Pain Medicine, 0(0), 2020, 1–10

doi: 10.1093/pm/pnz331
Original Research Article

Downloaded from https://academic.oup.com/painmedicine/advance-article-abstract/doi/10.1093/pm/pnz331/5697247 by University of Waterloo user on 09 January 2020

High-Dose Intravenous Immunoglobulin Is Effective in
Painful Diabetic Polyneuropathy Resistant to Conventional
Treatments. Results of a Double-Blind, Randomized,
Placebo-Controlled, Multicenter Trial
Stefano Jann, MD,* Raffaella Fazio, MD,† Dario Cocito, MD,‡ Antonio Toscano, MD,§
Angelo Schenone, MD,¶ Gerolama Alessandra Marfia, MD,k Giovanni Antonini, MD,kj
Luisa De Toni Franceschini, MD,** Anna Mazzeo, MD,†† Marina Grandis, MD,¶ Daniele Velardo, MD,†
Giorgia Mataluni, MD,k and Erdita Peci, MD‡
*Department of Neurology, Niguarda General Hospital, Milan, Italy; †Department of Neuromuscular Disease, San Raffaele Hospital, Milan, Italy;
‡
Department of Neuroscience, University of Turin, Torino, Italy; §Department of Neuroscience, Psychiatry and Anesthesiology, University of Messina,
Messina, Italy; ¶Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genoa,
Italy; kDepartment of Neuroscience, University Tor Vergata, Rome, Italy; kjDepartment of Neuroscience, Mental Health and Sensory Organs, Rome
University “Sapienza,” Sant’Andrea Hospital, Rome, Italy; **Department of Neurology, Alesssandro Manzoni General Hospital, Lecco, Italy;
††
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

Correspondence to: Stefano Jann, MD, Department of Neurology, Niguarda Hospital, Piazza Ospedale Maggiore 3, 20162 Mialn, Italy.
Tel: 0264442348; Fax: 0264442819; E-mail: stefano.jann@gmail.com.

Funding sources: This study was funded by Grifols (Barcelona, Spain), manufacturer of Flebogamma DIF 5%.

Disclaimer: Grifols, the funder of the study, had no role in data interpretation or in the decision to submit the manuscript for publication. Grifols sup-
ported reporting of study results by procuring medical writing assistance. All authors had full access to all data in the study and had final responsibility
for the decision to submit for publication.

Conflicts of interest: The authors state that they have no conflicts of interest.

Abstract
Objectives. The efficacy and safety of high-dose intravenous immunoglobulin (IVIG) in treatment-resistant diabetic
painful polyneuropathy (DPN) were assessed. Design. This was a randomized, double-blind, placebo-controlled, mul-
ticenter trial (EudraCT 2010–023883–42). Setting. This trial was conducted at eight sites in Italy with a neurology spe-
cialist level of care. Subjects. Twenty-six diabetic patients with DPN who reported baseline severity of pain >60 units
(mm) on a VAS scale at enrollment and were resistant to antidepressants and antiepileptic drugs were enrolled;
23 were randomized (11 in the IVIG arm and 12 in the placebo arm). All patients completed the study and were evalu-
ated. All patients were Caucasian, 15 were male, and 21 had a diagnosis of type II diabetes. Methods. IVIG (0.4 g/kg/d)
or placebo was given for five consecutive days. Pain intensity (visual analog scale, Neuropathic Pain Symptom
Inventory) and quality of life (36-Item Short-Form Health Survey, Clinical/Patient Global Impression of Change ques-
tionnaires) assessments were performed at visits: baseline, start of therapy (one week later), end of therapy (five
days later), and follow-up (four and eight weeks later). Results. The study achieved its prespecified primary end point
of 50% pain reduction at four weeks after IVIG, achieved in seven of 11 patients (63.6%) in the IVIG group vs zero of
12 in the placebo group (P ¼ 0.0013). Only two adverse events were reported during the study: one patient in the
treatment arm reported a mild “dermatitis psoriasiform,” whereas one patient from the placebo group reported a
mild “influenza.” Conclusions. Treatment with IVIG at the dose given was efficacious and safe for patients with DPN
resistant to standard therapies.

Key Words: Intravenous Immunoglobulin; Diabetic Painful Polyneuropathy; Clinical Trial; Visual Analog Scale (VAS); Neuropathic Pain
Symptom Inventory (NPSI)

