Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Vitamin B combination and diabetic neuropathy DOI: https://doi.org/10.31351/vol32iss1pp202-218 202 Physicians’ Perception and Practice of Prescribing Vitamin B Combination Versus Antiepileptic Drugs for Diabetic Neuropathy: Content Validity, Reliability and Pilot Study Narmin S. Essa*,1 and Mohammed I. Aladul* *Department of Clinical Pharmacy, College of Pharmacy ,University of Mosul, Nineveh, Iraq Abstract Diabetic neuropathy (DN) is the most common complication of diabetes mellitus causing increased morbidity and mortality. Although international guidelines did not include vitamins and dietary supplements in any line of management, these agents were prescribed by a significant number of physicians either as preventive or treatment of DN. This study aimed to develop a validated questionnaire that examines the physicians’ perception and practice towards prescribing vitamins or dietary supplements for DN treatment. The questionnaire was developed upon literature review via PubMed, Medline, Web of Science, Scopus, and Google Scholar. The questionnaire was revised upon experts’ views and opinions. The constructed questionnaire was validated by the means of content validity and internal consistency. Finally, the developed questionnaire was piloted in a small representative sample of the original future aimed research target population, to test its applicability and feasibility. A total of 22 items questionnaire were developed in two domains (knowledge and perception domain and practice domain). Content validity analysis results met a satisfactory level, in which the S-CVI/UA value was 0.86 for both clarity and relevance. The questionnaire also showed good reliability, in which the Cronbach’s alphas was 0.805. In conclusion, this study showed the that constructed questionnaire had a good level of validity (content validity) and reliability that is able to cover different aspects of the current state of perception and practice among physicians regarding the management of DN. The preliminary results of the pilot study showed a good knowledge and perception of the respondents with DN. Even in the absence of a local guideline, the respondents followed the international guidelines in choosing anti-neuropathic agents however, they tended to add vitamin B complex/B12 as an adjuvant in their management plan. Keywords: Diabetic neuropathy, neurotrophic B vitamins, physician, vitamins. عتالل وصف مزيج فيتامين ب مقابل األدوية المضادة للصرع الفي تهمتصور األطباء وممارس ب السكري: صحة المحتوى والموثوقية والدراسة التجريبية اعصاال *محمد ابراهيم العدولو 1*،نرمين سعيد عيسى ق ، العرا نينوىفرع الصيدلة السريرية، كلية الصيدلة، جامعة الموصل ، * خالصةال على الرغم من . والوفيات ضاعتالل األعصاب السكري هو أكثر المضاعفات شيوًعا لمرض السكري مما يؤدي إلى زيادة معدالت المر من خط أي في الغذائية والمكمالت الفيتامينات تتضمن لم الدولية اإلرشادية الدالئل العالج أن انه، خطوط الي اال هذه وصف الغذائية تم مكمالت م التحقق ثوير استبيان هدفت هذه الدراسة إلى تط. وقاية او عالج لمرضى اعتالل االعصاب السكريمن قبل عدد كبير من األطباء إما ك والفيتامينات تم تطوير االستبيان بناًء على .اعتالل االعصاب السكريمنه لفحص تصور األطباء وممارستهم تجاه وصف الفيتامينات أو المكمالت الغذائية لعالج الخبراء افكارلى تم تنقيح االستبيان بناء ع. Google Scholarو Scopusو Web of Scienceو Medlineو PubMedمراجعة األدبيات عبر أخيًرا، تم تجريب االستبيان المطور في عينة . تم التحقق من صحة االستبيان الذي تم إنشاؤه من خالل صحة المحتوى واالتساق الداخلي. وآرائهم المستقبل، المجتمع تمثلصغيرة في للبحث وجدواهوذلك المستهدف للتطبيق قابليته مجموعه .الختبار ما تطوير مجالي فق 22تم في استبيان رة والممارسة) قيمة (. اإلدراك كانت حيث مرٍض، مستوى المحتوى صدق تحليل نتائج والمالءمةل S-CVI / UA 0.86حققت أظهر . لوضوح كرونباخ ألفا كانت حيث جيدة، موثوقية أيًضا من . 0.805االستبيان جيد بمستوى يتمتع كان إنشاؤه تم الذي االستبيان أن الدراسة هذه أظهرت بعالج مرض الصالحية )صحة المحتوى( والموثوقية القادرة على تغطية الجوانب المختلفة للحالة الحالية لإلدراك والممارسة بين األطباء فيما يتعلق مرض اعتالل االعصاب ة التجريبية معرفة جيدة وتصور المستجيبين الذين يعانون من اعتالل االعصاب السكري. أظهرت النتائج األولية للدراس مرض االدوبة المناسبة لعالج الدولية في اختيار البروتوكوالتمحلية، اتبع المشاركون بروتوكوالت عالجية. حتى في حالة عدم وجود السكري عالجية. خطة الالكعامل مساعد في 12فيتامين ب المركب / ب اعتالل االعصاب السكري ومع ذلك، فإنهم يميلون إلى إضافة . ، طبيب ، فيتامينات لالعصاب مقويةالكلمات المفتاحية: اعتالل األعصاب السكري ، فيتامينات ب ال Introduction Diabetes mellitus is defined as a metabolic disorder caused by multifactorial aetiologies and presented by chronic hyperglycemia with defects in carbohydrate, fat, and protein metabolism resulted from either abnormal insulin secretion, insulin action or both (1). In 2021, the International Diabetes Federation stated that there are about 537 *Corresponding author E-mail: nermeen.gul@hotmail.com. Received: 6/4 /2022 Accepted: 13/6 /2022 Iraqi Journal of Pharmaceutical Science https://doi.org/10.31351/vol32iss1pp202-218 Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 203 million diabetes cases, and this number is projected to reach 643 million by 2030, and 783 million by 2045 (2). The rapid escalation in the number of cases will be accompanied by a direct increase in the prevalence of the chronic complications of the disease (3). Diabetic neuropathy (DN) is the most common complication of diabetes mellitus (4) causing increased morbidity and mortality (5) furthermore causing a great burden on health care expenditure (6). DN is defined as a neurodegenerative disorder that affects the somatic and/ or autonomic peripheral nervous system in the setting of diabetes mellitus without other causes of neuropathy (7). Despite its heavy burden on healthcare systems and the better understanding of the multifactorial pathogenesis of the disease, DN still underdiagnosed and undertreated (8). In the