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Home , Carpal tunnel syndrome, Meralgia paraesthetica, Sciatica

Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2014; 18: 2766-2771 in obstetrics: efficacy and safety of α-lipoic acid supplementation M. COSTANTINO, C. GUARALDI 1, D. COSTANTINO 2, S. DE GRAZIA 3, V. UNFER 3

Chemistry and Pharmaceutical Technologies, University of Ferrara, Ferrara, Italy 1Obstetrics and Gynaecology Unit, Ospedale di Valdagno (VI), Italy 2Female Centre, Azienda USL, Ferrara, Italy 3A.G.UN.CO. Ostetric and Gynecological Center, Rome, Italy

Abstract. – OBJECTIVE : Neuropathic more prone to the development of neuropathic during is a common condition due to syndromes. First and foremost, the physical the physical changes and compression around changes caused by the enlargement of the uterus pregnancy and childbirth that make pregnant women more prone to develop several medical and the development of the foetus cause postural conditions such as syndrome, sci - changes and nutation of the pelvic girdle that fa - atica, and other en - cilitate the development of low and en - trapment syndromes. Most of the treatments trapment neuropathies. The mutation of the usually performed to counteract neuropathic pelvic girdle is favoured during pregnancy also pain are contraindicated in pregnancy so that, by the presence of high concentrations of relaxin, the management of these highly invalidating conditions remains an issue in the clinical prac - which is produced from the tenth week of gesta - tice. We aimed to review the efficacy and safety tion and causes a laxity in the joints not only in of alpha lipoic acid supplementation in the treat - the pelvis, but also on a vertebral level, which ment of neuropathic pain. makes pregnant women more prone to low back DISCUSSION: Lipoic acid is a co-factor essen - pain, and pelvic pain. tial in the regulation of mitochondrial energy. It The data available in literature suggest there is has been demonstrated that lipoic acid supple - mentation is involved in several biochemical a close relationship between low back or pelvic processes and actions, exerting important an - pain during and after pregnancy and physically tioxidant and anti-inflammatory activity and sig - demanding jobs, the presence of nificantly improving pain and paraesthesia in pa - before pregnancy and pelvic pain during preg - tients with sciatica, and nancy. On the other , there would not appear . to be any significant relationship with weight CONCLUSIONS: Efficacy of lipoic acid is com - 1 bined with a high safety profile, making this mol - gain during pregnancy . ecule a novel candidate for the management of Most of the medications usually several diseases. Data reported so far are used to treat neuropathic pain are contraindicated promising and dietary supplementation with in pregnancy, as is to resolve the nerve lipoic acid seems a useful tool to contrast neuro - impingement. The best approach to these often pathic pain during pregnancy. highly invalidating conditions during pregnancy, Key Words: therefore, remains a matter for debate. Neuropathic pain, Nerve entrapment syndromes, To restrict the administration of potentially Pregnancy, Lipoic acid . dangerous medication, it is appropriate to inter - vene with rehabilitation therapies and consider administration of neuroprotectors, which are not Introduction contraindicated during pregnancy and have been seen to be efficacious in the treatment of pain Neuropathic pain is common during pregnan - and paraesthesia in peripheral neuropathies 2. cy . Pregnant women are particularly prone to the Alpha-lipoic acid (ALA), also known as thioc - development of neuropathies such as carpal tun - tic acid, and its reduced form, dihydrolipoic acid nel syndrome, sciatica, meralgia paraesthetica (DHLA) are naturally occurring compounds with and other nerve entrapment syndromes. There are one chiral centre (Figure 1). The R form is the a number of factors that make pregnant women only enantiomer synthetized and used in the bio -

2766 Corresponding Author: Demetrio Costantino, MD; e-mail: [email protected] Peripheral neuropathy in obstetrics: efficacy and safety of α-lipoic acid supplementation

