Peran Vitamin Neurotropik untukKasus Neuropati

Dr. dr. Rizaldy Pinzon, MKes, SpSRS Bethesda/ FK UKDW Yogyakarta

Email: drpinzon17@gmail.com

Yang terjadi saat belajar daring

Kasus

• Seorang laki-laki 64 tahun, penderita diabetes mellitus tipe 2, tidak kontrolteratur, datang dengan keluhan rasa baal dan nyeri seperti terbakar dantersengat listrik di kedua telapak kaki. Keluhan memberat pada malam hari. Keluhan berlangsung progresif lambat. Diagnosis banding yang paling mungkin untuk kasus ini adalah:A. Polineuropati diabetikaB. Meralgia perestikaC. Tarsal tunnel syndrome bilateralD.Phantom limb painE. Peroneal palsy bilateral

3 L: Listen, look, locate

3 L: Listen, look, locate

Terapi neuropati

Terapi kausa

V: vaskulitisI : infeksiT : traumaA : autoimunM : metabolicI : intoksikasiN : neoplasmaC :congenital D : defisiensi/ degenerasi

Terapi gejala

Analgetika adjuvan, opioid, vitamin, ALA

Perbaiki saraf

ALA, vitamin B, vitamin D, L-carnitin

Kasus• Pada pasien tadi pemeriksaan neurologis menunjukkan penurunan

sensibilitas, penurunan kekuatan dorsofleksi ibu jari kaki, kulitsangat kering, callus (+), penurunan refleks tendo achiless danpatella. Nyeri derajat sedang sampai berat, mengganggu tidur. Terapi yang anda anjurkan:A. Perbaiki kadar gula darahB. Perbaiki faktor risiko vaskuler lain

C. Analgetika adjuvant D.Vitamin neurotropik

E. Semua jawaban diatas

Kasus

• Apakah terapi pilihan yang akan anda berikan untuk rasa nyeri, gangguan tidur, dan rasa baal :

A. NSAID dan vitaminB. Analgetika adjuvant C. Paracetamol dan vitaminD. NSAID dan adjuvantE. Analgetika adjuvant dan vitamin

Mekanisme : sensitisasi dan disinhibisi. Obat pilihan utama: analgetika adjuvant (gabapentin, pregabalin, amitryptilin, duloxetine)

Kasus

• Pasien mendapat terapi 100 mg gabapentin, titrasi sampai dengan300 mg dua kali sehari, nyeri masih mengganggu, penambahanamitriptilin menyebabkan efek samping mengantuk, penambahantramadol tidak ditoleransi baik (mual), pertanyaan apa yang pentinganda ajukan:A. Apakah kadar gula terkendali baik ?B. Apakah faktor risiko vaskuler lain terkendali baik ?C. Apakah saya perlu menambahkan obat patogenesis?D.Apakah bijak membrikan terapi kombinasi ?E. Semua jawaban diatas benar

The treatment algorithm

1.9 with virtually complete pain relief[6,10,34-36] (Table 1). Oxcarbazepine can, and should, be substituted for car-bamazepine if there is an unacceptable side effect pro-file

[10,34-36] (Table 1).For management of NP, there are several TCAs avail-

able, but amitriptyline and nortriptyline are commonly used, and exhibit NNT values of 1.3-3.6[32,37-39]; NNH values are 3-6 for minor, and 14-28 for major, harm. The analgesic properties of TCAs are independent of their antidepressant effects, and several mechanisms, in

with caution in elderly patients because of the risk of falls and cognitive impairment[15,16]. Recommendations are also made regarding the duration of adequate trials at maximum tolerated dosages to evaluate the impact on self-reported pain.

