Diabetic Neuropathy: A Position
Statement by the American
Diabetes Association
Diabetes Care 2017;40:136–154 | DOI: 10.2337/dc16-2042
Diabetic neuropathies are the most prevalent chronic complications of diabetes. This
heterogeneous group of conditions affects different parts of the nervous system and
presents with diverse clinical manifestations. The early recognition and appropriate man-
agement of neuropathy in the patient with diabetes is important for a number of reasons:
1. Diabetic neur opathy is a diagnosis of exclusion. Nondiabetic neuropathies may
be present in patients wi th diabetes and may be treatable by specific measures.
2. A number of treatment option s exist for symptomatic diabetic neuropathy.
3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not
recognized and if preventive foot care is not implemented, patients are at risk
for injuries to their insensate feet.
4. Recognition and treatment of autonomic neuropathy may improve symptoms,
redu ce sequelae, and improve quality of life.
Among the various forms o f diabetic neuropathy, distal symmetric polyneurop-
athy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular au-
tonomic neuropathy (CAN), are by far the most studied (1–4). There are several
atypical forms of diabetic neuropathy as well (1–4). Pati ents with prediabetes may
also develop ne uropathies that are similar to diabet ic neuropathies (5–10). Table 1
provides a comprehensi ve classification scheme for the diabetic neuropathies.
Due to a lack of treatments that target the underlying nerve damage, prevention
is the key component of diabetes car e. Screen ing for symptoms and signs of diabetic
neuropathy is also critical in clinical practice, as it may detect the earliest stages of
neuropathy, enabling early intervention. Although screening for rarer atypical forms
of diabetic neuropat hy may be warrante d, DSPN and autonomic neuropath y are the
most common forms encountered in practice. The strongest available evidence
regarding treatment pertains to these fo rms.
This Position Statement is based on several recent technical reviews, to which the reader
is referred for detailed discussion and relevant references to the literature (3,4,11–16).
PREVENTION
Prevention of diabetic neuropathies focuses on glucose control and lifestyle modifica-
tions. Available evidence pertains only to DSPN and CAN, and most of the large trials
that have evaluated the effect of glucose control on the risk of complications have
included DSPN and CAN as secondary outcomes or as post hoc analyses rather than as
primary outcomes. In addition, in some of these trials, the outcome measures used to
evaluate neuropathy may have limited ability to detect a benefit, if present.
Recommendations
c Optimize glucose control as early as possible to prevent or delay the devel-
opment of distal symmetric polyneuropathy and cardiovascular autonomic
neuropathy in people with type 1 diabetes. A
c Optimize glucose cont rol to prevent or slow the progression of distal symmet-
ric polyneuropathy in people with type 2 diabetes. B
c Consider a multifactorial approach targeting glycemia among other risk factors to
prevent cardiovascular autonomic neuropathy in people with type 2 diabetes. C
1
Division of Metabolism, Endocrinology & Diabe-
tes, Department of Internal Medicine, University
of Michigan, Ann Arbor, MI
2
University of Manchester and the Royal Infirmary,
Manchester, U.K.
3
Department of Neurology, University of Michigan,
Ann Arbor, MI
4
Department of Neurology, University of Toronto,
Toronto, Ontario, Canada
5
Department of Neurology, Harvard Medical
School, Boston, MA
6
Department of Medicine, Weill Cornell Medicine-
Qatar, Doha, Qatar and New York, NY
7
Division of Endocrinology, University of Miami
Miller School of Medicine, Miami, FL
8
German Diabetes Center D
¨
usseldorf, Leibniz
Center for Diabetes Research at Heinrich Heine
University, and Depart ment of Endocrinology
and Diabetology, Medical Faculty, Heinrich
Heine University, D
¨
usseldorf, Germany
Corresponding author: Rodica Pop-Busui, rpbusui@
umich.edu.
This position statement was reviewed and ap-
proved by the American Diabetes Association
Professional Practice Committee in Sept ember
2016 and ratified by the American Diabetes As-
sociation Board of Directors in October 2016.
R.P.-B. and A.J.M.B. served as co-chairs of the
writing committee.
© 2017 by the American Diabetes Association.
Readers may use this article as long as the work
is properly cited, the use is educational and not
for profit, and the work is not altered. More infor-
mation is available at http://www.diabetesjournals
.org/content/license.