IκB, a protein that inhibits NF- κB, and in direct - ly reducing the expression of NF- κB and of MMP-9s (matrix metalloproteinase-9), an en - α-Lipoic Acid (ALA) Oxidized zyme responsible for the degradation of the ex - tracellular matrix 5. On the basis of these mechanisms, ALA sup - plementation has been seen to exert important antioxidant and anti-inflammatory activity and to Dihydrolipoic acid (DHLA) significantly improve pain and paraesthesia in Reduced patients with sciatica, carpal tunnel syndrome and diabetic neuropathy 6-9 . Figure 1. The oxidized and reduced forms of lipoic acid. Low Back Pain and Sciatica Epidemiological studies have shown that 49- logical system as a co-factor essential to α-ke - 56% of pregnant women suffer from low back toacid dehydrogenase activity, playing a funda - pain; in most cases the pain appears between the mental role in regulating mitochondrial energy 5th and 7 th month of pregnancy. Another interest - metabolism. In addition to being synthesised in - ing fact is that the pain often does not disappear side the body, ALA can also be taken in through after childbirth, rather it tends to become chronic. food or dietary supplements and it has been ob - The causes of low back pain include the in - served that, following absorption, it is involved in crease in the biomechanical load that alters the a number of biochemical processes and actions, normal load balances on the spine and the in - rather than being used as a co-factor 3. crease in the laxity of the collagen tissue, due to Several studies indicate that the intake of ALA the action of relaxin, which acts above all on the supplements provides various therapeutic op - sacroiliac joint and on the pubic symphysis, but tions, given its potent antioxidant and detoxify - may also affect the spine, causing articular prob - ing actions, which help to overcome cardiovascu - lems also in the region. lar, cognitive and neuromuscular deficits and In some cases, simple low back pain can be as - modulate various inflammatory pathways. ALA sociated with a radicular syndrome, sciatica. Sci - inhibits the production of vascular and intracellu - atica is a form of peripheral neuropathy charac - lar adhesion molecules (VCAM-1 and ICAM-1), terised by pain in the lumbar and lumbosacral reduces the expression of CD4 on the surface of spine that irradiates to the lower limb in the sciat - blood mononuclear cells, reduces the secretion of ic nerve territory. Sciatica is the most common tumour necrosis factor (TNF)- α and inhibits the cause of neuropathic pain. The involvement of activation and cytotoxicity of natural killer (NK) the , due to the impingement of the cells 4. In addition, given ’s oxida - sensory nerve roots in the intervertebral disk tive nature and considering that the events related spaces (primarily L4-L5 or L5-S1), characterises to it are associated with the activation of the tran - the clinical presentation of the sciatica. In this scription factor NF- κB, ALA’s anti-inflammatory case, the low back pain irradiates to the gluteus action has also been evaluated in terms of its di - and leg. The pain caused by nerve impingement rect inhibitory action against this factor. NF- κB () is associated with numbness, tin - plays a fundamental role in the expression of var - gling, weakness and movement difficulties, par - ious genes involved in inflammatory response ticularly after long periods of sitting. The most and in cell apoptosis processes. Its activation is common cause is the loss of the intervertebral connected to the cell’s exposure to lipopolysac - disks’ cushioning function. The intervertebral charides, inflammatory cytokines (TNF- α and in - disks are essential for absorbing the pressure pro - terleukin-1), growth factors, lymphokines, free duced by spine movements and their degenera - radicals and many other physiological and non- tion greatly reduce spinal mobility and favours physiological stimuli. It has been observed that friction between vertebral bodies and the crush - treatment with ALA causes a down-regulation of ing of the nerve roots passing through the inter - 10,11 NF- κB, which, being a redox-sensitive molecule, vertebral foramens . suffers its oxidative effects. In particular, acute In sensitive/motor , the clinical treatments with ALA have been found to be ef - presentation is characterised by acute pain symp - fective both in inhibiting the degradation of the toms that often require the use of nonsteroidal