Initial and subsequent agentsFor management of classical TN (characterized by parox-ysmal, unilateral pain), carbamazepine is the first choice,

but otherwise it is not used; this agent has a NNT around

27 June 9, 2014|Volume 3|Issue 2|WJP|www.wjgnet.com

Step 1

Step 2

Step 3

Step 4

Step 5

Assess pain and establish a diagnosis of NP employing screening testsIdentify relevant comorbidities that may be relieved or exacerbated by pharmacological therapy

Take a thorough medication history. Initiate pharmacological treatment

Reassess pain and health-related quality of life in 4 wk (PTSS)If substantial pain relief (pain ≤ 3/10 on subjective pain rating scale (0 = no pain, 10 = worst pain experienced) and tolerable side effects continue treatmentIf partial pain relief (pain remains ≥ 4/10) after an adequate trial and tolerable side effects, add one of the other first line agents to treatmentIf no or inadequate pain relief (≤ 30% reduction from baseline) at target dosage and an adequate trial, switch to an alternative first-line agent

If trials of first line agents fail, consider 2nd and 3rd line agents alone or in sequential combination

If treatment not effective, try new combination medications and/or refer to pain clinic

Figure 1 Assessment and management of neuropathic pain. NP: Neuropathic pain; PTSS: Pain treatment satisfaction scale.

Ineffective or not tolerated

Partial treatmentresponse

Ineffective or not tolerated

Partial treatmentresponse

Ineffective or not tolerated

Initiate first-line drug monotherapyFor TN: carbamazepine

For NP: TCA, SNRI, Ca2+ channel modulator

Switch to alternative 1st-line drug as monotherapy

Consider adding another 1st line drug or combining with 2nd line agent

Initiate monotherapy with 2nd or 3rd line agents Consider adding tramadol or opioid analgesic

Refer patient to pain specialty clinic for consideration of interventional treatments and pain rehabilitation programs

Figure 2 Management of neuropathic pain or trigeminal neuralgia in the Atlantic Lateral Skull Base Clinic. NP: Neuropathic pain; TN: Trigeminal neuralgia; SNRI: Serotonin-norepinephrine reuptake inhibitor.

Hebb ALO et al . Pharmacological management of neuropathic pain

The problem: inadequate pain relief

• The NNT is “the number of patients needed to treat with a specific drug to obtain 1 patient with a defined degree of pain relief.”• If the NNT 5: 1 in 5 patients will have adequate pain relief, and the

other 4 still have significant pain intensity.• Typically, NNTs range between 3.7 and 5 patients for the first-line

agents, which illustrates the need to use combination therapeutic approaches when managing patients with neuropathic pain to provide adequate analgesia.• Tolerability issue if we use higher dose and combination .

The unmet need. If the NNT 7 (pregabalin): only 1 in 7 patients achieved more than 50% pain reduction

The problem: inadequate pain relief

• If we use combination : side effects increase• We need other treatment option : not only for symptom control, can

be use in long period, safe• The treatment should improve the nerve function.• Is there any benefit of vitamin B ?• Vitamin B has a long history in the management of many nerve

problem.• The previous pre-clinical and clinical studies are promising.

Pertanyaan kritis

• Esesmen: multidimensional, terapi : multimodal• Terapi simptomatik tidak merubah perjalanan penyakit.• Apakah terapi kausatif bisa diberikan ?• Apakah sudah diberikan obat untuk patomekanisme dan memperbaiki

fungsi saraf ?• Apakah bisa dikombinasi obat gejala dan obat untuk patomekanisme ?• Kita perlu obat yang aman untuk jangka panjang dan mampu

memperbaiki fungsi saraf, dan bukan hanya memperbaiki gejala.

The promising vitamin B

Vitamin B

Low vitamin B12 in diabetic neuropathy: metformin users, aging, dietary restriction, PPI user, intrinsic factors. Vitamin B12 deficiency is the independent cause of neuropathy.

32 Asian Journal of Medical Sciences | Jan-Feb 2018 | Vol 9 | Issue 1

Management of peripheral neuropathy symptoms with a fixed dose combination of high-dose vitamin B1, B6 and B12: A 12-week prospective non-interventional study in IndonesiaManfaluthy Hakim1, Nani Kurniani2, Rizaldy Pinzon3, Dodik Tugasworo4, Mudjiani Basuki5, Hasnawi Haddani5,6, Pagan Pambudi7,8, Aida Fithrie9,10, Audry Devisanty Wuysang11