Rodica Pop-Bu sui,
1
Andrew J.M. Boulton,
2
Eva L. Feldman,
3
Vera Bril,
4
Roy Freeman,
5
Rayaz A. Malik,
6
Jay M. Sosenko,
7
and
Dan Ziegler
8
136 Diabetes Care Volume 40, January 2017
POSITION STATEMENT
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Glucose Control
Enhanced glucose control i n people with
type 1 diabetes dramatica lly reduces the
incid ence of DSPN (78% relative risk re-
duction) (17–19). In cont rast, enhanced
glucose control in people with type 2 di-
abetes reduces the risk of developing
DSPN modestly (5%–9% relative risk re-
duction) (20,21). In a small trial of Japa-
nese patients with early type 2 diabetes,
intensive insulin treatment was ass oci-
ated with improvement i n selected
DSPN meas ures (22), and the Action to
Control Cardiovascular Risk in Di abetes
(ACCORD) trial reported a modest but
significant DSPN risk reduction with
the glycemia intervention in individuals
with ty pe 2 diabetes after 5 years of
follow-up (21). Yet, no e ffects are ob-
served in other large trials (20,23–25).
This discrepancy highlights the differ-
ences between type 1 and type 2 diabe-
tes and e mphasizes the point that many
people with type 2 diabetes develop
DSPN despite adequate glu cose control
(20,25). The presence of multiple comor-
bidities, polypharmacy, hy poglycemia,
and weight gain might have attenuated
the effects of glucose control in these
trials and contributed to inconsistent
findin gs (25). Specific glucose -lowering
strategies may also contribute to the dis-
crepancy. For example, participants, par-
ticularly men, in the Bypass Angioplasty
Revascularization Investigation in Type 2
Diabetes (BARI 2D) study treated with in-
sulin sensitizers had a lower incidence of
DSPN over 4 years than those treated
with insulin/sulfonylurea (26). This out-
come may be a result of less weight gain
and less hypoglycemia (26). Last, the fact
that many patients have had asymptom-
atic hyperglycemia for many years prior
to the diagnosis of type 2 diabetes may
also explain the limited benefitinthese
patients.
Similar to the findings in DSPN, the
most robust evidence for CAN preven-
tion was reported in type 1 diabetes.
Intensive glucose control designed to
achieve near- normal glycemia reduced
the risk of incident CAN during the Di-
abetes Control and Complications Trial
(DCCT) by 45% and by 31% in its follow-up
study, the Epidemiology of Diabetes In-
terventions and Complications (EDIC)
study (27). The highly reproducible and
sensitive testing protocol, the robust
definitions used for CAN, and the large
sample size in DCCT/EDIC enhance the
validity of the results and support the
rationale for implementing and main-
taining tight glucose control as early as
possible in the course of type 1 diabetes.
In contrast, glycemic control in type 2
diabetes has not consistently lowered
the risk of CAN (25). However, a multi-
factorial intervention, including a life-
style component, targeting glucose and
cardiovascular disease risk factors re-
duced the risk of CAN by 60% in people
with type 2 diabetes (28).
Lifestyle Modifications
The bes t models to date regarding pa-
rameters for an evidence-based, inten-
sive lifestyle intervention come from the
Diabetes Prevention Program (DPP)
(29), the Steno-2 Study (28), the Italian
supe rvised treadmill study (30), and th e
University of Uta h type 2 diabetes study
(31). The latter study recently reported
nerve fiber regeneration in patients with
type 2 diabetes e ngaged in an exercise
program compared with loss of nerve fi-
bers in those who only followed standard
of care. Overall, such an approach focuses
on either exercise alone (supervised aer-
obic and/or resistance training) (30,31) or
combined dietary modification and exer-
cise. There is no consensus regarding di-
etary regimens, and although the DPP
used a low-calorie, low-fat diet, others
have championed a Mediterranean diet
that is moderately lower in carbohydrate
(45%) and higher in fat (35%–40%), with
less than 10% of saturated fat.
Although the DPP (32) and the Impaired
Glucose Tolerance Neuropathy (IGTN)
study (33) reported benefits of lifestyle
interventions on measures of CAN and
DSPN, respectively, these trials did not in-
clude subjects with established diabetes.
In addition, in the DPP, indices of CAN
improved with the lifestyle intervention
and did not change in the other arms (32).
