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Neurology International 2016; volume 8:6322

Neuropathic treatment: Differently, central NP is infrequent, including pain due to spinal cord injury; pain is multiple Correspondence: Bruno Lima Pessoa, still a challenge sclerosis (MS), post-stroke pain, and etc.2 Division of the Usually, patients with NP can present with Neurology/Neuroscience Clinical Research Osvaldo J.M. Nascimento,1 Bruno L. lancinating, shooting and/or burning pain Subunit of Antonio Pedro University Hospital, Pessoa,1 Marco Orsini,2 Pedro Ribeiro,2 along with tingling sensation. Positive sensory Universidade Federal Fluminense (UFF), RuaSiqueira Campos, 53/1204, Copacabana, Rio Eduardo Davidovich,1 Camila Pupe,1 symptoms such as spontaneous or evoked pain Pedro Moreira Filho,1 de Janeiro, RJ, 22031-071 Brazil. in response to noxious or non-noxious stimuli E-mail: [email protected] Ricardo Menezes Dornas,1 (hyperalgesia and allodynia, respectively) may Lucas Masiero,1 Juliana Bittencourt,2 also occur.3,4 Besides, a well-performed history Key words: Neurology; pain; treatment. Victor Hugo Bastos3 and physical examination are the best tools for 1Neuropathic Pain Division, the correct diagnosis. Electrophysiological Contributions: the authors contributed equally. Neurology/Neuroscience Clinical tests, imaging, and at times histological exam- ination points to the diagnosis, although NP is Conflict of interest: the authors declare no poten- Research Subunit, Antonio Pedro still diagnosed based on clinical aspects.4 tial conflict of interest. University Hospital, Federal Fluminense Initially, the management of NP consists of University, Niterói; 2Brain Mapping Received for publication: 24 November 2015. drug therapy and interdisciplinary approaches. Accepted for publication: 6 June 2016. Department, Federal University of Rio de As the last resource, surgical intervention Janeiro, IPUB, Rio de Janeiro; might be demanded, mainly in patients with This work is licensed under a Creative Commons Department of Medicine, Severino refractory NP.5,6 This review will focus on new Attribution NonCommercial 4.0 License (CC BY- Sombra University, Vassouras, Rio de pharmacological treatments for NP. NC 4.0). Janeiro; 3Piaui Federal University, Physical Therapy School, Brazil ©Copyright O. J.M. Nascimento et al., 2016 Licensee PAGEPress, Italy Pharmacological interventions Neurology International 2016; 8:6322 doi:10.4081/ni.2016.6322only Abstract The pharmacological treatment of NP is based on antidepressant and antiepileptic Neuropathic pain (NP) is the result of a drugs. Still, use can also be considered,useAcetyl-L- series of conditions caused by diseases or but are commonly regarded controversial. lesions to the somatosensory system. Due to These drugs are well studied and established ALC is an ester produced by the human the better understanding of NP pathophysiolo- in clinical practice, but their estimated pain brain, liver, and kidney. ALC seems to increase gy previously unexplored therapies have been relief is not higher than 40-50%.6 Also, placebo the uptake of Acetyl-CoA into the mitochondria used with encouraging results. In this group, effects may range from 30% bringing uncer- and exerts cholinomimetic effects because it is acetyl-L-carnitine, alpha-lipoic-acid, cannabi- tainty about the effectiveness of these drugs in similar in structure to acetylcholine.12,13 In a noids, , EMA401, botulinum toxin some patients. We have been observed this controlled randomized trial performed by Sima type A and new voltage-gated channel effect in real life and a daily basis.7 Among the Anders and colleagues,13 ALC was demonstrat- blockers, can be included. Besides, changing new therapeutic options, some studies have ed to be efficacious in reducing NP, as well as paradigms may occur with the advent of opto- been highlighted Acetyl-L-carnitine (ALC), improving nerve fiber regeneration in patients genetics and a better understanding of epige- Alpha-lipoic-acid (ALA), products, with .13 