ORIGINAL INVESTIGATION

Randomized Double-blind Study

Comparing the Efficacy of Gabapentin
With Amitriptyline on Diabetic Peripheral
Neuropathy Pain
Candis M. Morello, PharmD; Susan G. Leckband, RPh, BCPP; Carol P. Stoner, PharmD, BCPS;
David F. Moorhouse, MD; Gregory A. Sahagian, MD

Background: Reports of gabapentin use in diabetic pe-
ripheral neuropathy pain stimulate a need for con-
trolled trials to determine its comparative efficacy to the
therapeutic standard of amitriptyline hydrochloride.
Objective: To determine the efficacy of gabapentin com-
pared with amitriptyline in treating diabetic peripheral
neuropathy pain.
Design: Prospective, randomized, double-blind, double-
dummy, crossover study.
Setting: Veterans Affairs San Diego Healthcare Sys-
tem, Ambulatory Care Clinic.
Patients: Twenty-eight veterans were referred by their
primary care providers. Two patients withdrew before ran-
domization because of no neuropathic pain after wash-
out; a third withdrew for unexpected surgery that re-
quired analgesics. Three patients withdrew because of
adverse effects and 1 for protocol violation.
Interventions: Patients with stable glycemic control and
neuropathic pain randomized to 6 weeks of therapy with
gabapentin, 900 to 1800 mg/d, or amitriptyline hydro-
chloride, 25 to 75 mg/d, with a 1-week washout before
crossover.
Main Outcome Measures: Pain relief measured by pain
scale with verbal descriptors and global pain score as-
sessment at treatment end.
Results: Participants and investigators were blinded
throughout. Mean dosages were of gabapentin, 1565 mg/d,
and of amitriptyline hydrochloride, 59 mg/d. Sixty-five
percent of patients reached maximum dose with gabap-
entin and 54% with amitriptyline. Mean score diary analy-
sis showed pain relief with gabapentin and amitripty-
line was not significantly different (P = .26). Global data
were obtained from 21 of 25 enrolled patients who com-
pleted the study. Moderate or greater pain relief was ex-
perienced in 11 (52%) of 21 patients with gabapentin and
14 (67%) of 21 patients with amitriptyline. There were
no significant period or carry-over effects (P = .35).
Conclusions: Although both drugs provide pain relief,
mean pain score and global pain score data indicate no sig-
nificant difference between gabapentin and amitripty-
line. Gabapentin may be an alternative for treating dia-
betic peripheral neuropathy pain, yet does not appear to
offer considerable advantage over amitriptyline and is more
expensive. Larger trials are necessary to define gabapen-
tins place in treating diabetic peripheral neuropathy pain.
Arch Intern Med. 1999;159:1931-1937

From the Veterans Affairs
San Diego Healthcare System
(Drs Morello, Stoner,
Moorhouse, and Sahagian and
Ms Leckband), and the
Department of Neurosciences,
University of California at
San Diego Medical Center
(Drs Moorhouse and
Sahagian), San Diego, Calif.
D
IABETIC PERIPHERAL neu-
ropathy (DPN) is one of
the most common symp-
tomatic, long-term com-
plications in patients with
both type 1 and type 2 diabetes mellitus.1
At initial diagnosis, 7.5% of patients will
already experience DPN pain, and ap-
proximately 45% will be afflicted with this
complication after 25 years.2 At this time,
however, the exact cause of DPN is not well
understood.3,4
Two main types of diabetic neuropa-
thy involve the autonomic or somatic
nervous systems.3,5 The most common
type of DPN is somatic or sensorimotor
neuropathy with peripheral symptoms
of burning, shooting, tingling, and allo-
dynia. 3 Typically, the sensorimotor
neuropathy presents in a distal symmet-
ric pattern, with a glove-and-stocking
distribution.
Although DPN pain is prevalent
among patients with diabetes, current
treatment options, including antidepres-
sants, anticonvulsants, antiarrhythmics,
and topical capsaicin, are limited by their
variable efficacy and adverse effects.6-12
Amitriptyline hydrochloride is effective in
approximately 60% to 75% of patients
treated for DPN, which is consistently
greater than that reported with other
agents.6,7 Of concern with all available drug
therapies are the extensive adverse ef-

