The study designed in cross-sectional survey model was performed on adult T2DM patients diagnosed with DPN in a time-span between 15 June 2019 and 5 October 2019.
The study was conducted at the Jordanian Ministry of Health. The three hospitals involved function under the Ministry of Health of Jordan. The researcher chose this setting because it receives referrals from all medical sectors in different parts of Jordan, based particularly on the assumption that the selected setting would provide a profile of patients with diabetes from different parts of Jordan. This center was established in 1921 in Jordan, Amman with an annual admission rate of 25,000 patients of all disease types, and provides services to all patients from all around Jordan. It also provides screening services for each patient presenting to the centers (clinics and hospitals) functioning under the Ministry of Health of Jordan. The services include the monitoring of patients with diabetes mellitus every three months, and in addition routine measurements of blood glucose HbA1c, blood pressure, weight, height, and waist circumference that are performed during each visit. Every day the medical staff responsible for records in each clinic pick up the patients’ medical files, and put them available for use on the nursing desk. Once the patients show up, they are received by a qualified nurse who performs some physical examinations required before the examination and treatment by the physician. There are also several clinics in centers specialized in addressing the complications of diabetes.
Sampling And Sample Size
The target population for this study consisted of adult patients (T2DM) having a DPN. The accessible population included all the patients presenting to the Ministry of Health of Jordan during the period between 15 June 2019 and 5 October 2019, and those who were ≥ 18 years of age and had been regularly monitored in the hospitals for at least six months were included in the study.
The sample size for this study was calculated using the equation (n=(Za/2)2 Pq / 2 ) with a confidence level (CL) of 95%, expected prevalence of 50%, and margin error of 5%. The calculation indicated a sample size of 375 participants . The researcher accordingly increased the sample size to 100% to compensate for the attrition rate and missing data. As a result, the final estimated sample included 400 participants.
Patients with T1DM were not included because they were beyond the purpose of the study. Adult patients who had undergone an amputation were also excluded from the study due to limited possibilities to perform a physical examination on them. Besides, patients who did not give consent or failed to respond to the questionnaire were not included in the study as well.
An assessment tool package consisting of five tools, namely (1) descriptive data (demographics, anthropometric measurements, laboratory measurements, and clinical data, (2) Douleur Neuropathique4 (DN4) questionnaire, (3) Physical exam (second section from the DN4 questioner), (4) Quality of Life Questionnaire (EQ-5D), (5) Numeric Pain Rating Scale (NRS) were used in the research project.
The first tool was developed by the researcher and consisted of the patients’ demographic data (such as file number, age, gender, marital status, income, working status, and level of education. Smoking status  included the categories of current smoker (namely one who has smoked 100 cigarettes in his/her lifetime), ex-smoker (adults who have smoked more than 100 cigarettes in their lifetime, but have not smoked in the last 28 days), and non-smokers (being an adult who has never smoked or one who has smoked less than 100 cigarettes in his/her lifetime). Besides, it also includes the type of treatment (which includes insulin, oral hypoglycemic agents (OHA's) or both OHA's and insulin) and type of medication (which includes metformin, anti-hypertensive treatment, and statin). Data regarding anthropometric measurements (based on the latest reading), laboratory measurements (also based on the latest reading), and clinical data were obtained from the clinical records of the subjects. These data procedures followed the following process:
Anthropometric measurements made under the following criteria included weight, height, waist circumference, and blood pressure systolic/diastolic.
Weight was measured for each patient; it was taken barefooted with light clothing rounded down to the nearest 0.5 kg using an electronic scale.
Height was measured in standing position without shoes rounded down to the nearest 0.5 cm using a stadiometer with the shoulder in a relaxed position and the arms hanging freely.
Waist circumference was measured in cm rounded down to the nearest cm using a non-stretchable tailor’s measuring tape at the midway level between the lower rib margin and the iliac crest in the horizontal plane. According to the adult treatment panel III (ATP III) criteria for metabolic syndrome, people with a waist circumference of ≥ 102 cm for men and ≥ 88 cm for women are considered to have abdominal obesity .
Body mass index (BMI)
Body mass index was obtained by dividing the weight in kilograms by the square of height in meters, and classified according to criteria set forth by the American Diabetes Association (ADA) , it included the categories of underweight (< 18.5 Kg/m2), normal weight (18.5-24.99 Kg/m2), overweight (25 -29.9 Kg/ m2), and weight evaluated as obesity (≥ 30 Kg/ m2).
