Diagnosis and Treatment of Pain in Small Fiber Neuropathy
Lastly, opioids and tramadol frequently are recommended as second- or third-line medications across all guidelines. Among expert opinions, there is consistent concern about the use of opioids for nonterminal neuropathic pain due to dependence. Some guidelines review different types of opioids (oxycodone, morphine, methadone, and levorphanol) as well as different types of neuropathic pain (painful polyneuropathy and post-herpetic neuralgia). The number of studies included ranged from five to eight and the NNT ranged from 2.5 to 2.7 based on the type of neuropathic pain and the drug [43, 44, 45•, 46, 47, 48••]. Some guidelines suggest that opioids, typically oxycodone, be used for severe breakthrough pain either for acute exacerbations or during titration of another agent. While effective for pain, opioids pose the potential for many side effects as well as overdosing and dependence.
Tramadol is consistently recommended as a second- or third-line choice for treatment of neuropathic pain. Concerns for dependence also are raised with tramadol use. The number of reviewed studies ranged from two to three among the guidelines and included painful diabetic neuropathy, mixed polyneuropathy, or postherpetic neuralgia. The NNT ranged from 3.4 to 4.8 based on the type of neuropathic pain and criteria applied [43, 44, 45•, 46, 47, 48••]. Tramadol and its active metabolite bind to central μ-opiate receptors and inhibit ascending pain pathways. Tramadol also causes serotonin and norepinephrine–reuptake inhibition, another potential mechanism of pain relief. Side effects of tramadol can include dyspnea and respiratory depression, and it is rarely associated with myocardial infarction, pancreatitis, seizure, and serotonin syndrome. It should be avoided in patients who are actively using central nervous system depressants such as alcohol, hypnotics, opioids, or psychotropic drugs. In addition, tramadol does have the potential to interact with most antidepressant medications, and care is required due to the potential duplicative serotonin- and norepinephrine-reuptake inhibition. Also, up to 10% of Caucasians are poor cytochrome P450 2D6 metabolizers and, therefore, are unable to metabolize the drug effectively, resulting in poor efficacy.
In the only published study specifically examining treatment of small fiber neuropathy, both gabapentin and tramadol were found to be effective . This study used an enrichment crossover design. Participants were included if they had biopsy-proven small fiber neuropathy and were self-identified as gabapentin responders. Patients first were treated with single-blinded gabapentin at their prestudy dose as well as matching diphenhydramine placebo, 50 mg, capsules for 1 week. Participants with a pain intensity score of 7.5 or higher were then allowed to continue to the second phase, in which patients were tapered off their gabapentin dose during the first week and continued on the diphenhydramine placebo for 2 weeks. Pain scores were assessed during the second week, and those participants with a pain score of 3 or higher and a 30% or greater increase from their initial phase pain scores then were randomized into a double-blind crossover phase. During the last phase of the trial, patients were randomized to three 2-week double-blind treatment periods with1-week washout periods between each treatment phase. Overall, 18 participants were treated in a randomized crossover design with 3 treatments: gabapentin at their prestudy dose, tramadol, 50 mg four times daily, and diphenhydramine 50 mg at bedtime. Three participants withdrew before completing all three treatment periods. There was a statistically significant improvement in pain scores for both gabapentin and tramadol groups when compared to diphenhydramine. The NNT for gabapentin was 4.6. The NNT for tramadol was 4.0. There was no statistically significant difference between the average pain scores during the gabapentin and tramadol treatment phases. There were no reported significant adverse events in either treatment group.
Other classes of medications have been used for the treatment of neuropathic pain including antiarrhythmics. This class typically is excluded from expert panel recommendations due to the large number of potential side effects. Selective serotonin reuptake inhibitors also are excluded as first- or second-line recommendations due to limited data on efficacy. For detailed descriptions of the guidelines, included studies, drugs and dosing, please refer to the recently published guidelines for neuropathic pain listed in Table 1 [43, 44, 45•, 46, 47, 48••].
Nonpharmacologic options also are important for pain management. Some patients may benefit from cool or warm soaks, soft socks, and foot tents. Other treatments such as transcutaneous electrical nerve stimulation, acupuncture, physical therapy and massage also have been used, but have not been examined in clinical trials for small fiber neuropathic pain [43, 44, 45•, 46, 47, 48••].