European Journal of General Practice, 2014; 20: 260–267
Original Article
Chronic pain in type 2 diabetic patients: A cross-sectional study in primary care setting
Orly Liberman1, Roni Peleg2 & Pesach Shvartzman2 Eur J Gen Pract Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
1Nursing
Department, Rekanati School for Community Health Professions, Ben-Gurion University of the Negev, Beer-Sheva, Israel, and Palliative Care Unit, Department of Family Medicine and Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel 2Pain
KEY MESSAGE: · Almost 50% of DM patients reported having pain of predominantly neuropathic origin. · Neuropathic pain is constant, worse at night and has a significant impact on daily activities.
ABSTRACT Background: Although diabetes mellitus (DM) is often associated with painful neuropathic syndromes, a significant number of DM patients suffer from non-neuropathic (nociceptive) pain. Unfortunately, there is insufficient data on the epidemiology of nociceptive pain in DM patients and its effect on their quality of life. Objective: To characterize pain in type 2 DM patients, and assess its effect on their quality of life. Methods: The study population included 342 type 2 DM patients, 18 years of age and above (mean age 70.7 ⫾ 9.7), who reported having pain. The study questionnaires included the Brief Pain Inventory (BPI), the S-LANSS scale to assess pain with neuropathic features, life impact, and socio-demographic data. Results: One hundred and fifty-five DM patients (46.5%) reported having pain of predominantly neuropathic origin. Almost 75% of patients with neuropathic pain were females, compared to 57.8% of patients with nociceptive pain (P ⫽ 0.002). More patients with neuropathic pain reported constant daily pain (57.6% vs. 42.4%, P ⬍ 0.0001), and worse pain during the night (53.3% vs. 46.7%, P ⫽ 0.045). The pain affected daily activities, walking capacity, and mood. Patients with neuropathic pain reported a greater negative effect of pain on their quality of life than those with nociceptive pain (41.0% vs. 15.3%, P ⬍ 0.0001). Conclusion: The impact of neuropathic pain in DM patients is much more significant than nociceptive pain and affects their quality of life and daily function to a greater degree. Keywords: Diabetes mellitus, neuropathic pain, musculoskeletal pain, quality of life
INTRODUCTION The prevalence of diabetes mellitus (DM) in developed countries has increased significantly over recent decades. In the year 2000, the prevalence was estimated to be 8.6% among individuals 20 years of age and above, and as high as 20.1% among individuals 65 years of age and older (1). According to the latest estimates of the International Diabetes Federation in 2012, there were more than 371 million people with DM. By 2030, this number is expected to reach 552 million (2). Various pain syndromes are associated with DM and are an integral part of the disease, contributing to its morbidity and affecting patients’ quality of life. One of
the well-recognized pain types is painful diabetic neuropathy (3). This is a debilitating disorder that occurs in nearly 50% of DM patients (4). However, other types of chronic non-neuropathic pain syndromes, such as frozen shoulder and abdominal pain, have been reported (5). The effect of DM on the musculoskeletal system has received significantly less research attention than its effect on the heart, brain, kidneys, eyes and nerves. Vascular changes in both small and large vessels and metabolic changes related to high blood glucose levels affect the musculoskeletal system. The prevalence of musculoskeletal pain is higher in DM patients than in the general population (6).
Correspondence: Roni Peleg, Department of Family Medicine, Ben-Gurion University, POB 653 Beer-Sheva, Israel, 84105. Tel: ⫹ 972 8 6477436. Fax: ⫹ 972 8 6477636. E-mail: [email protected] (Received 6 March 2013; accepted 7 January 2014) ISSN 1381-4788 print/ISSN 1751-1402 online © 2014 Informa Healthcare DOI: 10.3109/13814788.2014.887674
Chronic pain in diabetic patients The goal of this study was to characterize pain syndromes in type 2 DM patients and assess the effect of pain on patients’ quality of life.
METHODS Study design
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The national health insurance system, implemented in Israel in 1995, provides healthcare to the entire population through non-profit health maintenance organizations (‘sick funds’). The Clalit Health Services, the largest HMO in Israel, insures about 55% of the Israeli population. Selection of study subjects The study population consisted of type 2 DM patients, 18 years of age and above, from four primary care clinics of the Clalit Health Services in the Negev region of Israel. The study population included 2251 type 2 DM patients listed in the four primary care clinics. Patients who agreed to participate were interviewed by nurses by telephone using a structured questionnaire. The interviews were conducted during the years 2006–2009. Only patients who reported pain, of any type, were included in the study. The Helsinki Committee (IRB) of the Soroka University Medical Center approved the study (approval No. 4310).
Measurements and outcomes Study questionnaires included: (a) The Brief Pain Inventory-Short Form (BPI-SF) was used to measure and characterize pain and its interference with the patients’ lives (reactive dimension). The BPI questionnaire includes a rating scale of 0 to 10 to measure pain and the effect of pain on different aspects of daily life (general activity, mood, sleep, relationships with others, and work). This tool was validated in Hebrew for a previous study (7) and has been used as an outcome measure in various clinical trials (8,9). The ‘life impact ’ variable was calculated as the mean of items relating to the effect of pain on life activities. (b) The S-LANSS Pain Scale self-report version is a self-report instrument for identifying neuropathic pain. Its aims are to identify pain of predominantly neuropathic origin, as distinct from nociceptive pain, without the need for clinical examination (10). The S-LANSS is a simple seven-item tool. Each item entails a binary response (yes or no) to the presence or absence of symptoms (five items) or clinical signs (two items). A score of 12 or more suggests pain of predominantly neuropathic origin. In the present
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study, we used the term neuropathic pain for patients suffering from pain of predominantly neuropathic origin. The questionnaires were translated from English to Hebrew using the backtranslation method (11) after which they underwent cultural adaptation. (c) Socio-demographic data. The questionnaire also included questions relating to pain location and duration. Statistical analyses Statistical analyses were performed using the SPSS 17 software. Continuous variables are shown as means and standard deviations. Categorical variables are described as frequencies. T-tests and χ-square tests were used to analyse statistically significant differences between neuropathic and nociceptive pain groups for continuous and categorical variables, respectively. As a result of missing data in the S-LANSS questionnaire, the total S-LANSS score could not be calculated for nine patients, and they were not included in the comparison between the neuropathic and nociceptive pain groups. Two-tailed P-values ⬍ 0.05 with a power of 80% were considered statistically significant. A logistic regression model was constructed to identify associations between patients’ characteristics and the presence of nociceptive pain. The conceptual framework was that age and gender would not be associated with the type of pain. We assumed that patients reported worse pain during the day and a lower effect of pain on daily activities would be reported by patients who suffer from nociceptive pain.