C 2020 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
V 1
2 IVIG for Painful Diabetic Neuropathy
Introduction
Diabetes is the most common cause of neuropathy in pri-
mary care in the Western world, and diabetic neuropathy
(DN) is the most common neurological problem associ-
ated with diabetes [1]. DN is a major cause of disability,
high mortality, and poor quality of life [1]. As the preva-
lence of diabetes increases, so does the prevalence and
morbidity of DN. Although up to 90% of diabetic
patients develop neuropathy [2], only 5.8–34% of DN is
painful [3, 4]. Patients with painful DN (DPN) experi-
ence lower health-related quality of life due to the pain
and its impact on daily functioning in life, and DPN has
an increasing burden in terms of health care costs [5]. To
date, diabetic neuropathic pain represents a therapeutic
challenge because pain relief is often unsatisfactory.
Despite multiple therapies, 50% of DPN remains severe
[6]. Neuropathic pain is multifactorial and incompletely
understood, which is one of the main reasons why its
treatment still represents an unmet need. DN results in
profound alterations in the function of primary sensory
neurons and their central projection pathways. Altered
expression of voltage-gated sodium channels in DRG
neurons and axons, leading to abnormal currents and in-
creased firing of nociceptors, has been found in experi-
mental DPN studies [7, 8]. Recent research suggests that
the immune system may also play a significant role, with
reports of overexpression of tumor necrosis factor alpha
(TNF-a) and other pro-inflammatory cytokines [9, 10].
Many of the cytokines and chemokines that coordinate
the cellular response to nerve injury can directly alter the
sensory transduction properties of nociceptive afferent
axons, upregulating sodium channels and causing ongo-
ing activity [11, 12]. In diabetic painful neuropathy, the
contribution of spinal cord microglia activation to cen-
tral sensitization is emerging as a new concept. Cytokines
released by the microglia can induce central sensitization
via distinct mechanisms. TNF-a enhances the amplitude
of glutamate-induced excitatory currents, and interleu-
kin-1Beta (IL-1b) increases excitatory synaptic
transmission and reduces inhibitory transmission [13].
Streptozotocin (STZ)-induced diabetic rats display an in-
crease in IL-1b and TNF-a expression in the spinal cord
[14, 15].
Intravenous immunoglobulins (IVIGs) are an immune-
modulating blood-derived product. The anti-
inflammatory effect of IVIGs has been the subject of con-
siderable investigation. IVIG putative anti-inflammatory
mechanisms include blockade of the Fc receptor, en-
hancement of antibody catabolism, and the suppression
of pro-inflammatory cytokines [16].
There are many anecdotal reports about rapid and
sustained pain relief in patients with chronic inflamma-
tory demyelinating polyneuropathy (CIDP) treated with
IVIG [17, 18], as well as a few reports supporting the use
of IVIGs in complex regional pain syndrome [19] and
other neuropathic chronic pain conditions [20]. Recently,
we published an open-label trial with IVIG in refractory
neuropathic pain [21]. With this background, it seems
reasonable to consider a possible beneficial effect of IVIG
in DPN. In this study, the efficacy and tolerability of
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IVIG to reduce refractory neuropathic pain in patients
with DPN were assessed.
Methods
Study Design and Objectives
This was a multicenter, randomized (1:1), double-blind,
placebo-controlled phase III clinical trial (EudraCT num-
ber: 2010–023883–42) to assess the efficacy of high-dose
IVIG (Flebogamma DIF 5%, Instituto Grifols, Barcelona,
Spain) for the treatment of patients with DPN resistant
to standard therapies. The primary objective of the study
was to evaluate IVIG efficacy in decreasing the intensity
of neuropathic pain. The secondary objectives were to as-
sess the tolerability of IVIG in the patients taking part in
the study and to assess changes in patient quality of life.
This study was conducted in compliance with a clini-
cal protocol approved by the Ethics Committee of
Niguarda General Hospital in Milan, Italy, regulatory
requirements, good clinical practice (GCP), and the ethi-
cal principles of the latest revision of the Declaration of
Helsinki as adopted by the World Medical Association.
All participants gave written informed consent before
participation in the study.
Patient Population
Patients were recruited from eight different sites in Italy.
The inclusion criteria at baseline were 1) male and female
outpatients aged 18 years; 2) who were willing to pro-
vide written informed consent; 3) with a diagnosis of
DPN of at least six months to a maximum of five years,
confirmed as per the Toronto Diabetic Neuropathy
Expert Group criteria [22]; 4) with intensity of pain 6
points on the visual analog scale (VAS) [23]; 5) with 4
points on the Douleur Neuropathique en 4 Questions
(DN4) questionnaire [24]; and 6) previously treated with
at least two lines of treatments (antidepressants [tricyclic
antidepressant {TCA} or serotonin-norepinephrine reup-
take inhibitor {SNRI}], anticonvulsants [gabapentin or
pregabalin], or opioids) that reached therapeutic doses
but did not obtain satisfactory results (resistance to treat-
ment: decrease in pain of <30% on the evaluation scale)
or who were unable to take conventional therapies due
to intolerable side effects. Paracetamol was the only res-
cue therapy permitted. Patients could continue their pre-
vious ineffective therapies, and they were aware of the
impossibility of modifying the single doses.
The exclusion criteria were 1) any condition that, in
the investigator’s opinion, might invalidate patient par-
