Botulinum Toxin for Postherpetic Neuralgia
Abstract & Commenatary
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: In a small, placebo-controlled trial, botulinum toxin treatment showed a significant benefit for postherpetic neuralgia.
Source: Apalla Z, et al. Botulinum toxin A in postherpetic neuralgia: A parallel, randomized, double-blind, single-dose, placebo-controlled trial. Clin J Pain 2013;29:857-864.
Rare in children and those under 60 years of age,
postherpetic neuralgia (PHN) causes persistent pain for months to years following resolution of the acute zoster rash, occurring in 6.9% of patients 60-69 years of age and in 18.5% of those 70 years or older, with increasing severity and persistence of PHN associated with advancing age. Current treatment options include tricyclic antidepressants, anticonvulsants, opioids, topical creams such as capsaicin or lidocaine, and intrathecal glucocorticoids. Botulinum toxin appears to be another, less invasive and reasonable, option.
Between April and November 2009, 30 adults, aged ≥ 18 years, with PHN of more than 3 months’ duration, were enrolled in a 4-week, randomized, double-blinded, two-arm, single-dose, placebo-controlled study examining the safety, efficacy, and tolerability of botulinum toxin A (BTX-A) for PHN. Complete responders were subsequently maintained in an open-label, 20-week follow-up phase to evaluate continued pain control. Study enrollment required a baseline pain score of at least 7, as measured by a visual analogue scale (VAS), and patients were excluded if they demonstrated cranial nerve involvement, skin disorders that might interfere with BTX-A injection, or severe non-PHN pain disorders that could interfere with pain measurements. Dose of BTX-A totaled 100 IU, and was injected over the affected area in a checkerboard fashion, with each patient receiving a total of 40 injections. Patients assessed their pain severity daily for 2 weeks on waking in the morning, using a VAS (0-10), and then every 2 weeks for 12 weeks, followed by every 4 weeks for 10 weeks. Quality of sleep was assessed using a five-item questionnaire, encompassing overall sleep quality, number of nights unable to sleep due to pain, number of times sleep was interrupted at night by pain, number of continuous hours of nightly sleep, and length of time until falling asleep. VAS score reduction was the primary outcome measure, and secondary outcome measures included sleep score improvement and maintenance of > 50% improvement of VAS score after treatment. Statistical analysis encompassed Fisher exact test and, where appropriate, Mann-Whitney U test or the Pearson X2 test.
Thirty PHN patients were enrolled, mean age was 73.2 years, with 15 enrolled in each arm. Of those receiving BTX-A, 13 patients (87%) experienced at least 50% reduction in VAS pain score, compared to none of the placebo patients, with improvement achieved within the first 2 weeks and maintained over a median of 16 weeks. Sleep score similarly improved within 2 weeks among BTX-A recipients and continued until week 16. BTX-A was well tolerated, with no patient discontinuing treatment or experiencing systemic side effects. Pain during injection was seen equally in both the BTX-A and placebo arms, was transient, and resolved within 24 hours. BTX-A is safe and effective for PHN.
Commentary
Initially introduced in the late 1970s for focal dystonias and strabismus, botulinum toxin presently enjoys widespread use for everything from anal spasm to vaginismus, including autonomic disorders such as hyperhidrosis, cosmetically troubling "crows-feet" and other troublesome facial lines, and even pain syndromes such as migraine and tension headaches. Best known for inhibiting acetylcholine release at the neuromuscular junction by interfering with calcium regulated synaptic vesicle exocytosis, its pain-modulating qualities appear to be independent of its effect on muscle contraction, suggesting alternate mechanisms for its analgesic capabilities. Evidence suggests that it both reduces Ia afferent fiber traffic and inhibits release of substance P, a neuropeptide with a significant role in pain perception and neurogenic inflammation. Formalin-induced pain in experimental animals, which results from direct stimulation of nociceptors followed by inflammation, rather than through muscle tension, is also reduced by botulinum toxin, supporting a direct effect on the nociceptor system, in addition to its neuromuscular junctional effect.
