Botulinum toxin type a induces direct analgesic effects in chronic neuropathic pain
Danièle Ranoux MD
Services de Neurologie, Neurochirurgie et Soins Palliatifs, Centre Hospitalier Universitaire de Limoges, Limoges, France
Search for more papers by this authorCorresponding Author
Nadine Attal MD, PhD
Institut National de la Sante et de la Recherche Médicale U-792, France
Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
Université Versailles-Saint-Quentin, Versailles, France
INSERM U-792, Centre de Traitement et d'Evaluation de la Douleur, CHU Ambroise Paré, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt cedex, FranceSearch for more papers by this authorFrancoise Morain
Clinical Research Assistant
Institut National de la Sante et de la Recherche Médicale U-792, France
Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
Université Versailles-Saint-Quentin, Versailles, France
Search for more papers by this authorD. Bouhassira
Institut National de la Sante et de la Recherche Médicale U-792, France
Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
Université Versailles-Saint-Quentin, Versailles, France
Search for more papers by this authorDanièle Ranoux MD
Services de Neurologie, Neurochirurgie et Soins Palliatifs, Centre Hospitalier Universitaire de Limoges, Limoges, France
Search for more papers by this authorCorresponding Author
Nadine Attal MD, PhD
Institut National de la Sante et de la Recherche Médicale U-792, France
Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
Université Versailles-Saint-Quentin, Versailles, France
INSERM U-792, Centre de Traitement et d'Evaluation de la Douleur, CHU Ambroise Paré, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt cedex, FranceSearch for more papers by this authorFrancoise Morain
Clinical Research Assistant
Institut National de la Sante et de la Recherche Médicale U-792, France
Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
Université Versailles-Saint-Quentin, Versailles, France
Search for more papers by this authorD. Bouhassira
Institut National de la Sante et de la Recherche Médicale U-792, France
Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France
Université Versailles-Saint-Quentin, Versailles, France
Search for more papers by this authorAbstract
Objective
Botulinum toxin type A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone, possibly by acting on neurogenic inflammation. Such a mechanism may be involved in peripheral neuropathic pain.
Methods
A possible direct analgesic effect of BTX-A pain processing was investigated in 29 patients with focal painful neuropathies and mechanical allodynia using a randomized, double-blind, placebo-controlled design. Patients received a one-time intradermal administration of BTX-A (20–190 units) into the painful area. Outcome measures, evaluated at baseline, then at 4, 12, and 24 weeks, included average spontaneous pain intensity, quantified testing of thermal and mechanical perception and pain, allodynia to brushing (area, intensity), neuropathic symptoms, clinical global impression, and quality of life.
Results
BTX-A treatment, relative to placebo, was associated with persistent effects on spontaneous pain intensity from 2 weeks after the injection to 14 weeks. These effects correlated with the preservation of thermal sensation at baseline (p < 0.05). BTX also improved allodynia to brush and decreased pain thresholds to cold, without affecting perception thresholds. There were sustained improvements in the proportion of responders (number needed to treat for 50% pain relief: 3.03 at 12 weeks), neuropathic symptoms, and general activity. Most patients reported pain during the injections, but there were no further local or systemic side effects.
Interpretation
These results indicate for the first time that BTX-A may induce direct analgesic effects in patients with chronic neuropathic pain independent of its effects on muscle tone and suggest novel indications for BTX-A in analgesia. Ann Neurol 2008
References
- 1 Ward AB, Molenaers G, Colosimo C, Berardelli A. Clinical value of botulinum toxin in neurological indications. Eur J Neurol 2006; 13( suppl 4): 20–26.
- 2 Brashear A, Gordon MF, Elovic E, et al; Botox Post-Stroke Spasticity Study Group. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002; 347: 395–400.
- 3 Heckmann M, Ceballos-Baumann AO, Plewig G; Hyperhidrosis Study Group. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med 2001; 344: 488–493.
- 4 Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 2005; 26: 785–793.
- 5 Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol 2004; 251( suppl 1): I1–I7.
- 6 Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol 2004; 44: 167–193.
- 7
Handwerker HO.
Nociceptors: neurogenic inflammation. In
F Cervero,
TS Jensen, eds. Handbook of clinical neurology. Vol
81.
Pain.
Amsterdam:
Elsevier,
2006:
23–33.
10.1016/S0072-9752(06)80007-2 Google Scholar
- 8 Ishikawa H, Mitsui Y, Yoshitomi T, et al. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol 2000; 44: 106–109.
- 9 Purkiss J, Welch M, Doward S, Foster K. Capsaïcin-stimulated release of substance P from cultured dorsal root ganglion neurons: involvement of two distinct mechanisms. Biochem Pharmacol 2000; 59: 1403–1406.
- 10
Meunier FA,
Colasante C,
Faille L, et al.
Upregulation of calcitonin gene related peptide at mouse motor nerve terminals poisoned with botulinum type-A toxin.
Pflugers Arch
1996;
431(
suppl 2):
R297–R298.
10.1007/BF02346386 Google Scholar
- 11 Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache 2004; 44: 35–42.
- 12 Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004; 107: 125–133.
- 13 Morenilla-Palao C, Planells-Cases R, Garcia-Sanz N, Ferrer-Montiel A. Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem 2004; 279: 25665–25672.
- 14 Luvisetto S, Marinelli S, Lucchetti F, et al. Botulinum neurotoxins and formalin-induced pain: central vs peripheral effects in mice. Brain Res 2006; 1082: 124–131.