RESULTS Study population The study population included 2251 type 2 DM patients listed in the four primary care clinics. One hundred and sixteen (5.2%) refused to participate in the study; 253 (11.2%) did not speak Hebrew, 180 (8%) had a wrong telephone number listed, 94 (4.2%) were unable to answer a telephone questionnaire (due to mental/physical status), 1 212 (53.8%) could not be located by telephone after several attempts, and 396 (17.6%) agreed to participate in the study. Of the 396 patients who agreed to participate in the study, only 54 (13.6%) did not report any pain. Study population characteristics The final study population consisted of the 342 DM patients who reported having pain. Their mean age was 70.7 ⫾ 9.7 years and 221 (66.4%) were women. Fifty-two
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per cent of the DM patients suffered from nociceptive pain. One hundred and fifty-five participants (46.5%) had neuropathic pain as determined by an S-LANSS score ⱖ 12. Most of these patients (61.4%) reported that the pain was accompanied by strange, unpleasant sensations on the skin like stabbing or tingling. These sensations suddenly appeared like a storm and were paroxysmal in nature. Fifty-five per cent were hypersensitive or felt numbness. Almost 75% of patients with neuropathic pain were women compared with 57.8% of patients with nociceptive pain (P ⫽ 0.002). No other statistically significant differences were found in the socio-demographic characteristics of patients with neuropathic and nociceptive pain (Table 1).
Characteristics of pain in DM patients The BPI questionnaire was used to record the pain characteristics of the study population. Pain was located mainly in the limbs (45%), the back (20%), and the head and neck (13%). The average duration of pain was 77.7 ⫾ 117.6 months (range: 1–816 months). Most patients (73.6%) reported having pain for more than 12 months. Patients who did not report pain were ineligible. Characteristics of patients with neuropathic and nociceptive pain are presented in Table 2. Constant daily pain was reported more by patients with neuropathic pain (57.6% vs. 42.4%, P ⬍ 0.0001). The worst pain was experienced during the night (53.3% vs. 46.7%, ⫽ 0.045). One hundred and thirty-two patients (38.6%) stated that
Table 1. Comparison of socio-demographic characteristics between patients with features of neuropathic and nociceptive pain.
Variable Age in years ⱕ 65 ⬎ 65 Mean ⫾ SD Range Missing Gender Male Female Missing Family status Married Other Missing Country of birth Israel Asia/Africa Eastern Europe (former USSR) Europe, North America, South America South Africa Missing Education Elementary High school Academic Missing Present work status Employed Unemployed Retired Missing How would you define your religiosity? Religious Traditional Secular Missing aDue
Total study populationa
Patients with neuropathic pain
Patients with nociceptive pain
(n ⫽ 333)
(n ⫽ 155)
(n ⫽ 178)
n (%)
n (%)
n (%)
93 (28.7) 231 (71.3) 70.6 ⫾ 9.7 38–98 9
48 (32.0) 102 (68.0) 69.8 ⫾ 10.3 38–98 5
45 (25.9) 129 (74.1) 71.2 ⫾ 9.2 43–89 4
111 (34.3) 213 (65.7) 9
38 (25.2) 113 (74.8) 4
73 (42.2) 100 (57.8) 5
241 (73.9) 85 (26.1) 7
106 (69.7) 46 (30.3) 3
135 (77.6) 39 (22.4) 4
26 (8.0) 135 (41.7) 127 (39.2)
16 (10.5) 62 (40.5) 61 (39.9)
10 (5.8) 73 (42.7) 66 (38.6)
36 (11.1) 9
14 (9.2) 2
22 (12.9) 7
85 (26.9) 163 (51.6) 68 (21.5) 17
44 (30.1) 74 (50.7) 28 (19.2) 9
41 (24.1) 89 (52.4) 40 (23.5) 8
37 (11.6) 64 (20.0) 219 (68.4) 13
17 (11.3) 29 (19.3) 104 (69.3) 5
20 (11.8) 35 (20.6) 115 (67.6) 8
P 0.193
0.002
0.129
0.352
0.408
0.947
0.859 57 (17.3) 156 (47.4) 116 (35.3) 4
25 (16.2) 75 (48.7) 54 (35.1) 1
to missing data in the S-LANSS questionnaire nine patients were excluded.
32 (18.3) 81 (46.3) 62 (35.4) 3
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Table 2. Pain characteristics in DM patients.
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Variable Average pain duration (months) 1–3 4–6 7–12 ⬎ 12 Mean ⫾ SD Range Missing What is the frequency of the pain? Constant Once a day Several times a day Several times a week Once a week or less Missing Is the pain worse during the day or at night? During the day At night Equally aDue
Total study populationa
Patients with neuropathic pain
Patients with nociceptive pain
(n ⫽ 333)
(n ⫽ 155)
(n ⫽ 178)
n
n%
n%
21 23 26 184 77.7 ⫾ 117.6 1–816 79
8 (6.7) 10 (8.3) 14 (11.7) 88 (73.3) 71.2 ⫾ 103.2 1–756 35
13 (9.7) 13 (9.7) 12 (8.9) 96 (71.6) 83.6 ⫾ 129.3 1–816 44
125 30 53 53 70 2
72 (57.6) 12 (40.0) 30 (56.6) 23 (43.4) 17 (24.3) 1
53 (42.4) 18 (60.0) 23 (43.4) 30 (56.6) 53 (75.7) 1
P 0.401
⬍ 0.0001
0.045 115 107 111
43 (37.4) 57 (53.3) 55 (49.5)
72 (62.6) 50 (46.7) 56 (50.5)
to missing data in the S-LANSS questionnaire nine patients were excluded.
