Repeated subcutaneous injections of botulinum toxin A (Botox, Allergan) provides analgesic relief to patients with neuropathic pain, a new randomized controlled trial has shown.
The study showed that two series of injections were safe and effective for treating peripheral neuropathic pain, especially in a subgroup of patients with allodynia.
This research is important because neuropathic pain is a debilitating condition and represents a “highly unmet need,” in that there are very few effective treatments that don’t have significant side effects, said lead author Nadine Attal, MD, PhD, associate professor of neurology, University Versailles Saint-Quentin, Paris, France, and a member of the Institut National de la Santé et de la Recherche Médicale Research Unit on pain.
“We need to increase the therapeutic options for these patients.”
The study was published online February 29 in Lancet Neurology.
Botulinum toxin type A, which blocks nerve signals and causes muscle paralysis, is widely used to treat muscle hyperactivity, but evidence that it may also have analgesic activity is now emerging.
The new analysis included 66 patients at two clinics in France and one in Brazil who met the criteria for probable or definite neuropathic pain and who had daily pain for at least 6 months attributable to a peripheral nerve lesion.
The most common cause of pain in these patients was post-traumatic or postsurgical neuropathic pain. Pain predominantly affected the hand, forearm, foot, or ankle.
Researchers randomly assigned these patients to receive subcutaneous injections of botulinum toxin (n = 34) or an indistinguishable placebo (n = 32). To reduce the pain of these injections, patients first received topical lidocaine and prilocaine cream, as well as sedation with 50% nitrous oxide and oxygen.
The amount of pain from injecting an agent into an already painful area depended on the location. The injections were much more painful in the hand and less so in the abdomen, noted Dr Attal.
The protocol involved injecting 5 units of botulinum toxin, or placebo, into each site 1.5 to 2 cm apart, up to a maximum of 60 sites (300 units). The dose was determined by the size of the painful area.
The series of injections was repeated after 12 weeks in 58 patients (32 in the botulinum and 26 in the placebo groups), with the dose being adjusted according to the pain level. Of these, 52 (29 and 23, respectively) completed the study.
The mean total dose injected was similar between the two groups: 199.0 units for the first and 176.8 units for the second administration of botulinum compared with 194.1 for the first and 187.5 for the second administration of placebo.
In daily diary logs, patients recorded their pain levels over the previous 24 hours on an 11-point numeric rating scale. Mean pain intensity was 6.5 at baseline and 4.6 at 24 weeks in the botulinum toxin group (mean change, 1.9) and 6.4 at baseline and 5.8 at 24 weeks in the placebo group (mean change, 0.6).
The study showed that over 24 weeks, two successive series of injections of botulinum toxin A was superior to placebo (adjusted effect estimate vs placebo, –0.77; 95% confidence interval, –0.95 to –0.59; P < .0001).
Although the proportion of responders, defined as those with at least a 50% reduction in pain intensity, didn’t differ between the groups at 24 weeks, the proportion of responders was higher in the botulinum group when a responder was considered to have experienced at least a 30% reduction in pain.
The second administration resulted in a significant therapeutic gain (least-squares mean for weeks 13 to 24, 0.91; P < .0001). After the second injection series, almost a quarter (22%) of patients went from nonresponders to responders.
“The study shows that there’s an effect, and that the effect was enhanced by the second injection,” commented Dr Attal.
The effects of botulinum toxin A were greater for patients with allodynia, as measured with the Neuropathic Pain Symptom Inventory (adjusted effect estimate, 0.56; P = .003).
Fifty-five patients (29 in the botulinum toxin group and 26 in the placebo group) underwent skin punch biopsies on the painful side before randomization and 4 weeks after the first treatment.
Half the samples were analyzed for intraepidermal nerve fiber density (IENFD); for the other half, researchers quantified concentrations of the neuropeptides substance P and calcitonin gene-related peptide.
Results showed neuropeptide concentrations were similar between groups at baseline and were not modified by treatment. However, they did find that responders to botulinum toxin A had a higher baseline mean IENFD than nonresponders.
The researchers noted that limited thermal deficits at baseline were associated with better response to botulinum toxin A and that the prevalence of thermal deficits was greater in patients without allodynia.
The sensory profile characterized by preserved small-fiber function and hyperalgesia has been described as “irritable nociceptors,” the authors write.
On the basis of these new results, the researchers believe that botulinum toxin may have a direct effect on nociceptive fibers and inhibits neurogenic inflammation through a blockade of neurotransmitter release.
“We suggest — and of course it’s only a suggestion but it’s also based on animal studies so is in line with animal data — that Botox has a central effect on pain,” said Dr Attal.
Patients most likely to benefit from botulinum toxin A injections are those with peripheral pain that is localized to a specific area, those with limited thermal deficits, and those with allodynia, commented Dr Attal.
She sees botulinum toxin A as an “add on” therapy for some patients. She noted that it’s not effective in all patients and, according to the study results, it’s not always effective in improving mood or quality of life.
“If patients have impaired function, and are in a lot of pain, they may also need other agents” to treat conditions such as sleep problems, said Dr Attal. “Botox would not be sufficient to control everything in these patients who are very disabled.”
In an accompanying comment, Ralf Baron, MD, and Andreas Binder, MD, Division of Neurological Pain Research and Therapy, Christian-Albrechts University, Kiel, Germany, noted that there are more than 40 botulinum toxin subtypes with potentially different neuronal target characteristics. These include the subtype A, which was used in the study, and subtype B, which has also been studied clinically.
Other subtypes might act more exclusively on pain fibers, sparing the effect on inhibitory interneurons, although this remains to be investigated, they said.
The editorial writers also pointed out that neuropathic pain can show different sensory profiles and that these varying profiles probably suggest different underlying pathophysiologic mechanisms of pain. These distinct patient groups probably respond differently to treatment, they said.
“Findings from the present study show that a sensory profiling approach is a valid method to identify responders to botulinum toxin A.”
Because the study protocol required lidocaine and prilocaine cream plus sedation, “new delivery techniques for the toxin are needed before this method can be widely used in the clinic,” they conclude.
Funding for the study was provided by Institut National de la Santé et de la Recherche Médicale (INSERM) and Fondation CNP (France). Dr Attal has received honoraria from Pfizer, Eli Lilly, Johnson & Johnson, Astellas, Sanofi Pasteur MSD, Grünenthal, and Teva for advisory boards, speakers bureaus, or clinical trials. Dr Baron has received grants or research support from Pfizer, Genzyme, Grünenthal, and Mundipharma and is a member of the IMI European collaboration, whose industry members are AstraZeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal, Eli Lilly, and Boehringer Ingelheim. He has received speaking fees from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer Schering, MSD, and bioCSL. He has been a consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Novartis, Bristol-Myers Squibb, Biogen Idec, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Glenmark Pharmaceuticals, and bioCSL. Dr Binder has received personal fees from Astellas, Grünenthal, Mundipharma, and Genzyme and grants and personal fees from Pfizer.
Lancet. Published online February 29, 2016
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