netic regulation. We reviewed the published botulinumcommercial toxin and angiotensin type 2 recep- Nevertheless, De Grandis and Minardi14 literature on the pharmacological treatment of tor antagonists.6 Additionally, the new voltage- observed similar results in a multicenter, ran- NP. Despite the interesting results, random- gated sodium channel blockers, among which domized, double-blind, placebo-controlled ized controlled trials are demanded the major- we highlight Nav1.7, Nav1.8, Nav1.3, and study including 333 diabetic patients with dia- ity of the therapies previously mentioned. In Nav1.9, are expected to be superior to other betic neuropathy. Randomization occurred to spite of several studies for the relief ofNon NP, pain sodium channel blockers. Since these NAV’s receive either ALC or a placebo. The active control continues being a challenge. are receptor specific, they may to less treatment group received 1 g of intramuscular- potential cardiac, motor, and CNS side effects.8 ly ALC for ten days following 2 g of orally ALC In the same way, the use of specific blockers of for 355 days. The ALC group demonstrated a the alpha-2-delta-1 (Cav 2 1) subunit of calci- 39% decrease in pain measured by VAS Introduction um channels has been studied as a potential (P<0.01 vs. baseline) in 12 months; vs. 8% antinociceptive drug, based on the concept of reduction in the placebo group. Significant Neuropathic pain (NP) is a condition due to these channels might be overexpressed in change in nerve conduction velocity was found diseases or lesions affecting the somatosenso- some pain states.9 Till now, there is a lack of in sural nerve (+7 m/sec in ALC vs. +1 m/sec ry nervous system pathways, either in the cen- enough evidence regarding the of the in placebo) and in the sensory ulnar nerve tral or the peripheral nervous systems.1 majority of these emerging treatments for NP. (+2.9 m/sec in LAC vs. +0,1 m/sec in place- Peripheral NP is the result of small fibers dys- Nevertheless, the paucity of randomized con- bo).14 function or lesions seen in polyneuropathies trolled trials (RCTs) and clinical evidence does (diabetes, chronic abuse, infections, not mean that we should abandon these new chemotherapy, amyloidosis, etc.). Other fre- modalities. Instead, new studies are demanded quent causes include trigeminal neuralgia, to prove their efficacy.10,11 Alpha-lipoic-acid herpes zoster, complex regional pain syndrome (CRPS), entrapment syndromes, and others.2 ALA is known for its properties

[page 36] [Neurology International 2016; 8:6322] Review and its role in mitochondrial dehydrogenase part of the routine treatment of NP. Despite a reactions. ALA has demonstrated protection Selective angiotensin II type 2- lack of convincing RCTs addressing the effica- against oxidative stress in models of ischemia- receptor antagonist: EMA401 cy of these new therapies, there is a need for reperfusion lesion, diabetes, neurodegenera- further studies. With advancing knowledge on the pathophysiology of pain, new methods tion, HIV activation and others. Recent studies This class of drug is considered a new alter- might be proposed, ensuring greater effective- suggest that ALA plays a much broader role native for NP. EMA401 is a selective angiotensin 15,16 ness of different therapies, with a lower per- than just simply being an antioxidant. II type 2-receptor antagonist. In a randomized, centage of patients with refractory pain. Doing A multicenter, randomized, double-blind, controlled, double blind, 181 so, a new paradigm for the treatment of chron- placebo-controlled trial with 181 diabetic patients received 100 mg EMA401 twice daily or ic pain will result. Despite the existence of sev- patients tested daily dose of 600 mg, 1200 mg, a placebo.25 The researchers found significantly eral studies for the relief of NP, pain control and 1800 mg of oral ALA, or placebo for NP. A less pain, after a week, compared with baseline continues being a challenge real pain reducing response with fewer side values in the EMA401 group, compared to the effects was found with the 600mg dose. placebo group, leading to a new possibility of References Furthermore, thioctic acid has a functional treatment for refractory NP.25 structure very similar to ALA and can be expected to have similar benefits to that of 1. Treede RD, Jensen TS, Campbell JN, et al. ALA.17,18 Neuropathic pain: redefinition and a grad- Cebranopadol ing system for clinical and research pur- poses. Neurology 2008;70:1630-5. 