DM was the source of their pain, and 33.3% thought there was no specific source. Life impact index The variable ‘life impact ’ was calculated as the mean for items in the BPI questionnaire relating to the effect of pain on life activities. The mean reported pain level was 6.3 ⫾ 2.5 on a scale from 0 to 10. The mean effect of pain on general daytime activity was 5.5 ⫾ 2.9. Pain affected mood (5.5 ⫾ 3.0) and the capacity to walk (5.5 ⫾ 3.1) to a similar degree. Only four of the participants (1.6%) did not report an association between pain and the Life Impact Index. Only 27.3% of patients reported a mild effect on quality of life while 45.1% reported a moderate effect, and 26.1% a severe effect. Patients with neuropathic pain reported a statistically significant higher impact of pain on life activities in all aspects (Table 3). In univariate analyses there was no association between the Life Impact Index and age, occupation, family status, gender, education, country of birth, or religious belief. Logistic regression model for predicting diabetes patients with nociceptive pain A logistic regression model was developed to predict patients’ characteristics associated with features of nociceptive pain (Table 4). The dependent variable was nociceptive pain, determined by an S-LANSS questionnaire score ⬎ 12. The independent variables gender and age, which did not have a statistically significant association
with nociceptive pain, were included in the model for adjustment. The independent variables found to be statistically significant in the model were not having constant pain (OR ⫽ 0.528, 95%CI: 0.322–0.865, P ⫽ 0.011) and lower impact of pain on daily activities (OR ⫽ 0.783, 95%CI: 0.767–0.919, P ⬍ 0.0001). The independent variable, the worst pain during the day, had a borderline statistical significance (OR ⫽ 1.629, 95%CI: 0.984–2.696, P ⫽ 0.058).
DISCUSSION Main findings Almost half of DM patients reported having pain of predominantly neuropathic origin. Most of the patients (73.6%) reported having suffered from pain for more than 12 months. Most patients with neuropathic pain were females. More patients with neuropathic pain reported constant daily pain and worse pain during the night. The pain affected daily activities, walking capacity, and mood. Patients with neuropathic pain reported a greater negative effect of pain on their quality of life. Interpretation of the study results Neural injury that causes neuropathic pain in DM is well recognized and has been reported frequently in the literature while nociceptive pain has received less attention. Diabetes neuropathy affects up to 50% of patients
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Table 3. The effect of pain on daily activity.
Total study populationa
Patients with neuropathic pain
Patients with nociceptive pain
(n ⫽ 333)
(n ⫽ 155)
(n ⫽ 178)
n%
n%
n%
3 (1.20) 69 (27.7) 112 (45.0) 65 (26.1) 84
0 (0) 14 (13.3) 48 (45.7) 43 (41.0) 50
3 (2.1) 55 (38.2) 64 (44.4) 22 (15.3) 34
6.3 ⫾ 2.5 0–10 1
7.1 ⫾ 2.1 0–10 1
5.7 ⫾ 2.5 0–10 –
5.5 ⫾ 2.9 0–10 1
6.4 ⫾ 2.6 0–10 1
4.8 ⫾ 2.9 0–10 –
5.5 ⫾ 3.0 0–10 1
6.2 ⫾ 2.7 0–10 1
4.9 ⫾ 3.2 0–10 –
5.5 ⫾ 3.1 0–10 1
6.2 ⫾ 2.8 0–10 1
4.8 ⫾ 3.2 0–10 –
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Variable Life Impact Index None Mild Moderate Severe Missing In general, how severe is the pain? Mean ⫾ SD Range Missing To what extent does the pain affect daily activities? Mean ⫾ SD Range Missing To what extent does the pain affect your mood? Mean ⫾ SD Range Missing To what extent does the pain affect your ability to walk? Mean ⫾ SD Range Missing To what extent does the pain affect the quantity and quality of your sleep? Mean ⫾ SD Range Missing To what extent does the pain affect your relationships with others? Mean⫾ SD Range Missing To what extent does your pain make you feel a need to rest in bed during the day? Mean ⫾ SD Range Missing To what extent does your pain affect your regular job? Mean ⫾ SD Range Missing To what extent does your pain interfere with sexual relationships? Mean ⫾ SD Range Missing To what extent does your pain interfere with your sexual functioning? Mean ⫾ SD Range Missing aDue
P ⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001 5.4 ⫾ 3.3 0–10 2
6.5 ⫾ 2.7 0–10 1
4.5 ⫾ 3.5 0–10 – ⬍ 0.0001
3.6 ⫾ 3.1 0–10 2
4.5 ⫾ 3.1 0–10 2
2.7 ⫾ 2.9 0–10 – ⬍ 0.0001
5.4 ⫾ 3.0 0–10 1
6.4 ⫾ 2.5 0–10 1
4.6 ⫾ 3.1 0–10 –
5.1 ⫾ 3.2 0–10 10
6.0 ⫾ 2.8 0–10 5
4.2 ⫾ 3.2 0–10 5
⬍ 0.0001
0.002 5.0 ⫾ 3.6 0–10 75
5.9 ⫾ 3.5 0–10 48
4.4 ⫾ 3.6 0–10 27 0.001
5.1 ⫾ 3.7 0–10 72
5.9 ⫾ 3.6 0–10 48
4.5 ⫾ 3.7 0–10 24
to missing data in the S-LANSS questionnaire nine patients were excluded.