Table 1—Classification for diabetic neuropathies
Diabetic neuropathies
A. Diffuse neuropathy
DSPN
c Primarily small-fiber neuropathy
c Primarily large-fiber neuropathy
c Mixed small- and large-fiber neuropathy (most common)
Auton omic
Cardiovascular
c Reduced HRV
c Resting tachycardia
c Orthostat ic hypotension
c Sudden death (malignant arrhythmia)
Gastrointestinal
c Diabetic gastroparesis (gastropathy)
c Diabetic enteropat hy (diarrhea)
c Colonic hypomotility (constipation)
Urogenital
c Diabetic cystopathy (neuroge nic bladder)
c Erectile dysfunction
c Female sexual dysfunction
Sudomotor dysfunction
c Distal hypohydrosis/anhidrosis,
c Gustatory sweating
Hypoglycemia unawareness
Abnormal pupillary function
B. Monon europathy (mononeuritis multiplex) (at ypical forms)
Isolated cranial or peripheral nerve (e.g., CN III, ulnar, median, femoral, peroneal)
Mononeuritis multiplex (if confluent may resemble polyneuropathy)
C. Radiculopathy or polyradiculopathy (atypical forms)
Radiculoplexus neuropathy (a.k.a. lumbosacral polyradiculopathy, proximal motor
amyotrophy)
Thora cic radiculopathy
Nondia betic neuropathies common in diabetes
Pressure palsies
Chronic inflammatory demyelinating polyneuropathy
Radiculoplexus neuropathy
Acute painful small-fiber neuropathies (treat ment-induced)
care.d iabetesjournals.org Pop-Busui and Associates 137
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DSPN
Most common among diabetic neu rop-
athies is chronic DSPN, accounting for
about 75% of the diab etic neu ropathies
(1,3). A sim ple definition of DSPN for
clinical practice is the presence of symp-
toms and/or signs of peripheral nerve
dysfunctio n in people wit h diabetes af-
ter the exclusion of other causes.
Experimental studies suggest a mul-
tifactorial pathogenesis of DSPN (Fig. 1),
but the causes remain unknown
(34–37). A prevailing view of the patho-
genesis is that oxidative and inflamma-
tory stress may, in the context of
metabolic dysfunction, damage nerve
cells (34–37).
Estimates of the incidence and prev-
alence of D SPN vary greatly (25,38–40),
but evide nce from several large obser-
vational coho rts (41,42) and the DC CT/
EDIC (27,43) suggests that DSPN occurs
in at least 20% of people with type 1 di-
abetes after 20 y ears of disease dura-
tion. DSPN may be present in at least
10%–15% of newly diagnosed patients
with type 2 diabetes (44,45), with rates
increasing to 50% after 10 years of disease
duration (25,26). Rates in youth with
type 1 and type 2 diabetes approach those
observed in adult popu lations (46).
DSPNhasbeenassociatedwithglyce-
mia (14,33–35), height (47) (perhaps
as a proxy for nerve length), smoking
(48), blood pressure, weight, and lipid
measures (49,50).
There is emerging evidence that
DSPN, especially the painful sma ll-fiber
neuropathy subtype, may be present in
10%–30% of su bjects with impaired glu-
cose tolerance, also known as prediabe-
tes (5 –10) or metabolic syndrome (51).
DSPN is the most important cause of
foot ulceration, and it is also a prereq-
uisite in the development of Charcot
neuroarthropathy (CN) (52). The reader
is referred to several other reviews that
cover this topic (52,53). Foot ulceration
and CN are both recognized as late com-
plications of DSPN (52,54). These late
complications drive amputation risk
and economic costs of diabetic neurop-
athy and are also predictors of mortality.
DSPN is also a major contributor to
falls a nd fractures (55–57), throu gh
more advanced small- and large-fiber
dysfunction, with loss of sensory, pro-
prioception, temperature discrimina-
tion, and pai n, all ultimately leading to
unst eadiness, recurrent minor injuries,
and an increased risk of falls. These re-
current minor injuries may further con-
tribute to the pathogenesis of CN (58).
