Effectiveness and safety of lidocaine patch 5%

To the editor:

As a recognized authority on neuropathic pain and as one of the primary academic investigators for the lidocaine patch 5% (Lidoderm), I would like to comment on the recently published article about treatment of postherpetic neuralgia (PHN).¹ Several erroneous statements regarding the lidocaine patch were made in the article that I would like to address.

First, the lidocaine patch has clearly demonstrated efficacy in randomized controlled trials.² The degree of pain relief demonstrated with topical lidocaine patch is comparable to that shown with systemic agents; eg, 53% of patients receiving lidocaine patch reported “moderate” or better pain relief, and 29% reported “a lot” or “complete” relief, comparable to gabapentin PHN study results. The lidocaine patch 5% remains the only drug that has been thoroughly evaluated by the US Food and Drug Administration (FDA) and granted an indication for the treatment of PHN, based on efficacy, safety, and tolerability. Second, unlike what is written in the article, lidocaine patch 5% can be used successfully for treating trigeminal PHN, based on personal experience and a prospective open-label trial (Katz NP, Davis MW, Dworkin RH. Topical lidocaine patch produces a significant improvement in mean pain scores and pain relief in treated PHN patients: results of a multicenter open-label trial. Presented at the American Pain Society 20th Annual Scientific Meeting, April 19–22, 2001, Phoenix, AZ).

Third, lidocaine patch 5% is a targeted peripheral topical analgesic that produces local analgesia without anesthesia and without any clinically meaningful systemic serum levels. No patient in any clinical study developed any cardiac adverse event deemed causally related to the lidocaine patch. No death or serious adverse event attributed to the lidocaine patch occurred in any clinical study. In addition, since its approval and availability in 1999, no systemic side effects have been associated with the drug when appropriately dosed. Moreover, recent pharmacokinetic studies have demonstrated that even with increased dosing to 4 patches continually administered every 12 hours, lidocaine serum levels (225 ng/mL) remain significantly below levels associated with cardiac arrhythmic effects and toxicity (cardiac activity begins at 1500 ng/mL and toxicity > 5000 ng/mL).

In conclusion, I am hopeful that these points of clarification will contribute to improved understanding of the data pertaining to the lidocaine patch 5% and will demonstrate its effectiveness and safety for treating one of the most refractory neuropathic pain conditions, PHN. I hope they will also show why the lidocaine patch is recommended as a first-line therapy for PHN by many neuropathic pain authorities,² as reflected by a recent New England Journal of Medicine editorial.³

Bradley S. Galer, MD
Vice President, Scientific Affairs
Endo Pharmaceuticals, Inc.
Chadds Ford, Pennsylvania
University of Pennsylvania School of Medicine
Philadelphia
E-mail: galer.bradley@endo.com

References

1. Alper BS, Lewis PR. Treatment of postherpetic neuralgia: a systemic review of the literature. J Fam Pract 2002; 51:121-8.
2. Argoff CE. New analgesics for neuropathic pain: the lidocaine patch. Clin J Pain 2000; 16:S62-6.
3. Watson CP. A new treatment for postherpetic neuralgia. N Engl J Med 2000; 343:1563-5.

Drs alper and Lewis respond:

We appreciate Dr Galer’s commentary and the opportunity to respond. The only published randomized controlled trial (RCT) of lidocaine patch to meet our inclusion criteria and demonstrate efficacy over placebo was an “enriched enrollment study” of 32 subjects who had previously demonstrated moderate to complete pain relief in an open-label compassionate use protocol.¹ An FDA reviewer² identified the limitations of applying results from this small, highly selected population and recommended further studies in PHN patients who had not previously been treated with the lidocaine patch.

The largest placebo-controlled RCT (150 subjects) in relatively unselected patients demonstrated insufficient difference between treatment groups to warrant FDA approval of the new drug application.³ The fact that we could not discover this trial in a conventionally published format is to us a glaring example of publication bias. Upon further investigation, we found that the manufacturer’s application was initially denied with the need for “one additional efficacy study,” and was then subsequently approved based on the enriched enrollment study above.⁴

Dr Galer states that lidocaine patch can be successfully used to treat trigeminal PHN. We do not have RCT evidence to support or refute this statement, noting that the larger trial did not enroll subjects with trigeminal PHN, and the enriched enrollment study did not state the location of PHN.

We concur that the patient death in the larger unpublished trial was likely unrelated to use of the patch, although a lidocaine blood level was not obtained. According to its product labeling, Lidoderm should be used with caution in patients with severe hepatic disease and in those receiving antiarrhythmic or local anesthetic drugs. It is not clear that the pharmacokinetic data cited by Dr Galer are generalizable to patients with PHN and multiple comorbidities.