants, anticonvulsants also are routinely recommended for the treatment of neuropathic pain. Gabapentin frequently is utilized as a first-line treatment of neuropathic pain. Most guidelines reviewed two to four studies and the NNT was 3.9 to 4 [43, 44, 45•, 46, 47, 48••]. It is effective for neuropathic pain (specifically postherpetic neuralgia and painful diabetic neuropathy). The mechanism of action is believed to be via the voltage-gated α2δ calcium channel, modifying the release of excitatory neurotransmitters. It is well tolerated and not known to cause significant drug–drug interactions. In rare circumstances, it has been associated with Stevens-Johnson syndrome.
Pregabalin is another anticonvulsant frequently used for first-line treatment of neuropathic pain. In the included guidelines, two to six studies on pregabalin in different types of neuropathic pain (postherpetic neuralgia, painful diabetic neuropathy, or both) were reviewed. For some guidelines, several studies were excluded based on concern that the methodology included enriched enrollment. The calculated NNT was 4.2 [43, 44, 45•, 46, 47, 48••]. Pregabalin’s mechanism of action also is believed to be through the voltage-gated α2δ calcium channels and is a presynaptic inhibitor of the release of glutamate, substance P, and calcitonin gene–related peptide (CGRP). It also is typically well tolerated, but should be used with caution in patients with congestive heart failure. Angioedema rarely has been described as a side effect.
Topical lidocaine frequently is recommended as a first- or second-line treatment of focal neuropathic pain. These recommendations are typically for the lidocaine patch, although there also is evidence available for lidocaine gel. The guidelines included three or four studies (primarily for postherpetic neuralgia) and the NNT is 4.4. It is generally most effective for patients with focal regions of pain and offers the advantage of less systemic side effects and drug interactions. It also may be used for breakthrough pain. It is believed to act by decreasing neuronal membrane permeability to sodium ions. Topical lidocaine is more expensive than some of the other treatments, but is generally well tolerated. It should be avoided in regions of skin breakdown. Rare allergic or anaphylactic reactions can occur.