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 PATIENTS AND METHODS
PATIENTS
From March 1997 to December 1997, patients who were vet-
erans were referred by primary care providers, neurolo-
gists, diabetologists, and anesthesiologists at the Veterans Af-
fairs San Diego Healthcare System (VASDHS). Patients were
included if they were 18 years or older, had diabetes melli-
tus with stable glycemic control defined as a hemoglobin A1c
level between 0.043 (4.3%) and 0.079 (7.9%) within 3
months, experienced chronic daily pain for more than 3
months, during which both the quality and location were
consistent with DPN pain, as diagnosed by a neurologist
(D.F.M. and G.A.S.), and had an estimated creatinine clear-
ance of 0.50 mL/s (30 mL/min) (Table 1 and Table 2).33
Patients were excluded from the study if they had non-
DPN pain more severe than DPN pain; allergy or adverse
reaction to gabapentin or amitriptyline; severe depression
by diagnosis or as assessed with the Beck Inventory34; were
pregnant; were receiving treatment for seizures; had car-
diovascular symptoms of postural hypotension, symptom-
atic coronary artery or peripheral vascular disease; or a cre-
atinine clearance of less than 0.50 mL/s (,30 mL/min).
Patients who had received prior treatment with gabapen-
tin or amitriptyline were not excluded, regardless of whether
treatment was deemed a success or failure. Patients were
excluded, however, if their previous dosage exceeded the
studys maximum dosage of either drug.
Use of any medications for DPN pain that patients were
taking before the study was discontinued for 2 weeks be-
fore entering the study and throughout the study period.
fects, particularly anticholinergic effects of the tricyclic
antidepressants.
In 1993, gabapentin, a g-aminobutyric acid ana-
log, received Food and Drug Administration approval for
adjunctive treatment of partial seizures, with and with-
out secondary generalization in adults with epilepsy.13
Despite extensive studies,14-18 gabapentins mechanism of
action is unknown. Yet, even without this mechanism of
action fully elucidated, there has been an increasing num-
ber of case reports of gabapentins use in neuropathic pain
syndromes such as reflex sympathetic dystrophy, post-
herpetic neuralgia, migraine, trigeminal neuralgia, eryth-
romelalgia, Guillain-Barre syndrome, or other intrac-
table pain states in dosages ranging from 900 to 2400
mg/d.18-31 Most recently, a placebo-controlled clinical
trial32 in patients with DPN pain has established the ef-
ficacy of gabapentin to provide pain relief.
Gabapentin, with its low adverse effect and drug in-
teraction profile, may offer an effective treatment for DPN
pain. The primary purpose of this study was to determine
the comparative efficacy of gabapentin with amitripty-
line, the standard therapy, in the treatment of DPN pain.
RESULTS
Twenty-eight patients were eligible for study; 3 with-
drew before randomization: 2 because of no neuro-
pathic pain after washout and 1 for unexpected surgery
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All other regular use of analgesics was discontinued; how-
ever, patients were allowed up to 4 doses per day of acet-
aminophen, 325 mg, for severe pain or pain other than DPN.
The study was approved by both the University of Califor-
nia at San Diego and VASDHS human subjects commit-
tees, and all patients gave informed, written consent.
TREATMENT
The study consisted of two 6-week treatment periods with
a 1-week washout period between treatment arms. The neu-
rologist (D.F.M. and G.A.S.) and clinical pharmacist (C.M.M.,
S.G.L., and C.P.S.) screened referred patients for study
inclusion, and baseline demographics were obtained. Pa-
tients receiving treatment for DPN pain began a 2-week wash-
out period before randomization. Patients were given a daily
pain diary and were randomized by the VASDHS clinical re-
search pharmacist, the only unblinded investigator for the
study, to receive either gabapentin or amitriptyline in a
double-blind design per protocol; all other investigators and
patients remained blinded until study termination. At the
end of each treatment period, patients were seen within 24
hours for a neurologic examination and to administer a global
pain assessment rating. The clinical pharmacist (C.M.M.,
S.G.L., and C.P.S.) conducted pill counts to assess study medi-
cation compliance at the end of each treatment period. Fol-
lowing a 1-week washout period, patients were crossed over
to the alternative drug therapy. Although 1 week was suffi-
cient for the complete elimination of either study drug, ef-
ficacy evaluation was based on the patients pain ratings re-
corded during the final week of each treatment, thus allowing
