DOI: 10.1111/papr.

13308

EVIDENCE -BASED REVIEW

Update of evidence-based interventional pain medicine according to clinical diagnoses

4. Painful diabetic polyneuropathy

Xander Zuidema MD, PharmD1,2 | Bastiaan de Galan MD, PhD3,4,5 |

Brigitte Brouwer MD, PhD1 | Steven P. Cohen MD6 | Sam Eldabe MB, ChB,
FFPMRCA7 | Charles E. Argoff MD8 | Frank Huygen MD, PhD, FIPP9,10 |
Jan Van Zundert MD, PhD, FIPP1,11

1
Department of Anesthesiology and Pain Abstract
Medicine, Maastricht University Medical
Centre, Maastricht, The Netherlands
Introduction: Pain as a symptom of diabetic polyneuropathy (DPN) significantly
2
Department of Anesthesiology and Pain
lowers quality of life, increases mortality and is the main reason for patients with
Management, Diakonessenhuis Utrecht/ diabetes to seek medical attention. The number of people suffering from painful
Zeist, Utrecht, The Netherlands diabetic polyneuropathy (PDPN) has increased significantly over the past decades.
3
Division of Endocrinology, Department of Methods: The literature on the diagnosis and treatment of diabetic polyneuropathy
Internal Medicine, Maastricht University
Medical Centre, Maastricht, The
was retrieved and summarized.
Netherlands Results: The etiology of PDPN is complex, with primary damage to peripheral
4
CARIM School for Cardiovascular nociceptors and altered spinal and supra-spinal modulation. To achieve better
Diseases, Maastricht University, patient outcomes, the mode of diagnosis and treatment of PDPN evolves toward
Maastricht, The Netherlands
5
more precise pain-phenotyping and genotyping based on patient-specific
Department of Internal Medicine,
Radboud University Medical Centre,
characteristics, new diagnostic tools, and prior response to pharmacological
Nijmegen, The Netherlands treatments. According to the Toronto Diabetic Neuropathy Expert Group, a
6
Department of Anesthesiology, Pain presumptive diagnosis of “probable PDPN” is sufficient to initiate treatment.
Medicine Division, Johns Hopkins School Proper control of plasma glucose levels, and prevention of risk factors are essential
of Medicine, Baltimore, Maryland, USA
7
in the treatment of PDPN. Mechanism-based pharmacological treatment should be
Department of Pain Medicine and
Anesthesiology, Durham University,
initiated as early as possible. If symptomatic pharmacologic treatment fails, spinal
Durham, UK cord stimulation (SCS) should be considered. In isolated cases, where symptomatic
8
Department of Neurology, New York pharmacologic treatment and SCS are unsuccessful or cannot be used, sympathetic
University School of Medicine, and Pain lumbar chain neurolysis and/or radiofrequency ablation (SLCN/SLCRF), dorsal
Management Center, North Shore University
Hospital, Manhasset, New York, USA
root ganglion stimulation (DRGs) or posterior tibial nerve stimulation (PTNS)
9
Department of Anesthesiology and Pain
may be considered. However, it is recommended that these treatments be applied
Management, Erasmus Medical Centre, only in a study setting in a center of expertise.
Rotterdam, The Netherlands Conclusions: The diagnosis of PDPN evolves toward pheno-and genotyping and
10
Department of Anesthesiology and Pain treatment should be mechanism-based.
Management, University Medical Center
Utrecht, Utrecht, The Netherlands
11
Department of Anesthesiology,
K EY WOR DS
Intensive Care, Emergency Medicine and anti-neuropathic drugs, evidence-based medicine, neuropathic pain, painful diabetic
Multidisciplinary Pain Center, Ziekenhuis polyneuropathy, spinal cord stimulation
Oost-Limburg, Belgium

Correspondence
Jan Van Zundert, Department of
Anesthesiology, Intensive Care, Emergency
Medicine and Multidisciplinary Pain
Center, Ziekenhuis Oost-Limburg,
Bessemersstraat, 478 3620 Genk/Lanaken,
Belgium.
Email: [email protected]

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.

308 | 
wileyonlinelibrary.com/journal/papr Pain Practice. 2024;24:308–320.
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ZUIDEMA et al.     | 309

