Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00087
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Title: PharmaNote
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Language: English
Publisher: College of Pharmacy
Place of Publication: Gainesville, Fla.
Publication Date: July 2010
Copyright Date: 2010
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Volume ID: VID00087
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Tarish Mehta, Pharm.D.

Diabetic Peripheral Neuropathy (DPN) is de-
fined as the presence of symptoms and/or
signs of peripheral nerve dysfunction in people
with diabetes after the exclusion of other causes.' But,
as per ADA guidelines, although DPN is a diagnosis of
exclusion, complex investigations to exclude other
conditions are rarely needed.2 DPN is a heterogeneous
group of disorders that affect different parts of the
nervous system leading to diverse subclinical and
clinical manifestation. This article will discuss the
classification, pathophysiology and review the current
management for treating peripheral diabetic neuropa-
thy, and briefly mentions future treatment options.


Diabetic neuropathy is common, especially in the
western world, and is present in up to 50% of the
older type 2 diabetic patients.4 Chronic neuropathic
pain is present in 13 26% of diabetic patients. DPN,
which is the most relevant clinical manifestation, af-
fects approximately 30% of the hospital-based popula-
tion and approximately 25% of community-based pa-
tients.3 The incidence of DPN is approximately 2% per
year and most patients remain asymptomatic for 5
years after diagnosis.
The total annual cost of DPN and its complications
in the US is $4.6 and $13.7 billion dollars respectively.
Up to 27% of the direct medical cost of diabetes may

be attributed to DPN.5
Even though numerous classifications have been
described, Thomas et al., originally propose the classi-
fication that was adapted by the ADA (Figure 1).
The diabetic neuropathies are heterogeneous, af-
fecting different parts of the nervous system, and pre-
sent with diverse clinical manifestations that may be
focal or diffuse. Most common among the neuropa-
thies are chronic sensorimotor distal symmetric poly-
neuropathy (primarily involving of the feet) and the
autonomic neuropathies.6,7
Generalized symmetric polyneuropathy is more
diffuse, commonly with an insidious onset, and usually
progressive. Half of patients can be asymptomatic. Ex-
amples of generalized symmetric polyneuropathy in-
clude acute sensory (rare and follows sudden changes
in glycemic control), chronic sensiromotor diabetic
neuropathy (most common with frequent pain, burn-
ing and stabbing sensation), and autonomic neuropa-
thy (diffuse subclinical dysfunction, usually confined
to one or two organ systems).8 Focal and multifocal
neuropathies have a sudden onset and improve over
These isolated peripheral nerve lesions may be a
feature in older diabetic patients -- examples include,
truncal neuropathy, cranial neuropathies, and diabetic






ih 1f



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July 2010

FIGURE 1. Classification scheme proposed by Thomas et al. (Adapted from Mahmood )


The pathology of DPN is characterized by poorly
controlled glycemia that leads to progressive nerve
fiber loss. Nerve fiber loss subsequently gives rise to
symptoms such as pain, parasthesiae and loss of sen-
sation. A number of biochemical mechanisms have
been proposed which may contribute to the develop-
ment of diabetic neuropathy (Table 1).


The main goal for the treatment and management
of diabetic neuropathy is proper glycemic control. Cur-
rent treatment algorithms recommend treatment with

tricyclic antidepressants, serotonin-norepinephrine
reuptake inhibitors, gabapentin/pregabalin, lidocaine,
or partial/full I-opioid agonists, depending on clinical
presentation and patient factors (Figure 2).