2767 M. Costantino, C. Guaraldi, D. Costantino, S. De Grazia, V. Unfer anti-inflammatory drugs (NSAIDs ) or other types CTS is the most common canal syndrome and of painkillers. In these cases, once the acute is caused by an increase in the pressure on the phase has passed, or even in association with the inside the carpal tunnel; it has a same , it is useful to introduce sub - prevalence of 5-16% in the general population, stances with an antioxidant and, therefore, anti- with a female:male ratio of 3:1. Pregnant and inflammatory and neurotrophic action. perimenopausal women are particularly at risk, Supplementation with antioxidants and neu - given the water retention related to the hormonal rotrophic agents is a pathogenetic approach, as condition. opposed to the purely symptomatic approach The incidence of CTS in pregnant women is 2 adopted when using analgesics, and not only re - to 3 times higher than in women who are not duces symptoms, but also avoids the progression pregnant. of the condition to the point in which it becomes CTS can be caused by any factor able to re - chronic. duce the dimensions of the tunnel or increase Pathogenetic treatments can also act on the the size of its content. The increase in pressure various clinical presentations of the neuropathy, on the median nerve by the transverse ligament, which helps to resolve the sensitive, motor and particularly during the extension and flexion of autonomic problems caused by the nerve conduc - the and fingers, damages the local lesser tion deficit. circulation, causing the generation of spurious Various studies have been conducted to eval - action potentials, demyelinization and axonal uate the effects of ALA administration in pa - damage. tients with sciatica. In one randomized, double- In the first phase of the condition (pain/irrita - blind study, 64 patients with sciatica were treat - tion phase), the patient complains of tingling and ed with l-acetyl-carnitine (ALC) 1180 mg/day burning or stabbing pain in the median nerve’s or ALA 600 mg/day for 60 days. ALA 600 distribution territory: thumb, index finger, middle mg/day was seen to be significantly superior to finger and part of the ring finger. Pain occurs pri - ALC in the treatment of sciatica, with an im - marily at night-time, due to the lymphatic and provement in symptom scores and a reduced circulatory stasis that occurs when the hand is need for analgesia. ALA also improved nerve immobile and with an intensity such as to repeat - conduction velocity 12 . edly awaken the patient. Other studies on patients with radiculopathies Subsequently, the condition may progress to evaluated the combination of physical and neu - the point where the patient complains of pain al - rotrophic and antioxidant therapies. One report so during the daytime. The pain, accompanied by on patients with radiculopathies evaluated treat - unpleasant paraesthesias, can irradiate to the ment with a combination of 600 mg/day of ALA, whole of the upper limb and shoulder. The pa - gamma-linolenic acid and vitamins with oxygen- tient’s quality of life suffers further because of ozone therapy compared to oxygen-ozone thera - the difficulties performing many movements and py alone 13 , whereas in another study the evalua - the frequent awakenings during the night. This tion was conducted on patients treated with reha - phase is known as the paraesthesia-pain phase. bilitation physiotherapy 14 . In both cases, a syner - Lastly, a patient with advanced phase disease getic action was observed between the adminis - may present muscular hypotrophy of the hand’s tration of ALA and the combined therapy, with , with consequent deformation significantly superior results on both symptoms and paralysis and nail dystrophy (-paraly - and functional deficits in the groups treated with sis phase). ALA. The diagnosis of CTS is based on the presence More recent researches have also shown the of pain and paraesthesia in the median nerve dis - positive effects of ALA administration, again tribution territory, the presence of nocturnal with an oral dose of 600 mg/day, in patients with symptoms, muscle weakness of the thenar mus - lower back pain 15 and in patients with cervico - cle and, above all, a positive Tinel’s sign. This brachial pain 16 . sign reveals median nerve irritation and is per - formed by tapping lightly on the flexor retinacu - Carpal Tunnel Syndrome lum to cause a tingling feeling in the nerve’s dis - Some 30-35% of pregnant women experience tribution territory. hand problems, which can often be attributed to Another important test for the diagnosis of carpal tunnel syndrome (CTS). CTS is the Phalen’s manoeuvre, which is per -