I N T RODUC T ION past decade, the number of people suffering from PDPN
has increased commensurately.19
This narrative review-update on painful diabetic poly- Although uncommon, poor glycemic control in type 1
neuropathy (PDPN) is part of the series “Update of diabetes can lead to PDPN within a few months.20 After
Evidence-based Interventional Pain Medicine accord- re-stabilization with strict glucose control, PDPN seems
ing to clinical diagnoses.” The first review of this guide- to be reversible in type 1 diabetes.21 In type 2 diabetes,
line series was published by Pluijms et al. in 2011.1 This optimization of glucose control does not seem to reduce
article adds a review of the literature from 2010 through pain.22 Chronification of PDPN is therefore more com-
2023. mon in type 2 DM.21,22
According to the ICD-11 systematics, PDPN is classi- DPN develops in about 50% of all people with diabe-
fied as chronic neuropathic pain (first level) of peripheral tes, about half of whom develop neuropathic pain. Why
origin (second level) caused by polyneuropathy (third half develop pain and the other half do not, is not clear
level).2,3 The definition of PDPN comes from an amalga- but almost certainly involves pathoanatomical and phys-
mation of the definitions of chronic (neuropathic) pain iological differences as well as genetic and psychosocial
and diabetic polyneuropathy.4–6 Consequently, PDPN reasons, similar to other chronic pain conditions.16,21
can be defined as the clinical presence of symptoms and/ Cross-sectional studies shown that there are a few dif-
or signs, including pain, of dysfunction in the somato- ferences in risk factors between DPN and PDPN. The
sensory system attributed to diabetes mellitus.6,7 Recent most consistent objective finding is that PDPN is associ-
insights into the onset of chronification of neuropathic ated with more profound sensory loss than DPN.4 Risk
pain in diabetes show influences of both peripheral and factors for developing PDPN include: (1) longer disease
central mechanisms.6,8 Furthermore, neuropathic pain duration; (2) female gender; (3) dyslipidemia; (4) exis-
has been reported to occur between 4% and upwards of tence of other complications of DM; (5) obesity; (6) older
40% in at a prediabetic stage.9,10 These two findings raise age; (7) smoking; (8) high alcohol intake; (9) HbA1C lev-
the question whether PDPN should be seen as a disease els; (10) sensory phenotype and severity of neuropathy;
entity “in its own right” or exclusively as part of a di- (11) genotype (tetrodotoxin sensitive sodium channels
abetic peripheral polyneuropathy spectrum.11 For this NaV1.3, NaV 1.7, NaV 1.8, and NaV1.9, elevated levels of
article, the latter view was adapted. miR-146a, miR-98, and miR-155); (12) increased serum
levels of TNF-alpha and other inflammatory cytokines
and chemokines; (13) increased methylglyoxal (MGO)
M ET HOD OL OGY (activation TRPA1 and NaV1.8); (14) decreased serum
Vitamin D; (15) decreased blood flow (increased hypox-
This narrative review is based on the article “Diabetic ia-inducible factor 1-alpha (HIF 1α) and von Willebrand
polyneuropathy” published in 2011.1 In 2015, an inde- factor (vWF).6,21,23–27
pendent company, Kleijnen Systematic Reviews (KSR), Although the complex pathogenesis of PDPN is not
performed a systematic review of the literature for the fully understood, different pathophysiological mech-
period 2009–2015, based on existing systematic reviews anisms have been hypothesized (Figures 1 and 2).
(SRs) and randomized controlled trials (RCTs).12,13 For Hyperglycemia has traditionally been considered a
the current article an updated search was conducted for major determinant of diabetic neuropathy. A complex in-
the period 2015–2022, using “diabetic neuropathies” and teraction of genetic, sensory phenotypic, psychological,
“painful” and “diagnosis” associated with individual in- and metabolic factors such as: (1) promotion of polyol
terventional pain management techniques, in this case metabolism, (2) promotion of production of advanced
“spinal cord stimulation” or “sympathetic” Additionally, glycation end products (AGEs), (3) increase in free rad-
the authors could select relevant missing articles based icals, (4) decrease in NO levels, and (5) promotion of
on PubMed, Google, and reference list searches. protein kinase C (PKC) activity, are postulated to play
a crucial role.28,29 Preclinical studies on the pathogen-
esis of PDPN show that oxidative stress is consistently
E PI DE M IOL OGY A N D associated with the release of inflammatory cytokines
PAT HOPH YSIOL OGY (ie, TNF-⍺ and IL-1β production after p38-MAPK and
PKC pathway activation). Neuropathic pain can occur
Depending on the diagnostic criteria, estimates on the because sorbitol accumulation in nerve cells causes en-
prevalence of PDPN ranges from 8% to 26%.6,10,11,14–17 dothelial changes, which in turn leads to a decrease in
Pain as a symptom of diabetic polyneuropathy (DPN) microvascular integrity at the dorsal horn and terminal
significantly lowers quality of life, increases 10-year axon. Damage occurs at the level of peripheral axons,
mortality and is the main reason for patients to seek associated Schwann cells, and the neuron perikarya in
medical attention.6,10,11,18 As the prevalence of diabetes dorsal root ganglia (DRG). Microvascular alterations,
mellitus has increased dramatically worldwide over the such as structural and functional abnormalities of the
 15332500, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/papr.13308 by Instituto Aragones De Ciencias, Wiley Online Library on [03/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
310 |    PAINFUL DIABETIC POLYNEUROPATHY

F I G U R E 1 Pathophysiological mechanisms leading to painful diabetic polyneuropathy (PDPN).6 AGE, advanced glycation end-products;
HIF-1α, hypoxia inducible factor 1α; NaV1,8, voltage-gated sodium ion channel subtype 1,8; PKC, Protein kinase C; TRPA1, transient receptor
potential channel ankyrin 1; VGSC, voltage-gated sodium channels; vWF, von Willebrand factor.