absence of evidence-based disease-modifying pharmacological agents, the mainstay of the management is based on glucose control, lifestyle changes, and pain management (9). Despite the relatively high prevalence of DN in Iraq (10), there is no local or regional guideline of DN management (11). Neurotropic B vitamins (B1, B6 and B12) were well-known to have a crucial role in maintaining healthy nervous system (12). It was suggested that these vitamins may increase the availability and effectiveness of noradrenaline and 5-hydroxytryptamine in the descending inhibitory nociceptive system (13, 14) furthermore, in some countries they were classified as analegesic drugs (14).It was hypothesized that neurotropic B vitamins support directing the Wallerian degeneration process (which is an active process that commenced after a nerve injury of degeneration of an axon) toward regeneration and remyelination (15), several clinical trials conducted to highlight the effect of administration of the neurotropic B vitamins together with different dose regimes (16 - 18), however the positive outcomes was limited to improvement in symptoms of pain numbness and paraesthesia with no improvement in neurophysiological parameters. Thiamin (B1) had been shown to serve as a cofactor for three important enzymes that were involved in carbohydrate metabolism (19), in addition to have an important role in abolishing the metabolic dysregulations caused by high glucose level including polyol pathway, protein kinase C pathway, hexosamine pathway and increased advanced glycation end products which are the proposed mechanisms of DN pathogenesis (19, 20). Benfotiamin which is a synthetic derivative of thiamin with better pharmacokinetic properties (21, 22) was shown to improve the Neuropathy Symptom Score in a double-blind randomized placebo- controlled phase III clinical study (BENDIP) (23). Despite the fact that the association between vitamin B6 level and diabetes mellitus was well established (24), two clinical trials of pyridoxin administration in patients with DN were failed to improve subjective and objective parameters of the disease (25, 26). Furthermore, concerns were raised about the safety profile of pyridoxin following several case reports about its possible toxic effects on nerves (27,28) which was proposed to be due to disruption of Gamma- Aminobutyric Acid (GABA) biosynthesis (29) which led several Food Safety Authorities is several countries to decrease the allowed upper limit of pyridoxin dose (30,31). A long-term trial was showed a significant effect of metformin on B12 and methylmalonic acid (MMA) level with concurrent worsening of neuropathy symptoms (32). Several clinical trials concluded a positive effect of methylcobalamin (active form of vitamin B12) on the symptoms of DN with no effects on the nerve study parameters (33 - 35) until recently (2021) a prospective one-year, randomized double-blind, placebo- controlled trial, concluded positive effects of 1 mg methylcobalamin on in sural nerve conduction parameters along with Michigan Neuropathy Screening Instrument Questionnaire (MNSIq), the level of pain, and the quality of life (36). Although the latest international guidelines did not include vitamins and dietary supplements in any line of management (e.g., the National Institute for Health and Care Excellence National (NICE) updated guideline in 2020 (37) and the American Diabetes Association (ADA) guideline in 2021(38)). A recent study, that was conducted in Saudi Arabia, found that a significant number of physicians were prescribing vitamin B12 either as preventive or treatment to their patients with DN (55). The supplements have a heavy economic burden for patients in a developing country like Iraq, which lacks national health insurance programs. In addition to the fact that the safety profile of some heavily prescribed vitamins is questionable (39). This study aimed to develop a validated questionnaire to assess physicians’ perception and practice towards the prescribing of vitamins and dietary supplements versus pharmacological agents for the management of DN. Methods The study design involves three phases. In phase one, the construction of the first draft of the questionnaire from an interpretation of the literature on the research topic. In phase two, the content validity of the drafted questionnaire was tested to verify the applicability and appropriateness. Finally, in phase three, the internal consistency of the questionnaires was piloted to ensure reliability and feasibility. Phase one The literature review was conducted between the 1st of October 2021 and the 30th of December 2021 for published articles before the time of the research (no time limit was set to get as many as possible articles on the research topic). The search was only for full articles, written in English or Arabic languages that are examining healthcare Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 204 professionals’ or physicians’ knowledge, attitude, perception, and practice toward neuropathic pain treatment or management. The exclusion criteria were; articles written in languages other than English or Arabic, abstracts, articles examining patients’ perspectives rather than physicians. The literature review was conducted by the first author, a master student and the chief investigator, which were trained to search for relevant articles via the available databases and search engines including PubMed, Medline, Web of Science, Scopus, and Google Scholar. The Medical subject headings (MeSH) terms used in the search were supplied as a supplementary file. The number of results retrieved from the literature review through the above-mentioned databases was 86 researches of a variety of formats. Following a screening of the retrieved researches and excluding irrelevant ones, the final number