an additional 5 weeks for dissipation of drug effects.
requiring analgesics. Twenty-five patients were en-
rolled in the study. Because of adverse effects, protocol
violation, or voluntary withdrawal, 4 patients withdrew
from the study (2 each from the gabapentin and amitrip-
tyline treatment arms). In addition, 3 patients were crossed
over early per protocol because of intolerable adverse ef-
fects (2) or intolerable pain (1); 1 of whom also dropped
out of the study. Thus, whereas 21 patients underwent
both treatment arms of the study, 19 completed 6 weeks
of treatment with both study drugs (Figure 1). For sta-
tistical analyses of mean pain diary scores, all patients
were included to prevent bias of study results by omit-
ting those with early crossover due to intolerable pain
or adverse effects. Data analysis excluding early cross-
over patients did not produce statistically significant dif-
ferences (P = .13).
Of the 25 enrolled patients, 12 were initially ran-
domized to the gabapentin treatment arm, 11 of whom
crossed over to amitriptyline. During the gabapentin treat-
ment arm, 1 patient experienced adverse events (diar-
rhea and ankle edema) and voluntarily withdrew from
the study. In addition, 2 patients taking gabapentin were
crossed over to amitriptyline early (week 4) because of
intolerable adverse effects (sedation and dizziness) or in-
tolerable pain, respectively; 1 of whom eventually with-
drew from the study because of adverse events.
Thirteen of the 25 patients were initially random-
ized to the amitriptyline treatment arm, 11 of whom
 During each treatment period, drug dosage was ti-
trated for 2 days to minimize adverse effects, after which
the dosage was adjusted based on the patients clinical re-
sponse and adverse effects (Table 3 and Table 4). Daily
doses of gabapentin ranged from 900 to 1800 mg, and ami-
triptyline hydrochloride, from 25 to 75 mg. To preserve the
double-blind study design, placebo was used to maintain
a 3-times-per-day dosage regimen for each study drug (Table
3). Patients received 2 bottles of study medication and were
instructed to take the 9 AM and 3 PM doses from the first
bottle and the 9 PM dose from the second bottle, which were
labeled accordingly.
The clinical pharmacist called patients on days 2, 4,
and 6 of the first week and days 1 and 4 of the fourth week
of each treatment arm to assess pain control and adverse
effects. Patients were interviewed for frequency and sever-
ity of the 20 most common adverse effects of the 2 study
drugs and any other adverse effects experienced. The pur-
pose of the call was to adjust drug dosage to the maximum
tolerated for pain control without intolerable adverse ef-
fects. Patients continued to take the maximum tolerated
dosage for the remainder of the treatment arm.
EVALUATION
The Pain Scale Rating System and Global Rating Scale were
used to measure pain relief. Patients rated their pain by com-
pleting a daily pain diary in which they chose from a scale
of 13 words describing pain intensity, ranging from none
to extremely intense.35-37 These verbal descriptors were quan-
tified, based on a ratio-scale technique described by Gracely
et al,35 which has been shown to be reliable and consistent
in previous studies35-39 involving human clinical and ex-
perimental pain; it distinguished active treatment from con-
trol. The pain diary was collected at the end of each treat-
ment period. A neurologist evaluated patients at baseline
and at the end of each treatment arm. In this evaluation,
the neurologist asked patients to make a global rating of
their overall pain relief (complete, a lot, moderate, slight,
none, or pain worse) at the end of each treatment arm com-
pared with their baseline pain before entering the study.
STATISTICAL ANALYSIS
For statistical purposes, the verbal descriptors in the pain
diary were converted to numerical equivalents using the
Pain Scale Rating System as described by Gracely et al.36
The mean pain scores in each final treatment week were
compared within patients by paired, 2-tailed t test. Period
and sequence effects were examined for scores in the final
treatment week by a t test. Global Rating Scale scores were
analyzed with a paired, 2-tailed Wilcoxon signed rank test.
A 1-sample sign test was used to analyze the frequency and
severity of adverse effects between amitriptyline and gaba-
pentin, and the Wilcoxon signed rank test was used to ana-
lyze the frequency and severity of adverse effects with time
for each medication.
STUDY DRUG PREPARATION
Study drugs were prepared at a Food and Drug Adminis-
trationregistered repackaging facility. Since this was a
double-blind design, all capsules were identical in taste,
color, size, and shape.