F I G U R E 2 DM induced alterations in de sensory nervous system contributing to painful diabetic polyneuropathy (PDPN).6 AGEs,
advanced glycation end products; ROS, reactive oxygen species.

vasa nervorum (in the skin) and altered regulation of DI AGNO SI S

peripheral blood flow (involving HIF-1α and vWF) are
associated with PDPN.6,21 Metabolic derangements, History
such as toxicity caused by elevated levels of triglycerides,
cholesterol, and other compounds may also contribute From a clinical point of view, a thorough history and
to nerve damage, though the precise relationship is still physical examination are crucial to associate the pa-
being elucidated.30 Diabetes structurally and function- tient's pain to an abnormality of the somatosensory nerv-
ally affects spinal, somatomotor, limbic (increased ce- ous system, as well as to distinguish it from other pain
rebral blood flow in the anterior cingulate), thalamic, components (nociceptive and nociplastic).6,35 Among
ascending, and descending modulatory systems as well the various neuropathies that can complicate diabetes,
as higher brain centers (somatomotor cortex and insula distal symmetric polyneuropathy is the most common,
atrophy).11,31,32 Peripheral neurons are damaged and accounting for greater than 75% of cases.16 Motor, au-
show altered expression of voltage-gated sodium, potas- tonomic, inflammatory neuropathies are also seen in
sium, and calcium channels.33 Greater corneal nerve loss patients with diabetes. Figure 3 shows other DM-related
at the inferior whorl has also been observed in patients neuropathies which can also cause pain.
with painful compared to painless DPN.34 In summary, The symptoms of (P)DPN usually occur first in
recent research shows that the entire sensory nervous the feet and gradually spread, which can be explained
system is targeted by diabetes, leading to (P)DPN. by the pathophysiological phenomena in which the
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ZUIDEMA et al.     | 311

FIGURE 3 DM-related neuropathies.4

FIGURE 4 Course of PDN with increase in severity.4

longest, most vulnerable nerves are damaged first. This sensations of heat or cold in the feet, persistent aching
is also called length-dependent diabetic polyneuropathy sensations in the feet, and spasmodic feelings in the legs.
(LDDP). This is followed by shorter fibers innervating Pain exacerbated by walking is often described as “walk-
the extremities, and in extreme situations, the trunk can ing barefoot on marbles” or “walking barefoot on hot
also be affected (Figure 4). sand,” attacks of shooting pain also occur.11 If the pain is
The Toronto Diabetic Neuropathy Expert Group has tolerable, variations in sensitivity can often be identified
defined minimal diagnostic criteria for DPN and PDPN making the diagnosis of diabetic polyneuropathy likely,
(Figure 5).36 Patients suffering from PDPN typically especially when this is associated with trophic disorders
complain of progressive unpleasant sensory sensations and poor wound healing. Recovery of sensory distur-
that are most pronounced at night. These sensations bances cannot be expected once loss of small fibers has
include tingling (paresthesias), burning pain, shooting occurred.37,38
pains (like “electric shocks”) in the legs (and later in the Various general questionnaires have been developed
hands / arms), “stabbing or knife-like” pains, evoked for the qualification and quantification of neuropathic
pain, often with clothing and bedding (allodynia), pain, including The Neuropathic Pain Questionnaire, The
 15332500, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/papr.13308 by Instituto Aragones De Ciencias, Wiley Online Library on [03/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
312 |    PAINFUL DIABETIC POLYNEUROPATHY

F I G U R E 5 Hierarchical structure of diagnosing PDPN according to The Toronto Diabetic Neuropathy Expert Group.16,36 DN, diabetic
neuropathy. (1) Possible DPN: symptoms or signs of DPN. (2) probable DPN: a combination of symptoms and signs including two or more
of the following: neuropathic symptoms, decreased distal sensation or decreased/absent ankle tendon reflexes. (3) confirmed DPN: an
abnormality of nerve conduction and symptom(s) or sign(s) of neuropathy; if nerve conduction is normal, an established attribute measure of
small fiber neuropathy might be used. (4) subclinical DPN: absence of signs/symptoms with concomitant abnormal nerve conduction studies
(NCS) or an established attribute of small fiber neuropathy.