1Head, Department of Neurology, Clinical Neurophysiology and Neuromuscular Disorder Division, Universitas Indonesia - CiptoMangunkusumo National General Hospital, Jakarta, 2Lecturer, Department of Neurology, Faculty of Medicine, University of Padjadjaran, Hasan Sadikin Hospital, Jawa Barat, 3Lecturer, Department of Neurology, Duta Wacana Christian University School of Medicine, Yogyakarta, 4Director, Department of Human Resource and Education, Dr. Kariadi General Hospital, Jawa Tengah, 5Coordinator, Department of Neurology Study Program, Faculty of Medicine, Airlangga University, 6Chairman of PERDOSSI (Indonesian Association of Neurologist) Palembang Chapter, 7Lecturer, Department of Medical, Faculty of Lambung Mangkurat Banjarmasin University, 8Head, Department of Neurology, Ulin General Hospital, Banjarmasin, 9Lecturer, Department of Medical Faculty, University of Sumatera Utara, 10Education Coordinator, Department of Neurology, Head of Neurophysiology Division, 11Student Program Coordinator, Department of Neurology, Hasanuddin University, Sulawesi Selatan, Indonesia

A B S T R A C T

ORIGINAL ARTICLE ASIAN JOURNAL OF MEDICAL SCIENCES

Background: Peripheral neuropathy is a common condition which can have a significant impact on quality of life. It occurs as a component of several common and rare diseases or can be idiopathic and can present with various symptoms. Aims and Objectives: This study is aimed at evaluating the effectiveness and safety of the fixed dose combination of vitamin B1, B6 and B12 in mild to moderate peripheral neuropathy of various etiologies in the Indonesian population. Materials and Methods: This was a prospective, open label, multi-center, single arm observational study (Indonesian Clinical Trial Registry No: INA-KPA0DYA). A total of 411 subjects with mild to moderate peripheral neuropathy of various etiologies, who met the eligibility criteria, were included in the study. A subject was considered to have “completed” the study if the study procedures, up to Visit 3 (one month of treatment) were accomplished. Procedural results and 12-week clinical outcomes are reported. Results: Treatment with combination of vitamin B1, B6 and B12 in subjects with symptoms of PN showed significant improvement in overall Total Symptom Score (TSS), within 14 days. The treatment also successfully reduced individual components of TSS from baseline to Visit 5. A significant percentage reduction was also observed for all the Visual Analogue Scale (VAS) parameters at the end of 12 weeks, while the Quality of Life (QoL) scores increased from baseline to the end of treatment. Conclusions: The fixed dose combination of vitamin B1, B6 and B12

was effective and well tolerated in subjects with mild to moderate peripheral neuropathy, of various etiologies.

Key words: Peripheral neuropathy, Vitamin B1, B6 and B12, Tingling, Numbness, Prospective study, Vitamin deficiency, TSS, VAS, SF-8, QoL

Access this article online

Website:

http://nepjol.info/index.php/AJMS

DOI: 10.3126/ajms.v9i1.18510 E-ISSN: 2091-0576 P-ISSN: 2467-9100

Submitted: 31-10-2017 Revised: 30-11-2017 Published: 01-01-2018

Address for correspondence: Dr. Manfaluthy Hakim, Department of Neurology, Faculty of Medicine - Universitas Indonesia-Cipto Mangunkusumo National General Hospital, Jakarta, Jl. Salemba Raya No. 6, Jakarta - 10430. Phone: +62 21 3190 3219. E-mail: hakim_dr@yahoo.com © Copyright AJMS

Method

• This prospective, open-label, single arm, this study was conducted in Indonesian population at 8 centers. • Subjects with PN of various etiologist• Subjects aged ≥18 years and ≤65 years and subjects with peripheral

neuropathy diagnosed by using either a Michigan Neuropathy Screening Instrument (MNSI) score of ≥7 in Patient Administered Questionnaire and Health care Professional Score of ≥2.5 OR Toronto Clinical Neuropathy Score (TCNS) of ≥6 were included in the study.