of researches chosen was 10 (Figure 1). Figure 1. Workflow showing the process of literature review for constructing the first draft of the questionnaire Based on the results of the literature review, the ten chosen articles were reviewed and used in the construction of the initial draft of the questionnaire. The questionnaire was constructed in English language since Iraqi physicians are more familiar with medical terminology in English rather than Arabic language. Then the questionnaire was sent independently to two experts in KAP (knowledge, attitude, and practice) tools at the University of Baghdad and the University of Duhok to verify the relevance and appropriateness of the questionnaires for the study topic. Based on the experts’ views, the first draft was amended accordingly to improve the clarity and the structure of the questionnaire. This was followed by a second review process by another independent reviewer at the college of Pharmacy, University of Mosul to evaluate the questionnaire and eliminate redundancy and ambiguity, and to develop a final draft of the questionnaire. The questionnaire was developed to explore the physicians’ perception and practice towards the prescribing of vitamins and dietary supplements versus pharmacological agents for the management of DN. Therefore, the items (questions) were allocated into two main domains (knowledge and perception domain and practice domain). The knowledge and perception domain aimed to closely examine the basic knowledge and the general perception of the physicians about DN (including the commonality of DN, its effect on patient’s Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 205 quality of life, mortality rate and the difficulty of treatment in addition to the perception about dietary supplements and vitamin B). The practice domain aimed to explore the physicians’ prescribing plans regarding anti-neuropathic agents and dietary supplements and indifferent cases. In addition to the factors that affect the choice of these agents. The time expected for completing the questionnaire (10 – 20 minutes) was enough for almost all of the respondents. Content validity The six steps of the content validity procedure were conducted as follow: (I) content validity form development, (II) assigning an expert review panel, (III) distributing the content validation form to the expert (d) reviewing the domain and items (e) setting a score to each item (f) determining the content validity index (CVI) (40). In which the CVI uses item-CVI (I-CVI) and scale-CVI (S-CVI) to report content validity in questionnaire development (41). The I-CVI is determined by dividing the total number of experts by the number of experts who rated each item on a scale of 'very relevant' (score 1), 'relevant' (score 1), 'irrelevant' (score 0), and 'very irrelevant' (scoring 0) (42). The I-CVI value range of 0.8 or more indicates that the item is relevant, however, if the value is less than 0.8 and more than 0.69, this would suggest item revision, while a value of less than 0.7 indicates an item to be eliminated. The sum of all items with I- CVI equal to 1 divided by the total number of items for the S-CVI yielded the universal agreement (UA) among experts (S-CVI/UA). A content validity index of S-CVI/UA 0.8 indicates outstanding content validity (43). Eight experts, including physicians and pharmacists from the University of Mosul and Ninevah University, as well as retired physicians, were recruited to judge the items using a scoring system ranging from 1 (the item is not relevant at all) to 4 (the item is highly relevant). If the items were scored lower than 3, in the comments, the experts were asked to offer a note or a suggestion to rephrase the item. Reliability Internal consistency is an indicator of a questionnaire's homogeneity (44). It reflects how close the questions (items) of a questionnaire are intercorrelated and hence measure the same concept. Cronbach's alpha (α) value is used as a measure of internal consistency (45). The internal consistency reliability of the two domains (knowledge and perception domain, and practice domain) was tested using Cronbach's alpha coefficient. Forty-five participants were enrolled to complete the questionnaire, the sample size was satisfying the Central Limit Theorem which assumed that the distributional assumption of the sample size of 30 or more to guarantee an equal mean between any sample and the target population (46). Pilot study To test the feasibility and usability of the questionnaire, a pilot study was conducted. A total of 45 physicians in different specialties were recruited. A convenience purposive sampling from Avicenna Hospital and Al-Quds primary health centre in Mosul, Iraq. Ethical approval was obtained from the Medical Research and Ethics Committee of the Department of clinical pharmacy, College of Pharmacy, University of Mosul. Ethical approval was also obtained from the Collegiate Committee for Medical Research Ethics at the University of Mosul (code: CCMRE-phA-22-2) to conduct the study. The physicians were contacted to participate in this pilot via telephone and verbal consent was given to participate in the study. On the day of the interview, written consent was given by the participants. The researcher discussed the aims of the research and handed the paper survey questionnaire. The questionnaires were filled out in 15 minutes (±3 minutes). The face-to-face data collection started from the 20th to the 31st of January 2022. Statistical analysis Data obtained from the respondents (for content validity, reliability and pilot study) were entered to Microsoft Excel (2016) software to calculate the content validity. Then the data was moved to the Statistical Package for the Social Sciences (SPSS) software version 24 to run the reliability test. Descriptive analyses (percentages and frequencies) were carried out using SPSS software for the pilot study. Results Phase one The process of reviewing the literature via PubMed, Medline, Web of Science, Scopus, and Google Scholar databases resulted in 86 researches of a variety of formats (abstracts, posters, full articles, and books). These materials were screened by means of the titles and abstracts to remove duplicates and irrelevant articles. Ten full-text articles were retrieved for further evaluation based on the inclusion and exclusion criteria (Figure 1). The final number of researches chosen was 10 (Table 1). Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 206 Table 1. Literature review articles Author Country Aim Sample size Participants ' profession Method Hall et al. (2006) (47) UK To report drug treatment of neuropathic pain as managed by UK primary care physicians. 686 primary care centers. NA Utilization analysis Aakash et al.(2008) (48) India To inquire about their prescribing preferences among the drug options that were provided, to treat painful diabetic neuropathy 89 Physician Survey Possidente et al, (2009) (49) UK To evaluate provider practices for identification and treatment of painful diabetic peripheral neuropathy 357 Physician, Nurse, Nurse practitioner, Physician assistant, Others, Pharmacist Survey Benzon et al. (2013) (50) US To determine prescription patterns and whether these practices reflect current expert opinion. 474 Physician Survey Mabrouk et al, (2013) (51) Egypt To assess family physicians’ knowledge, attitude, and practice regarding DN. 60 Physician Survey Lalonde et al. (2014) (52) Canada To evaluate and identify the determinants of the KAP of primary care physicians and pharmacists. 248 physician & pharmacist Survey Malik et al. (2017) (53) Hong Kong, Malaysia, the Philippines , Taiwan, and Thailand To examine the physician perceptions of painful DN and clinical practice behaviours in five countries in South- East Asia. 100 Physician Survey Provenzano et al, (2018) (54) US To assess the knowledge and practice of PCPs in the management of chronic pain 300 Primary care physicians Survey Aldossari et al, (2021) (55) Saudi Arabia To investigate local physicians’ knowledge and tendency to prescribe vitamin B12 or vitamin B complex for the treatment or prevention of diabetic peripheral neuropathy. 412 Physician Survey Moon et al. (2021) (56) Korea To analyze the pharmacological treatments for DN. NA NA Utilization analysis The questionnaire was developed from the tools of the retrieved articles with modification to meet the aims of the developed questionnaire and to make it more suitable for the Iraqi healthcare system, which differs massively from other healthcare systems where other articles were conducted. The questions were allocated into two main domains, namely, the knowledge and perception domain, including eight items, and the practice domain including 16 items. The first draft of the questionnaire was reviewed by two experts; these include deletion of two questions for redundancy and irrelevance. The experts also requested to rephrase three more questions to improve the clarity of the questions. On the second round of review, an expert suggested adding a “not sure” for questions with an answer of “yes” or “no” for closed-ended questions. The final draft consisted of 22 items (seven items in knowledge and perception domain and fifteen items in the practice domain) (Table 2). Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 207 Table 2. Questionnaire’s domains Knowledge and perception domain Item 1 Knowledge about DN Response DN is a common complication of diabetic patients Agree, neutral, disagree DN affects patient’s quality of life Agree, neutral, disagree DN increases mortality rate Agree, neutral, disagree DN is difficult to manage Agree, neutral, disagree DN management plan is based on symptomatic relief Agree, neutral, disagree DN can be reversed by strict blood glucose control Agree, neutral, disagree DN incidence can be decreased by maintaining strict glucose control Agree, neutral, disagree Item 2 Do you think that there is a definite treatment for DN? Yes, No, Not sure Item 3 Is there any local guideline for the management of diabetic neuropathy? Yes, No, Not sure Item 4 Knowledge about dietary supplements in DN Vitamins and dietary supplements are approved by the FDA Agree, neutral, disagree Vitamins and dietary supplements’ manufacturing undergoes quality control just like chemical medicines Agree, neutral, disagree Vitamins and dietary supplements are safe on long term use Agree, neutral, disagree Vitamins and dietary supplements have no side effects Agree, neutral, disagree Vitamins and dietary supplements have no interactions with other medications Agree, neutral, disagree The cost of vitamins and dietary supplement worth the efficacy (outcome) provided. Agree, neutral, disagree Item 5 Knowledge about vitamin B complex/B12 Vitamin B complex/ B12 supplementation can prevent the development of DN Agree, neutral, disagree Vitamin B complex/ B12 supplementation can treat DN Agree, neutral, disagree Vitamin B complex/ B12 supplements are safe for long term use in treatment of DN Agree, neutral, disagree Item 6 What is the most common cause of DN? Toxic effects of glucose, Oxidative stress, Vascular damage, Vitamin B12 deficiency Item 7 What is (are) the source of information does you follow in managing DN? Information from senior colleagues, Information from colleagues of different specialty, Internet and social media Reputable international guidelines, like American diabetes association (ADA), NICE, etc. Textbooks or scientific journals, Own practice Practice domain Response Item 1 Do you recommend/ prescribe a dietary supplement to your patients with DN Yes No Item 2 If you answered to the previous question with Yes, how