2. Dworkin RH, Backonja M, Rowbotham MC, This agent is an / et al. Advances in neuropathic pain: diag- products orphanin FQ peptide (NOP) as well as an opi- nosis, mechanisms, and treatment recom- oid receptor . It has high antinocicep- mendations. Arch Neurol 2003;60:1524-34. In a randomized trial using smoked tive and anti-hypersensitive effects without 3. Jensen TS, Baron R. Translation of symp- cannabis for chronic NP, the authors selected causing respiratory and motor side effects. In toms and signs into mechanisms in neuro- 23 patients. They concluded that a single many rat models of acute and onlypathic pain. Pain 2003;102:1-8. inhalation of 25 mg of 9.4% tetrahydrocannabi- (tail-flick, rheumatoid arthritis, bone cancer, 4. Woolf CJ, Mannion RJ. Neuropathic pain: nol herbal cannabis three times daily for five spinal nerve ligation, diabetic neuropathy) its aetiology, symptoms, mechanisms, and days may cause pain relief, improve the quality results have been proven positive for amelio- management. Lancet 1999;353:1959-64. of sleep and is well tolerated.19,20 rating NP.26 In spite of this, other studies are use 5. Schug SA, Goddard C. Recent advances in In another study, patients with MS were necessary before the usage in humans the pharmacological management of acute tested by using an oral spray with 2.7 mg of becomes possible. and chronic pain. Ann Palliat Med and 2.5 of delta-9- 2014;3:263-75. . After five weeks, cannabis spray 6. Schestatsky P, Vidor L, Winckler PB, et al. was superior to placebo in reducing pain and Promising treatments for neuropathic sleep disorders in MS patients with and central Botulinum toxin type A pain. Arquivos de Neuro-Psiquiatria pain. Despite these results, controversies are 2014;72:881-8. still present related to cannabinoids use, since Botulinum Toxin type A (BTX-A) has been a 7. Bittar C, Nascimento OJ. Placebo and other randomized study did not reveal signifi- 27,28 subject of some studies for NP. Ranoux, nocebo effects in the neurological prac- cant results, but instead showed same effects 27 Attal and colleagues investigated the effect of tice. Arquivos de neuro-psiquiatria as the placebo group.21,22 intradermal injection of BTX-A in 29 patients 2015;73:58-63. In a systematic review and meta-analysis commercialwith NP and allodynia of different etiologies. 8. Theile JW, Cummins TR. Recent develop- about cannabinoids for medical use, Whiting The BTX-A injection improved the sponta- ments regarding voltage-gated sodium et al. showed only moderate evidence for the neous pain from 2 weeks to 12 weeks (NNT) of channel blockers for the treatment of use of cannabinoids in chronic pain conditions 3.03 for 50% pain relief), and reduced allody- inherited and acquired neuropathic pain and spasticity. However, its usage was related nia without decrease of sensibility to pain.27 In syndromes. Front Pharmacol 2011;2:54. 23 to significant short-term side effects.Non a double-blind crossover trial of intradermal 9. Chang E, Chen X, Kim M, et al. Differential BTX-A for diabetic NP in 18 patients, Yuan et effects of voltage-gated channel al.28 found a reduction in VAS≥3 after 3 blockers on calcium channel alpha-2-delta- months of 44% of the patients who received 1 subunit protein-mediated . Topical treatment: clonidine BTX-A injection compared to the placebo arm Eur J Pain 2015;19:639-48. of the study. Also, improvement in sleep quality 10. Gorski DH, Novella SP. Clinical trials of Clonidine has emerged as adjuvant therapy in those patients was noted. Despite the excit- integrative medicine: testing whether