Table 1. Patient Characteristics Table 2. Painful Diabetic Neuropathy Characteristics

Study Group No. of

Characteristics (N = 25) Characteristics Patients*
Sex, M/F 24/1 Duration of pain, mean SD, y 5.7 4.2
Ethnicity Distribution of pain
White 23 Feet 5
African American 2 Feet, legs 15
Age, mean SD, y 60.4 10.8 Feet, legs, hands 4
Type of diabetes, 1/2 3/22 Feet, legs, hands, thigh 1
Duration of diabetes, mean SD, y 13.4 11.3 Quality of pain
Diabetes treatment, No. of patients Pins and needles 18
Diet 16 Tingling 17
Insulin 16 Burning 16
Metformin 9 Sharp 10
Sulfonylurea 7 Aching 8
Troglitazone 1 Shooting 8
Diabetic control, mean SD Allodynia 7
Initial hemoglobin A1c* 0.071 0.005 Cramping 7
Final hemoglobin A1c 0.069 0.006 Cold 6
Creatinine clearance, mL/s 1.26 0.37 Jabbing 3

*To convert hemoglobin A1c to a percentage, divide by 0.01. *Data are presented as number of patients unless otherwise indicated.
To convert creatinine clearance from milliliters per second to milliliters
per minute, divide by 0.01667.

crossed over to gabapentin. During the amitriptyline treat- after crossover because of increasing pain from arthritis
ment arm, 1 patient experienced adverse events (bilateral that exceeded DPN pain. One patient taking amitripty-
ankle edema and dizziness), which resulted in discontinu- line crossed over to gabapentin early (week 4) because of
ation of drug use, and 1 voluntarily withdrew from the study intolerable adverse effects (sedation and constipation).

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 Table 3. Dose Titration to Maximum Tolerated*

Dose Level 9 AM Dosage 3 PM Dosage 9 PM Dosage Total Daily Dosage

Initiation phase day 1 Placebo Placebo 12.5 mg of amitriptyline or 12.5 mg of amitriptyline or
Placebo Placebo 300 mg of gabapentin 300 mg of gabapentin
Initiation phase day 2 Placebo or 300 mg of Placebo 25 mg of amitriptyline or 25 mg of amitriptyline or
gabapentin Placebo 300 mg of gabapentin 600 mg of gabapentin
Level 1 Placebo or 300 mg of Placebo or 300 mg 25 mg of amitriptyline or 25 mg of amitriptyline or
gabapentin of gabapentin 300 mg of gabapentin 900 mg of gabapentin
Level 2 Placebo or 300 mg of Placebo or 300 mg 2 3 25 mg of amitriptyline or 50 mg of amitriptyline or
gabapentin of gabapentin 2 3 300 mg of gabapentin 1200 mg of gabapentin
Level 3 2 3 placebo or 2 3 300 Placebo or 300 mg 3 3 25 mg of amitriptyline or 75 mg of amitriptyline or
mg of gabapentin of gabapentin 3 3 300 mg of gabapentin 1800 mg of gabapentin

*Amitriptyline was given as amitriptyline hydrochloride.

Registered or Eligible Patients

Table 4. Dosage Titration Algorithm*
(N = 28)

No Intolerable Tolerable Intolerable

Not Randomized (n = 3)
Pain Control Adverse Effects Adverse Effects Adverse Effects Reasons:
No pain Maintain at Maintain at Reduce to No DPN Pain After Initial Washout (n = 2)
same level same level lower level Unexpected Surgery Requiring Analgesics (n = 1)
Tolerable pain Advance to Advance to Reduce to
higher level higher level lower level
Randomization (N = 25)
Intolerable pain Advance to Advance to Crossover or
higher level higher level discontinue

Randomized to Receive Randomized to Receive

*Patients were telephoned on days 2, 4, and 6 of the first week and days 1
Gabapentin as Treatment 1 Amitriptyline as Treatment 1
and 4 of the fourth week of each treatment arm to assess pain control and
(n = 12) (n = 13)
adverse effects.