ticipation in the study; 2) presence of another type of
pain that might create confusion when evaluating painful
polyneuropathy; 3) having been treated with IVIG in the
Jann et al.
six months before the start of the study; 4) IgA serum
concentration <70 mg/dL; 5) decompensated cardiovas-
cular disease that was not pharmacologically controlled,
renal insufficiency, hepatic insufficiency, severe altera-
tions in blood cell count (leukopenia, thrombocytopenia,
pancytopenia) or psychiatric disturbances; 6) amputa-
tions; 7) pregnancy and lactation; and 8) participation in
other clinical studies during the 30-day period before the
start of this study.
In a second phase of inclusion, patients meeting all the
above-mentioned inclusion and none of the exclusion crite-
ria at baseline were asked to complete the VAS test daily
and record the results in a diary. To be eligible to start the
treatment (Visit 2), patients had to have a mean of 6 cm
on the VAS test in the seven days after the baseline visit
and have completed at least 50% of their diary entries.
Randomization and Masking
Assignment of patients to the treatment groups (IVIG/
placebo) was carried out by means of a randomization
list generated by an independent, unmasked statistical
team at a contract research organization (Sintesi
Research S.r.l.). Block randomization was used to bal-
ance the quantitative asymmetry of patients assigned to
the groups both during and after enrolment. The investi-
gators were not informed about the size of the blocks.
The study was in a double-blind format: Throughout the
study, the patients, physicians, and staff members in-
volved (co-investigators, nurses, laboratory staff) and
assessors did not know which treatment was allocated,
so that they could not be influenced by that knowledge.
The randomization codes were not open until all the data
were entered and the database was sealed, except in the
case of a severe adverse event presumably related to the
treatment product.
Blue opaque bags and yellow infusion kits were used
for the blind procedure. The blue bags had corresponding
labels that specified the patient for whom they were
intended. The blinding procedure was carried out at the
same centers by qualified nurses who checked the drug
vials being dispensed from the pharmacy service and fit-
ted the vials into the blue bags. The nurses were commit-
ted to concealing the identity of treatments from
investigators and patients involved in the study. These
nurses were not otherwise involved in the trial.
Study Procedures and Infusions
The duration of the study was 12 weeks and included five
visits: Visit 1 (baseline), Visit 2 (start of therapy, one
week after Visit 1), Visit 3 (end of therapy, five days after
Visit 2), Visit 4 (follow-up, four weeks after Visit 3), and
Visit 5 (follow-up, eight weeks after Visit 3).
During the baseline visit (Visit 1), eligible patients
meeting all the inclusion and none of the exclusion crite-
ria were randomized (1:1) to either the IVIG-treated
group or the placebo/control group. During this
3
screening visit, the investigators recorded all the informa-
tion regarding patients’ medical/neurological history, as
well as details about personal characteristics (age, sex,
weight, height), duration of DN glucose control, previous
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analgesic therapies, and ongoing therapies for concomi-
tant pathologies.
At Visit 2, patients eligible to start the treatment were
treated with placebo (intravenous [IV] saline) or IVIG.
Regardless of randomization, patients continued taking
other medications at unchanged doses for the remainder
of the study.
Patients enrolled in the IVIG treatment group received
Flebogamma 5% DIF at 0.4 g/kg/d for five consecutive
days (total dose 2 g/kg) in addition to their regular drug
therapy. The study product was infused IV at an initial
rate of 0.01–0.02 mL/kg/min during the first 30 minutes.
If well tolerated (absence of adverse reaction associated
with the infusion), the administration rate was gradually
increased to a maximum of 0.1 mL/kg/min.
Data from the study were recorded by the investigator
in electronic case report forms (e-CRFs) while ensuring
patient anonymization.
Sampling and Pain Testing
Blood samples were drawn at baseline to assess IgA se-
rum concentration (mg/dL).
The following pain intensity and quality of life assess-
ments were performed at every visit: a) VAS [23], b)
Italian version of Neuropathic Pain Symptom Inventory
(NPSI) [25], and c) 36-Item Short-Form Health Survey
(SF-36) [26, 27].
Patients were also asked to complete the VAS scale daily
and record the results in a diary during the window be-
tween Visits 1–2 (seven days, week 1), Visits 2–3 (five days,
week 2), Visits 3–4 (one month, weeks 3, 4, 5, and 6), and
Visits 4–5 (one month, weeks 7, 8, 9, and 10). Throughout
the study, four diaries covering a total of 10 weeks were
handed out to each patient at Visits 1, 2, 3, and 4.
Additionally, at Visits 3, 4, and 5, both the patient
and the physician had to complete the Clinical/Patient
Global Impression of Change (CGIC/PGIC) question-
naires [28].
Efficacy Assessments
The primary efficacy end point was the proportion of
patients with pain reduction 50% of the baseline value.
These changes in pain relief were assessed by VAS scale
as the average of the last seven days registered in the pa-
tient diary before Visit 4 (four weeks after end of ther-
apy) and before treatment (Visit 2).
Secondary efficacy end points were evaluating the in-
tensity of pain (assessed by the VAS scale, taken from
both the patient diary and assessed at each visit); identify-
ing the type of pain using the NPSI questionnaire (overall
score and single question scores), evaluated at the three
control visits; assessing quality of life using the SF-36