in diabetic patients who suffer from painful ing results, the authors agree that larger sam- magic works? Trends in molecular medi- diabetic neuropathy. In a randomized, double- ples are demanded to reveal the real efficacy of cine 2014;20:473-6. blind, placebo-controlled study, Campbell and BTX-A usage in diabetic NP.28 11. Greenhalgh T, Howick J, Maskrey N. colleagues24 included 179 patients with painful Evidence based medicine: a movement in diabetic neuropathy to receive either 0.1% top- crisis? BMJ 2014;348:g3725. ical clonidine gel or placebo gel. As a result, 12. [No authors listed]. Acetyl-L-carnitine. patients who received topical clonidine gel Conclusions Monograph. Altern Med Rev. 2010;15:76- obtained pain relief in the foot when compared 83. to placebo.6,24 Some clinical therapies for NP have 13. Sima AA, Calvani M, Mehra M, Amato A. emerged over the last decade. With the accept- Acetyl-l-carnitine improves pain, nerve ance of their use, these drugs might become, a regeneration, and vibratory perception in

[Neurology International 2016; 8:6322] [page 37] Review

patients with chronic diabetic neuropathy 2365-70. 2015;313:2456-73. an analysis of two randomized placebo- 19. Lynch ME, Campbell F. Cannabinoids for 24. Campbell CM, Kipnes MS, Stouch BC, et al. controlled trials. Diabetes Care 2005;28: treatment of chronic non-cancer pain; a Randomized control trial of topical cloni- 89-94. systematic review of randomized trials. Br dine for treatment of painful diabetic neu- 14. De Grandis D, Minardi C. Acetyl-L-carni- J Clin Pharmacol 2011;72:735-44. ropathy. Pain 2012;153:1815-23. tine (levacecarnine) in the treatment of 20. Ware MA, Wang T, Shapiro S, et al. Smoked 25. Rice AS, Dworkin RH, McCarthy TD, et al. diabetic neuropathy. A long-term, ran- cannabis for chronic neuropathic pain: a EMA401, an orally administered highly domised, double-blind, placebo-controlled randomized controlled trial. CMAJ selective angiotensin II type 2 receptor study. Drugs R D 2002;3:223-31. 2010;182:E694-701. antagonist, as a novel treatment for pos- 15. Shay KP, Moreau RF, Smith EJ, et al. Alpha- 21. Rog DJ, Nurmikko TJ, Young CA. therpetic neuralgia: a randomised, double- as a : molec- Oromucosal delta9-tetrahydrocannabinol/ blind, placebo-controlled phase 2 clinical ular mechanisms and therapeutic poten- cannabidiol for neuropathic pain associat- trial. Lancet 2014;383:1637-47. tial. Biochim Biophys Acta ed with multiple sclerosis: an uncon- 26. Linz K, Christoph T, Tzschentke TM, et al. 2009;1790:1149-60. trolled, open-label, 2-year extension trial. Cebranopadol: a novel potent analgesic 16. Packer L, Witt EH, Tritschler HJ. Alpha- Clin Ther 2007;29:2068-79. nociceptin/orphanin FQ peptide and opioid Lipoic acid as a biological antioxidant. 22. Langford RM, Mares J, Novotna A, et al. A Free Radic Biol Med 1995;19:227-50. double-blind, randomized, placebo-con- receptor agonist. J Pharmacol Exp Ther 17. Mijnhout GS, Kollen BJ, Alkhalaf A, et al. trolled, parallel-group study of THC/CBD 2014;349:535-48. Alpha lipoic acid for symptomatic peripher- oromucosal spray in combination with the 27. Ranoux D, Attal N, Morain F, Bouhassira al neuropathy in patients with diabetes: a existing treatment regimen, in the relief D. Botulinum toxin type A induces direct meta-analysis of randomized controlled of central neuropathic pain in patients analgesic effects in chronic neuropathic trials. Int J Endocrinol 2012;2012:456279. with multiple sclerosis. J Neurol 2013;260: pain. Ann Neurol 2008;64:274-83. 18. Ziegler D, Ametov A, Barinov A, et al. Oral 984-97. 28. Yuan RY, Sheu JJ, Yu JM, et al. Botulinum treatment with alpha-lipoic acid improves 23. Whiting PF, Wolff RF, Deshpande S, et al. toxin for diabetic neuropathic pain: a ran- symptomatic diabetic polyneuropathy: the Cannabinoids for medical use: a systemat- domized double-blind crossover trial. SYDNEY 2 trial. Diabetes Care 2006;29, ic review and meta-analysis. JAMA Neurologyonly 2009;72:1473-8. use

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