McGill Pain Questionnaire, The Brief Pain Inventory, Additional tests

Pain Detect, The Leeds Assessment of Neuropathic
Symptoms and Signs (LANSS), Douleur Neuropathique In general, additional tests are not necessary in the diag-
4 questionnaire (DN4), and the Neuropathic Pain nosis of PDPN. The level “probable PDPN” (history and
Symptom Inventory.4,39 The sensitivity and specificity of physical examination) according to the Toronto Diabetic
these screening tools are around 80–85% but were vali- Neuropathy Expert Group is considered sufficient to ini-
dated before formalization of the category of nociplas- tiate treatment.4,6
tic pain which shares many overlapping variables. Such However, in science, additional tests are often used
questionnaires can be used as screening tools for neuro- for a better understanding of the pathophysiology of (P)
pathic pain, but since they can miss up to 20% of cases of DPN or to help develop diagnostic and/or prognostic
neuropathic pain, they cannot be used to exclude PDPN tools. Potential candidates for additional tests are briefly
and therefore cannot replace a comprehensive history elaborated below.
and physical examination.4,6 In instrument validation
studies, physician designation is always considered the
reference standard. Nerve conduction and direct nerve imaging

Several diagnostic tests are available for (P)DPN and

Physical examination neuropathic pain in general.
These tests include skin biopsies with quantifica-
Proper neurological evaluation is important as part of tion of intra-epidermal and dermal nerve fiber density
the additional clinical examination. The neurological (IENFD), measurements of small nerve fibers in the
examination should include: (1) examination of all quali- cornea using corneal confocal microscopy (CCM), and
ties of somatosensory function, taking symmetry and a assessment of neurogenic flare with laser Doppler as a
distal-proximal gradient into account; (2) reflexes; and measure of small nerve fiber (C-fiber) function. CCM
(3) muscle strength.4 Acceptable reliability for the detec- shows greater corneal nerve loss at the inferior whorl
tion of nerve fiber deterioration was found with the vi- in patients with painful compared to painless DPN.34
bration perception threshold (VPT) (performed with a There are also assessments of sudomotor function and
biothesiometer, neurothesiometer, or maxivibrometer), quantitative sensory tests (QST). With QST, thermal
ankle reflexes, and the four-site monofilament test.40 A and mechanical detection of pain thresholds, vibration
128 Hz tuning fork is not considered a suitable instru- thresholds, dynamic mechanical allodynia, wind-up
ment for screening and monitoring of (P)DPN because of ratio, and pressure pain threshold can be investigated.16
the wide range in reported reliability and only moderate These different tests measure the function of Aβ, Aδ
diagnostic capability.40 (cold sensing), and C (heat sensing) fibers. It has been
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ZUIDEMA et al.     | 313

suggested that alterations in the processing of noci- Radiological diagnostics

ceptive signals occur in the pain modulatory system of
the central nervous system, resulting in decreased in- MRI studies show that people with PDPN in combina-
hibition, and increased amplification in patients with tion with sensory function loss have a reduced volume of
PDPN. This can be evaluated with dynamic QST mea- spinal cord neurons and primary somatosensory cortical
sures (such as conditioned pain modulation and tem- gray matter compared with patients with painless DPN.
poral and special summation).38 In QST, mechanical Furthermore, patients with PDPN at rest appear to have
hyperalgesia and temporal summation may indicate greater vascularity in the posterolateral nucleus of the
central sensitization, while heat hyperalgesia suggests thalamus (VPL) with increased cerebral blood flow com-
a predominance of peripheral sensitization.41 Although pared to diabetic patients without DPN and painless
highly subjective and time consuming, QST may be DPN.11,38 This suggests that hypervascularity in the VPL
particularly useful in patients suspected of having (P) is present in patients with painful DPN, whereas hypo-
DPN with normal nerve conduction studies (NCS) or vascularity in the thalamus is a feature in patients with
when definitive quantitative structural assessment of painless DPN.11
small nerve fibers (skin biopsy or CCM) cannot be fMRI studies have reported an increased blood-ox-
performed.39 QST can help cluster phenotypes of neu- ygen-level dependent (BOLD) response in PDPN com-
ropathic pain conditions and has been used to predict pared with painless DPN.31 Areas identified included the
response to different treatments.42,43 anterior cingular cortex (ACC), medial thalamus, ante-
Small fiber impairment precedes large fiber impair- rior insula, sensory cortices, and lentiform nucleus.
ment, suggesting that small fiber testing, by skin biopsy, (f)MRI and spectroscopic studies show (1) differences
could be appropriate for early screening and treatment. in the cross-sectional area of the spinal cord, particu-
Although most studies have demonstrated a relation- larly in subclinical DPN; (2) volumetric differences and
ship between pain and morphological and functional spectroscopic density of sections differences indicative
markers IENFD, some have not.31 Moreover, whether of parenchymal atrophy in the primary sensory cortex;
loss of intraepidermal nerve fibers merely serves as a (3) hyperperfusion in painful DPN and hypoperfusion
biomarker for disease burden or can actually cause pain in painless DPN in the thalamus; (4) neurochemical
remains unknown. Due to a lack of robust evidence on changes indicative of abnormal neuronal thalamic func-
their added value, QST, CCM, and skin biopsy are not tion; (5) changes in GABA-Glx spectral resonances and
yet recommended for routine use by international guide- the excitatory-inhibitory neurotransmitter balance; and
lines but only for consideration in patients in whom the (6) complex variability in the BOLD response to an ex-
diagnosis of (P)DPN is unclear.21,44 ternal painful stimulus in DPN. Although (f)MRI and
spectroscopy techniques have great potential in reveal-
ing the nature of CNS involvement in PDPN, current use
Biomarkers is limited to research settings.11

