Evidence Tables NEUR2Is gabapentin effective for the treatment of painful neuropathy in people with type 2 diabetes?

ReferenceStudy type Evidence levelNumber of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresEffect sizeSource of funding
M. Backonja, A.
Beydoun, K. R.
Edwards, S. L.
Schwartz, V.
Fonseca, M. Hes, L. Lamoreaux, and E. Garofalo.
Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial.[see comment]. JAMA 280 (21):1831–1836, 1998.
RCT, double blind, multicentre

1++
N=165

(approximately 75% T2D)
Inclusion criteria: type 1 or 2 diabetes, pain from diabetic neuropathy for 1–5yrs, pain rating of ≥40mm on the VAS of the SF-MPQ, av pain score ≥ 4 on an 11-point Likert scale, ≥ 4 observations in daily pain diaries in a week, HbA1c ≤0.11Exclusion criteria: other severe pain, renal impairment, prohibited medications.

Patient demographics at baseline were similar between groups.
N=84
gabepentin TID, titrated dose

(week 1, 900 mg/d; week 2, 1800 mg/d; week 3, 2400 mg/d; week 4, 3600 mg/d)


Medication doses for diabetes remained stable during the study
N=81 matched placebo TID15 weeks

7 week screening phase, 4-week dose titration and 4-week fixed dose
Pain severity rating (recorded in diaries), sleep interference, SF-MPQ scores, PGIC, CGIC and quality of life (SF-36 QOL)All CI 95%
*

Mean pain score

There was a significant difference from gabapentin to placebo at the end point in decrease in pain score; −1.2 (−1.9 to −0.6), p<0.001. Analysed per week this difference was significant from week 2 to week 8 (p<0.05).

*

Mean sleep interference

There was a significant decrease in sleep interference for gabapentin compared with placebo at the end point; −1.47 (−2.2 to −0.8), p<0.001.

*

SF-MPQ

For the total SF-MPQ scores there was a significant decrease for gabapentin compared with placebo; −5.9 (−8.8 to −3.1), p<0.001. This was also noted for both the VAS; −16.9 (−25.3 to −8.4), p<0.001 and the PPI scale; −0.6 (−0.9 to −0.3), p<0.001.

*

PGIC and CGIC

For both of these scales patients treated with gabapentin had significantly greater improvement in pain than patients randomised to placebo (p=0.001)

*

SF-36 QOL

There were significant increases (denotes improvement) in three areas of the SF-36 for gabapentin compared with placebo:

-

bodily pain, 7.8 (1.8 to 13.8), p=0.01

-

mental health, 5.4 (0.5 to 10.3), p=0.03

-

vitality, 9.7 (3.9 to 15.5), p=0.001

*

Adverse events

There was a significantly higher number of adverse events of dizziness (n=20 gabapentin, n=4 placebo, p<0.001) and somnolence (n=19 gabapentin, n=5 placebo, p=0.004)for those in the gabapentin group compared with placebo

Not stated
*Discontinuationn(%)
Gabapentin1416.7
-

adverse events

78.3
Placebo1619.8
-

adverse events

56.2
F. J. GomezPerez, A.
PerezMonteverde, O. Nascimento, P. Aschner, M. Tagle, K. Fichtner, P. Subbiah, E. M. Mustiya, and B. Parsons.
Gabapentin for the treatment of painful diabetic neuropathy: Dosing to achieve optimal clinical response. British Journal of Diabetes & Vascular Disease 4 (3):173–178, 2004.
Open-label, multi centre

1+
N=339 (N=303 T2D)

33 Latin American centres
Inclusion criteria: Type 1 or 2 diabetes, experienced painful polyneuropathy for 1–5yrs, HbA1c ≤11%, pain intensity score of ≥40mm on the VAS of SF-MPQ

Exclusion criteria: Pain due to other causes, other neurological conditions, other serious diseases, prohibited medications.

Groups were well matched, though the titration to clinical effect group had a longer mean duration of diabetes (12.9yrs) than the fixed dose group (10.7yrs).
N=170
Gabapentin, fixed-dose 300mgs TID
N=169
Gabapentin TID, titrating dose (900, 1200, 1800, 2400, 2700 and 3600 mg/day) up to the end of week 3, stable dose weeks 4–7

(Titrated to clinical effect ≥50% reduction in pain)
8 week

1 week screening, 7-week treatment
Per cent reduction in final weekly mean pain score (11-point Likert scale),

Responder rate, VAS of SF-MPQ, sleep interference, CGIC, PGIC, SF-36 QOL
The mean daily dose in the titration-to-clinical-effect group was 1,936mg/day
*

Mean pain score

Gabapentin showed significantly greater reduction in final weekly mean pain scores when titrated to clinical effect compared with a fixed-dose of 900mg/day; 53.6% vs 43.3%, p=0.009.