- 15 Bach-Rojecky L, Relja M, Lackovic Z. Botulinum toxin type A in experimental neuropathic pain. J Neural Transm 2005; 112: 215–219.
- 16 Luvisetto S, Marinelli S, Cobianchi S, Pavone F. Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain. Neuroscience 2007; 145: 1–4.
- 17 Park HJ, Lee Y, Lee J, et al. The effects of botulinum toxin A on mechanical and cold allodynia in a rat model of neuropathic pain. Can J Anesth 2006; 53: 470–477.
- 18 Zieglgansberger W, Berthele A, Tolle TR. Understanding neuropathic pain. CNS Spectr 2005; 10: 298–308.
- 19 Cline MA, Ochoa J, Torebjork HE. Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 1989; 112: 621–647.
- 20 Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998; 5: 209–227.
- 21 Petersen KL, Fields HL, Brennum J, et al. Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 2000; 88: 125–133.
- 22 Hall GC, Carroll D, Parry D, McQuay HJ. Epidemiology and treatment of neuropathic pain: the UK primary care perspective. Pain 2006; 122: 156–162.
- 23 Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006; 367: 1618–1625.
- 24 Attal N, Haanpaa M, Hansson P, et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006; 13: 1153–1169.
- 25 Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005; 118: 289–305.
- 26 Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2005; 2: 164.
- 27 Argoff CE. A focused review on the use of botulinum toxins for neuropathic pain. Clin J Pain 2002; 18: S177–S181.
- 28 Freund B, Schwartz M. Subcutaneous BTX-A in the treatment of neuropathic pain: a pilot study. Presented at: 38th Interagency Botulism Research Coordinating Meeting; October 17–19, 2001; Easton, MD.
- 29 Jabbari B, Maher N, Difazio MP. Botulinum toxin A improved burning pain and allodynia in two patients with spinal cord pathology. Pain Med 2003; 4: 206–210.
- 30 Liu HT, Tsai SK, Kao MC, Hu JS. Botulinum toxin A relieved neuropathic pain in a case of post-herpetic neuralgia. Pain Med 2006; 7: 89–91.
- 31 Naumann M, Flachenecker P, Brocker EB, et al. Botulinum toxin for palmar hyperhidrosis. Lancet 1997; 349: 252.
- 32 Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994; 23: 129–138.
- 33 Wallace MS, Rowbotham MC, Katz NP, et al. A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology 2002; 59: 1694–1700.
- 34 Attal N, Rouaud J, Brasseur L, et al. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology 2004; 62: 218–225.
- 35 Ducreux D, Attal N, Parker F, Bouhassira D. Mechanisms of central neuropathic pain: a combined psychophysical and fMRI study in syringomyelia. Brain 2006: 129: 963–976.
- 36 Bouhassira D, Attal N, Fermanian J, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004; 108: 248–257.
- 37 Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–370.
- 38 Gazerani P, Staahl C, Drewes AM, Arendt-Nielsen L. The effects of botulinum toxin type A on capsaicin-evoked pain, flare, and secondary hyperalgesia in an experimental human model of trigeminal sensitization. Pain 2006; 122: 315–325.
- 39 Tugnoli V, Capone JG, Eleopra R, et al. Botulinum toxin type A reduces capsaicin-evoked pain and neurogenic vasodilatation in human skin. Pain 2007; 130: 76–83.
- 40 Blersch W, Schulte-Mattler WJ, Przywara S, et al. Botulinum toxin A and the cutaneous nociception in humans: a prospective, double-blind, placebo-controlled, randomized study. J Neurol Sci 2002; 205: 59–63.
- 41 Krämer HH, Angerer C, Erbguth F, et al. Botulinum toxin A reduces neurogenic flare but has almost no effect on pain and hyperalgesia in human skin. J Neurol 2003; 250: 188–193.
- 42 Schulte-Mattler WJ, Opatz O, Blersch W, et al. Botulinum toxin A does not alter capsaicin-induced pain perception in human skin. J Neurol Sci 2007; 260: 38–42.
- 43 Sycha T, Samal D, Chizh B, et al. A lack of antinociceptive or antiinflammatory effect of botulinum toxin A in an inflammatory human pain model. Anesth Analg 2006; 102: 509–516.
- 44 Voller B, Sycha T, Gustorff B, et al. A randomized, double-blind, placebo controlled study on analgesic effects of botulinum toxin A. Neurology 2003; 61: 940–944.
- 45 Ranoux D, Gury C, Fondarai J, et al. Respective potencies of Botox and Dysport: a double-blind, randomized, cross-over study in cervical dystonia. J Neurol Neurosurg Psychiatry 2002; 72: 459–462.
- 46 Dong M, Yeh F, Tepp WH, et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006; 312: 592–596.
- 47 Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand 1999;( suppl 173): 12–24.
- 48 Bouhassira D, Lanteri-Minet M, Attal N, et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain (in press).
- 49 Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 2006; 7: 281–289.
- 50 Jensen MP, Chodroff MJ, Dworkin RH. The impact of neuropathic pain on health-related quality of life: review and implications. Neurology 2007; 68: 1178–1182.
- 51 Smith BH, Torrance N, Bennett MI, Lee AJ. Health and quality of life associated with chronic pain of predominantly neuropathic origin in the community. Clin J Pain 2007; 23: 143–149.
- 52 Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132: 237–251.
- 53 Vadoud-Seyedi J, Simonart T. Treatment of axillary hyperhidrosis with botulinum toxin type A reconstituted in lidocaine or in normal saline: a randomized, side-by-side, double-blind study. Br J Dermatol 2007; 156: 986–989.
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