4 IVIG for Painful Diabetic Neuropathy
Health Survey questionnaire (by considering the SF-36
modules: physical function, role and physical health,
pain, general health, energy/vitality, social functioning,
role-mental, mental health, and changes in health status);
and evaluating overall clinical judgment, assessed by the
physician and the patient (CGIC/PGIC questionnaire).
The mean VAS results obtained at Visits 3, 4, and 5
for the IVIG-treated and placebo groups were compared
against their corresponding mean VAS scores obtained at
Visit 2. The weekly means of the VAS daily scores were
used to evaluate the pain decrease in each treatment
group, comparing the values obtained during the week
before Visit 4 and Visit 5 with the mean value registered
the last seven days before Visit 2.
The mean NPSI results obtained for each individual
question at Visits 3, 4, and 5 for the IVIG-treated and
placebo groups were compared against their correspond-
ing mean NPSI individual question scores obtained at
Visit 2. Also, the Total NPSI score for each visit was cal-
culated as the sum of the corresponding 12 questions’
(Q1 to Q12) mean scores.
For the SF-36 questionnaire, the influence of the treat-
ment in the nine modules evaluated was assessed: The
mean value per module recorded during Visits 3, 4, and 5
was compared against the specific module results
obtained during Visit 2. Additionally, randomized
patients who received at least one dose of the study drug
were asked to self-assess for each visit their general
health status (HS) as “a little better than one year ago”/
“approximately equal to one year ago”/“a little worse
than one year ago”/“much worse than one year ago.”
The CGIC/PGIC questionnaire was performed during
Visits 3, 4, and 5, and the proportions obtained for each
study arm were evaluated for statistical significance.
Safety Assessments
All adverse events (AEs) occurring for a participating pa-
tient from the first IVIG infusion to the end of the study pe-
riod were registered, along with the number and percentage
of patients with each type of event. The severity of AEs was
classified as “mild,” “moderate,” or “severe” in accordance
with the protocol. Based on the investigator’s opinion, the
relationship of the AE with the study drug was classified as
“not associated,” “improbable,” “possible,” “probable,”
or “definitely related.”
Statistical Analysis
The study was initially planned to enroll 54 patients in
total, to have a 90% power to detect a difference be-
tween the IVIG-treated group and the placebo group at a
significance alpha level of 0.01. However, to compensate
for patients who might drop out, this sample size was in-
creased by 30%; therefore, 70 patients (35 for each study
group) were expected to enroll in the study.
The safety population used for the safety analysis con-
sisted of all enrolled subjects who had received at least
one infusion of IVIG/placebo, whereas the population
used for the efficacy analysis included all enrolled
patients with at least one infusion of IVIG/placebo and at
least one follow-up efficacy analysis.
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For qualitative variables, the absolute number and
proportions are provided. For quantitative variables, the
mean, range, SD of the mean, and 95% confidence inter-
val (CI) of the mean are presented.
For a pain intensity reduction 50% (the primary effi-
cacy parameter), the two treatment groups were com-
pared by chi-square test (Fisher exact test). Moreover,
the mean values of the percent pain reduction of the two
treatment groups were compared using the Wilcoxon
rank-sum test. Secondary efficacy parameters (intensity
of pain as assessed by the VAS scale, SF-36 modules,
NPSI questionnaire) were analyzed as changes vs baseline
values by Wilcoxon rank-sum test at each visit. The over-
all clinical judgment, assessed by the physician and the
patient, of the two treatment groups was compared by
chi-square test.
Statistical significance was set at P  0.05. Analysis
was performed using SAS software, version 9.2 (SAS
Institute Inc., Cary, NC, USA). The contract research or-
ganization (Sintesi Research S.r.l.) oversaw the study and
analyses.
Results
Patients and IVIG Administration
A total of 26 patients were screened at the baseline visit.
Three patients were eligible but failed before starting treat-
ment (Visit 2): One declined to participate, and two did not
meet the additional inclusion criterion (reaching a mean of
6 cm on the VAS test in the seven days after the baseline
visit). The remaining 23 patients were randomized to the
treatment group (N ¼ 11) or the placebo group (N ¼ 12).
All patients completed the study. All patients completed the
study and were evaluated for efficacy and safety. The flow
of patients is shown in Figure 1.
Most patients were male (N ¼ 15, 65.2%), Caucasian
(100%), and had a diagnosis of type II diabetes (N ¼ 21),
with age between 28 and 77 years, weight at baseline be-
tween 63 and 112 kg, IgA level between 70 and 497 mg/
mL, and severity of pain at baseline between 7 and
10 cm. No statistically significant differences between the
treatment and placebo groups were found for baseline
characteristics (Table 1).
Previous analgesic therapies (before screening visit) in
both patient groups included antidepressants (N ¼ 15,
65.2%), opioids (N ¼ 10, 43.5%), and anticonvulsants
(N ¼ 17, 73.9%). One patient (4.4%) in the IVIG group
took nonsteroidal anti-inflammatory drugs (NSAIDs).
During the study, seven patients (63.6%) from the
IVIG group and seven patients (58.3%) from the placebo
group were treated with at least with one concomitant
analgesic therapy (including ongoing medication at base-
line visit): opioids (N ¼ 6, 26.1%, four from the IVIG
Jann et al. 5