often do you recommend/ prescribe supplements to your patients with DN? Always Sometimes Rarely Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 208 Continued table (2) Item 3 Vitamins and dietary supplements in DN are usually prescribed by physicians as: Treatment (monotherapy), Adjuvant, Tonic only, prophylaxis, satisfy the patient (placebo) Item 4 The effectiveness of an agent is an important factor in choosing DN medication Agree, neutral, disagree Item 5 The safety of an agent is an important factor in choosing DN medication Agree, neutral, disagree Item 6 Patient preference is an important factor in choosing DN medication Agree, neutral, disagree Item 7 Drug - drug interaction is an important factor in choosing DN medication Agree, neutral, disagree Item 8 Cost of an agent is an important factor in choosing DN medication Agree, neutral, disagree Item 9 Patient factors including co-morbidity are important factors in choosing DN medication Agree, neutral, disagree Item 10 Medical advertisement of an agent is an important factor in choosing DN medication Agree, neutral, disagree Item 11 A 45 years old male diabetic patient (normal BMI and no comorbidities) is complaining of burning and tingling sensation pain in his feet especially at night, what is the drug of choice for this patient? Amitriptyline, Carbamazepine, Duloxetine, Gabapentin, Pregabalin, Vitamin B complex, Vitamin B12 Item 12 The extent of influences of international guidelines on your practice I never use them, I consult them occasionally, They are fundamental to my practice Item 13 Management plan of [Mild DN] Life style change (diet, exercise), Strict control on blood sugar, Supplements (vitamin B complex / Vit B12, Anticonvulsants or TCA or SNRI, Combination of (anticonvulsant+ TCA and/or SSRI+ supplement) Item 14 Management plan of [Moderate DN] Life style change (diet, exercise), Strict control on blood sugar, Supplements (vitamin B complex or Vit B12,…etc), Anticonvulsants or TCA or SNRI, Combination of (anticonvulsant+ TCA and/or SSRI+ supplement) Item 15 Management plan of [Severe DN] Life style change (diet, exercise), Strict control on blood sugar, Supplements (vitamin B complex or Vit B12,…etc), Anticonvulsants or TCA or SNRI, Combination of (anticonvulsant+ TCA and/or SSRI+ supplement) Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 209 Phase two (content validity) To determine the content validity of the preliminary version of the questionnaire, an expert panel of eight healthcare professionals was recruited. The experts rated the items’ (questions’) clarity and relevance on a scale from (1 - 4) to calculate the I-CVI, S-CVI, and S-CVI/UA. Tables 2 and 3 show the calculation of the validity indices for both clarity and relevance. The validity indices met satisfactory levels (Tables 3, 4 and 5). Table 3. Calculations of the content validity for relevance It e m E x p e r t1 E x p e r t2 E x p e r t3 E x p e r t4 E x p e r t5 E x p e r t6 E x p e r t7 E x p e r t8 E x p e r t in a g r e e m e n t I- C V I U A 1 4 4 4 4 4 4 4 4 8 1 1 2 4 4 4 3 4 4 4 4 8 1 1 3 4 4 4 3 4 3 3 4 8 1 1 4 4 4 4 4 4 4 4 4 8 1 1 5 4 4 4 4 2 4 3 3 7 0.875 0 6 3 4 4 4 3 4 4 4 8 1 1 7 4 4 4 4 3 4 4 4 8 1 1 8 4 4 3 4 3 4 4 4 8 1 1 9 4 4 4 4 4 4 3 4 8 1 1 10 4 4 4 3 3 4 3 4 8 1 1 11 4 4 4 4 4 4 4 4 8 1 1 12 4 4 4 4 4 4 4 4 8 1 1 13 4 4 4 4 4 4 4 4 8 1 1 14 4 4 4 4 3 4 4 4 8 1 1 15 4 4 4 4 4 4 1 3 7 0.875 0 16 4 4 4 3 3 4 3 4 8 1 1 17 4 4 4 4 4 4 3 1 7 0.875 0 18 4 4 4 4 4 4 3 4 8 1 1 19 4 4 4 4 4 4 4 4 8 1 1 20 4 4 4 4 4 4 4 4 8 1 1 21 4 4 4 4 4 4 4 4 8 1 1 22 4 4 4 4 4 4 4 4 8 1 1 Table 4. Calculations of the content validity for Clarity It e m E x p e r t1 E x p e r t2 E x p e r t3 E x p e r t4 E x p e r t5 E x p e r t6 E x p e r t7 E x p e r t8 E x p e r t in a g r e e m e n t I- C V I U A 1 4 3 4 4 4 4 4 2 7 0.875 0 2 4 4 4 3 4 4 4 4 8 1 1 3 4 4 4 3 4 3 4 4 8 1 1 4 4 4 4 4 4 3 4 3 8 1 1 5 3 4 4 4 4 3 4 4 8 1 1 6 4 4 4 4 4 4 4 4 8 1 1 7 4 4 4 4 4 3 4 4 8 1 1 8 4 4 4 4 4 4 4 4 8 1 1 9 4 4 4 3 4 4 3 4 8 1 1 10 4 4 4 4 4 4 4 4 8 1 1 11 4 2 4 4 4 4 4 4 7 0.875 0 12 4 4 4 4 2 4 4 4 7 0.875 0 13 4 4 4 4 3 4 4 4 8 1 1 14 4 3 4 4 4 4 4 4 8 1 1 15 4 3 4 4 4 4 4 4 8 1 1 Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 210 Continued table4. 16 4 3 4 4 4 4 4 4 8 1 1 17 4 4 4 3 4 3 4 4 8 1 1 18 4 4 4 4 4 3 4 3 8 1 1 19 3 4 4 4 4 3 4 4 8 1 1 20 4 4 4 4 4 4 4 4 8 1 1 21 4 4 4 4 4 3 4 4 8 1 1 22 4 4 4 4 4 4 4 4 8 1 1 Table 5. Validity indices (clarity and relevance) Validity Index Clarity Relevance I-CVI 0.98 0.98 S-CVI 0.98 0.98 S-CVI/UA 0.86 0.86 Phase three For the two domains, the calculated Cronbach’s alpha coefficient for internal consistency was 0.804 which is in the range of accepted reliability. For the knowledge and perception domain, the Cronbach’s coefficient was 0.726 while for the practice domain the coefficient was 0.823 suggesting a satisfactory result for reliability (Table 6). Table 6. Calculated Cronbach’s alpha coefficient for internal consistency of each domain Knowledge and perception domain Reliability Statistics Cronbach's Alpha N of Items 0.726 7 Item-Total Statistics Mean Std. Deviation Corrected Item-Total Correlation Cronbach's Alpha if Item Deleted Item 1 17.31 2.076 0.226 0.743 Item 2 2.53 0.625 0.539 0.669 Item 3 2.33 0.739 0.389 0.706 Item 4 12.36 3.009 0.556 0.665 Item 5 6.22 1.795 0.58 0.659 Item 6 2.20 0.968 0.519 0.674 Item 7 0.69 0.468 0.28 0.731 Practice domain Reliability Statistics Cronbach's Alpha N of Items 0.823 15 Item-Total Statistics Mean SD. Corrected Item-Total Correlation Cronbach's Alpha if Item Deleted Item 1 1.8 0.404 0.326 0.82 Item 2 2.422 0.811 0.279 0.823 Item 3 2.622 0.575 0.55 0.806 Item 4 2.511 0.757 0.545 0.806 Item 5 2.533 0.757 0.652 0.799 Item 6 1.711 0.726 0.429 0.814 Item 7 2.244 0.908 0.584 0.803 Item 8 2.155 0.705 0.678 0.797 Item 9 2.422 0.753 