Blood pressure was measured in sitting position with the arm at heart level, after 5 minutes of rest, after which time the cuff was deflated at the rate of 2–3 mmHg per second, systolic blood pressure was taken upon the heart first sound, and diastolic blood pressure taken upon complete disappearance of KorotK of sound (phase V). It was measured by using a standardized sphygmo-manometer EN1060 (Riester) with a cuff circumference of 24–32 cm to cover 80% of the upper arm (for obese patients larger cuff circumference was used (42–50 cm)).
Correspondingly, the anthropometric measurements were documented according to the latest reading of the medical file that was taken at the end of the interview. These measurements were documented by qualified staff nurses working in the involved hospitals in conformity with the standardized measuring standards set out by the Ministry of Health of Jordan.
Laboratory measurements made under the following criteria included the latest recorded values of glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), or random blood glucose (RBG). Besides, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), vitamin B12 levels, and low-density lipoprotein (LDL) were also assessed.
Glycosylated Hemoglobin (HbA1c%) levels
The latest record of HbA1c was taken from the medical file after the participants had been examined by the physician. HbA1c was classified into two categories according to ADA : controlled if HbA1c < 7, uncontrolled if HbA1c ≥ 7.
Fasting blood glucose (FBG) and random blood glucose (RBG) levels
To measure the level of blood glucose, patients were asked not to eat anything or drink no fluid other than water for at least 8 hours (fasting). It is considered to be abnormal if the patient has FPG ≥ 126 mg/dl (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours according to ADA. According to ADA, it is considered to be abnormal if the patient has RBG ≥ 200 mg/dl (11.1 mmol/L) . FBG or RBG was analyzed by the enzymatic reference method with hexokinase supplied by COBAS INTEGRA systems provided by Roche Diagnostics.
Plasma lipid profile levels
According to the Ministry of Health of Jordan, total cholesterol (TC) levels below 200 mg/dl are classified as "desirable blood cholesterol", and those 200 mg/dl and above as "high blood cholesterol". Triglyceride (TG) levels below 150 mg/dl, on the other hand, are classified as "desirable blood Triglyceride", and those 150 mg/dl and above as "high blood triglyceride". Low-density lipoprotein (LDL) levels below 100 mg/dl and those above this value are classified as "desirable blood lipoprotein " and "high blood lipoprotein ", respectively. While high-density lipoprotein (HDL) levels of < 40 mg/dl in men or those of < 50 mg/dl in women are classified as "undesirable blood lipoprotein ", and those of ≥ 40 mg/dl in men or ≥ 50 mg/dl in women are classified as “desirable blood lipoprotein ".
Vitamin B12 levels
Serum vitamin B12 level was measured by ARCHITECT B12 assay which is a chemiluminescent micro-particle intrinsic factor assay for the quantitative determination of vitamin B12 in human serum or plasma. Normal level ranges between (208–963 pg/ml). In cases when the patient is already on a vitamin B12 treatment, it is taken within 6 months.
Consistently, the laboratory measurements were documented according to the latest reading from the medical file that was taken at the end of the interview. These measurements were documented according to the standardized measurement rules set by the Ministry of Health of Jordan.
Clinical data included complications of diabetes and comorbidities. The complications of diabetes were neuropathy, nephropathy, and retinopathy. Comorbidities included hypertension, dyslipidemia, and cardiovascular disease described under the following criteria:
Hypertension is defined as a condition when the patient is already on antihypertensive drugs, or have a blood pressure of ≥ 130 mmHg systolic and/or ≥ 80 mmHg diastolic on at least two occasions according to ADA .
Retinopathy was diagnosed as positive if it was so documented by either the ophthalmologist or the treating physician in the medical records.
Nephropathy was diagnosed as positive if it was so documented by either the nephrologists or the treating physician in the medical records.
The patients were considered to have dyslipidemia in cases where the TC of the patient is ≥ 200 mg/dl, TG ≥ 150 mg/dl, LDL ≥ 100 mg/dl and HDL < 40 mg/dl in men or < 50 mg/dl in women or where the patients are on medications for any of the above conditions, according to ADA .
Cardiovascular diseases were considered to be positive if there was a history of heart diseases such as angina, myocardial infarction, heart failure, coronary artery disease, arrhythmias, congenital heart failure, and atherosclerosis as well as an ongoing treatment with drugs prescribed for cardiovascular diseases, or the presence of a pathological electrocardiogram.
Correspondingly, the clinical data were documented according to the physician’s diagnosis, with duration of diabetes, type of treatment, and type of medication that was documented in the medical file.