Enrolled patients
(n= 26)
Not included (n= 3)
• Screening failure (n= 2)
• Withdrawn consent (n= 1)

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Randomized
(n= 23)

Treatment Placebo
(n= 11) (n= 12)

Discontinued Discontinued
(n= 0) (n= 0)

Completed and Completed and

evaluable evaluable
(n= 11) (n= 12)
Figure 2. Pain–visual analog scale (VAS; cm). Visit assessment.
Figure 1. Flow of patients through the study. Changes vs start of the therapy (Visit 2). N ¼ 11–12 (intravenous
immunoglobulin–placebo); Mean 6 95% confidence interval;
*P < 0.05.
Table 1. Demographics and clinical characteristics at baseline

Characteristics IVIG (N ¼ 11) Placebo (N ¼ 12) group and zero in the placebo group (P ¼ 0.0013). The
Sex, male, No. (%) 7 (63.6) 8 (66.7) mean percent pain decrease at four weeks was significant,
Race, Caucasian, No. (%) 11 (100) 12 (100) in favor of IVIG treatment vs placebo (–44.2% 6 34.5%
Age, median (range), y 63 (32–70) 64 (28–77) vs –5.2% 6 12.0%, P  0.027).
Baseline weight, mean 6 SD, kg 88.4 6 15.7 81.3 6 14.3
Diabetes type I, No. (%) 1 (9.1) 1 (8.3)
Diabetes type II, No. (%) 10 (90.9) 11 (91.7) Secondary Efficacy Analysis
Duration of diabetes, median (range), y 11.5 (1–23) 15 (4–30)
Duration of DPN, median (range), y 2.6 (1–5) 2.4 (0.5–4)
The VAS score values at Visit 2 were 8.7 6 1.1 and
VAS score at baseline, mean 6 SD 8.4 6 1.1 8.9 6 1.1 9.3 6 1.0 for the IVIG and placebo groups, respectively.
IgA, mean 6 SD, mg/dL 181.8 6 114.2 176.5 6 128.0 The score changes with respect to Visit 2 observed in
Medication failures before the study Visits 3–5 are shown in Figure 2. The difference was sta-
Opioids, No. (%); MME 5 (45.5); 60 5 (41.7); 60 tistically significant at Visits 3 (P ¼ 0.032) and 4
Anticonvulsants, No. (%) 7 (63.6) 10 (83.3)
Antidepressants, No. (%) 7 (63.3) 8 (66.7)
(P ¼ 0.048). A similar trend was observed for the VAS
Other drugs, No. (%) 1 (9.1) 0 score change obtained from pain intensity registered in
Cointerventions during the study the patient diary at Visit 4 (–4.20 6 3.32 vs –0.46 6 1.01
Opioids, No. (%); MME 4 (36.4); 60 2 (16.7); 60 for the IVIG and placebo groups, respectively, P ¼ 0.035)
Anticonvulsants, No. (%) 0 6 (51.0) and Visit 5 (–3.66 6 3.43 vs –0.22 6 0.94 for the IVIG
Antidepressants, No. (%) 3 (27.3) 3 (25.5)
Other drugs, No. (%) 6 (54.5) 4 (33.3)
and placebo groups, respectively, P ¼ 0.078).
The NPSI total score values at Visit 2 were 8.6 6 1.4
DPN ¼ diabetic peripheral neuropathy; MME ¼ morphine milligram and 9.0 6 0.6 for the IVIG and placebo groups, respec-
equivalents, average daily dose; VAS ¼ visual analog scale (intensity of pain). tively. The score change with respect to Visit 2 observed
in Visits 3–5 is shown in Table 2. The difference was sta-
group and two from the placebo group), antidepressants tistically significant for all three visits (P ¼ 0.014,
(N ¼ 6, 26.1%, three from each group), and anticonvul- P ¼ 0.002, and P ¼ 0.018, respectively). Regarding the
sants (N ¼ 9, 39.1%, six from the IVIG group and three NPSI single questions, the score change with respect to
from the placebo group). The most widely used nonanal- Visit 2 was statistically significant, in favor of IVIG treat-
gesic concomitant medications were blood glucose–low- ment (Table 2).
ering drugs, excluding insulin, administered in 14 out of The comparison of SF-36 scores evidenced improve-
23 patients (seven patients in both treatment groups), ment in favor of IVIG treatment. For the general health
and insulin and analogues, administered in nine out of 23 module, the score change difference was statistically sig-
patients (four patients in the IVIG group and five in the nificant with respect to Visit 2 in all three subsequent vis-
placebo group). its (P ¼ 0.008 at Visit 3, P ¼ 0.015 at Visit 4, and
P ¼ 0.014 at Visit 5) (Table 3). Regarding the other mod-
Primary Efficacy Analysis ules, pain, mental health, role and physical health,
The number of patients at Visit 4 (four weeks after end mental health, energy/vitality, social functioning, role-
of therapy) with a pain intensity decrease 50% with re- mental, and physical function, at Visit 3 P was nonsignif-
spect to the baseline level was seven (63.6%) in the IVIG icant. At Visits 4 and 5, the score change was statistically
 6 IVIG for Painful Diabetic Neuropathy

0.08 6 0.90
0.17 6 1.03
0.17 6 0.94
–0.33 6 1.07
–0.08 6 1.16
–0.08 6 0.79
–0.17 6 1.40
–0.50 6 1.93
–0.08 6 0.90
0.50 6 1.62
–0.33 6 0.78
–0.08 6 0.90
0.33 6 7.78
Table 2. Neurophatic Pain Symptom Inventory (NPSI). Score change versus Visit 2 (start of the therapy) of Visit 3 (end of therapy), Visit 4 (4-week follow-up) and Visit 5 (8-week follow- significant for all modules (Table 3) except physical func-
tion (nonsignificant at Visit 4) and role and physical