Screening and Diagnosis
Recommendations
c All patients should be ass essed for
distal symmetric p olyneuropathy
starting at diagnosis of type 2 di-
abetes and 5 years after the diag-
nosis of type 1 diabetes and at
least annually thereafter. B
c Consider screening patients w ith
prediabetes who have symptoms
of peripheral neuropathy. B
c Assessment should include a care-
ful history and either temperature
or pinprick sensation (small-fiber
function) and vibration sensation
using a 128-Hz tuning fork (large-fiber
function). All patients should have an
annual 10-g monofilament testing to
assess for feet at risk for ulceration
and amputation. B
c Electrophysiological testing or re-
ferral to a neurologist i s rarely
needed for screening, except in
situations where the clinical fea-
tures are atypical, the diagnosis is
unclear, or a different etiology is
suspected. Atypical features in-
clude motor greater than sensory
neuropathy, rapid onset, or asym-
metrical presentation. B
Patients with type 1 diabetes for 5 or
more years and all patients with type 2
diabetes should be assessed annually
for DSPN using medical history and
simple clinical tests. Up to 50% of pa-
t i ents may experience sympt oms o f
DSPN (Table 2), wher eas t he rest are
asymptomatic. Patients may not volun-
teer symptoms but on inquiry may reveal
that they are experiencing numbness or
other positive symptoms of DSPN.
Symptoms vary according to the class
of sensory fibers involved. The most
common early symptoms are induced
by the involvement of small fibers and
include pain an d dysesthesias (unpleas-
ant sensations of burning) (1,4,59,60).
Neuropathic pain may be the first symp-
tom that prompts patients to seek med-
ical care and is present in up to 25% of
individuals w ith DSPN (61–63). Charac-
teristically, the pain is burning, lancinating,
tingling, or shooting (electric shock–like);
occurs with paresthesias; presents in
Figure 1—Mechanisms of diabetic neuropathy. Factor s linked to type 1 diabetes (yellow), type 2
diabetes (blue ), and both (green) cause DNA damage, endoplasmic reticulum stress, mitochon-
drial dysfunction, cellular injury, and irreversible damage. The relative importance of the path-
ways in thi s network will vary with cell type, disease profile, and ti me. ER, endoplasmic
reticulum; FFA, free fatty acids; PI3-K, phos phatidylinositol-3 kinase; RN S, reactive nitrogen
species; ROS, reactive oxygen species. Adapted and reprinted from Callaghan et al. (20), with
permission from Elsevier.
138 Position Statement Diabetes Care Volume 40, January 2017
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varying combinations; and is typically
worse at night. Neuropathic pain may be
accompanied by an exaggerated response
to painful stimuli (hyperalgesia) and pain
evoked by contact, e.g., with socks, shoes,
and bedclothes (allodynia). Neuropathic
pain can lead to interference with daily
activities, disability, psychosocial impair-
ment, and reduced health-related quality
of life (64–66). The direct and indirect eco-
nomic burden associated with neuro-
pathic pain is substantial (67–69).
The involve ment of large fibers may
cause numbnes s, tingling without pain,
and loss of protective sensat ion. Loss of
protective sensation indicates the pre s-
ence of DSPN and is a risk fact or for d i-
abetic foot ulceration. Patients can also
initially present with an in sensa te, numb
foot due to the loss of large fibers. Patients
frequently state that their feet feel like
they are wrapped in wool or they are walk-
ing on thick socks. It is the loss of the “gift
of pain” that permits patients with plantar
neuropathic ulcers to walk on the lesions,
inducing chronicity, frequently complicated
by infection (70).
The following clinical tests may be
used to assess small- and l arge-fiber
function distal to proximal (Table 2):
1. Small-fiber function: pinprick and
temperature sen sation
2. L a rg e - fiber function: vibration per-
cept ion, proprioception, 10-g mono-
filament, and ankle reflexes
A 128-Hz tuning fork can be used for
the assessment of vibration perception.
Assessment of light-touch p erception
using a 10-g monofilament should include
evaluation on the dorsal aspect of the
great toe bilaterally as previously validated
by Perkins et al. (71). The 10-g monofila-
ment is a useful clinical tool mainly for
detecting more advanced neuropathy
and identifying patients at increased risk
of ulceration and amputation (72).
Assessments should follow the typical
DSPN pattern, starting distally (the dor-
sal aspect of the hal lux) on both sides
and move proximally until a sensory
threshold is identified (72). Combining
at least t wo examinations will in crease
the sen sitivity and specificity of detect-
ing DSPN, as demonstrated in several
cohorts of patients with t ype 1 and
type 2 diabetes including children and
adolescents (26,46,73–79).
