Since its initial use to treat muscle hyperactivity, botulinum toxin type A (BoNT-A), a bacterially derived toxin that blocks neurotransmitter release, has been studied for possible analgesic effects. Several studies in patients have suggested that BoNT-A can alleviate peripheral neuropathic pain, but those studies have been small, making firm conclusions impossible. Moreover, the largest trial to date (which went unpublished), from the pharmaceutical company Allergan, reported negative results. But now, a trial spanning three clinics finds that repeated administration of BoNT-A reduces neuropathic pain, without systemic side effects.
Led by Nadine Attal, French Institute of Health and Medical Research, Boulogne-Billancourt, France, researchers conducted a randomized, double-blind, placebo-controlled clinical trial showing that patients with peripheral neuropathic pain who received two subcutaneous injections of BoNT-A in the painful area of the body reported long-lasting relief. In addition, they found that those with more severe mechanical allodynia and greater density of intra-epidermal nerve fibers, as well as preserved temperature detection, responded best to the treatment.
“This trial is important, as we desperately need new options for treating neuropathic pain, and regional treatment can avoid systemic side effects,” wrote David Bennett, University of Oxford, UK, in an email to PRF. “Furthermore, it illustrates the value of patient stratification,” he added.
The trial was published online February 29 in The Lancet Neurology.
Going beyond pilot studies
In 2008, Attal and colleagues found that a single dose of BoNT-A could mitigate peripheral neuropathic pain in patients (Ranoux et al., 2008). However, “it was a pilot study, and since then there have only been studies with small samples,” said Attal. In addition, all patients in Attal’s study had allodynia, “so we wanted to see whether there were similar results in a larger group of patients” with diverse symptoms, she added. The researchers were also interested in whether administering BoNT-A a second time could provide benefits that exceeded those of a single dose.
For the new trial, the researchers included 66 patients with diverse causes of peripheral neuropathic pain from three outpatient clinics—two in France, one in Brazil—more than doubling the number of participants included in their earlier study. Patients, aged 18-85 years and split equally between groups in terms of sex, cause of pain, and other patient characteristics, received two subcutaneous administrations of either BoNT-A or placebo in the painful area of the body, with the second injection administered 12 weeks after the first. Subjects rated the intensity of pain (from 0 to 10) before and after treatment for 24 weeks.
Patients who received BoNT-A, but not placebo, reported a statistically significant decrease in self-reported mean pain intensity during each week of the study. At the end of the study, the two administrations of BoNT-A significantly decreased self-reported mean pain intensity compared to placebo (adjusted effect estimate -0.77); thus, the trial met its primary endpoint. When the researchers classified responders as those patients with at least 50 percent pain relief, the proportion of responders in the BoNT-A and placebo groups did not differ 24 weeks after the first administration. Yet, upon considering patients with at least 30 percent relief, the BoNT-A group had a higher proportion of responders. In sum, repeated injections of BoNT-A offered prolonged relief from peripheral neuropathic pain.
The second administration of BoNT-A did not just maintain the effect of the first in those who responded, but also appeared to enhance the drug’s analgesic effect, turning a quarter of patients who failed to respond to the first dose of the toxin into responders. Because of this finding, the authors suggest that two administrations may be necessary to know whether a patient will benefit from BoNT-A.
To test the safety of BoNT-A treatment, the researchers also examined sensory and pain thresholds after 12 and 24 weeks. Here, they found that patients who received BoNT-A displayed no abnormalities. Moreover, patients did not report muscle weakness, wounds, severe itching, or swelling from fluid buildup, suggesting that pain relief provided by the toxin was not accompanied by systemic side effects. Equal proportions of patients in the BoNT-A and placebo groups did say that the injections were painful, even with a numbing cream and light sedation.
Overall, “the study is a very well-conducted, randomized, controlled trial of repeated botulinum toxin treatment showing efficacy in reducing neuropathic pain intensity,” said Bennett.
The current results are in contrast to the larger, unpublished trial from Allergan, which found the toxin to be ineffective for post-herpetic neuralgia—one form of neuropathic pain—relative to placebo. “The reason for this isn’t clear,” said Attal, but she thinks patients given the placebo in the Allergan study may have recovered spontaneously; that study included only patients who had post-herpetic neuralgia for more than three months, a time after which some patients are known to recover on their own.
Who is helped the most?
The authors next asked if they could determine which patients would benefit the most from BoNT-A. To this end, they used Quantitative Sensory Testing (QST) as well as the Neuropathic Pain Symptom Inventory (NPSI) to measure a host of pain symptoms before treatment. For both QST and NPSI, they found that the degree of allodynia predicted how responsive patients were to BoNT-A—those with more severe mechanical allodynia responded the best—consistent with results from the investigators’ pilot study (Ranoux et al., 2008). They also found that fewer deficits in temperature detection at baseline predicted better responses. “This shows that there is a subgroup of patients who are very prone to respond to the toxin, and a subgroup who are not,” said Attal.
To address how BoNT-A relieved neuropathic pain, the investigators analyzed study participants’ skin biopsies from the painful area before and after treatment. “Our first hypothesis was that BoNT-A would act through an effect on neurogenic inflammation,” said Attal. Contrary to this idea, skin biopsies from the BoNT-A and placebo groups had similar concentrations of substance P and calcitonin gene-related peptide (CGRP), two neuropeptides involved in inflammation, four weeks after treatment.
Nonetheless, the authors found that those who responded to BoNT-A had a greater density of intra-epidermal nerve fibers before treatment than those who did not. While this finding suggests that BoNT-A reduced pain via effects on peripheral nociceptors, it does not exclude central actions, said Attal (see PRF related story). “There are suggestions in animals that BoNT-A is retrogradely transported to central targets, but we don’t have clear evidence for this from our study,” she added.
What does the future look like?
With the current results in hand, Attal has begun to use BoNT-A off-label in the clinic to treat neuropathic pain; at the moment, migraine is the only chronic pain condition for which BoNT-A treatment is approved. But because injecting the toxin is painful, “new delivery techniques are needed before this method can be widely used in the clinic,” wrote Ralf Baron and Andreas Binder, Christian-Albrechts-Universität zu Kiel, Germany, in an accompanying commentary on the trial. “This is a problem,” agreed Attal. “The idea would be to have a toxin that would not be delivered subcutaneously,” she added.
Matthew Soleiman is a neuroscientist-turned-science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.
Image: 3-D ribbon model of botulinum neurotoxin serotype A (botox). Credit: Wikimedia Commons