with DM (12). As observed in this study neuropathic pain has a significant impact on function and quality of life in DM, and has a negative effect on patient ’s quality of life. In a study from Turkey, the prevalence of diabetic
neuropathy, determined by clinical examination alone, was 40.4% and increased to 62.2% when nerve conduction studies were added to the clinical examination (13). A small study found that quality of life was significantly
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Table 4. Logistic regression model to predict nociceptive pain in DM patients. Variables Age (continuous) Gender Male Female Pain frequency Constant Other Worse pain During the day At night/equally day or night The extent pain affects daily activities (continuous)a
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aScale
Odds ratio
95%CI
P
1.019
0.994–1.045
0.145
1.543 1
0.919–2.591
0.101
0.528 1
0.322–0.865
0.011
1.629 1 0.783
0.984–2.696
0.058
0.767–0.919
⬍ 0.0001
from 0 ⫽ active as usual to 10 ⫽ not active at all.
more impaired among patients with diabetic neuropathy than among patients without it. Patients with diabetic neuropathy had greater impairment in emotional reactions, energy, pain, physical mobility, and sleep (14). In a cross-sectional evaluation of function and healthrelated quality of life in patients with neuropathic pain, the pain intensity on a five-point visual analogue scale was 2.8 ⫾ 1.0. Pain substantially interfered with normal work (5.9, 0 - 10 scale), social activities (5.7), and family life (5.3) (15). Painful diabetic neuropathy was associated with decrements in many aspects of patients’ levels of physical and emotional functioning, and it affected symptoms and sleep. The negative impact was higher in patients with greater pain severity (16). Musculoskeletal pain is more prevalent in DM patients than in the non-diabetic general population (6). The prevalence of frozen shoulder and shoulder joint adhesions ranges from 11–20% among DM patients to 2–10% in the healthy population (17,18). Limited joint function is reported to a range from 8–50% in DM to 0–26% in non-diabetics (19,20). Pain from local inflammation of the palm tendons is ten times more prevalent in DM (21), and a similar ratio was found for carpal tunnel syndrome (22,23). Another typical pain syndrome in the palm is Dupuytren’s contracture, which is also much more prevalent in DM patients (24,25). Degenerative changes in the vertebrae, as in other joints, is more common in DM. Diffuse idiopathic skeletal hyperostosis is particularly prevalent in DM with an incidence rate that reaches 13–49% compared to 1.6–13% in non-diabetics (22,26,27). Over one third of the study population (37.6%) reported constant pain, particularly in the limbs, the back, and the head and neck. In another study that assessed the prevalence of chronic pain among CHS members in Israel, 46% of the participants reported chronic pain. Prevalent pain sites were the back (32%), limbs (17%) and head (13%) (28). The mean pain severity reported in this study for any type of pain, neuropathic or nociceptive, was 6.3 ⫾ 2.5
on a scale of 0–10. The pain affected daily activities in general, as well as mood and capacity to ambulate. Data collected in six European countries on neuropathic pain in DM, using the Short-form Brief Pain Inventory, found a mean pain level of 5.0 ⫾ 2.0, with a negative effect on employment in 35%. The severity of pain was associated significantly with a decrease in the general health status, greater pain interference score, lower employment rates, and more physician visits (29). We found that only 1.6% did not report an association between pain and Life Impact Index. Among those who reported that pain did affect their lives, 71.2% reported that the effect was moderate or severe. More patients with neuropathic pain reported constant daily pain (P ⬍ 0.0001) and more severe life impact index score (P ⬍ 0.0001). Strengths and limitations We used the S-LANSS, a self-report instrument, to identify neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at the peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but they require further validation for epidemiological purposes (30,31). The study was conducted in a single geographical area, and a similar study in other areas of Israel or other countries may have yielded different results. However, since DM and pain are worldwide conditions, we believe that our results are likely to reflect the situation around the world. Another study limitation is a potential selection bias related to the low response rate. Our study population included elderly patients interviewed by telephone. In the elderly population there is a high prevalence of pain. It is possible that those DM patients who were unable to answer the questionnaire may have suffered from a higher prevalence of pain. If that is the case our findings
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regarding pain could be an underestimate of the real prevalence. Furthermore, since we used a telephone interview we were unable to locate many patients. Participation rates for epidemiological studies have declined over the past 30 years (32). In a study that compared response rates for postal, Internet and telephone modes of recruitment the highest response rate was for telephone interviews and that was only 27.3% (273 of 1000 contacted) (33).
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Implications In DM patients reporting the same severity of pain, neuropathic pain has a greater negative effect than nociceptive pain. This is probably the reason that it has gained more attention in the medical literature. For this reason, neuropathic pain should be treated more aggressively. Pain is an integral part of DM in many patients and has a significant effect on their quality of life and daily function. Nociceptive pain is reported frequently by DM patients. This study, like others (34,35), shows a gap in the literature and highlights the need for greater awareness of the presence and effect of pain in type 2 DM patients in the primary care setting. This could contribute to a better understanding of painful DM and promote the development of more targeted and effective treatments. Conclusion Clinicians should be aware of the high prevalence of pain of any kind in type 2 DM. Neuropathic pain is constant, worse at night and has a significant impact on daily activities. Decisions on appropriate pain management should be tailored to the nature of the pain (neuropathic or nociceptive). Further research is needed to develop other effective treatment options for neuropathic and nociceptive pain in DM. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. REFERENCES 1. Powers AC. Diabetes mellitus. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. New York: McGraw Hill; 2005. pp. 2153–80. 2. IDF. Diabetes Atlas, 5th edn. Brussels: International Diabetes Federation; 2011. Available at http://www.idf.org/diabetesatlas (accessed 9 September 2013). 3. Marchettini P, Teloni L, Formaglio F, Lacerenza M. Pain in diabetic neuropathy case study: Whole patient management. Eur J Neurol. 2004;11( Suppl. 1):12–21.
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32. Galea S, Tracy M. Participation rates in epidemiologic studies. Ann Epidemiol. 2007;17:643–53. 33. Sinclair M, O’Toole J, Malawaraarachchi M, Leder K. Comparison of response rates and cost-effectiveness for a community-based survey: Postal, internet and telephone modes with generic or personalised recruitment approaches. BMC Med Res Methodol 2012;12:132. 34. Barrett AM, Lucero MA, Le T, Robinson RL, Dworkin RH, Chappell AS. Epidemiology, public health burden, and treatment of diabetic peripheral neuropathic pain: A review. Pain Med 2007;8:S50–62. 35. Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: Epidemiology, natural history, early diagnosis, and treatment options. Pain Med 2008;9:660–74.