Placebo
health (statistically significant at both Visits 4 and 5).
The SF-36 Change in Health Status survey also

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revealed a statistically significant differences in favor of
IVIG treatment at Visits 3 (P ¼ 0.022), 4 (P ¼ 0.022), and
Visit 5 vs Visit 2

–3.91 6 3.08**

–3.91 6 3.94**

–4.73 6 1.95**
–3.82 6 2.75**
–3.27 6 3.29**
–4.27 6 3.52**
–3.73 6 2.76**
–3.64 6 4.32*

–39.7 6 33.5*
–2.64 6 4.59 5 (P ¼ 0.028) (Figure 3).
–2.64 6 4.50

–1.55 6 1.69
–1.64 6 1.96
Concerning the CGIC/PGIC questionnaires, a statisti-
cally significant difference in favor of IVIG treatment
IVIG

was obtained at all visits in both the physician (Visit 3,

P ¼ 0.013; Visit 4, P ¼ 0.008; Visit 5, P ¼ 0.003) and pa-
tient assessments (Visit 3, P ¼ 0.006; Visit 4, P ¼ 0.010;
–0.75 6 0.97
–0.33 6 0.65
–0.25 6 1.14
–0.67 6 0.65
–0.25 6 1.14
–0.08 6 1.08
–0.75 6 1.48
0.50 6 1.93
–0.67 6 1.44
0.08 6 1.83
0.17 6 0.72
–0.25 6 0.87
–3.58 6 6.26
Visit 5, P ¼ 0.003) (Figure 4).
Placebo

Safety Analysis
Only two AEs were reported during the study: One pa-
tient in the treatment arm reported a mild “dermatitis
Visit 4 vs Visit 2

psoriasiform,” judged by the investigator as possibly re-

–6.00 6 1.95**
–4.91 6 2.59**
–4.09 6 2.66**

–3.72 6 2.41**

–47.9 6 27.0**
–3.64 6 3.23*
–4.00 6 3.35*
–4.18 6 3.34*
–4.18 6 3.52*

–4.82 6 3.09*

–1.73 6 1.49*
–1.91 6 1.58*
–3.91 6 3.05

lated to the study treatment, whereas one patient from

the placebo group reported a mild “influenza,” judged by
IVIG

the investigator as not related to the study treatment

(Table 4).
–1.00 6 0.95
–1.00 6 1.28
–0.83 6 1.19
–1.58 6 1.31
–0.67 6 1.97
–1.25 6 0.75
–0.92 6 1.62
–0.42 6 1.56
–1.25 6 1.54
–0.08 6 1.83
–0.33 6 0.65
–0.25 6 0.62
–9.92 6 11.0

Discussion
Placebo

This is the first randomized, double-blind, placebo-con-

trolled clinical trial exploring the possible beneficial ef-
fect of IVIG in DPN. Even with a relatively small sample
size, our results showed statistically significant improve-
Visit 3 vs Visit 2

–3.73 6 2.69*

–3.27 6 2.45*
–3.73 6 2.49*
–3.73 6 2.76*
–3.64 6 1.96*
–3.00 6 2.32*
–2.73 6 1.74*
–3.18 6 2.79*
–0.42 6 1.62*
–1.45 6 1.29*
–1.36 6 1.29*
–35.4 6 19.2*

ment in favor of IVIG in both primary and secondary

–2.64 6 2.38

outcomes.
All patients were diabetics with a long history of pain-
IVIG

ful neuropathy. According to the Toronto Diabetic

Neuropathy Expert Group, the diagnosis of DPN is a
IVIG ¼ intravenous immunoglobulin; NPSI ¼ Neuropathic Pain Symptom Inventory.

clinical one, which relies on the patient’s description of

9.00 6 0.60
8.42 6 1.62
8.33 6 2.10
8.83 6 0.83
8.17 6 1.64
8.83 6 1.70
9.17 6 1.11
8.17 6 2.08
8.75 6 1.06
8.83 6 1.70
4.83 6 0.39
4.67 6 0.78
96.0 6 12.0

pain, hyperalgesia, and frequently allodynia upon exami-

Placebo

nation [22]. Importantly, all centers involved in this

study had neurologists trained in painful neuropathies.
The primary efficacy end point evidenced that IVIG
was highly effective in decreasing pain intensity in DPN
patients. After treatment, almost two-thirds of patients
8.64 6 1.36
6.73 6 3.47
7.00 6 2.90
8.27 6 1.79
7.91 6 2.21
8.45 6 2.58
8.27 6 2.05
7.18 6 3.34
7.91 6 2.30
8.55 6 1.51
4.73 6 0.47
4.27 6 1.12
87.9 6 20.6

showed that pain intensity decreased by half or more

Visit 2

compared with baseline intensity. All secondary end

IVIG
up). N ¼ 11–12 (IVIG-Placebo); Mean 6 SD

points supported this finding. Information from the NPSI

questionnaire, particularly, allowed discriminating and
quantifying five distinct sorts of pain (Q1, Q2, Q3, Q5,
Q5: Is the pain like an electric shock?

and Q6) and feelings (Q11 and Q12), as well as measur-

Q11: Do you feel pins and needles?
Q2: Is it a sort of tightening pain?