2768 Peripheral neuropathy in obstetrics: efficacy and safety of α-lipoic acid supplementation formed by flexing the wrist gently, as far as pos - Meralgia Paraesthetica sible, and the holding the position until symp - The entrapment of the lateral femoral cuta - toms occur. In this case, the faster the numbness neous nerve (sensitive nerve) is known as meral - develops, the more advanced the condition. gia paraesthetica and commonly occurs during Phalen’s manoeuvre is defined as being posi - the third trimester of pregnancy. tive when pain and/or paraesthesia develop in the The symptoms of lateral femoral cutaneous fingers innervated by the median nerve after one nerve entrapment include loss of sensitivity, pain minute of wrist flexion 17 . and dysaesthesia on the side of the . Given Lastly, the Durkan test involves the application the absence of muscular innervations, the syn - of firm pressure on the palm above the nerve for drome is purely sensitive. Symptoms worsen a maximum of 30 seconds to cause the appear - when the subject is standing or walking. Patients ance of symptoms 18 . complain of walking difficulties and knee insta - Median nerve decompression surgery is the bility, depending on the severity of the lesion. treatment of election in most cases of CTS. How - The entrapment of the lateral femoral nerve ever, the treatment of CTS in pregnant women is usually occurs in the inguinal ligament and dif - exclusively conservative. ferential diagnosis includes lumbosacral radicu - As far as conservative treatment is concerned, lopathies and disk problems with impingement of one Cochrane review highlighted that the evi - the nerve roots in L2 and L3. dence on the efficacy of pharmacological treat - The causes of entrapment may be intrapelvic ments is unsatisfactory in the long term 19 . When (pregnancy, abdominal tumours, uterine fibroids, managing pregnant CTS patients, intervention diverticulosis or appendicitis) or extrapelvic (pelvic should focus on adequate ergonomic measures traumas, or diabetic ). (braces), rehabilitation therapy and the adminis - In addition to pregnancy, the most frequent tration of neuroprotectors. cause of femoral nerve neuropathy is diabetic An approach targeting the pathogenetic mech - amyotrophy. Nerve impingement and damage anisms of nerve damage in CTS has become can also be caused when retractors are used dur - more popular in recent years, as it can have a ing childbirth or pelvic surgery. positive effect on median nerve damage and, The treatment of meralgia paraesthetica during therefore, on pain and paraesthesia symptoms pregnancy can be tackled, as for other compression and on nerve conduction deficits and the loss of neuropathies (CTS, radiculopathies), with anal - hand function. More specifically, anti-oxidants gesics that are not contraindicated during pregnancy and neurotrophic agents reduce symptoms and (paracetamol) combined with antioxidants and neu - protect the nerve from further degeneration 20,21 . rotrophic agents, such as ALA, as the pathogenetic As far as carpal tunnel syndrome is concerned, mechanism underlying the neuropathy is common ALA (600 mg/day) has been seen to significantly to the various forms of compression neuropathy 22 . improve nerve conduction velocity and pain symptoms and paraesthesia after three months of Safe Use of ALA in Pregnancy treatment. One study on patients with carpal tun - The use of ALA as a dietary supplement has nel syndrome 8, compared the efficacy of a fixed risen greatly in recent years, and for this reason, combination of ALA 600 mg/day, EFAs 360 various studies have been conducted to explore mg/day and vitamins B1, B2, B5, B6 and E and not only the efficacy, but also the safety of this selenium (ALAnerv ®, Alfa Wassermann) with a substance. In humans, oral ALA supplementation vitamin B complex preparation (Vit B6 150 mg, at doses of up to 2400 mg/day has not shown any Vit B1 100 mg, Vit B12 500 g a day) for 90 adverse effects. Intravenous administration of days. A good reduction was observed in both 600 mg/day has also been seen to be safe 5. symptom scores and functional deficit (Boston At the current time, there are currently no clin - questionnaire) in the ALAnerv group, whereas ical studies available that show the safety of ALA the group treated with the vitamin B complex in pregnant women; however, several studies preparation showed a slight improvement in highlight its positive effects in contrasting the symptoms and a worsening in the function score. weakening of human fetal membranes 23,24 . also showed statistically sig - Furthermore, animal studies have shown that nificant improvements in the velocity of nerve ALA has a protective effect on the foetus in conduction with ALAnerv ®, but not with the vita - mothers who are diabetic, alcoholic or exposed min B complex preparation. to toxic pollutants such as dioxin 25,26 .

