Therapies not proved effective
Therapies of uncertain benefit that have not been adequately studied in randomized controlled trials include lidocaine patch, benzydamine cream, tramadol, and vincristine (and/or dimethylsulfoxide) iontophoresis.
Therapies unlikely to be beneficial based on single trials include lorazepam, fluphenazine, dextromethorphan, memantine, acyclovir, and acupuncture. Most of the negative trials did not report power; therefore, potential benefits of these treatments cannot be excluded.
Safety and tolerability
The rates of adverse effects are high in all effective oral and topical therapies (Table 1). This situation is of special concern in elderly patients who have comorbid conditions and are taking multiple medications. Two tricyclic antidepressant trials16,21 report a decreased incidence of side effects over time. The researchers emphasize the importance of starting at the lowest available dose with oral therapies and titrating slowly as indicated and tolerated.
No clinical complications were observed in the intrathecal steroid trials; specific side effects were not reported.
Lidocaine patch therapy has been promoted as causing clinically insignificant serum levels, no systemic side effects, and no drug–drug interactions.11 However, the largest lidocaine patch RCT was too small to rule out significant but uncommon risks such as ventricular arrhythmia.10 One death that could potentially be attributed to lidocaine absorption occurred in a patient with diffuse vascular disease who was on chronic hemodialysis for renal failure. Blood lidocaine levels were not obtained because venous access was poor.
Limitations
Variations in outcomes limit comparative conclusions. Sindrup and Jensen37 reviewed treatments for neuropathic pain and presented data based on a successful outcome defined as 50% reduction in pain scores, 50% pain relief, or categorical ratings of excellent, good, or moderate pain relief. Most studies used visual analog scales, but it is not clear that a 50% reduction in these measures is equivalent to clinically meaningful benefits at all levels of pain. We attempted to determine NNT data based on clearly meaningful outcomes such as “excellent or good,” “complete,” or “marked” pain relief as distinct from “moderate” or “some,” but found these data unavailable in most reports. Quality-of-life measures, such as sleep and disability ratings, may be more important than measures of pain, but were reported in only one third of the trials.
We may have failed to include relevant trials. We identified 7 potentially relevant non–English language studies. Five had no abstracts available.38-42 One single-blind trial reported reduced pain scores with topical prostaglandin E1 dissolved in Vaseline.43 One trial compared iontophoresis with lidocaine and iontophoresis with 3 different calcium channel blockers in 10 patients. The authors found that all 4 treatments reduced pain, but had not included a placebo control group.44 We also contacted 15 content experts to identify reports of unpublished trials; none of the 6 responses received identified such reports.
The evidence base for treatment of PHN is limited. Among the RCTs reviewed, 78% enrolled 50 or fewer patients. Because most of the subjects had PHN lasting longer than 1 year, our conclusions may not apply to patients with PHN of shorter duration. The latter group represents the majority of subjects with PHN presenting to primary care physicians.
We used the Jadad scale7 as an attempt to quantitatively assess the methodologic quality of the studies we reviewed. In general, explicit validity checklists with summary scores have not consistently been shown to provide more reliable assessments of validity than qualitative assessments.45-4 The Jadad scale is the first validity checklist that has some rigorous evidence supporting its use,7,48 although its inter-rater reliability has been questioned.49 We found the Jadad scale had an inherent bias against therapies that could not be adequately double-blinded. Thus 2 trials with a score of 1 were included.29,36 In 1 trial of vincristine iontophoresis, the authors described the trial as single-blinded and provided ample explanation of why double-blinding was not achieved.29 In 1 trial of sympathetic blocks, the treatment studied included an invasive procedure; therefore, there was no apparent way for the procedure itself to be double-blinded.36
The Jadad scale does not account for some threats to validity of included studies. We encountered numerous methodologic flaws, such as lack of intention to treat analysis in parallel trials (11) and lack of washout periods in crossover trials (4). Further limitations to interpretation of selected study results included potentially significant baseline differences between groups (8), small numbers, and short study durations. A list of the studies with these specific methodologic concerns is available in Table W3.
Conclusions
For patients with PHN lasting less than 6 months, spontaneous resolution is common and treatment decisions are largely empiric and not evidence based. For PHN of longer duration, treatments shown to be more effective than placebo include tricyclic antidepressants, topical capsaicin 0.075%, gabapentin, and controlled-release oxycodone. These treatments all have adverse effects or costs that need to be considered on an individual basis. Lidocaine patch therapy may be safer for most patients but may be no more effective than placebo and is not suitable for patients with trigeminal PHN. Patients with PHN refractory to the currently available and studied topical and oral agents should be considered for intrathecal steroid therapy.