The clinical characteristics of the patients enrolled 1 Patient Withdrew Because of Adverse 1 Patient Withdrew Because of
Event/Protocol Violation Adverse Events
in the study were consistent with the general diabetic 1 Patient Early Crossover Because of 1 Patient Withdrew Because of
population, with the exception of a higher male-to- Intolerable Adverse Effects Protocol Violation
female ratio (Table 1). Study patients experienced typi- 1 Patient Early Crossover Because of 1 Patient Early Crossover Because of
Intolerable Pain Intolerable Adverse Effects
cal features of DPN pain (Table 2), for which they had
received prior treatment, including amitriptyline (14),
nonsteroidal anti-inflammatory drugs (3), nortriptyline Crossed Over to Receive Crossed Over to Receive
Amitriptyline as Treatment 2 Gabapentin as Treatment 2
hydrochloride (1), gabapentin (1), carbamazepine (1), (n = 11) (n = 11)
opioid analgesics (1), and capsaicin (1). Only 1 patient
had prior treatment with 2 medications and 1 with 4 medi-
cations. At the time of study enrollment, only 1 patient 1 Patient Withdrew Because
of Adverse Event
was receiving gabapentin and 9 receiving amitriptyline
required washout before study entry.
Completed Trials With Early Crossover Completed Trials With Early Crossover
PAIN RELIEF: (n = 10) (n = 11)
PAIN INTENSITY SCORE ANALYSIS Fully Completed Two 6-Week Trials Fully Completed Two 6-Week Trials
(n = 9) (n = 10)

After excluding data of patients who did not fully com-
plete both treatment arms, the weekly mean pain scores
of the remaining 19 patients are shown in Figure 2. In
patients treated with gabapentin followed by amitripty-
line, pain scores steadily declined during the first 2 weeks
of dosage titration, followed by a plateau effect of pain
relief. The pain returned during the 1-week washout pe-
riod and then declined during the second treatment arm.
A similar response was seen in patients treated with ami-
triptyline followed by gabapentin.
Comparing the baseline pain scores in 21 patients
who underwent both treatment arms to the end-of-
treatment pain scores, there was a statistically signifi-
cant difference in pain score reduction in patients treated
with both gabapentin (P,.001) and amitriptyline
(P,.001) by 2-tailed, paired Student t test. However, the
Figure 1. Profile of the study. DPN indicates diabetic peripheral neuropathy.
Amitriptyline was given as amitriptyline hydrochloride.
mean difference between drugs in pain intensity scores
during the final week of treatment favored amitriptyline
by 0.091 unit (95% confidence interval, 0.074 to 0.256),
in which 0.35 units was the difference between moder-
ate and mild pain.35 Thus, there was no statistically sig-
nificant difference in pain intensity scores between gaba-
pentin and amitriptyline by the end of treatment (P = .26).
PAIN RELIEF:
GLOBAL PAIN SCORES ANALYSIS
Based on the global description of pain relief for pa-
tients who underwent each treatment arm (Table 5),