The diagnosis of DSPN is principally a
clinical one (Table 2). A combination of
typical symptomatology and symmetrical
distal sensory loss or typical signs in the
absence of symptoms in a patient with
diabetes is highly suggestive of DSPN
and may not require additional evaluation
or referral. As up to half of the patients
may be asymptomatic, a diagnosis may
only be made on examination or, in
some cases, when the patient presents
with a painless foot ulcer.
Clinicians should note that the 10-g
monofilament test included for the
annual DSPN screening and diagnosis
is different than the diagnosis of the
“high-risk foot” for ulceration, a late
DSPN complication that requires that
four sites (first, third, and fifth metatarsal
heads and plantar surface of distal hallux)
be tested on each foot (80).
Consider excluding neuropathy with
causes other than diabetes (Table 3) by
undertaking a family and medication history
and performing relevant investigations (e.g.,
serum B
12
, folic acid, thyroid function, com-
plete blood count, metabolic panel, and a
serum protein immunoelectrophoresis) (81).
Electrophysiological testing or referral
to a neurologist is rarely needed for di-
agnosis, except in situations where the
clinical features are atypical, the diagn os is
is unclear , or a different etiology is sus-
pected (2,38,40,80). Atypical features that
warrant referral include motor greater than
sensory neuropathy, asymmetry of symp-
toms and signs, and rapid progression.
Foot Complications
The simple yet comprehensive clinical
exam is principally designed to identify
those at risk for the late complications
whoneededucationonpreventative
foot self-care and regular podiatric
foot care. Recently an even simpler
Table 2—Symptoms and signs of DSPN
Large myelinated nerve fibers Small myelinated nerve fibers
Function Pressure, balance Nociception, protective sensation
Symptoms§ Numbne ss, tingling, poor balance Pain: burning, electric shocks, stabbing
Examination
(clinically diagnostic)**
Ankle re flexes: reduced/absent
Vibration perception: reduced/absent
10-g monofilament: reduced/absent
Proprioception: reduced/absent
Thermal (cold/hot) discrimination: reduced/absent**
Pinpri ck sensation: reduced/absent**
§To document the presence of symptoms for diagnosis; **Documented in symmetrical, distal to proximal pat tern.
Table 3—Differential diagnosis of
diabetic neuropathies
Metabolic disease
Thyroid disease (common)
Renal disease
Systemic disease
Systemic vasculitis
Nonsystemic vasculitis
Paraproteinemia (common)
Amyloidosis
Infectious
HIV
Hepatitis B
Lyme
Inflamm atory
Chronic inflammatory demyelinating
polyradiculoneuropathy
Nutritional
B
12
*
Postg astropla sty
Pyridoxine
Thiamine
Tocopherol
Industrial agents, drugs, and metals
Industrial agents
Acrylamide
Organophosphorous agents
Drugs
Alcohol
Amiodarone
Colchicine
Dapsone
Vinka alkaloids
Platinum
Taxol
Metals
Arsenic
Mercury
Hereditary
Hereditary motor, sensory, and
autonomic neuropathies
*B
12
deficiency is more co mmonly
associated with malabsorption rather than
nutritional deficiency.
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foot exam, t he “3-minute diabetic foo t
exam,” has been proposed (82). This is
intended not only for physicians but also
for other health care professionals who
may only have 15 min for the entire dia-
betes annual review; it requires no equip-
ment and provides simple advice on
education on preventative foot self-care.
Management
Recommendations
c Tight glucose control targeting
near-normal glycemia in patients
with type 1 diabetes dramatically
reduces the incidence of distal
symmetric polyneuropathy and is
recommended for distal symmet-
ric polyneuropathy prevention in
type 1 diabetes. A
c In patients with type 2 diabetes
with more advanced disease and
multiple risk factors and comorbid-
ities, intensive glucose control
alone is modestly effective in pre-
venting distal symmetric polyneur-
opathy and patient-centered goals
should be targeted. B
c Lifestyle interventions are recom-
mended for distal symmetric poly-
neuropathy prevention in patients
with prediabetes/metabolic syn-
drome and type 2 diabetes. B
Prevention
Please refer to PREVENTION on page 136.
Pathogenetic Therapies
Despite the recent major advances in
elucidating the pathogen esis of diabetic
neuropathy, there remains a lack of
treatment options that effe ctively tar-
get the natura l history of DS PN (83) or
reverse DSPN once established. Several
pathogenetic pharmacotherapies have
been investigated (36), but evidence
from randomized clinical trials is very
limited (81,83,84). Advances in DSPN
disease m odification need to be con-
firmed with further robust evidence
from clinical trials, together with a bet-
ter understanding of the mechanisms of
action of promising treatments (83).