Tricyclic Antidepressants (TCAs)
TCAs have been evaluated extensively in the treat-
ment of DPN (Table 2). The assumed mechanism of
pain relief is via the inhibition of norepinephrine and/
or serotonin reuptake at synapses of central descend-
ing pain control systems. These agents also antagonize
NDMA receptors that mediate hyperalgesia and allo-
dynia. Amitriptyline, imipramine and clomipramine
induce a balance reuptake inhibition of both norepi-
nephrine and serotonin, whereas, desipramine, is a
relatively selective norepinephrine reuptake inhibi-

TABLE 1. Theoretical biochemical mechanisms in diabetic neuropathy.6

Nonenzymatic Glycation

Oxidative Stress

Polyol Pathway

Nerve Growth Factor

PKC-beta Pathways

Excess glucose, reacts with proteins, nucleotides and lipids to form advanced glycation end
products which induce biochemical damage and impair nerve blood flow.
Increased production of free radicals, whose mechanism is not fully understood. May lead to
direct damage of the blood vessels, resulting in nerve ischemia and advanced glycation end-
product reactions.
Intracellular glucose levels are raised in nerves, leading to saturation of the normal pathway,
and reduced nerve myoinositol, decreased membrane Na/K ATPase activity, impaired axonal
transport and structural breakdown of nerves, causing abnormal action potentials.
Decreased expression of nerve growth factor and its receptor, trk A, reduces retrograde ax-
onal transport of nerve growth factor and diminishes Substance P and calcitonin gene re-
lated peptide, which are potent vasodilators, leading to hypoxia and nerve conduction veloc-
ity, and ultimately degradation of axonal structure.

Hyperglycemia activates this complex intracellular signaling cascade process, leading to vas-
cular contractility and permeability, ultimately leading to degradation of axonal structure.


Volume 25, Issue 10 i July 2010


FIGURE 2. Proposed algorithm for the treatment of peripheral neuropathic pain.11
* Pain relieving effect of topical lidocaine had been shown in patients with allodynia.
TCA = tricyclic antidepressants; SNRI = serotonin norepinephrine reuptake inhibitor

tor. 12
Amitriptyline is frequently the drug of first choice,
but alternatively, nortriptyline or desipramine may be
chosen for their less pronounced sedative and anticho-
linergic effects. The onset of efficacy for TCAs usually
occurs within two weeks.12
Numerous placebo-controlled RCTs show TCAs to
be efficacious in providing pain relief caused by some
peripheral neuropathies. Studies generally demon-
strate that when TCAs are compared vs. placebo, they
are significantly superior in relieving pain (Table 3).
Finnerup et al., combined separate randomized, pla-
cebo-controlled trials using a numbers needed to treat
(NNT) analysis. HE showed that 1 patient would be
expected to obtain 50% pain relief for every 3.1 (2.7
- 3.7) patients treated."1 Sindrup et al.,15 and Vrethem
et al.,16 compared imipramine vs. venlafaxine and
amitriptyline vs. maprotiline, respectively, with both

studies using a placebo-controlled group. They found
no difference between treatment arms with respect to
pain relief. TCA adverse effects include sedation, dry
mouth and cardiac toxicity (Table 2). However, due to
their low cost, once daily dosing, and efficacy studies,
TCAs are often chosen as first line therapy in periph-
eral diabetic neuropathy or peripheral neuropathic

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Two SNRIs, duloxetine and venlafaxine have
shown efficacy in diabetic peripheral neuropathic
pain. Duloxetine; in doses of 60mg and 120mg/day
significantly improved pain relief and reduced the av-
erage 24-hour pain intensity score (Table 4).17,18,19
There was no significant difference between 60mg and
120mg daily doses of duloxetine. Ziegler et al., demon-
strated that for every 1 patient to achieve >50% pain