Original Article
Chronic pain in type 2 diabetic patients: A cross-sectional study in primary care setting
Orly Liberman1, Roni Peleg2 & Pesach Shvartzman2 Eur J Gen Pract Downloaded from informahealthcare.com by Nyu Medical Center on 02/14/15 For personal use only.
1Nursing
Department, Rekanati School for Community Health Professions, Ben-Gurion University of the Negev, Beer-Sheva, Israel, and Palliative Care Unit, Department of Family Medicine and Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel 2Pain
KEY MESSAGE: · Almost 50% of DM patients reported having pain of predominantly neuropathic origin. · Neuropathic pain is constant, worse at night and has a significant impact on daily activities.
ABSTRACT Background: Although diabetes mellitus (DM) is often associated with painful neuropathic syndromes, a significant number of DM patients suffer from non-neuropathic (nociceptive) pain. Unfortunately, there is insufficient data on the epidemiology of nociceptive pain in DM patients and its effect on their quality of life. Objective: To characterize pain in type 2 DM patients, and assess its effect on their quality of life. Methods: The study population included 342 type 2 DM patients, 18 years of age and above (mean age 70.7 ⫾ 9.7), who reported having pain. The study questionnaires included the Brief Pain Inventory (BPI), the S-LANSS scale to assess pain with neuropathic features, life impact, and socio-demographic data. Results: One hundred and fifty-five DM patients (46.5%) reported having pain of predominantly neuropathic origin. Almost 75% of patients with neuropathic pain were females, compared to 57.8% of patients with nociceptive pain (P ⫽ 0.002). More patients with neuropathic pain reported constant daily pain (57.6% vs. 42.4%, P ⬍ 0.0001), and worse pain during the night (53.3% vs. 46.7%, P ⫽ 0.045). The pain affected daily activities, walking capacity, and mood. Patients with neuropathic pain reported a greater negative effect of pain on their quality of life than those with nociceptive pain (41.0% vs. 15.3%, P ⬍ 0.0001). Conclusion: The impact of neuropathic pain in DM patients is much more significant than nociceptive pain and affects their quality of life and daily function to a greater degree. Keywords: Diabetes mellitus, neuropathic pain, musculoskeletal pain, quality of life
INTRODUCTION The prevalence of diabetes mellitus (DM) in developed countries has increased significantly over recent decades. In the year 2000, the prevalence was estimated to be 8.6% among individuals 20 years of age and above, and as high as 20.1% among individuals 65 years of age and older (1). According to the latest estimates of the International Diabetes Federation in 2012, there were more than 371 million people with DM. By 2030, this number is expected to reach 552 million (2). Various pain syndromes are associated with DM and are an integral part of the disease, contributing to its morbidity and affecting patients’ quality of life. One of
the well-recognized pain types is painful diabetic neuropathy (3). This is a debilitating disorder that occurs in nearly 50% of DM patients (4). However, other types of chronic non-neuropathic pain syndromes, such as frozen shoulder and abdominal pain, have been reported (5). The effect of DM on the musculoskeletal system has received significantly less research attention than its effect on the heart, brain, kidneys, eyes and nerves. Vascular changes in both small and large vessels and metabolic changes related to high blood glucose levels affect the musculoskeletal system. The prevalence of musculoskeletal pain is higher in DM patients than in the general population (6).
Correspondence: Roni Peleg, Department of Family Medicine, Ben-Gurion University, POB 653 Beer-Sheva, Israel, 84105. Tel: ⫹ 972 8 6477436. Fax: ⫹ 972 8 6477636. E-mail: [email protected] (Received 6 March 2013; accepted 7 January 2014) ISSN 1381-4788 print/ISSN 1751-1402 online © 2014 Informa Healthcare DOI: 10.3109/13814788.2014.887674
Chronic pain in diabetic patients The goal of this study was to characterize pain syndromes in type 2 DM patients and assess the effect of pain on patients’ quality of life.
METHODS Study design
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The national health insurance system, implemented in Israel in 1995, provides healthcare to the entire population through non-profit health maintenance organizations (‘sick funds’). The Clalit Health Services, the largest HMO in Israel, insures about 55% of the Israeli population. Selection of study subjects The study population consisted of type 2 DM patients, 18 years of age and above, from four primary care clinics of the Clalit Health Services in the Negev region of Israel. The study population included 2251 type 2 DM patients listed in the four primary care clinics. Patients who agreed to participate were interviewed by nurses by telephone using a structured questionnaire. The interviews were conducted during the years 2006–2009. Only patients who reported pain, of any type, were included in the study. The Helsinki Committee (IRB) of the Soroka University Medical Center approved the study (approval No. 4310).