Biomarkers may be used to facilitate diagnosis, as sur-

rogate outcome measures, and to identify treatment Differential diagnosis
responders. For (P)DPN, biomarkers can be roughly
divided into four groups: (1) AGE-related molecules The diagnosis of PDPN is usually made based on sen-
(methylglyoxal and glyoxalase I) as causative agents of sory, motor, and autonomic clinical symptoms. There is
(P)DPN, (2) molecules that participate in the progres- much clinical overlap between different causes of pain-
sion of inflammation (e.g. Toll-like receptors, TNF-α, ful polyneuropathy.46 The presence of diabetes makes
miR-146a, adiponectin) (3) molecules associated with the diagnosis of polyneuropathy resulting from diabetes
nerve damage (nerve-specific enolase and semaphorin) very likely.
and (4) molecules involved in nerve protection (nerve However, painful polyneuropathy has many other
growth factor and HSP27).28 Biomarkers from groups etiologies including alcohol abuse, uremia, hypo-
2–4 manifest at a later stage of disease progression. thyroidism, monoclonal gammopathy, vitamin B12
Of all biomarkers, TNF-α might be the most promis- deficiency, peripheral arterial disease, cancer, inflam-
ing.26,45 Indeed, higher serum TNF-α levels have been matory or infectious diseases, neurotoxic drugs, and
found in patients with DPN as compared to patients others. More than one etiology can be present in a
without DPN, as well as in patients with PDPN as com- person with painful polyneuropathy. Additional lab-
pared to those with painless DPN.26 Although promis- oratory testing to establish differential diagnosis and
ing, biomarkers are not routinely used in the diagnosis rule out non-diabetic causes should include a complete
of PDPN.28 blood count, serum creatinine, C-reactive protein,
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314 |    PAINFUL DIABETIC POLYNEUROPATHY