Volume 25, Issue 10 i July 2010


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TABLE 3. Clinical trials of TCAs for the treatment of diabetic peripheral neuropathy.
Max, et al.13 6 wk, DB, PC, Amitriptyline 25mg 150mg Amitriptyline superior to PL in relieving pain at week 3 -
(1987) CO vs. active placebo 6.
N = 29 (benztropine 1mg + diazepam
Sindrup, et al.14 6 wk, DB, CO, Clomipramine 50mg 75mg Clomipramine and desipramine significantly reduced
(1990) PC vs. desipramine 50mg symptoms vs. PL.
N = 19 200mg vs. PL No difference between clomipramine and desipramine.
Sindrup, et al.15 12 wk, R, DB, Venlafaxine 225mg vs. Venlafaxine and imipramine significantly reduced the
(2003) PC, CO Imipramine 150mg vs. PL sum of individual pain scores compared with PL
N = 40 No difference between venlafaxine and imipramine
NNT: 5.2 for venlafaxine, 2.7 for imipramine.
Vrethem, et al.16 4 wk, DB, R, Amitriptyline 75mg vs. Using GAPR, amitriptyline and maprotiline significantly
(1997) PC, CO Maprotiline 75mg vs. placebo reduced pain to a greater extent than PL
N = 37 No difference between amitriptyline and maprotiline
wk = week; DB = double-blind; PC = placebo-controlled; CO = cross-over; R = randomized; PL = placebo

reduction, 5.2 (3.8 8.3, 95% CI for 60mg), and 4.9 amino acid transporters, thus changing pain transmis-
(3.6 7.6, 95% CI for 120mg) patients needed to be sion and modulation. However, the exact mechanism
treated respectively.12 The most frequent adverse of action of these drugs on neuropathic pain is not
events in these trials included nausea, somnolence, fully understood. Pregabalin has a six fold higher bind-
dizziness, constipation, dry mouth and reduced appe- ing affinity for a2 6 subunit than gabapentin, thus
tite. Rowbotham et al., evaluated venlafaxine and ob- making it more specific. Pregabalin's shorter titration
served significant pain reduction at higher doses when period may allow for a faster onset of action vs. gabap-
compared to placebo.20 In addition, Sindrup et al.,15 entin at providing pain relief.12,21,22 Gabapentin and
compared venlafaxine to imipramine and showed no pregabalin significantly improve pain compared to
significant difference between active drugs in relieving placebo (Table 5). Treatment of 4.7 (4.0 5.6, 95%
pain. The equivalent efficacy at higher doses vs. TCAs CI) patients results inl patient achieving 50% reduc-
provides an option in the treatment of diabetic periph- tion in neuropathic pain." Gilron et al.,23 and Morello
eral neuropathy. et al.,25 compared gabapentin against morphine and
amitriptyline, respectively, and found no significant
Calcium Channel Modulators (a2 6 ligands) difference between the drugs when used alone. How-
Gabapentin and pregabalin are the two calcium ever, combination of morphine and gabapentin to-
channel modulators that are used in diabetic periph- gether at lower doses significantly improved pain re-
eral neuropathy. These agents bind voltage-gated cal- lief when compared to either drug alone. Both gabap-
cium channels (at a2 6 subunit) and interact with L- entin and pregabalin share the same adverse event

TABLE 4. Clinical trials of SNRIs for the treatment of diabetic peripheral neuropathy.
Wernicke, et al.17 12 wk, R, DB, Duloxetine 60mg and 120mg Both doses improved 24 hr mean PSS more than PL,
(2006) PC vs. PL beginning at wk 1
N = 334 No significant differences between the 2 doses
Goldstein, et al."8 12 wk, R, MC, Duloxetine 60mg and 120mg Both doses improved 24 hr mean PSS more than PL at
(2005) DB, PG vs. PL wk 1
N = 457
Raskin, et al.19 12 wk, R, MC, Duloxetine 60mg and 120mg Both doses improved 24 hr mean PSS more than PL
(2005) DB, PG vs. PL 120mg group had more frequent adverse events vs.
N = 348 other groups
Rowbotham, et al.20 6 wk, R, MC, Venlafaxine ER 75mg and Higher doses of venlafaxine significantly reduced VAS-
(2004) DB, PC 150-225 mg vs. PL P1 and VAS-PR compared with PL
N = 244
wk = week; R = randomized; DB = double-blind; PC = placebo-controlled; MC = multi-center; PG = parallel group; PL = placebo; PSS = pain sever-
ity score; VAS-PI = visual analog scale pain intensity; VAS-PR = visual analog scale pain relief