0.682 0.797 Item 10 1.622 0.805 0.447 0.813 Item 11 0.755 0.434 0.44 0.813 Item 12 2.33 0.639 0.285 0.823 Item 13 1.77 0.901 0.185 0.829 Item 14 2.977 1.544 0.137 0.832 Item 15 3.4 2.038 0.418 0.814 Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 211 Pilot study A total of 45 physicians (56% male and 44% female) were recruited in piloting the final draft of the questionnaire. The age group of the majority (64%) of the participants was between 35-54 years. They were from different professional levels ranging from consultants (11%), specialists (51%), residents (22%), and general practitioners (16%). They were from different specialties (family medicine 29%, internal medicine 24%, general surgery 11%, and other specialties 36%). About half (49%) of the respondents were working in governmental hospitals while 36% were in primary care centers. Only 42% of them were working in private clinics. More than half (56%) of the respondents have more than 10 years of experience in their field of specialty (Table 7). Table 7. Demographics of the pilot study respondents Variables N (%) Gender Male Female 25 (56%) 20 (44%) Age group 25- 34 years 35- 44 years 45- 54 years 55 years or more 7 (15.5%) 15 (33.3%) 14 (31.2%) 9 (20%) Professional level Consultants Specialists Residents General practitioner 5 (11%) 23 (51%) 10 (22%) 7 (16%) Specialty Family medicine Internal medicine General surgery Rheumatology Cardio-surgery Neurology Orthopedic No specialty 13 (29%) 11 (24%) 5 (11.1%) 4 (9.5%) 3 (6.6%) 3 (6.6%) 3 (6.6%) 3 (6.6%) Work setting Primary care centers Governmental hospitals Tertiary care center Academia Retired 16 (36%) 22 (49%) 4 (9%) 1 (2%) 2 (4%) Working in a private clinic Yes No 19 (42%) 26 (58%) Years of experience Less than 5 years 5 - 10 years More than 10 years 6 (13%) 14 (31%) 25 (56%) Knowledge and Perception domain In the knowledge and perception domain, the majority of the respondents presented good knowledge of DN in terms of its commonality and effect on patients’ quality of life. While only about half of the respondents had good knowledge on the management plan’s mainstay and its difficulty along with the effect of DN on mortality rate. In the context of the effect of blood glucose control on DN, the majority of the respondents thought that controlling blood glucose could decrease the incidence of DN while only about one-quarter of the physicians thought that blood glucose control cannot reverse DN (Table 8). Regarding the knowledge of physicians towards vitamins and dietary supplements, about one half of the respondents thought that the dietary supplements are approved by the American Food and Drug Administration (FDA) and that they are quality controlled just like chemical medicines. While about one half of the respondents disagreed with the idea of vitamins and dietary supplements’ safety on long-term use, the lack of associated side effects and their lack of tendency to interact with other medications. The respondents were evenly split between supporters and opponents regarding the cost-benefit of vitamins and dietary supplements. About one-half of the respondents believed that vitamin B complex/ B12 has no role in the treatment of DN, nor in the prevention of DN. However, near half of the respondents believed that vitamin B complex/ B12 supplements are safe for long-term use in the treatment of DN. One-half of the respondents stated that no local (Iraqi) guideline for the management of DN is available and about 34% of them were not sure if such guideline exists. Similarly, about two- thirds of the respondents thought that there was no Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 212 definite treatment for DN while about one-third were not sure about the availability of such treatment in the current time. More than one-half of the respondents believed that vascular damage, toxic effects of glucose, and vitamin B12 deficiency are the most common causes of DN. Regarding the source of information for the management of DN, respondents rated textbooks and scientific journals, and international guidelines as the most important sources of knowledge (Table 8). Table 8. Participants’ responses in knowledge and perception domain Knowledge and perception domain Agree Neutral Disagree DN knowledge DN is a common complication of diabetic patients 32 (71.1%) 13 (28.9%) 0 (0%) DN affects patient’s quality of life 42 (93.3%) 3 (6.7%) 0 (0%) DN increases mortality rate 20 (44.4%) 18 (40%) 7 (15.6%) DN is difficult to manage 28 (62.2%) 11 (24.4%) 6 (13.3%) DN management plan is based on symptomatic relief 28 (62.2%) 7 (15.6%) 10 (22.2%) DN can be reversed by strict blood glucose control 21 (46.7%) 9 (20%) 15 (33.3%) DN incidence can be decreased by maintaining strict glucose control 35 (77.8%) 6 (13.3%) 4 (8.9%) Knowledge of Dietary supplement in DN Vitamins and dietary supplements are approved by the FDA 22 (48.9%) 13 (28.9%) 10 (22.2%) Vitamins and dietary supplements’ manufacturing undergoes quality control just like chemical medicines 19 (42.2%) 17 (37.8%) 9 (20%) Vitamins and dietary supplements are safe on long term use 12 (26.7%) 15 (33.3%) 18 (40%) Vitamins and dietary supplements have no side effects 8 (17.8%) 9 (20%) 28 (62.2%) Vitamins and dietary supplements have no interactions with other medications 11 (24.4%) 10 (22.2%) 24 (53.3%) The cost of vitamins and dietary supplement worth the efficacy (outcome) provided. 