Method

• Exclusion:• Subjects with clinically significant cardiovascular, pulmonary, gastrointestinal,

hematological, hepatic, renal problem• Genetic neuropathy • Unstable medical or psychiatric condition • Subjects with intake of vitamin B complex products for more than 1 week

consecutively in the last 3 months before consent • Subjects with severe neuropathy [TCNS ≥12 or visual analogue scale (VAS) ≥7

for pain] • Patient who were on therapy with NSAIDs, gabapentin, pregabalin, or any

other pain medication

Method

• The eligible subjects received the study drug (Vitamin B1/ Thiamine Mononitrate, 100 mg,Vitamin B6/Pyridoxol Hydrochloride 100 mg and Vitamin B12/Cyanocobalamin 5000 mcg marketed as Neurobion® Forte in Indonesia) orally once daily for 12 weeks.

• Subjects were followed up, post 14 days of treatment, and on a monthly basis for up to 3 months.

Method

• Primary outcome• Total Symptom Score (TSS): TSS (stabbing pain, burning pain, paresthesia, and

numbness) was scored by the physician or a trained nurse regarding their frequency and intensity.

• Comparison of TSS for every visit was made with baseline scores which ranged from 0 (no symptoms) to a maximum of 14.64 points (all symptoms are severe and [almost] continuously present).

• Secondary outcome• VAS• Quality of life• Safety

Result

• Of 414 subjects screened, 411 subjects (297 females and 114 males) who met the eligibility criteria were enrolled in the study. • The baseline characteristics of study subjects are shown in Table 1.• A total of 399 subjects completed and 12 subjects discontinued the

study. • The mean age of the subjects was 50.9±8.25 years (22 to 65 years).

The baseline characteristic

Hakim, et al.: Vitamin B and Peripheral Neuropathy Symptoms

34 Asian Journal of Medical Sciences | Jan-Feb 2018 | Vol 9 | Issue 1

anti-inflammatory drugs were excluded from the study. Subjects who were on any treatment like methotrexate which interferes with neuropathy or any other cytostatic drug treatment were excluded. Subjects with pregnancy, planning to become pregnant or breastfeeding were also excluded from the study.

Study DrugThe eligible subjects received the study drug (Vitamin B1/Thiamine Mononitrate, 100 mg,Vitamin B6/Pyridoxol Hydrochloride 100 mg and Vitamin B12/Cyanocobalamin 5000 mcg marketed as Neurobion® Forte in Indonesia)orally once daily for 12 weeks. Subjects were followed up, post 14 days of treatment, and on a monthly basis for upto 3 months.

Outcome measuresPrimary outcome measureTotal Symptom Score (TSS): TSS (stabbing pain, burning pain, paresthesia, and numbness) was scored by the physician or a trained nurse regarding their frequency and intensity.24 Total Symptom Scores were recorded at baseline and at each study visit. Comparison of TSS for every visit was made with baseline scores which ranged from 0 (no symptoms) to a maximum of 14.64 points (all symptoms are severe and [almost] continuously present).

Secondary outcome measures1. Visual Analogue Scale (VAS) score: Change in severity of each symptom of neuropathy (e.g. pain, burning, paresthesia, numbness, etc,) from baseline up to 3 months of treatment was recorded by the subject using a VAS ranging from 0-10 (0 indicating no symptoms and 10 worst possible symptoms).

2. Short Form-8 (SF-8) Health Survey Questionnaire (QoL): At baseline and at 4 weeks interval was recorded on Visits 1, 3, 4 and 5. 25

3. Evaluation of safety was based on the occurrence of any adverse event (AE) during the 12 week study period and was graded based on the severity, onset and the course of AE.

Statistical analysisAny significant differences in change from baseline to other follow-up visits for variables such as TSS, QoL scores and VAS scores were assessed by exploratory analysis, using appropriate statistical tests which included Wilcoxon signed rank test, independent t-test, Cochran-Armitage Trend Chi-square test, etc. depending on the type and distribution of data. Mean percentage reduction from baseline, of overall TSS and individual symptom scores, of VAS score for each symptom, and QoL data were summarized. Univariate and multivariate logistic regression analysis was performed to

identify the factors contributing to the QoL [(physical component summary (PCS) and mental component summary (MCS), physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health scores]. Statistical analyses were made utilizing SAS Version 9.1.3 (NC, USA).