Q4: Spontaneous pain (past 24 h)

Q3: Is it a sort of squeezing pain?

Q8: Pain increased by brushing?

ing changes due to IVIG treatment (Q8 to Q10, in all

Q9: Pain increased by pressure?
Q10: Pain increased by cold?

three questions with very significant improvement).

Q7: Pain attacks (past 24 h)
Q12: Do you feel tingling?
Q6: Is it a stabbing pain?

Response to IVIG was consistent, in contrast to the de-

Q1: Is it a burning pain?

*P < 0.05; **P < 0.01.

scribed heterogeneity in response to duloxetine/pregaba-

lin treatment in patients with DPN, associated with
distinct pain characteristics at baseline [29].
Total score
NPSI Item

The rate of improvement that we observed is one of

the highest in neuropathic pain trials. Moreover, it is un-
usual to reach such significance in this setting (double-
Jann et al. 7

Table 3. Change versus Visit 2 (start of the therapy). Score change versus Visit 2 (start of the therapy) of Visit 3 (end of therapy),
Visit 4 (4-week follow-up) and Visit 5 (8-week follow-up). N ¼ 11–12 (IVIG-Placebo); Mean 6 SD

Visit 2 Visit 3 vs Visit 2 Visit 4 vs Visit 2 Visit 5 vs Visit 2

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SF-36 Item IVIG Placebo IVIG Placebo IVIG Placebo IVIG Placebo
Physical function 30.5 6 24.3 23.8 6 25.8 4.55 6 11.06 –0.83 6 19.4 4.6 6 11.1 –0.8 6 19.4 30.9 6 27.4* –2.08 6 30.5
Role and physical health 9.09 6 23.1 0.00 6 0.00 15.9 6 32.2 0.00 6 0.00 15.9 6 32.2 0.00 6 0.00 54.6 6 49.8 10.5 6 29.1
Pain 7.7 6 13.2 5.50 6 9.95 18.3 6 16.4 5.25 6 8.30 18.3 6 16.4** 5.25 6 8.30 45.6 6 27.7** 2.42 6 5.96
General health 14.1 6 17.3 9.875 6 15.2 16.2 6 13.6** 0.67 6 7.50 16.2 6 13.6* 0.67 6 7.50 40.8 6 34.8* –0.83 6 8.21
Energy/vitality 33.2 6 10.6 35.0 6 12.6 9.09 6 9.17 6.25 6 13.0 9.09 6 9.17** 6.25 6 13.0 20.0 6 18.2* 2.08 6 8.38
Social functioning 17.1 6 33.7 11.5 6 18.8 12.5 6 18.5 6.25 6 11.3 12.5 6 18.5* 6.25 6 11.3 43.2 6 43.4* 4.17 6 17.1
Role-mental 9.09 6 15.6 16.7 6 33.3 9.09 6 39.7 0.00 6 14.2 9.09 6 39.7* 0.00 6 14.2 66.7 6 51.6* 5.56 6 13.0
Mental health 32.0 6 10.3 34.0 6 11.0 10.6 6 13.5 0.17 6 8.29 10.6 6 13.5** 0.17 6 8.29 32.0 6 10.3* –2.67 6 9.08

IVIG ¼ intravenous immunoglobulin; SF-36 ¼ 36-Item Short-Form Health Survey.

*P < 0.05; **P < 0.01.

100
* * *

80 Much better
Percentage

A little better
60
Approximately equal

40 A little worse
Much worse
20

0
Treatm ent: IVIG Plac IVIG Plac IVIG Plac IVIG Plac IVIG Plac
Visit: 1 (baseline) 2 3 4 5

Figure 3. Thirty-Six-Item Short-Form Health Survey. Change in health status (intravenous immunoglobulin [IVIG]–placebo). For
Visits 1 and 2, patients were asked to self-assess their general health status as “a little better than one year ago”/“approximately
equal to one year ago”/“a little worse than one year ago”/“much worse than one year ago” (see the Methods section). Percentage
of patients; N ¼ 11–12 (IVIG-placebo); *P < 0.05.

100
* ** ** ** * **

80 Much improved
Percentage

Moderately improved
60
Slightly improved

40 No changes
Slightly worsened
20

0
IVIG Plac IVIG Plac IVIG Plac IVIG Plac IVIG Plac IVIG Plac
Tratment:
Visit: 3 4 5 3 4 5

Assessment: By physician By patient

Figure 4. Overall clinical judgment. Physician and patient assessment (intravenous immunoglobulin [IVIG]–placebo). Percentage of
patients; N ¼ 11–12 (IVIG-placebo); *P < 0.05; **P < 0.01.