Measurements and outcomes Study questionnaires included: (a) The Brief Pain Inventory-Short Form (BPI-SF) was used to measure and characterize pain and its interference with the patients’ lives (reactive dimension). The BPI questionnaire includes a rating scale of 0 to 10 to measure pain and the effect of pain on different aspects of daily life (general activity, mood, sleep, relationships with others, and work). This tool was validated in Hebrew for a previous study (7) and has been used as an outcome measure in various clinical trials (8,9). The ‘life impact ’ variable was calculated as the mean of items relating to the effect of pain on life activities. (b) The S-LANSS Pain Scale self-report version is a self-report instrument for identifying neuropathic pain. Its aims are to identify pain of predominantly neuropathic origin, as distinct from nociceptive pain, without the need for clinical examination (10). The S-LANSS is a simple seven-item tool. Each item entails a binary response (yes or no) to the presence or absence of symptoms (five items) or clinical signs (two items). A score of 12 or more suggests pain of predominantly neuropathic origin. In the present
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study, we used the term neuropathic pain for patients suffering from pain of predominantly neuropathic origin. The questionnaires were translated from English to Hebrew using the backtranslation method (11) after which they underwent cultural adaptation. (c) Socio-demographic data. The questionnaire also included questions relating to pain location and duration. Statistical analyses Statistical analyses were performed using the SPSS 17 software. Continuous variables are shown as means and standard deviations. Categorical variables are described as frequencies. T-tests and χ-square tests were used to analyse statistically significant differences between neuropathic and nociceptive pain groups for continuous and categorical variables, respectively. As a result of missing data in the S-LANSS questionnaire, the total S-LANSS score could not be calculated for nine patients, and they were not included in the comparison between the neuropathic and nociceptive pain groups. Two-tailed P-values ⬍ 0.05 with a power of 80% were considered statistically significant. A logistic regression model was constructed to identify associations between patients’ characteristics and the presence of nociceptive pain. The conceptual framework was that age and gender would not be associated with the type of pain. We assumed that patients reported worse pain during the day and a lower effect of pain on daily activities would be reported by patients who suffer from nociceptive pain.
RESULTS Study population The study population included 2251 type 2 DM patients listed in the four primary care clinics. One hundred and sixteen (5.2%) refused to participate in the study; 253 (11.2%) did not speak Hebrew, 180 (8%) had a wrong telephone number listed, 94 (4.2%) were unable to answer a telephone questionnaire (due to mental/physical status), 1 212 (53.8%) could not be located by telephone after several attempts, and 396 (17.6%) agreed to participate in the study. Of the 396 patients who agreed to participate in the study, only 54 (13.6%) did not report any pain. Study population characteristics The final study population consisted of the 342 DM patients who reported having pain. Their mean age was 70.7 ⫾ 9.7 years and 221 (66.4%) were women. Fifty-two
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per cent of the DM patients suffered from nociceptive pain. One hundred and fifty-five participants (46.5%) had neuropathic pain as determined by an S-LANSS score ⱖ 12. Most of these patients (61.4%) reported that the pain was accompanied by strange, unpleasant sensations on the skin like stabbing or tingling. These sensations suddenly appeared like a storm and were paroxysmal in nature. Fifty-five per cent were hypersensitive or felt numbness. Almost 75% of patients with neuropathic pain were women compared with 57.8% of patients with nociceptive pain (P ⫽ 0.002). No other statistically significant differences were found in the socio-demographic characteristics of patients with neuropathic and nociceptive pain (Table 1).
Characteristics of pain in DM patients The BPI questionnaire was used to record the pain characteristics of the study population. Pain was located mainly in the limbs (45%), the back (20%), and the head and neck (13%). The average duration of pain was 77.7 ⫾ 117.6 months (range: 1–816 months). Most patients (73.6%) reported having pain for more than 12 months. Patients who did not report pain were ineligible. Characteristics of patients with neuropathic and nociceptive pain are presented in Table 2. Constant daily pain was reported more by patients with neuropathic pain (57.6% vs. 42.4%, P ⬍ 0.0001). The worst pain was experienced during the night (53.3% vs. 46.7%, ⫽ 0.045). One hundred and thirty-two patients (38.6%) stated that
Table 1. Comparison of socio-demographic characteristics between patients with features of neuropathic and nociceptive pain.
Variable Age in years ⱕ 65 ⬎ 65 Mean ⫾ SD Range Missing Gender Male Female Missing Family status Married Other Missing Country of birth Israel Asia/Africa Eastern Europe (former USSR) Europe, North America, South America South Africa Missing Education Elementary High school Academic Missing Present work status Employed Unemployed Retired Missing How would you define your religiosity? Religious Traditional Secular Missing aDue
Total study populationa
Patients with neuropathic pain
Patients with nociceptive pain
(n ⫽ 333)
(n ⫽ 155)
(n ⫽ 178)
n (%)
n (%)
n (%)
93 (28.7) 231 (71.3) 70.6 ⫾ 9.7 38–98 9
48 (32.0) 102 (68.0) 69.8 ⫾ 10.3 38–98 5
45 (25.9) 129 (74.1) 71.2 ⫾ 9.2 43–89 4
111 (34.3) 213 (65.7) 9
38 (25.2) 113 (74.8) 4
73 (42.2) 100 (57.8) 5
241 (73.9) 85 (26.1) 7
106 (69.7) 46 (30.3) 3
135 (77.6) 39 (22.4) 4
26 (8.0) 135 (41.7) 127 (39.2)
16 (10.5) 62 (40.5) 61 (39.9)
10 (5.8) 73 (42.7) 66 (38.6)
36 (11.1) 9
14 (9.2) 2
22 (12.9) 7
85 (26.9) 163 (51.6) 68 (21.5) 17
44 (30.1) 74 (50.7) 28 (19.2) 9
41 (24.1) 89 (52.4) 40 (23.5) 8
37 (11.6) 64 (20.0) 219 (68.4) 13
17 (11.3) 29 (19.3) 104 (69.3) 5
20 (11.8) 35 (20.6) 115 (67.6) 8
P 0.193
0.002
0.129
0.352
0.408
0.947
0.859 57 (17.3) 156 (47.4) 116 (35.3) 4
25 (16.2) 75 (48.7) 54 (35.1) 1
to missing data in the S-LANSS questionnaire nine patients were excluded.
32 (18.3) 81 (46.3) 62 (35.4) 3
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Table 2. Pain characteristics in DM patients.