A sample size of 411 subjects was estimated by assuming a 50% improvement in clinical symptoms of PN as evaluated by TSS (baseline up to 3 months of treatment) and a precision of 5.5%, confidence interval 95%, level of significance 5% and a dropout rate of 20%. All statistical tests were two-tailed and performed with The Statistical Package for Social Science (SPSS Inc., Chicago, USA; version 15.0 for Windows).

RESULTS

Of 414 subjects screened, 411 subjects (297 females and 114 males) who met the eligibility criteria were enrolled in the study. The baseline characteristics of study subjects are shown in Table 1. A total of 399 subjects completed and 12 subjects discontinued the study. The mean age of the subjects was 50.9±8.25 years (22 to 65 years).

Total symptom scoreThe mean (±SD) TSS at baseline was 5.45 (±2.036) and 4.35 (±1.914) at Visit 2. The mean TSS change from baseline to Visit 2 (1.090±1.4097) was statistically significant

Table 1: Demographic characteristicsN=411 (100%) Min; Max

EtiologiesDiabetic 104Carpal tunnel syndrome 44Idiopathic 112Other 25Combination* 126

Gender, n (%)Male 114 (27.7)Female 297 (72.3)

Age (years)Mean±SD 50.9±8.25 22; 65

Ethnicity, n (%)Javanese 151 (36.7)Sundanese 27 (6.6)Malay 33 (8.0)Madurese 0 (0.0)Batak 38 (9.2)Other 162 (39.4)

Height (cm)Mean±SD 157.9±7.51 105; 180

Weight (kg)Mean±SD 62.5±10.86 34; 98

Body mass index (kg/m2)Mean±SD 25.07±4.034 13.6; 49.9

Values represent the mean±standard deviation. *Combination included Diabetic & Nutritional or Diabetic & Carpel tunnel syndrome & Idiopathic etc

The improvement of total symptom score

0

20,1

34,9

48,9

62,9

0

10

20

30

40

50

60

70

Baseline (Visit 1) Visit 2 Visit 3 Visit 4 Visit 5

TSS

% im

pro

vem

ent

at

each

vis

it f

rom

bas

elin

e

+ 62,9%

0

10

20

30

40

50

60

70

80

90

100

V2 V3 V4 V5 V2 V3 V4 V5 V2 V3 V4 V5 V2 V3 V4 V5 V2 V3 V4 V5

Total Score Stabbing Pain Burning Pain Paresthesia Numbness

TSS %

Cha

nge

from

Bas

elin

e

+81% +56%+61%+65%+63%

The improvement of total symptom score

• All observed symptoms have been treated effectively• For all symptoms the relief was higher than 50-60% at visit 5• Good pain medication: more than 50% relief

100-300 mg, B6 = 50-600 mg and B12 = 200-5000mcg; oral or parenteral) for more than 1 weekconsecuti vely in the last 3 months, subjects withsevere neuropathy (TCNS ≥12 or visual analoguescale (VAS) ≥7 for pain) who were on therapy withNSAIDs, gabapentin, pregabalin, or any other anti-infla mmatory drugs and also subjects with severeconcomitant diseases except diabetes mellitus.

The eligible subjects received the study drug(Vitamin B1, Thiamine Mononitrate 100 mg,Vitamin B6, Pyridoxol Hydrochloride 100 mg andVitamin B12 Cyanocobalamin 5000 mcg, marketedas Neurobion® Forte in Indonesia) orally oncedaily. Baseline/Screening Visit was considered asVisit 1. Visits 2, 3 4 and 5 were at 14±3, 30±3, 60±3,and 90±3 days from the Baseline Visit respectively.The subject was considered as a completedsubjec t if the study procedures up to Visit 3 werecompleted. Subject information was collectedregular ly, during the normally scheduled clinicassessment Visits.