Pain Management
Recommendations
c Consider either pregabalin or
duloxetine as the initial approach
in the symptomatic treatment for
neuropathic pain in diabetes. A
c Gabapentin may also be used as
an effective initial approach, taking
into account patients’ socioeco-
nomic status, comorbidities, and
potential drug interactions. B
c Although not approved by the U.S.
Food and Drug Administration, tri-
cyclic antidep ressants ar e also ef-
fective for neuropathic pain in
diabetes but should be used with
caution given the higher risk of se-
rious side effects. B
c Given the high risks of addiction
and other complications, the use
of opioids, including tapentadol
or tramadol, is not recommended
as fir st- or second-line agents for
treating the pain associated with
DSPN. E
No compelling evidence exists in support
of glycemic control or lifestyle manage-
ment as therapies for neuropathic pain in
diabetes or prediabetes (33,85), whi ch
leaves only pharmaceutical interventions.
At present, pregabalin and duloxetine
have received regulatory approval for the
treatment of neuropathic pain in diabetes
by the U.S. Food and Drug Administration
(FDA), Health Canada, and the European
Medicines Agency. The opioid, tapentadol,
has regulatory approval in the U.S. and
Canada, but the evidence of its use is
weaker (15).
A large evidence base supports phar-
macological treatment of neuropathic
pain in diabetic neuropathy using other
agents of different class es, as docu-
mented by several recent guidelines
and systematic reviews (15,16,20,86,87).
It is important to mention that only a
fewtrialsthattargetedpaininperipheral
neuropathic pain were carried out in DSPN
alone. However, the results of studies per-
formed on peripheral nondiabetic neuro-
pathic pain or mixed neuropathic pain may
be applicable to patients with neuropathic
pain due to DSPN.
Although there are broad general
agreements among the recommenda-
tions, there are some inconsistencies that
are, in part, a consequence of whether the
guidelines are specificforpainfulDSPNor
whether they address neuropathic pain
due to all causes (15,16,20,86,87).
Below we summarize the available ev-
idence on the most effective agents for
DSPN pain starting with the currently ap-
proved drugs and continuing with the
other agents based on mechanism of ac-
tion and strength of evidence. Evidence
levels are assigned based on the strength
of the published clinical evidence for the
efficacy and safety of the agents for the
treatment of DSPN pain, which should be
considered in clinical decision making.
However, a certain degree of publication
bias should be conside red, given that
many negative trials may not have been
published (15).
Additional information on dose titra-
tion, adverse effects, number needed to
treat, and safety is presented in Table 4.
Approved Medications
Pregabalin and duloxetine have r e-
ceived regulatory approv al for the treat-
ment of neuropathic pain in diabetes in
the U.S., Europe, and Canada.
Pregabalin, a calcium channel a2-d
subunit ligand, is an effective treatment
for neuropathic pain associated with
DSPN. It is t he most extensively studied
drug by far in D SPN, wit h the majo rity
of studies being positive regarding
the proportion of responders with at
le a st 30%–50% improvement i n pain
(15,86,88–94). There is also some evi-
dence suggesting a dose response, with a
weaker effect with 300 vs. 600 mg/day
(88). However, not all trials with pregaba-
lin have been positive (15,86,95,96), espe-
cially when treating advanced refractory
patients (93). Pregabalin, in contrast to
gabapentin (see below), has a linear,
dose-proportional absorption in the thera-
peutic dose range (150–600 mg/day)
(88). In addition, pregabalin has a more
rapid onset of action and more limited
dosage range that requires minimal titra-
tion. Adverse effects may be more se-
vere in older patients (97) and may be
attenuated by lower starting doses and
more gradual titration.
Duloxetine is a selective norepineph-
rine and serotonin reuptake inhibitor.
Doses of 60 and 120 mg/day showed ef-
ficacy in the treatment of pain associated
with DSPN in multicenter randomized tri-
als, although some of these had a rather
high drop-out rate (15,86,94,96,98–101).
Duloxetine was also suggested to in-
duce improvement in neuropathy-related
quality of life (100). In longer-term stud-
ies, a small increase in A1C was reported
in people with diabetes treated with du-
loxetine com pared with placebo (102).
Adverse events may again be more severe
in older people but may be attenuated
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