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Variable Average pain duration (months) 1–3 4–6 7–12 ⬎ 12 Mean ⫾ SD Range Missing What is the frequency of the pain? Constant Once a day Several times a day Several times a week Once a week or less Missing Is the pain worse during the day or at night? During the day At night Equally aDue
Total study populationa
Patients with neuropathic pain
Patients with nociceptive pain
(n ⫽ 333)
(n ⫽ 155)
(n ⫽ 178)
n
n%
n%
21 23 26 184 77.7 ⫾ 117.6 1–816 79
8 (6.7) 10 (8.3) 14 (11.7) 88 (73.3) 71.2 ⫾ 103.2 1–756 35
13 (9.7) 13 (9.7) 12 (8.9) 96 (71.6) 83.6 ⫾ 129.3 1–816 44
125 30 53 53 70 2
72 (57.6) 12 (40.0) 30 (56.6) 23 (43.4) 17 (24.3) 1
53 (42.4) 18 (60.0) 23 (43.4) 30 (56.6) 53 (75.7) 1
P 0.401
⬍ 0.0001
0.045 115 107 111
43 (37.4) 57 (53.3) 55 (49.5)
72 (62.6) 50 (46.7) 56 (50.5)
to missing data in the S-LANSS questionnaire nine patients were excluded.
DM was the source of their pain, and 33.3% thought there was no specific source. Life impact index The variable ‘life impact ’ was calculated as the mean for items in the BPI questionnaire relating to the effect of pain on life activities. The mean reported pain level was 6.3 ⫾ 2.5 on a scale from 0 to 10. The mean effect of pain on general daytime activity was 5.5 ⫾ 2.9. Pain affected mood (5.5 ⫾ 3.0) and the capacity to walk (5.5 ⫾ 3.1) to a similar degree. Only four of the participants (1.6%) did not report an association between pain and the Life Impact Index. Only 27.3% of patients reported a mild effect on quality of life while 45.1% reported a moderate effect, and 26.1% a severe effect. Patients with neuropathic pain reported a statistically significant higher impact of pain on life activities in all aspects (Table 3). In univariate analyses there was no association between the Life Impact Index and age, occupation, family status, gender, education, country of birth, or religious belief. Logistic regression model for predicting diabetes patients with nociceptive pain A logistic regression model was developed to predict patients’ characteristics associated with features of nociceptive pain (Table 4). The dependent variable was nociceptive pain, determined by an S-LANSS questionnaire score ⬎ 12. The independent variables gender and age, which did not have a statistically significant association
with nociceptive pain, were included in the model for adjustment. The independent variables found to be statistically significant in the model were not having constant pain (OR ⫽ 0.528, 95%CI: 0.322–0.865, P ⫽ 0.011) and lower impact of pain on daily activities (OR ⫽ 0.783, 95%CI: 0.767–0.919, P ⬍ 0.0001). The independent variable, the worst pain during the day, had a borderline statistical significance (OR ⫽ 1.629, 95%CI: 0.984–2.696, P ⫽ 0.058).
DISCUSSION Main findings Almost half of DM patients reported having pain of predominantly neuropathic origin. Most of the patients (73.6%) reported having suffered from pain for more than 12 months. Most patients with neuropathic pain were females. More patients with neuropathic pain reported constant daily pain and worse pain during the night. The pain affected daily activities, walking capacity, and mood. Patients with neuropathic pain reported a greater negative effect of pain on their quality of life. Interpretation of the study results Neural injury that causes neuropathic pain in DM is well recognized and has been reported frequently in the literature while nociceptive pain has received less attention. Diabetes neuropathy affects up to 50% of patients
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Table 3. The effect of pain on daily activity.
Total study populationa
Patients with neuropathic pain
Patients with nociceptive pain
(n ⫽ 333)
(n ⫽ 155)
(n ⫽ 178)
n%
n%
n%
3 (1.20) 69 (27.7) 112 (45.0) 65 (26.1) 84
0 (0) 14 (13.3) 48 (45.7) 43 (41.0) 50
3 (2.1) 55 (38.2) 64 (44.4) 22 (15.3) 34
6.3 ⫾ 2.5 0–10 1
7.1 ⫾ 2.1 0–10 1
5.7 ⫾ 2.5 0–10 –
5.5 ⫾ 2.9 0–10 1
6.4 ⫾ 2.6 0–10 1
4.8 ⫾ 2.9 0–10 –
5.5 ⫾ 3.0 0–10 1
6.2 ⫾ 2.7 0–10 1
4.9 ⫾ 3.2 0–10 –
5.5 ⫾ 3.1 0–10 1
6.2 ⫾ 2.8 0–10 1
4.8 ⫾ 3.2 0–10 –
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Variable Life Impact Index None Mild Moderate Severe Missing In general, how severe is the pain? Mean ⫾ SD Range Missing To what extent does the pain affect daily activities? Mean ⫾ SD Range Missing To what extent does the pain affect your mood? Mean ⫾ SD Range Missing To what extent does the pain affect your ability to walk? Mean ⫾ SD Range Missing To what extent does the pain affect the quantity and quality of your sleep? Mean ⫾ SD Range Missing To what extent does the pain affect your relationships with others? Mean⫾ SD Range Missing To what extent does your pain make you feel a need to rest in bed during the day? Mean ⫾ SD Range Missing To what extent does your pain affect your regular job? Mean ⫾ SD Range Missing To what extent does your pain interfere with sexual relationships? Mean ⫾ SD Range Missing To what extent does your pain interfere with your sexual functioning? Mean ⫾ SD Range Missing aDue
P ⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001
⬍ 0.0001 5.4 ⫾ 3.3 0–10 2
6.5 ⫾ 2.7 0–10 1
4.5 ⫾ 3.5 0–10 – ⬍ 0.0001
3.6 ⫾ 3.1 0–10 2
4.5 ⫾ 3.1 0–10 2
2.7 ⫾ 2.9 0–10 – ⬍ 0.0001
5.4 ⫾ 3.0 0–10 1
6.4 ⫾ 2.5 0–10 1
4.6 ⫾ 3.1 0–10 –
5.1 ⫾ 3.2 0–10 10
6.0 ⫾ 2.8 0–10 5
4.2 ⫾ 3.2 0–10 5
⬍ 0.0001
0.002 5.0 ⫾ 3.6 0–10 75
5.9 ⫾ 3.5 0–10 48
4.4 ⫾ 3.6 0–10 27 0.001
5.1 ⫾ 3.7 0–10 72
5.9 ⫾ 3.6 0–10 48
4.5 ⫾ 3.7 0–10 24
to missing data in the S-LANSS questionnaire nine patients were excluded.