thyroid-stimulating hormone, vitamin B12, folic acid, Symptomatic pain treatment

and liver enzymes.47 Specific differentiation from toxic The goal of pharmacological treatment of neuropathic
forms of painful polyneuropathy is important, because pain in general, and thus also in PDPN, is to reduce
of potential reversibility upon cessation of exposure to peripheral sensitization, ectopic activity, and central
the causative toxin. sensitization to include brain and spinal cord amplifica-
tion of nociceptive signaling and enhanced descending
modulation.
T R E AT M E N T OP T ION S Systematic review studies show that selective nor-
epinephrine reuptake inhibitors (SNRI: duloxetine,
Conservative management venlafaxine), α2δ-subunit calcium channel blockers (α2δ-
sCCB: pregabalin, gabapentin), sodium channel block-
Non-pharmacological treatment ers (oxcarbazepine), tricyclic antidepressants (TCA:
amitriptylin, nortriptylin), various opioids, and botuli-
Of the non-pharmacological symptomatic pain num toxin are more effective in relieving pain intensity
treatments, cognitive behavioral therapy (GBT), than placebo.10,51,52 However, other patient-reported out-
transcutaneous electrical nerve stimulation (TENS), fre- come measures (PROMS) are often incompletely or not
quency-modulated electromagnetic stimulation (FMES), included in analyses at all. Follow-up of these studies is
exercise and physiotherapy (EPT) have been systemati- often short (a few weeks), whereas the therapy is intended
cally investigated. TENS and FMES were found to be to last for years. In addition, the number of patients who
ineffective. No or insufficient evidence could be found discontinue their medication during short follow-ups due
on GBT and EPT.48 to side effects is significant (around 10%).10,52 In a study
comparing combination therapy of duloxetine 60 mg plus
pregabalin 300 mg daily to high-dose (pregabalin 600 mg
Pharmacological treatment or duloxetine 120 mg monotherapy (COMBO-DN), the
researchers found no difference between groups in the
PDPN mechanism-directed treatment percentage who experienced 2-point reduction in the
In general, optimal glucose control is essential for the Brief Pain Inventory (BPI) score, the primary endpoint.
prevention of all microvascular complications of dia- However, in a secondary analysis, duloxetine 60 mg/day
betes, including (P)DPN. As secondary prevention, was found to be more effective than pregabalin 300 mg/
interventions to reduce risk factors for (P)DPN are day in the first 8-week run-in phase.53 An exploratory
recommended, including lifestyle modification and post hoc analysis showed that high-dose monotherapy
multifactorial measures to reduce cardiovascular risk, was more effective in patients with severe pain, while
as hypertension and cardiovascular disease have been combination therapy was more favorable in patients with
shown to be independent risk factors for (P)DPN.10,49 mild to moderate pain. Patients who received duloxetine
Spontaneous recovery of PDPN cannot be expected once (60 mg/day) as initial therapy compared with pregabalin
symptoms have developed. (300 mg/day) also had a better response to combination
The efficacy of agents related to the pathogenesis therapy.54 PDPN patients with dysesthetic paresthesia
have been investigated in several randomized clinical tri- benefited more from high-dose duloxetine (120 mg/day)
als. These agents target the underlying causal pathways. compared to high-dose pregabalin (600 mg/day).39
Of these, α-lipoic acid (an antioxidant), benfotiamine In a randomized, double-blind, active-control, cross-
(an advanced glycation end product (AGE) inhibitor), over clinical trial, low-dose naltrexone (1,5–4,5 mg/day)
and actovegin (a poly adenosine diphosphate-ribose was found to be as effective and safer than amitripty-
polymerase (PADRP) inhibitor) have been approved line.55 Low-dose naltrexone antagonizes opioid recep-
in some countries for the treatment of (P)DPN. In one tors and Toll-like receptor 4 (found on macrophages,
multicenter, randomized, placebo-controlled study, including microglia), which may increase the body ‘s
oral treatment with α-lipoic acid (600–1800 mg/day) for production of endorphins and have an anti-inflamma-
5 weeks reduced pain, paresthesia, and numbness com- tory effect.56
pared to placebo in 181 patients with PDPN, with no Beneficial effects of opioid agonists in PDPN have
difference between doses.10,48,50 Other non-registered also been demonstrated.57–59 Opioids are often used as
examples include aldose reductase inhibitors (alrestatin, supplementary therapy in combination with another
sorbinil, ponalrestat, tolrestat, epalrestat, zopolrestat, pharmacological approach. If indicated, we recommend
zenarestat, fidarestat, and ranirestat), antioxidants (vi- using opioids only for refractory patients at the lowest
tamin E), protein kinase C (PKC) inhibitors (ruboxistau- possible dose, for a limited duration of time or with se-
rin), prostacyclin (PGI2) analogues (iloprost, beraprost), rial evaluations for continued effectiveness, and under
prostaglandin derivatives (PGE1aCD), c-linolenic acid, universal precautions.60
trandolapril, nerve growth factor (NGF), vascular endo- Capsaicin is a selective agonist for the “transient re-
thelial growth factor (VEGF), and C-peptide. ceptor potential vanilloid 1” (TRPV1). Initially, capsaicin
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ZUIDEMA et al.     | 315