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 moderate or greater pain relief was experienced in 11
(52%) of 21 patients during gabapentin treatment and
14 (67%) of 21 patients during amitriptyline treatment.
There was no statistically significant difference in pain
relief between groups (P..1 by 2-tailed, paired Wil-
coxon signed rank test), significant period or carryover
effects were not detected, and there was no correlation
between global score and maximum dosage achieved.
PAIN RELIEF:
CHANGES FROM BASELINE
Figure 3 shows the mean changes in pain intensity dur-
ing the first 6 weeks of each study drug for the 19 pa-
tients who fully completed their first treatment arm. Mean
(SE) pain diary scores decreased by 0.31 0.064 unit
when patients were treated with gabapentin and
0.44 0.089 unit with amitriptyline. Although the mean
pain score change from baseline favored amitriptyline,
there was no statistically significant difference by paired
t test (P = .3).
Crossover From Amitriptyline to Gabapentin
Crossover From Gabapentin to Amitriptyline
1.2 Washout
Moderate
1.0
Mean Pain Score
0.8
Mild
0.6
Weak
0.4
0.2
None
0 1 2 3 4 5 6 7 8 9 10
Week
Figure 2. Pain diary or pain intensity scores. Weekly mean pain intensity
scores are plotted for 19 patients who completed pain diary entries for both
6-week treatment arms. Each curve depicts a single group of patients receiving
both arms of consecutive drug treatments and the intervening washout period,
with groups crossing over, either from amitriptyline hydrochloride to
gabapentin (solid squares) or from gabapentin to amitriptyline (circles). Four
verbal descriptors are shown next to equivalent numerical pain scores. No
statistically significant differences were found between each weekly pain score
within each treatment group, ie, amitriptyline at week 0 vs gabapentin at week
7, amitriptyline at week 1 vs gabapentin at week 8, etc (by 1-way analysis of
variance and Fisher Protected Least Significant Difference post hoc test for
comparing weekly mean pain scores between drugs).
Table 5. Global Ratings of Pain Relief in Patients With Diabetic Peripheral Neuropathy*
Drug Complete A Lot
Gabapentin 5 24
Amitriptyline hydrochloride 5 19
*Data are from the 21 patients who were treated with both gabapentin and amitriptyline. There was no statistically significant difference between gabapentin and
amitriptyline ( P..1 by 2-tailed, paired Wilcoxon signed rank test).
Total does not equal the sum of the components because of rounding.
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ADVERSE EFFECTS
Symptoms possibly related to study drugs caused 3 pa-
tients to withdraw from the study (1 receiving gabapen-
tin and 2 receiving amitriptyline) and 2 patients (1 each
receiving gabapentin and amitriptyline) to cross over early
to the alternative treatment arm. Seventeen patients re-
ceiving amitriptyline and 18 patients receiving gabapen-
tin experienced adverse effects (Table 6). With the ex-
ception of weight gain with amitriptyline, there was no
statistically significant difference in occurrence of ad-
verse effects between drugs (P..05). Prevalent adverse
effects included sedation, dry mouth, dizziness, pos-
tural hypotension, weight gain, ataxia, and lethargy.
Comparing the frequency and severity of adverse ef-
fects at study weeks 1 and 4 showed that, with amitrip-
tyline, dry mouth worsened with time (P,.005) and pru-
ritus was worse than with gabapentin at week 1 (P,.03)
but was not statistically significant from gabapentin at
week 4. The frequency and severity of dizziness with gaba-
pentin diminished with time (P = .02).
AVERAGE DOSAGE AND
PATIENT COMPLIANCE
After dosage titration based on individual response, the
mean dosages of gabapentin and amitriptyline hydro-
chloride were 1565 and 59 mg, respectively. Of patients
treated with gabapentin, 65% reached 1800 mg/d, 26%
reached 1200 mg/d, and 9% were maintained with 900
mg/d. With amitriptyline, 54%, 29%, and 17% of pa-
tients reached 75, 50, and 25 mg/d, respectively. Medi-
cation compliance, defined as the total percentage of doses
taken, was 94.8% with gabapentin and 96.4% with ami-
triptyline.
COMMENT
11 12 13
This study was designed to evaluate the efficacy and safety
of gabapentin compared with amitriptyline, the current
standard of therapy for DPN pain. Study results indicate
that, although both gabapentin and amitriptyline pro-
vide statistically significant pain relief by the end of treat-
ment, there was no statistically significant difference be-
tween the 2 drugs, as measured by daily pain diary scores
and global ratings of pain relief. As expected, amitripty-
line provided moderate or greater pain relief in 67% of
patients, which is consistent with previously reported ef-
ficacy rates.6,7 Gabapentin provided moderate or greater
Pain Relief at End of Treatment Period, %
Pain Total of Complete,
Moderate Slight None Worse A Lot, and Moderate
24 14 28 5 52
43 19 14 0 67
1935
 Amitriptyline Table 6. Adverse Effects
0
Gabapentin