blind clinical trials in painful neuropathy). In reporting a
recent systematic review and meta-analysis of pharmaco-
logic therapies for DPN that included 58 studies and
11,883 patients, Snedecor et al. [30] observed that de-
spite the large number of treatments available, the rela-
tive equivalence of their treatment effects means that
“the best treatment is only slightly better than the
worst.”
We are aware that a significant P value does not al-
ways have clinical relevance or mean that the trial is posi-
tive. A limitation of this trial was that the recruitment
target was not met due to extremely selective inclusion
8 IVIG for Painful Diabetic Neuropathy
Table 4. Adverse events
Treatment Group Adverse Event
IVIG Dermatitis psoriasiform (N ¼ 1)
Placebo Influenza (N ¼ 1)
criteria, and this can be considered a weakness of the
study. The main problem for enrollment was the absence
of renal involvement. Nevertheless, enrolled patients
were all resistant to conventional treatments or com-
plained of intolerable side effects. They had poor quality
of life and were exhausted by intractable pain.
Additionally, intensive glucose control was not requested
for enrolled patients. Although strong evidence impli-
cates poor glycemic control as a pathogenic mechanism
in the etiology of DN, there is no proof from randomized
controlled trials that this is the case for pain symptom-
atology [31, 32] To our knowledge, controlled clinical
trials to demonstrate whether intensive diabetes therapy
improves extant DPN have not yet been published.
One noteworthy point was that the placebo effect was
less evident than expected. In the inactive arm, there was
only a 10% pain reduction, while 30% was expected
[33]. A possible explanation is that all patients had previ-
ous ineffective participation in several clinical trials, they
had severe pain unresponsive to therapies, and they had a
negative attitude towards other trials. In this setting, a
possible nocebo effect could be expected. The same evi-
dence has been described in a meta-analysis of chronic re-
gional pain syndrome clinical trials [34].
How can we explain these results? Many researchers
have proposed a new direction for the pathogenesis of
diabetic neuropathic pain. Multiple preclinical [35] and
clinical [36] studies demonstrate a pathogenic role for
inflammation, especially cytokine and chemokine pro-
duction, in the development of DPN. Accumulated evi-
dence suggests that proinflammatory cytokines and
chemokines play a part in the pathogenesis of neuro-
pathic pain. The expression of proinflammatory cyto-
kines such as IL-1b, TNF-a, and IL-6 (which are
upregulated in peripheral nerve injury) elicits the inflam-
matory process and subsequently elicits neuropathic
pain [9, 10, 12, 37–39].
Overexpression of pro-inflammatory cytokines can
upregulate sodium channels Nav 1.3 and 1.8. In He
et al., perisciatic administration of recombinant rat TNF-
a (rrTNF) without any nerve injury was shown to pro-
duce lasting mechanical allodynia and to upregulate
Nav1.3 and Nav1.8 in DRG neurons in vivo, and rrTNF-
a was also shown to enhance the expression of Nav1.3
and Nav1.8 in cultured adult rat DRG neurons in a dose-
dependent manner. Furthermore, inhibition of TNF-a
synthesis, which has been demonstrated to prevent neu-
ropathic pain, strongly inhibited the upregulation of
Nav1.3 and Nav1.8 [12]. Randomized controlled trials
are currently ongoing to investigate further the prelimi-
nary evidence that IgG may be an effective treatment for
Severity Relation with Study Product
Mild Possible
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Mild No relation
some chronic pain conditions. IVIG can significantly re-
duce pro-inflammatory cytokine levels. Sharief et al. [40]
showed that in patients with Guillain-Barre syndrome,
TNF-a and IL-1b decreased on day 3 and significantly by
day 5 after IVIG infusion. IL-10 and IL-2 were not af-
fected by IVIG treatment. Other researchers have con-
firmed this evidence in patients with post-polio syndrome
and Guillain-Barre syndrome [41, 42]. Reducing pro-in-
flammatory cytokine levels can downregulate sodium
channels’ expression and induce pain relief. The possibil-
ity that IVIG treatment has a normalizing effect on mem-
brane potential, reflecting modulation of Naþ currents,
has been speculated to explain the rapid course of clinical
improvement after IVIG treatment in some CIDP patients
[43]. In these patients, the rapid course of clinical im-
provement after IVIG treatment would be more sugges-
tive of a change in axonal function (e.g., related to ion
channel properties) than of structural change. Moreover,
all these possible mechanisms of action can explain an ef-
fect of IVIG on pain that is unusual for an analgesic
drug: With onset generally after two to three days, the
maximal effect, achieved by three to five days, can be
dramatic, including on “soft symptoms” such as sleep,
fatigue, general malaise [19].
We had no significant side effects in our patients, even
at the dose of 2 g IVIG/kg. This was probably related to
the administration of a 5% concentration of immunoglo-
bulins over five days, in addition to the good safety profile
of IVIG, including in patients with neurologic diseases.
In conclusion, treatment with IVIG was deemed effi-
cacious and well tolerated for patients with DPN resis-
tant to standard therapies. The present study was
designed as a randomized, double-blind, placebo-con-
trolled clinical trial. It confirms previous data concerning
significant pain relief with IVIG in patients with DPN re-
sistant to standard therapies. Further investigations are
necessary to confirm our data. More patients need to be
enrolled. We hope to involve more centers worldwide for
a larger clinical trial.
Acknowledgments
Jordi Bozzo PhD, CMPP (Grifols), is acknowledged for med-
ical writing assistance and editorial support in the prepara-
tion of this manuscript, under the direction of the authors.
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