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TABLE 5. Clinical trials of calcium channel modulators for the treatment of diabetic peripheral neuropathy.

wk = week; R = randomized; DB = double-blind; APC = active placebo-controlled; PC = placebo-controlled; MC = multi-center; PG = parallel
group; DD = double dummy; CO = cross-over; PL = placebo; SF-MPQ = Short Form McGill Pain Questionnaire; MSDA = mean score diary analysis;
SF-36 = Short Form Health Survey; POMS = Profile of Mood States; PGIC = Patient Global Impression of Change; CGIC = Clinical Global Impression
of Change.

profile, including sedation, dizziness, peripheral
edema. These drugs should be used with caution in
patients with renal insufficiency.

Opioids are potent i-receptor agonists and medi-
ate analgesia by changes in the perception of pain at
the spinal cord.28 Strong opioids like morphine, oxy-
codone and several others exhibit analgesic effects
similar to TCAs and gabapentin in the setting of
DPN.23,25 However, opioids are not recommended as
first line therapy due to concern over long term safety.
In addition, opioids produce more side effects com-

pared to gabapentin.23 Opioids carry the potential for
abuse, and are therefore not recommended as 1st line
Tramadol, a weak opioid, is a partial LI agonist and
also inhibits reuptake of 5-HT and NE.29 Sindrup et
al.32 and Harati et al.33 showed tramadol significantly
lowers overall pain when compared to placebo (Table
6). For one patient to achieve 50% neuropathic pain
reduction, 2.5 (2.0 3.2, 95% CI) and 3.9 (2.7 6.7,
95% CI) patients need to be treated with strong
opioids and tramadol, respectively.
The most common side effects with opioids are
constipation, nausea, and sedation (Table 2).

TABLE 6. Clinical trials of opioids for the treatment of diabetic peripheral neuropathy.
Watson, et al.30 4 wk, R, DB, CO Oxycodone CR 10mg 40mg CR oxycodone significantly lowered mean daily pain,
(2003) Q 12 H vs. APC of benztropine steady pain, brief pain, skin pain, and total pain com-
N = 45 0.25mg 1mg Q 12 H pared to PL.
Gimbel, et al.31 6 wk, R, DB, PC, Oxycodone CR 10mg 60mg CR oxycodone provided more analgesia vs. PL in the
(2003) PG, MC Q 12 H vs. PL overall daily pain intensity.
N = 159
Sindrup, et al.32 4 wk, R, DB,PC, Tramadol 200mg/day to Tramadol lowered pain (p=0.001), paraesthesia
(1999) CO 400mg/day vs. PL (p=0.001), touch-evoked pain (p<0.001), allodynia
N = 45 (p=0.012) vs. PL.
Harati, et al.33 42 days, R, DB, Avg. tramadol 210 mg/day vs. Tramadol more effective (P < 0.001) than PL in MPIC.
(1998) PC, PG, MC PL
N = 131
wk = week; R = randomized; DB = double-blind; APC = active placebo-controlled; PC = placebo-controlled; MC = multi-center; PG = parallel
group; CO = cross-over; PL = placebo; MPIC = mean pain intensity score

n6 N V l 25 I1. 10 l01

Gilron, et al.23
N = 57

Backonja, et al.24
N = 165
Morello, et al.25
N = 28
Rosenstock, et al.26
N = 146

Lesser, et al.27
N = 338

4 wk, R, DB, Morphine 120mg alone vs.
APC, CO Morphine 60mg and
Gabapentin 2400mg vs.
Gabapentin 3200mg vs.
Lorazepam 1.6mg
8 wk, R, DB, Gabapentin 900mg to
PC, MC 3600mg vs. PL

6 wk, R, DB, Gabapentin 900mg -
DD, CO 1800mg vs. Amitriptyline
25mg -75mg
8 wk, R, DB, Pregabalin 300mg/day vs.

