by Elena Moro
For June 2016 we have selected: Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. Attal N, et al. Lancet Neurol 2016;15:555-565.
The treatment of neuropathic pain is very challenging for neurologists and pain specialists since pain medications often have important adverse events or are partially effective. Botulinum toxin type A has been successfully used for many years to treat dystonia, spasticity, and other disorders with muscle hyperactivity. More recently, botulinum toxin has been found to have analgesic properties that are independent from its effects on muscles. Previous small pilot studies have also suggested that botulinum toxin could be effective in treating neuropathic pain.
In this three-centers (two in France, and one in Brazil) randomized, double-blind, placebo-controlled study the authors assessed the efficacy and safety of subcutaneous botulinum toxin treatment in patients with neuropathic pain. Sixty-eight patients who met the criteria for probable or definite neuropathic pain accordingly to the International Association for the Study of Pain, and with a score of at least four out of ten on the ‘douleur neuropathique en 4 questions” (DN4) questionnaire, were randomized to receive two subcutaneous administrations of botulinum toxin or placebo, 12 weeks apart. The primary outcome was the efficacy of botulinum toxin versus placebo comparing the self-reported mean weekly pain intensity at baseline and over a 24-week period of time from the first treatment. A generalized linear mixed-model repeated-measures analysis was used to treat the results. The most common cause of neuropathic pain was post-traumatic postsurgical neuropathic pain. In the 34 patients who received active treatment, pain intensity was significantly reduced (95% CI –0.95 to -0.59; p<0.0001) over the 24 weeks compared to the 32 patients with placebo. The mean number of injection sites was similar between groups (39.8 and 42.0), as well as the mean total dose injected (199 and 194 units). In the botulinum toxin group there was a significant therapeutic gain of the second administration. Patients with allodynia improved with botulinum toxin significantly more than those without allodynia. This response was predicted by the severity of brush-induced allodynia and pressure hyperalgesia. Overall, less thermal deficits and stronger mechanical allodynia were associated with greater efficacy of botulinum toxin. The most frequent side effect was pain from the injections (55% of patients).
“Our results show that botulinum toxin can be as effective as most recommended drugs to alleviate neuropathic pain, and without any systemic side-effects”, says the leading author, Prof. Nadine Attal, Pain Clinic, CHU Ambroise Pare, Paris, France. “However, since there has been no improvement in sleep disturbances and anxiety, we suggest that botulinum injections can be proposed as an add-on treatment to neuropathic pain.”
“This is a very important study supporting the efficacy of botulinum toxin in neuropathic pain”, says Prof. Giorgio Cruccu, Department of Neurology and Psychiatry, Sapienza University of Rome, Italy. “To note, allodynia and limited thermal deficit at baseline predicted a better response to botulinum treatment, suggesting that botulinum toxin is more efficacious when the nociceptors are spared, as demonstrated by a greater density of intraepidermal nerve fibres in responders than in non-responders. Indeed, botulinum toxin is expected to be efficacious when the pain is supposedly generated by peripheral sensitization or the so-called “irritable nociceptors” mechanism. Perhaps it is worth reminding that widespread pain or central pain cannot be treated by botulinum injections: botulinum toxin is a topical treatment and thus its optimum target are patients with a relatively small territory of pain, such as those with focal painful neuropathy.
The other nominees for the June’s paper of the month are:
- Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomized trial. Lancet Neurology 2016;15:566-573. In this multicenter, prospective, open-label, blinded-endpoint trial, 50 patients with intracranial hemorrhage related to vitamin K antagonists (VKA-ICH) and INR ≥2 were randomized to receive 20 mL/kg of intravenous fresh frozen plasma (FFP) or 30 IU/kg of intravenous four-factor prothrombin complex concentrate (PCC). Four-factor PCC was superior to FFP in normalizing the INR. Moreover, the faster INR normalization was associated with smaller hematoma expansion.
- Berende A, ter Hofstede HJM, Vos FJ, et al. Randomized trial of longer-term therapy for symptoms attributed to Lyme disease. N Engl JMed 2016;374:1209-1220. In this randomized, double-blind, placebo controlled European trial, the efficacy of a 12-week antibiotic treatment of persistent symptoms attributed to Lyme disease was studied in 280 patients. Quality of life, measured by the RAND-36 Health Status Inventory score, was similar between patients receiving clarithromycin plus hydroxychloroquine or doxycyclyne or placebo. This study does not support the use of long-term antibiotic treatment to treat persistent symptoms in Lyme disease patients.
- Amarenco P, Lavall PC, Labreuche J, et al., for the TIAregistry.org Investigators. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med 2016;374:1533-1542. A TIA registry was set up with the contribution of 21 countries, including 4,789 patients who had TIA or minor stroke within the previous 7 days. The Kaplan–Meier estimate of the 1-year event rate of the composite cardiovascular outcome was 6.2%, thus lower than previously reported. Multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD2 score of 6 or 7 were each associated with more than a doubling of the risk of stroke.