No. of Patients
0.1
Amitriptyline
Mean Change From Baseline

Adverse Effect Hydrochloride Gabapentin

0.2 Sedation 8 12
Dry mouth 8* 4
Dizziness 2 7
0.3 Postural hypotension 5 6
Weight gain 6 0
Ataxia 2 5
0.4 Constipation 3 5
Lethargy 5 4
Edema 2 3
0.5 Headache 3 2
0 1 2 3 4 5 6 Pruritus 3 1
Week
Unpleasant taste 1 2
Figure 3. Pain intensity score change from baseline. Each curve plotted Nausea and/or dyspepsia 1 2
represents the mean change in pain intensity score from baseline for the first Diarrhea 1 2
treatment arm in the 9 patients who received gabapentin and 10 who Blurred vision 2 1
received amitriptyline hydrochloride for the full 6 weeks of treatment. A Other 4 3
0.35-unit reduction was the difference between moderate and mild pain. Any adverse effect 17 18
Although mean change from baseline pain relief favored amitriptyline, there
was no statistically significant difference at the end of treatment with a paired
t test ( P = .3). *Incidence and severity worsened with time ( P,.005).
Incidence and severity diminished with time ( P = .02).
P = .01.
Incidence and severity worse than gabapentin at week 1 ( P,.03) but not
pain relief in 52% of patients and reduced pain diary scores statistically significant compared with gabapentin at week 4.
by 0.31 unit, indicating a less-than-moderate impact on
pain relief compared with a 0.44-unit reduction with ami- the manufacturers guidelines for seizure treatment. Higher
triptyline (Figure 3). This is similar to the recently re- dosage ranges may have achieved greater efficacy and
ported efficacy of 60% for gabapentin compared with 33% should be evaluated in future studies. To measure the full
for placebo.31 potential of each drug, it might be useful to titrate the
The limited number of patients enrolled in our study dosage upward, either to complete pain relief or to the
introduces the probability of a type II (b) error.40 Sample maximum tolerated dosage.
size could not be determined since there were no pub- All study patients were initiated with a 2-day dos-
lished studies describing gabapentins efficacy in DPN pain age titration to diminish the occurrence of benign ef-
at study initiation. Post hoc analysis revealed that a sample fects. Although gabapentin is often cited as having a rela-
size of approximately 260 patients per paired crossover tively safe adverse effect profile, both gabapentin and
study would be necessary to provide 80% power to de- amitriptyline had a similar rate of adverse effects. The fre-
tect a mean difference between treatments of approxi- quency and severity of reported adverse effects did not
mately one third of the difference between mild and mod- appear to subside with time, with the exception of wors-
erate pain at a .05 significance level. Larger controlled ening dry mouth with amitriptyline and resolving diz-
trials are needed to determine if there is any detectable ziness with gabapentin. Similarly, dizziness and somno-
difference in efficacy between amitriptyline and gaba- lence were predominant adverse events reported by
pentin. Backonja et al32; however, this was attributed to a forced
Accepting patients with well-controlled diabetes 4-week dosage titration to 3600 mg/d. This information
might have limited the study size, yet hyperglycemia can may be useful for patients when initiating therapy with
decrease the pain threshold, thereby interfering with study either agent, since a slower dosage titration may de-
results. Our patients maintained a stable hemoglobin A1c crease the frequency and severity of adverse effects.
level throughout the study, reducing the potential of hy-
perglycemia interference. Allowing patients who had re- CONCLUSIONS
ceived prior treatment with either gabapentin or ami-
triptyline into the study may have potentially introduced Both gabapentin and amitriptyline in the dosages used
bias, since those who were taking one of these drugs and in this study appear to provide pain relief in DPN pain;
in whom DPN pain had been successfully controlled however, mean pain diary and global pain relief score data
would not likely volunteer to discontinue use of the drug, indicate no statistical difference between them. With the
whereas those who entered the study were more likely exception of weight gain, dry mouth, and dizziness, the
to experience treatment failure. frequency and severity of adverse effects were similar with
Dosage ranges in this study were based on current each drug.
literature and practice standards at the VASDHS. Re- Although gabapentin provides pain relief in pa-
view of amitriptyline for neuropathic pain within our in- tients with DPN pain, it should be reserved as an alter-
stitution indicated that 25 to 75 mg/d was the most preva- native to patients in whom a less costly agent fails, such
lent dosage range. Gabapentin dosage remained within as amitriptyline, or for whom tricyclic antidepressants

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1999 American Medical Association. All rights reserved.

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 are contraindicated. Our results suggest that larger con-
trolled trials are necessary to further define gabapen-
tins place in the treatment of DPN pain.
Accepted for publication January 25, 1999.
We acknowledge Stephen D. Funk, PharmD, VASDHS
research clinical pharmacist, who maintained the integrity
of the double-blind design as the unblinded investigator;
Veterans Affairs Clinical Research Pharmacy Coordinat-
ing Center at Albuquerque, NM, Mike R. Sather, RPh, MS,
Frank Lueddeke, and Roy W. Fetter, who aided in the prepa-
ration of study drug; Christopher S. Morello, PhD, Univer-
sity of California at San Diego, who performed statistical
analysis of the data; Patricia Hlavin, MD, independent phy-
sician reviewer of adverse events for the study duration; and
Philip O. Anderson, PharmD, manuscript reviewer.
Corresponding author: Candis M. Morello, PharmD,
Veterans Affairs San Diego Healthcare System, Pharmacy
Service (119), 3350 La Jolla Village Dr, San Diego, CA
92161.
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