The second tool is Douleur Neuropathique4 DN4, an interview questionnaire . The questionnaire diagnosis of DPNP among adult T2DM patients with DPN was made by a score of ≥ 3. The DN4 score was derived by counting the number of positive responses to each of the first 7 items in the questionnaire, which included burning sensation, painful cold sensation, electric shocks, tingling, pins and needles, numbness, itching, hypoesthesia to touch, hypoesthesia to prick, and brushing . Only those who completed all 10 items of the DN4 questionnaire were included in the analysis performed to estimate the prevalence of DPNP. The responses to the questionnaire were either yes or no. Scores ≥ 3 with a sensitivity of 89.9% were used to identify the patients with DPNP among adult T2DM patients with DPN, while using a cut-off score point of 3 items out of 7 had a sensitivity 78% and specificity of 81.2% in identifying patients with DPNP . This questionnaire was reported by the International Association for the Study of Pain in 2004 by Bouhassira et al. (2005) . The analysis of the psychometric properties of the DN4 questionnaire included face validity, factor analysis, and logistic regression to identify the discriminate properties of items or combinations of items for the diagnosis of neuropathic pain. The reliability and validity studies of the DN4 questionnaire in Arabic was performed by Terkawi et al. in 2017. The results showed Arabic DN4 to have a good diagnostic accuracy, with an area under the curve of 0.88. As with the original version, a score of ≥ 4 was found to be the best cut-off for the diagnosis of DPN, with a sensitivity of 88.31%, the specificity of 74.47%, a positive predictive value of 85%, and a negative predictive value of 80%. The Cronbach’s alpha value of the revised scale was 0.67 .
The third tool is the physical examination that is the second section in the DN4 questionnaire; it includes hypoesthesia to touch, hypoesthesia to prick, and brushing . The researcher filled in each questionnaire using face to face interviews in Arabic language.
The fourth tool is the quality of life questionnaire titled EQ-5D . This standardized instrument includes four domains that measure the QoL, namely mobility, self-care, routine activities, discomfort, and anxiety /depression. Each dimension has five levels, namely no problems, slight problems, moderate problems, severe problems, and extreme problems. The participants were asked how good or bad they self-rated their health status. Responses were rated on a scale ranging from 0 to 100, with 100 indicating the best self-rated health status, and 0 indicating the poorest one . The EQ-5D was translated by the researcher and checked by two professional academic instructors working in the field of nursing to ensure the consistency of the information obtained in the interviews. The reliability and validity studies of the EQ-5D in Jordan were performed by Abu-Shennar, Bebis, and Bayraktar in 2020. The Cronbach’s alpha value of the revised scale was 0.88 .
In addition to the above measurements, the researcher measured the intensity of pain using the Numeric Pain Rating Scale (NRS). Each patient was asked to indicate the number that represented the intensity of his/her current pain experience.
Data were collected in five stages in the following way:
Each weekday, the researcher assessed the adult T2DM participants with DPN who met the criteria of inclusion in the study.
A face-to-face structured interview was performed with the adult T2DM patients with DPN while waiting for his/her turn to be treated by the physician after their laboratory check and nursing examination. Descriptive data were obtained, and Douleur Neuropathique4 DN4 was administered to evaluate DPNP. Each interview took about 10 to15 minutes.
After the interviews, a physical examination was performed on each participant using the second section of the DN4 for evaluation of DPNP, and patients with DPNP were determined.
The intensity of pain was measured using the Numeric Pain Rating Scale (NRS) among the DPNP patients.
Finally, the quality of life questionnaires titled EQ-5D were collected from the patients having DPNP.
Statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS, version 25). Descriptive statistics were obtained such as mean and stander deviation values for continuous and proportions for categorical variables. Chi-square was used to test the independent distribution of categorical variables where appropriate. Spearman's Rank-Order Association Coefficient (Spearman's Rho) was also used to measure the direction and strength of the correlation between the two variables. The Kolmogorov-Smirnov test and the Shapiro-Wilk test were used to measure the value of the Shapiro-Wilk Test. While values greater than 0.05 indicated the normality of data, those below 0.05 indicated that the data significantly deviated from a normal distribution. Binary logistic regressions were also used to examine the net effect for each of the proposed variables on DPNP. P-values smaller than 0.05 were considered to be statistically significant.
Data were collected after approval by the ethical committee in the Ministry of Health of Jordan. We obtained approval from a consultant specialized in neurology to administer the DN4 as required by the Ethical Committee of the Ministry of Health of Jordan The data were only used for scientific research. Since the study was based on data obtained from medical records and structured questionnaires, it inflicted no harm at all on adult patients (T2DM) with DPN. Verbal consent was obtained from those eligible to participate, who were assured about the confidentiality of information.