activates cutaneous nociceptors with TRPV1 expression, oxcarbazepine, expressed as a lower number needed to
leading to burning and erythema due to the release of va- treat (NNT), than patients with a non-IN phenotype
soactive neuropeptides. Subsequently, there is a decrease (NNT, 3.9 vs. 6.9).72–75 In a subgroup of patients with
in cutaneous nociceptors and pain-transmitting neuro- preserved nociceptive function (screened with 0.1%
peptides such as substance P, which reduces sensitivity capsaicin), clonidine significantly reduced foot pain in
to various stimuli, a phenomenon known as defunction- PDPN.76 Furthermore, PDPN patients with Nav 1.7 vari-
alization.61 It is believed that this process of peripheral ants exhibited more severe pain in diabetes, at shorter
desensitization underlies the analgesic effect. Topical durations.77 This could have clinical implications be-
capsaicin 0.075% cream, applied to the painful areas for cause carriers of Nav1.7 genetic variants may respond
approximately 8 weeks, has been shown to reduce pain, better to the antiepileptic drug lacosamid.29
which may lead to clinical improvements in walking, PDPN patients with less efficient conditioned pain
working, and sleeping in patients with PDPN.62 modulation (CPM), indicative of impaired pain modula-
In a randomized, placebo-controlled study, capsa- tion by the monoaminergic descending pathway—a key
icin 8% patch has been shown to be effective in reliev- feature of central sensitization—demonstrated a better
ing pain up to 24 weeks after application.63 It has also effect from duloxetine treatment.78 Genetic variations
been shown to provide pain relief in a disease-modify- might even suggest differential responses to medication
ing manner via nerve regeneration and restoration of stratified by gender.79 Thus, more precise pain-pheno-
function in PDPN.64 A recent publication notes that typing and genotyping using specific patient characteris-
some patients treated with the capsaicin patch may re- tics, incorporating new diagnostic tools, and considering
quire two or three treatments before an initial response a patient's response to previous pharmacological treat-
is observed.65 ments, are becoming increasingly important to optimize
Studies have evaluated the application of local an- treatment outcomes.
esthetics in PDPN. The efficacy of lidocaine 5% patch Current guidelines on the pharmacological approach
compared to pregabalin was investigated in a two-phase, of symptomatic pain treatment in PDPN recommend
adaptive, randomized, controlled, open-label, multi-cen- roughly the same treatment strategy for all patients.39
ter study.66 After 4 weeks of treatment, 65.3% of patients SNRI's or TCA's and α2δ-sCCB's (or in combination)
treated with lidocaine 5% patch and 62.0% receiving as first- and second-line treatments, and capsaicin 8%
pregabalin responded with a reduction in pain inten- and lidocaine 5% patch or IV lidocaine as third-line
sity from baseline of ≥2 points on the 11-item numerical treatments.39 There are now numerous controlled stud-
rating scale (NRS). Both treatments improved second- ies that demonstrate increased effectiveness in diabetic
ary endpoints: ≥30% and ≥50% pain reduction, changes neuropathy and other neuropathic pain conditions for
in neuropathic pain symptom inventory (NPSI) scores combination therapy with drugs that have complemen-
and allodynia severity. Patients administered lidocaine tary mechanisms of action compared to unimodal ther-
5% patch experienced fewer drug-related adverse events apy (antidepressants, membrane stabilizers, opioids).80,81
(3.9% vs. 39.2%) and there were significantly fewer dis- However, initiating combination therapy may also result
continuations due to drug-related adverse events (1.3% in more adverse effects and limit a clinician's ability to as-
vs. 20.3%). sess the effectiveness of individual agents. In the future,
The effectiveness of intravenous lidocaine 5 and the diagnosis precision treatment of PDPN will continue
7.5 mg/kg infused in 4 h (vs. saline) in PDPN was in- to evolve toward more accurate pheno- and genotyping.
vestigated in a small double-blind, placebo-controlled
crossover study of two doses of intravenous lidocaine (5
and 7.5 mg/kg).67 Both doses of lidocaine significantly re- Interventional management
duced the severity of pain compared to placebo (saline)
at 14 and 28 days. The qualitative nature of pain was also Minimal invasive treatment
significantly altered by lidocaine compared with placebo
for up to 28 days. Studies suggest that patients with an A systematic review found short-term (up to 18 months)
irritable nociceptor phenotype may be more likely to re- benefits for pain relief from acupuncture compared to
spond to both intravenous and topical lidocaine.68,69 standard treatment. Acupuncture can be considered a
The use of detailed phenotyping has been proposed to complementary or alternative therapy with minimal side
identify dysfunction of descending inhibitory pathways effects for patients with PDPN.82
to enable “precision medicine”.70,71 Sympathetic lumbar chain neurolysis and/or radiofre-
As alluded to above, studies suggest that more accu- quency ablation (SLCN, SLCRF) ablation can provide
rate phenotyping and genotyping of PDPN may identify pain relief up to 12 months after treatment in refractory
subgroups of patients likely to respond better to existing cases of PDPN.83,84 Although the evidence is based on
pharmacological treatments. Using QST for phenotyp- small, uncontrolled studies, SLCN and/or SLCRF can
ing, it has been shown that patients with an excitable be considered in refractory cases with proven sympathet-
nociceptor (IN) phenotype have a better response to ically maintained pain (eg, demonstrated by controlled
 15332500, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/papr.13308 by Instituto Aragones De Ciencias, Wiley Online Library on [03/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
316 |    PAINFUL DIABETIC POLYNEUROPATHY