14 (31.1%) 17 (37.8%) 14 (31.1%) Knowledge of Vitamin B supplements Vitamin B complex/ B12 supplementation can prevent the development of DN 11 (24.4%) 10 (22.2%) 24 (53.3%) Vitamin B complex/ B12 supplementation can treat DN 12 (26.7%) 15 (33.3%) 18 (40%) Vitamin B complex/ B12 supplements are safe for long term use in treatment of DN 20 (44.4%) 15 (33.3%) 10 (22.2%) Yes No Not sure Do you think that there is a definite treatment for DN? 3 (6.7%) 27 (60%) 15 (33.3%) Is there any local guideline for the management of DN? 7 (15.6%) 22 (48.9%) 16 (35.6%) Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 213 Continued table 8 . What is the most common cause of DN? (multiple response allowed) Vitamin B12 deficiency 25 (55.6%) Toxic effects of glucose 27 (60%) oxidative stress 15 (33.3%) Vascular damage 31 (68.9%) What is (are) the source of information does you follow in managing DN? Information from senior colleagues 11 (24.4%) Information from colleagues of different specialty 11 (24.4%) Internet and social media 7 (15.6%) Reputable international guidelines, like American diabetes association (ADA), NICE, etc. 18 (40%) Textbooks or scientific journals 26 (57.8%) Own practice 16 (35.6%) Practice domain The majority (80%) of respondents expressed their willingness to prescribe vitamins and/or dietary supplements to their patients with DN in a frequent manner. Vitamin B complex was the most commonly mentioned dietary supplement when they were asked to give an example of dietary supplement that they recommend for their patients. And they recommend these dietary supplements (vitamin B complex) as adjuvant therapy. More than one-half of the respondents considered the effectiveness, safety, cost and patient factors as very important factors in choosing medications for the treatment of DN. More than two-thirds of the respondents chose one of the first line anti- neuropathic agents according to the latest guidelines for DN management, in which, gabapentin was the most chosen agents for the treatment of DN.The respondents’ opinions regarding the influence of international guidelines on their practice were in between consulting the guideline and utilizing the guideline. Regarding their management plan of different degrees of DN, more than two-thirds of the respondents recommended the following lines of treatment: lifestyle change, strict control of blood sugar and dietary supplements (including vitamins) for the different severities of the disease. More than half of the respondents recommended an anticonvulsant as an option in managing moderate and severe DN, while about half of the respondents stated their recommendation of combining anti- convulsant, tricyclic antidepressant (TCA), a dietary supplement with or without serotonin- norepinephrine reuptake inhibitor (SNRI) in managing severe DN (Table 9). Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 214 Table 9. Participant’s responses in practice domain Practice Domain Do you recommend/ prescribe a dietary supplement to your patients with DN Yes 36 (80%) No 9 (20%) If you answered to the previous question with Yes, how often do you recommend/ prescribe supplements to your patients with DN? Always 28 (62.3%) Sometimes 8 (17.8%) Rarely 9 (20%) Vitamins and dietary supplements in DN are usually prescribed by physicians as: Treatment 7 (15.6%) Adjuvant 26 (57.8%) Tonic only 8 (17.8%) prophylaxis 3 (6.7%) Satisfy the patient (placebo) 1 (2.2%) The effectiveness of an agent is an important factor in choosing DN medication Agree 26 (57.8%) Neutral 17 (37.8%) Disagree 2 (4.4%) The safety of an agent is an important factor in choosing DN medication Agree 27 (60%) Neutral 11 (24.4%) Disagree 7 (15.6%) Patient preference is an important factor in choosing DN medication Agree 9 (20%) Neutral 16 (35.6%) Disagree 20 (44.4%) Drug - drug interaction is an important factor in choosing DN medication Agree 19 (42.2%) Neutral 18 (40%) Disagree 8 (17.8%) Cost of an agent is an important factor in choosing DN medication Agree 21 (46.7%) Neutral 14 (31.1%) Disagree 10 (22.2%) Patient factors including co-morbidity are important factors in choosing DN medication Agree 20 (44.4%) Neutral 19 (42.2%) Disagree 6 (13.4%) Medical advertisement of an agent is an important factor in choosing DN medication Agree 10 (22.2%) Neutral 11 (24.4%) Disagree 24 (53.4%) A 45 years old male diabetic patient (normal BMI and no comorbidities) Amitriptyline 5 (11.1%) Carbamazepine 2 (4.4%) Duloxetine 3 (6.7%) is complaining of burning and tingling sensation pain in his feet especially at night, what is the drug of choice for this patient? Gabapentin 18 (40%) Pregabalin 7 (15.6%) Vitamin B complex 7 (15.6%) Vitamin B12 1 (2.2%) The extent of influences of international guidelines on your practice I never use them 4 (8.9%) I consult them occasionally 22 (48.9%) They are fundamental to my practice 19 (42.2%) Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 215 Continued table 9. Management plan of [Mild DN] Life style change (diet, exercise) 37 (82.2%) Strict control on blood sugar 29 (64.4%) Supplements (vitamin B complex or Vit B12,…etc) 28 (62.2%) Anticonvulsants or TCA or SNRI 9 (20%) Combination of (anticonvulsant+ TCA and/or SSRI+ supplement) 1 (2.2%) Management plan of [Moderate DN] Life style change (diet, exercise) 29 (64.4%) Strict control on blood sugar 38 (84.4%) Supplements (vitamin B complex or Vit B12,…etc) 34 (75.6%) Anticonvulsants or TCA or SNRI 22 (48.9%) Combination of (anticonvulsant+ TCA and/or SSRI+ supplement) 7 (15.6%) Management plan of [Severe DN] Life style change (diet, exercise) 27 (60%) Strict control on blood sugar 33 (73.3%) Supplements (vitamin B complex or Vit B12,…etc) 31 (68.9%) Anticonvulsants or TCA or SNRI 25 (55.6%) Combination of (anticonvulsant+ TCA and/or SSRI+ supplement) 22 (48.9%) Discussion The literature review process revealed no validated questionnaire that is targeted to explore physicians’ perception and practice towards the prescription of vitamins and other medicines in DN management. However, the review process found two articles that explored the utilization patterns of anti-neuropathic i.e (TCA, SNRI, anticonvulsants, and opioids) in the UK and Korea (47, 56). The prescribing preferences of healthcare professionals (physicians, pharmacists, and nurses) regarding anti- neuropathic medications, their knowledge, and beliefs about DN were examined in six researches (48-53). While Provenzano et al., (2018) have investigated the practice of primary care physicians about the management of chronic pain (54). Aldossari et al., (2021) had assessed the physicians’ knowledge and the tendency of prescribing vitamin B12 exclusively for the treatment or prevention of DN in primary care settings (55). Our study illustrated the ability to produce a questionnaire with good psychometric properties on the physicians’ perception and practice toward prescribing vitamin B combination versus antiepileptic drugs in the management of DN along with the factors affecting their choice and the influence of the international guidelines to their current practice. The questionnaire of this study was developed by adapting items from the former-mentioned studies in addition to the self-constructed questions. The content validity was measured in this study since it is an essential step in questionnaire’s development. Furthermore, it is an acceptable and important method to reflect the relevance and clarity of the instrument (57). The content validity indices ranged from 0.8 to 0.9 for both relevance and clarity which is satisfactory and reveals that the questions were relevant and representative of the intended aim of the developed tool (58). Shi et al., (2012) indicated that I-CVIs ≥ 0.78, S-CVI/UA, and S-CVI/Ave ≥ 0.8 are considered excellent indices for relevance and clarity. The content validity indices of the constructed questionnaire of this study were within the above-mentioned ranges (59). The use of Cronbach’s alpha in the multiple-item questionnaire was considered as a routine in knowledge, attitude, and practice studies (60), which is used to test and determine the internal consistency (reliability) of a questionnaire in applied research (61). Nunnally and Bernstein (1978) hypothesized that an alpha value of 0.70 and higher is an acceptable value in the early stages of developing a questionnaire (i.e., exploratory research) (62). On the other hand, George and Mallery (2003) ranked alpha values according to acceptability into excellent ≥ 0.9, good ≥ 0.8, acceptable ≥ 0.7, questionable ≥ 0.6, poor ≥ 0.5, and unacceptable ≤ 0.5. The Cronbach’s alpha coefficient for internal consistency of this study was 0.804 which is considered good (63). Although the pilot study is time-consuming and leads to considerable data loss, it ensures the feasibility of the developed questionnaire, in other words, it detects any inappropriate and/or complicated questions that would ultimately end up by potential failure of the questionnaire. In our pilot study, the clarity of the questions was confirmed by face-to- Iraqi J Pharm Sci, Vol.32(1) 2023 Vitamin B combination and diabetic neuropathy 216 face short interviews with the respondents from different specialties (family medicine, internal medicine, general surgery, endocrinology, rheumatology, and neurology). As expected, the physicians showed a good perception of the commonality of DN, the impact of the disease on quality of life, and the role of glucose control in the etiology of DN and the management plan of the disease. Diverse opinions were noticed regarding the process of manufacturing, FDA approval, safety profile, and the cost-effectiveness of vitamins and dietary supplements. The lack of a local guideline was raised by the respondents as a reason for their different perspectives regarding the use of vitamins and medicines for the management of DN, in which their main source of information were reputable international guidelines like the American diabetes association (ADA) and NICE along with textbooks and scientific journals. However, physicians opted gabapentin, pregabalin, and duloxetine as their first pharmacological choice which was in line with the current international guidelines, the percentage of Iraqi physicians who were adhered to international guidelines was higher than the percentage of the recent Saudi study (55). Although we expected that physicians would prioritize the efficacy and safety in their treatment choice, they also prioritized cost as an important factor in choosing the medication. Interestingly, physicians are willing to prescribe vitamins and supplements for therapeutic purposes as an adjuvant which was consistent with the results of the Saudi study (55) in which about half of the physicians rated the efficacy of vitamin B12 as moderate in both prevention and treatment of DN. Regarding the management of mild, moderate, and severe DN, although the physicians adhered to the international guidelines that recommended lifestyle changes and strict blood glucose control as a primary intervention for DN. However, they unfollowed these guidelines by recommending vitamins and dietary supplements as an adjuvant treatment. This study has some limitations; first is that despite the fact that Cronbach’s alpha is a commonly used test to determine the internal consistency in the literature it has limitations when used as a sole index for internal consistency. Second, the small number of participants in the pilot study was the consequence of the fact that the target population (physicians) are limited in number and hard to reach, and that those who are participated in the pilot study would not be included in the main study (since this article is a part of a larger study and Master degree dissertation); therefore, losing this number would affect the power of the main study. To the best of our knowledge, this study is the first to develop and validate a tool to explore physicians’ perceptions and practices regarding the use of vitamins and dietary supplements in the management of DN in different specialties. 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