2769 M. Costantino, C. Guaraldi, D. Costantino, S. De Grazia, V. Unfer

The data obtained in one recent study in ani - importance of ALA in the treatment of peripheral mal models on the effects in foetuses whose nerve injuries, suggesting that its supplemetation mothers were exposed to dioxin showed that the may be appropriate even during pregnacy due to suppression of pituitary gonadotropin biosynthe - its high safety profile. However, additional long sis in the foetus is mediated by the reduction in term and thorough clinical studies are needed to ALA levels caused by dioxin. ALA is fundamen - better explain the mechanisms of its neuroprotec - tal for the production of the energy needed for tive effects and to further investigate the efficacy gonadotropin biosynthesis. ALA deficiency is of its supplementation. therefore responsible for the foetus’ development deficit 27 . –––––––––––––––– –-– –– Another study on an animal model showed Conflict of Interest that the administration of ALA reduces the neu - The Authors declare that there are no conflicts of interest. ronal apoptosis that takes place in the foetus fol - lowing alcohol consumption by the mother 28 . Alcohol has a neurotoxic effect as it increases References oxidative stress and induces neuronal apoptosis. Although it is appropriate to point out that the 1) GUTKE A, O STGAARD HC, O BERG B. Pelvic girdle pain and lumbar pain in pregnancy: a cohort study of use of any dietary supplement must always be the consequences in terms of health and func - decided by the doctor based on a risk-benefit tioning. Spine 2006; 31: E149-155. evaluation, it can be stated that use of ALA dur - 2) LEE FH, R AJA SN . Complementary and alternative ing pregnancy does not present contraindications. medicine in . Pain 2011; 152: 28-30. Furthermore, ALA supplementation plays an im - 3) SHAY KP, M OREAU RF, S MITH EJ, S MITH AR, H AGEN TM . portant role in the treatment of pain and lumbar Alpha-lipoic acid as a dietary supplement: molec - and pelvic paraesthesia and in nerve entrapment ular mechanisms and therapeutic potential. syndromes, with an additional neuroprotective Biochim Biophys Acta 2009; 1790: 1149-1160. action on the foetus in conditions of increased 4) SALINTHONE S, Y ADAV V, S CHILLACE RV, B OURDETTE DN, CARR DW . Lipoic acid attenuates inflammation via oxidative stress (mothers who are diabetic, alco - cAMP and protein kinase A signaling. PloS One holic or exposed to environmental pollutants). 2010; 5: sic. 5) GORACA A, H UK -K OLEGA H, P IECHOTA A, K LENIEWSKA P, CIEJKA E, S KIBSKA B. Lipoic acid--biological activity Conclusions and therapeutic potential. Pharmacol Rep 2011; 63: 849-858. Neurophatic pain is a common condition in 6) TAN EC, B AHRAMI S, K OZLOV AV, K URVERS HA, T ER pregnancy resulting in several medical conditions LAAK HJ, N OHL H, R EDL H, G ORIS RJ. The oxidative response in the chronic constriction injury model that negatively influence the quality of life of the of neuropathic pain. J Surg Res 2009; 152: 84-88. patients. Drugs usually prescribed to counteract 7) ZIEGLER D, A METOV A, B ARINOV A, D YCK PJ, G URIEVA I, these medical conditions and reduce the symp - LOW PA, M UNZEL U, Y AKHNO N, R AZ I, N OVOSADOVA toms are not indicated in pregnancy so that reha - M, M AUS J, S AMIGULLIN R. Oral treatment with alpha- bilitation and the intake of neuroprotectors repre - lipoic acid improves symptomatic diabetic sent the best therapeutic choices. As reviewed polyneuropathy: the SYDNEY 2 trial. herein, a growing body of evidence suggests that Care 2006; 29:2365-2370. ALA significantly improve the neurophaties 8) DI GERONIMO G, C ACCESE AF, C ARUSO L, S OLDATI A, PASSARETTI U. Treatment of carpal tunnel syndrome through a pathogenetic approach, as opposed to with alpha-lipoic acid. Eur Rev Med Pharmacol the purely symptomatic approach of analgesics . Sci 2009; 13: 133-139. A number of experimental as well as clinical 9) BERTOLOTTO F, M ASSONE A. Combination of alpha trials report the usefulness and safety of ALA as lipoic acid and superoxide dismutase leads to a therapeutic agent for such medical conditions. physiological and symptomatic improvements in di - The increase of oxidative stress could be one of abetic neuropathy. Drugs in R&D 2012; 12: 29-34. the causes of the nerve damage responsible for 10) NOVAES FS, S HIMO AK, L OPES MH . [Low back pain neuropathies and the strong antioxidant nature of during gestation]. Revista Latino-Americana de Enfermagem 2006; 14: 620-624. ALA combined with its anti-inflammatory activi - ty may be the main mechanism through which 11) WANG SM, D EZINNO P, M ARANETS I, B ERMAN MR, C ALD - WELL -A NDREWS AA, K AIN ZN . Low back pain during this molecule exerts beneficial effects on these pregnancy: prevalence, risk factors, and out - pathological conditions. Our review reports the comes. Obstet Gynecol 2004; 104: 65-70.

2770 Peripheral neuropathy in obstetrics: efficacy and safety of α-lipoic acid supplementation

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