diagnostic blocks) when no other treatment options are the patient lying in prone position. The first step in the
available.13,82 procedure is to place an epidural lead containing mul-
tiple electrodes via a small incision in the back. The
number and position of the electrodes used can vary
Electrical stimulation of neural structures depending on the patient's specific pain condition. The
lead is positioned in such a way that the target area of
Spinal cord stimulation (SCS) was first reported as a the dorsal columns is precisely stimulated. The next
treatment for pain by Shealy and Taslitz in 1967.85 Up to step is to connect the lead to the pulse generator (PG),
now, the efficacy and safety of electrical stimulation of which provides the electrical stimulation. Usually, the
the dorsal column of the spinal cord in PDPN has been lead is connected to an external PG via an extension
investigated in multiple RCTs in patients, refractory to cable to provide a trial phase of at least 1 week to evalu-
conservative treatment.86–88 ate the patient's response to the treatment. In case of
SCS is a medical procedure that involves the use of an a positive treatment response, the electrode is discon-
implanted device to deliver electrical current to the dor- nected form the extension lead and an internal PG is
sal part of the spinal cord for the management of chronic placed. The internal PG is implanted under the skin in a
pain. subcutaneous pocket, usually paramedian to the spine,
Paresthesia and non-paresthesia-based stimula- the buttock, or the abdomen. The PG is programmed
tion paradigms are effective in terms of pain relief and to deliver the optimal stimulation parameters for the
PROMS measuring functionality and quality of life. In patient. This involves adjusting the frequency, ampli-
paresthesia-based SCS, 65% of responders are likely to tude, and pulse width of the electrical current delivered
still benefit from this therapy even after 8–10 years of to the spinal cord. The programming is done using an
treatment.7 Long-term treatment failure was associated external programmer that communicates with the pulse
with greater severity of neuropathy.89 In 10 kilohertz generator via a wireless connection.97–100
SCS (HF-10) stimulation, 63.6% and 85% of patients ex-
perienced ≥50% pain reduction after 1 year of treatment
in intention to treat (ITT) and modified intention to Complications of interventional management
treat (mITT) analyses, respectively.90 Guidelines recom-
mend SCS in PDPN patients refractory to pharmacolog- Serious adverse events with acupuncture are very rare.
ical treatment.44,82,91,92 Although the initial cost of SCS In hands of qualified persons, it is considered a safe
is high, its pain relief is clinically relevant in a significant intervention.101
proportion of patients with PDPN.93 Future research on Common complications of SLCN, SLCRF include
SCS for PDPN should focus on pheno- and genotyping bleeding, bruising, swelling, and soreness at the site of
to optimize long-term prediction of SCS responders and injection. These are usually self-limited and resolves
conducting post-marketing multi-center studies devoid within hours to days after the procedure. Some patients
of bias, as significant differences in outcomes have been have also reported transient dizziness, headache, hy-
reported between industry-sponsored and non-indus- potension, numbness, and weakness of the leg on the
try-sponsored studies.94 side that was injected due to extravasation to somatic
Dorsal root ganglion stimulation (DRGS) was stud- nerves. More serious complications include infection,
ied in a small retrospective cohort study and several case visceral injury, intravascular injection, intralymphatic
studies.91,95 Patients with good paresthesia capture of the injection, ureteral injury, kidney damage, Horner's
painful area responded well for up to 12 months of ther- syndrome, and allergic reaction to the medication, al-
apy.95 Stimulation of the posterior tibial nerve (PTNS) though these are exceedingly rare. Anterior thigh pain,
has not been studied in a homogeneous population of presumably due to damage to the genitofemoral nerve
PDPN patients yet.91 An observational study in a het- and lateral femoral cutaneous nerve, may occur in some
erogeneous population of peripheral neuropathic pain patients.102
treated with PTNS showed promising results.96 More ro- Hardware failure (eg, lead fractures, implanted pulse
bust research is needed to investigate the use of DRGS generator (IPG), and lead migrations), pocket pain, and
and PTNS for PDPN as most cases of diabetic neuropa- loss of therapeutic effect are frequently reported com-
thy involve bilateral pain in a stocking-like distribution plications related to SCS treatment and have been re-
which may not be covered by focal nerve or nerve root ported up to 10 years of follow-up.7,103 Infection at the
stimulation. IPG site occurs in around 5–10% of cases and can usu-
ally be treated with antibiotics and removal of the im-
plant.1 Technical adverse events can be solved by lead
Implantation technique for SCS replacement, repositioning of the pulse generator, or
reprogramming of stimulation parameters. Serious ad-
The procedure is usually performed under local anes- verse events after SCS implantation, like meningitis, spi-
thesia with sedation or under general anesthesia, with nal hemorrhage leading to spinal cord compression, or
 15332500, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/papr.13308 by Instituto Aragones De Ciencias, Wiley Online Library on [03/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ZUIDEMA et al.     | 317

F I G U R E 6 Represents the treatment algorithm for PDPN based on the available evidence. DRG, dorsal root ganglion stimulation; PTNS,
posterior tibial nerve stimulation; SLCN or RF, sympathetic lumbar chain neurolysis or radiofrequency ablation.

spinal cord damage are very rare. Developing hardware DATA AVA I L A B I L I T Y STAT E M E N T
that is more robust and software that improves capture Data sharing is not applicable to this article as no new
rate and reduces “tolerance” are important focuses for data were created or analyzed in this study.
optimizing SCS therapy.
ORC I D
Sam Eldabe https://orcid.org/0000-0002-9250-1886
SU M M A RY OF T H E I N FOR M AT ION Jan Van Zundert https://orcid.
org/0000-0002-5389-2036
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