The primary outcome included Total SymptomScore (TSS). The secondary outcome measuresincluded VAS, QoL and safety. Subgroup analysiswas carried out based on the Baseline characteris-tics for primary and secondary endpoints e.g. onTSS, VAS score for each symptom of neuropathy(pain, burning, paresthesia, numbness, tingling)and QoL scores. The major subgroups were basedon types of neuropathies, severity of neuropathyat Baseline (Mild, Moderate, Severe age groups(<45 years, 45 to <55 years, 55 to ≤65 years) and,gender (male, female). Other subgroups anaysedwere based on BMI (<25 kg/m2, ≥25 kg/m2),Tea/Coffee consumption (Yes, No), tobaccoconsump tion (Smoker, Nonsmoker), alcoholconsumpt ion (Yes, No), intake of Vitamin Bcombinati on products containing B1, B6 and B12 inpharmacological dosages (taken, not taken),intake of any antacids, H2 blockers or protonpump inhibitors (taken, not taken), intake of painkil lers (NSAIDS, Gabapentin, Pregabalin, etc)(taken, not taken), and study treatment com-pleters (1 month, >1-2 months, >2 months). Thescores were summarized using descriptivestatistic s in each subgroup.

Evaluation of safety was based on the occur-rence of any adverse event (AE) and was gradedbased on the severity, onset and the course ofAEs.

Statistical analysisSample size of 411 subjects was arrived by

assuming a 50% impro vement in c l in ica lsymptom s of PN according to TSS (Baseline upto 3 months of treatment) and a precision of5 .5%, conf iden ce interva l 95%, leve l o fsignificanc e 5% and considering a dropout rateof 20%.

Any significant differences in change fromBaseline to other follow up Visits for variablessuch as TSS, VAS scores and QoL among sub-groups were assessed by exploratory analysis,using appropriate statistical tests which includedWilcoxon signed rank test, independent t-test,Cochran-Armitage Trend Chi-square test etcdepending on the type and distribution of data.Descriptive statistics were used for the meanreduction scores of TSS and individual symptomscores, VAS symptom scores and SF-8 Question -naire (QoL) data. To identify the factors contribut-ing to the QoL, univariate and multivariate logisticregression analysis was performed. Statisticalanalyses were made utilizing SAS Version 9.1.3(NC, USA).

ResultsOf the 414 subjects screened, 411 subjects who

met the eligibility criteria were enrolled in thestudy and 297 of them were women and 114 weremen. A total of 399 subjects completed the studyand 12 subjects (2.9%) discontinued the study.

The treatment with the study drug was associ-ated with a significant improvement in TSS, VASand QoL from Baseline to follow up Visits for sub-jects with all types of etiologies including diabeticneuropathy, carpal tunnel syndrome, idiopathic

MANFALUTHY HAKIM, NANI KURNIANI, RIZALDY PINZON, DODIK TUGASWORO,MUDJIANI BASUKI, HASNAWI HADDANI, PAGAN PAMBUDI, AIDA FITHRIE, AUDRY DEVISANTY WUYSANG. 43–49

Jurnal Kedokteran Indonesia Vol. 4, No. 2 l Maret - April 2018 45

Table 1. Mean Percentage reduction from Baseline ofVAS by Total

Safety

• Of 411 subjects enrolled in the study, 14 subjects (3.4%) experienced at least one AE during the study period. • Three subjects had at least one treatment-related AE and three

subjects had at least one AE leading to study termination. • Of the 3 subjects with AE (2 were with gastrointestinal disorders

which included dyspepsia and nausea, and skin problem in one subject.

Synergism effect

• Cobalamin has been shown to improve neuropathy symptoms by neutralizing superoxide and peroxynitrite and restoring normal glutathione levels.• Pyridoxal has been reported to prevent formation of advanced

glycation end products (AGEs) thereby reducing microvascular disease.• Thiamine diphosphate also has a role in preventing microvascular

complications in diabetes.

Kesimpulan

• Neuropati kasus yang umum dijumpai dalam praktek dengan berbagaikausa• Pendekatan terapi : terapi terhadap kausa, terapi gejala, dan terapi

untuk memperbaiki fungsi saraf• Vitamin B1, B6, B12 bekerja sinergis untuk memperbaiki fungsi saraf• Studi klinis menunjukkan kombinasi vitamin B1 100 mg, vitamin B6

100 mg, dan vitamin B12 5000 mcg terbukti bermanfaat untuk kasusneuropati