with DM (12). As observed in this study neuropathic pain has a significant impact on function and quality of life in DM, and has a negative effect on patient ’s quality of life. In a study from Turkey, the prevalence of diabetic
neuropathy, determined by clinical examination alone, was 40.4% and increased to 62.2% when nerve conduction studies were added to the clinical examination (13). A small study found that quality of life was significantly
Chronic pain in diabetic patients
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Table 4. Logistic regression model to predict nociceptive pain in DM patients. Variables Age (continuous) Gender Male Female Pain frequency Constant Other Worse pain During the day At night/equally day or night The extent pain affects daily activities (continuous)a
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aScale
Odds ratio
95%CI
P
1.019
0.994–1.045
0.145
1.543 1
0.919–2.591
0.101
0.528 1
0.322–0.865
0.011
1.629 1 0.783
0.984–2.696
0.058
0.767–0.919
⬍ 0.0001
from 0 ⫽ active as usual to 10 ⫽ not active at all.
more impaired among patients with diabetic neuropathy than among patients without it. Patients with diabetic neuropathy had greater impairment in emotional reactions, energy, pain, physical mobility, and sleep (14). In a cross-sectional evaluation of function and healthrelated quality of life in patients with neuropathic pain, the pain intensity on a five-point visual analogue scale was 2.8 ⫾ 1.0. Pain substantially interfered with normal work (5.9, 0 - 10 scale), social activities (5.7), and family life (5.3) (15). Painful diabetic neuropathy was associated with decrements in many aspects of patients’ levels of physical and emotional functioning, and it affected symptoms and sleep. The negative impact was higher in patients with greater pain severity (16). Musculoskeletal pain is more prevalent in DM patients than in the non-diabetic general population (6). The prevalence of frozen shoulder and shoulder joint adhesions ranges from 11–20% among DM patients to 2–10% in the healthy population (17,18). Limited joint function is reported to a range from 8–50% in DM to 0–26% in non-diabetics (19,20). Pain from local inflammation of the palm tendons is ten times more prevalent in DM (21), and a similar ratio was found for carpal tunnel syndrome (22,23). Another typical pain syndrome in the palm is Dupuytren’s contracture, which is also much more prevalent in DM patients (24,25). Degenerative changes in the vertebrae, as in other joints, is more common in DM. Diffuse idiopathic skeletal hyperostosis is particularly prevalent in DM with an incidence rate that reaches 13–49% compared to 1.6–13% in non-diabetics (22,26,27). Over one third of the study population (37.6%) reported constant pain, particularly in the limbs, the back, and the head and neck. In another study that assessed the prevalence of chronic pain among CHS members in Israel, 46% of the participants reported chronic pain. Prevalent pain sites were the back (32%), limbs (17%) and head (13%) (28). The mean pain severity reported in this study for any type of pain, neuropathic or nociceptive, was 6.3 ⫾ 2.5
on a scale of 0–10. The pain affected daily activities in general, as well as mood and capacity to ambulate. Data collected in six European countries on neuropathic pain in DM, using the Short-form Brief Pain Inventory, found a mean pain level of 5.0 ⫾ 2.0, with a negative effect on employment in 35%. The severity of pain was associated significantly with a decrease in the general health status, greater pain interference score, lower employment rates, and more physician visits (29). We found that only 1.6% did not report an association between pain and Life Impact Index. Among those who reported that pain did affect their lives, 71.2% reported that the effect was moderate or severe. More patients with neuropathic pain reported constant daily pain (P ⬍ 0.0001) and more severe life impact index score (P ⬍ 0.0001). Strengths and limitations We used the S-LANSS, a self-report instrument, to identify neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at the peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but they require further validation for epidemiological purposes (30,31). The study was conducted in a single geographical area, and a similar study in other areas of Israel or other countries may have yielded different results. However, since DM and pain are worldwide conditions, we believe that our results are likely to reflect the situation around the world. Another study limitation is a potential selection bias related to the low response rate. Our study population included elderly patients interviewed by telephone. In the elderly population there is a high prevalence of pain. It is possible that those DM patients who were unable to answer the questionnaire may have suffered from a higher prevalence of pain. If that is the case our findings
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regarding pain could be an underestimate of the real prevalence. Furthermore, since we used a telephone interview we were unable to locate many patients. Participation rates for epidemiological studies have declined over the past 30 years (32). In a study that compared response rates for postal, Internet and telephone modes of recruitment the highest response rate was for telephone interviews and that was only 27.3% (273 of 1000 contacted) (33).
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Implications In DM patients reporting the same severity of pain, neuropathic pain has a greater negative effect than nociceptive pain. This is probably the reason that it has gained more attention in the medical literature. For this reason, neuropathic pain should be treated more aggressively. Pain is an integral part of DM in many patients and has a significant effect on their quality of life and daily function. Nociceptive pain is reported frequently by DM patients. This study, like others (34,35), shows a gap in the literature and highlights the need for greater awareness of the presence and effect of pain in type 2 DM patients in the primary care setting. This could contribute to a better understanding of painful DM and promote the development of more targeted and effective treatments. Conclusion Clinicians should be aware of the high prevalence of pain of any kind in type 2 DM. Neuropathic pain is constant, worse at night and has a significant impact on daily activities. Decisions on appropriate pain management should be tailored to the nature of the pain (neuropathic or nociceptive). Further research is needed to develop other effective treatment options for neuropathic and nociceptive pain in DM. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. REFERENCES 1. Powers AC. Diabetes mellitus. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. New York: McGraw Hill; 2005. pp. 2153–80. 2. IDF. Diabetes Atlas, 5th edn. Brussels: International Diabetes Federation; 2011. Available at http://www.idf.org/diabetesatlas (accessed 9 September 2013). 3. Marchettini P, Teloni L, Formaglio F, Lacerenza M. Pain in diabetic neuropathy case study: Whole patient management. Eur J Neurol. 2004;11( Suppl. 1):12–21.
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