5 wk, R, DB, Pregabalin 300mg/day vs.
MC, PC Pregabalin 600mg/day vs.

. Total scores on the SF-MPQ were 14.4 with PL, 10.7 with
. gabapentin, 10.7 with morphine, and 7.5 with the
gabapentin-morphine combination (p<0.05 for the com-
bination vs. each other group).

. Gabapentin significantly reduced mean daily pain score
compared with PL

. No significant differences in MSDA scores between the
two treatments
. No significant period or carry-over effects seen.
. Significantly greater improvement with pregabalin for
mean pain scores, mean sleep interference scores, total
SF-MPQ scores, SF-36 scores and POMS scores com-
pared with PL
. Both doses showed early and sustained improvement in
mean pain score, weekly pain score, sleep interference
score, PGIC, CGIC, SF-MPQ and SF-36 vs. PL.

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TABLE 7. Clinical trials of topical agents for the treatment of diabetic peripheral neuropathy.
Meier, et al.35 7 day, R, MC, Lidocaine 5% patch vs. PL Lidocaine 5% patch effective in reducing ongoing pain (P =
(2003) PC, TW, CO 0.017), allodynia (P = 0.023) during the 1st 8 hours and over a
N = 40 period of 7 days (P = 0.018) in diverse focal PNPS.
The Capsaicin 8 wk, R, MC, DB Capsaicin 0.075% cream 4 Capsaicin significantly improved pain as measured by PGES,
Study Group36 times a day vs. PL (vehicle decreased pain intensity and offered greater pain relief com-
N = 252 cream) pared with PL
wk = week; R = randomized; MC = multi-center; PC = placebo-controlled; TW = two-way; CO = cross-over; DB = double-blind; PL = placebo; MPIC
= mean pain intensity score; PNPS = peripheral neuropathic pain syndrome; PGES = Physician's Global Evaluation Scale

TopicalAgents: Lidocaine & Capsaicin
Lidocaine produces analgesia via reversible nerve
conduction blockade.34 Conversely, capsaicin reduces
substance P and flare response.12 Both of these can be
used as an add-on therapy for localized, pain. Lido-
caine 5% patch effectively reduces ongoing pain and
allodynia during the first 8 hours over a period of
seven days.25 Capsaicin significantly decreases overall
pain relief. Finnerup et al., demonstrated that 1 patient
would be expected to obtain _> 50% pain relief for
every 6.7 (95% CI, 4.6 12) patients treated with cap-
saicin. Similarly, 4.4 (95% CI, 2.5 17) patients need
to be treated with lidocaine for 1 patient to see 50%
pain relief. Skin irritation, erythema, and rash are com-
mon side effects with both drugs.


DPN is a heterogeneous disease diagnosed by ex-
clusion of other causes. There are numerous theories
of DPN's pathophysiology, all of which result in nerve
fiber loss. First line therapy for DPN is usually a TCA
amitriptylinee) due to their once daily dosing and low
cost. SNRIs (duloxetine, venlafaxine) are higher cost
alternatives with similar efficacy when compared to
TCAs. Strong evidence supports gabapentin as equally
efficacious to TCAs. Although no head to head trial ex-
ists, pregabalin works the same as gabapentin with
higher affinity.
Due to lack of long term safety data and potential
concerns regarding abuse, strong opioids (morphine)
are second line therapy. Weak opioids (tramadol) may
be a better alternative than strong opioids. For pa-
tients whose DPN is not completely controlled with
monotherapy, add-on treatment with either lidocaine
patch or capsaicin may be effective.



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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacotherapy and Translational
University of Florida

John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor

[* w w y w w y w w w

Pha rma Note Volume 25, Issue 10 July 2010


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