*

Responder rate

Responder rate (≥50% reduction in final weekly pain score from baseline) was significantly higher in the titration to clinical effect group compared with the fixed dose group (64.5% VS 47.5%, P=0.002)

*

SF-MPQ VAS

This score showed a significant decrease in favour of the titration to clinical effect group compared with fixed dose (p<0.001)

*

Sleep interference

There was a significantly greater reduction in final weekly mean sleep interference score for the titration to clinical effect group compared with fixed dose (57% vs 37.2%, p=0.013)

*

CGIC

There was a significant improvement in CGIC for the titration to clinical effect group compared with the fixed dose group (p=0.02)

*

PGIC

There was no significant difference between the two groups in improvements in PGIC

*

SF-36 QOL

There was no significant difference between the two groups in SF-36 QOL domains

*

Adverse events

The most common adverse events in the titration to clinical effect group and fixed dose groups were somnolence (20.1% vs 15.3%) and dizziness (16.6% vs 13.5%)

Pfizer
*Discontinuationn(%)
Total164.8
Fixed dose
-

adverse events

95.3
Titration doses
-

adverse events

74.1
C. M. Morello, S. G.
Leckband, C. P.
Stoner, D. F.
Moorhouse, and G. A. Sahagian.
Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 159 (16):1931–1937, 1999.
RCT, double blinded, crossover, single centre

1+
N=25 (N=22 T2D), USAInclusion criteria: >18yrs, stable glycaemic control defined as HbA1c between 4.3% and 7.9% within 3 mths, chronic daily pain >3mths consistent with diabetic neuropathic pain

Exclusion criteria: non-neuropathic pain, severe depression, other serious conditions

Patient characteristics given for all participants not per group.
N=12

Gabapentin, titrated for 2 days and dosage adjusted based on clinical response and adverse events.

Doses for gabapentin were; 65% 1800mg/day, 26% 1200 mg/day and 9% 900 mg/day.
N=13

Amitriptyline, titrated for 2 days and dosage adjusted based on clinical response and adverse events.

Doses for amitriptyline were: 54% 75 mg/day, 29% 50 mg/day and 17% 25 mg/day
15 weeks

2 week wash out of any medications being used to treat neuropathic pain, 6 week treatment periods with 1 week washout, followed by 6 week crossover
Pain Scale Rating System, Global Rating Scale
*

Pain intensity score

There were significant reductions in the end of treatment pain scores for both gabapentin (p<0.001) and amitriptyline (p<0.001).

However, there was no statistically significant difference in pain scores between gabapentin and amitriptyline at the end of treatment.

*

Global pain score

There was no statistical difference in pain relief between the groups.

*

Adverse events

With the exception of weight gain with amitriptyline (p<0.03) there was no significant difference in occurrence of adverse vents between the drugs. Adverse effects included sedation, dry mouth, dizzness, postural hypotension, weight gain, ataxia and lethargy.

*

Discontinuation

19 (76%) participants completed 6 weeks of treatment with both study arms, 2 (one from each group) crossed over early due to adverse events and completed the study

Not stated
D. A. Simpson. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. Journal of Clinical Neuromuscular Disease 3 (2):53–62, 2001.RCT, double-blind
*

Reporting only on part 1 of the study – gabapentin vs placebo.



1+
N=60 (N=49 T2D)Inclusion criteria: pain attributed to diabetic neuropathy for 3mths-1.5yrs, type 1 or 2 diabetes from 6mths-17yrs, pain score of ≥40mm on the VAS of SF-MPQ, av score of 4 on an 11-point Likert scale over one week.
Exclusion criteria: other severe pain, renal failure, prohibited medications.

Groups were similar for demographics.
N=30 gabapentin

4 week titration period up to 3600mg/day, 1200mg TID as tolerated1, followed by 4 week fixed dose
N=30 placebo9 weeks

1 week screening, 8 weeks treatment
Mean pain scores ( 11-point Likert scale)

Sleep interference, PGIC, CGIC, SF-36 QOL
*

Mean pain score

There was a significant decrease in mean pain score for gabapentin compared with placebo, −2 vs −0.5, p<0.01.

*

SF-MPQ, sleep interference and SF-36 QOL

Changes in mean sleep interference scores, the SF-36 QOL and SF-MPQ total pain scores also revealed significant improvement in the gabapentin-treated group

*

PGIC and CGIC

There were 55.5% (n=15) in the much/moderately improved category in the gabapentin treated group compared with 25.9%(n=7) in the placebo group; 41% (n=11) compared with 59.3% (n=16) in the minimally improved/no change group and 3.5% (n=1) compared with 14.8% (n=4) who considered they were worse.

Not stated
*Discontinuationn(%)
Gabapentin310
-

due to adverse events

26.6
Placebo310
-

due to adverse events

26.6
K. C. Gorson, C. Schott, R. Herman, A. H. Ropper, and W. M. Rand.
Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol.Neurosurg.Psychiatry 66 (2):251–252, 1999.
RCT, double-blind, crossover

1−
N=40 (number T2D not specified)Inclusion criteria: diabetes for >6 mths on a stable dosage of insulin or oral hypoglycaemic agent, daily neuropathic pain for >3 mths Exclusion criteria: renal insufficiency, other painful conditions, other causes of neuropathyN=19 gabapentin increased up to 900mg/day maintenance dose first phase, 3 week wash out and crossoverN=21 placebo first phase, 3 week wash out, followed by crossover15 weeks

6 weeks dosed, 3 weeks wash out, crossover and 6 weeks dosed
MPQ, global assessment of pain relief
*

MPQ and global assessment of pain

The mean decrease in the MPQ score was 8.9 with gabapentin compared with 2.2 for placebo (p=0.03). There were no differences in the VAS and PPI scores.

The global assessment of pain relief showed no significant differences between gabapentin and placebo.
*

Adverse events

Adverse events were significantly more common with gabapentin compared with placebo (p<0.001), commonest with the gabapentin were drowsiness (n=6), fatigue (n=4) and imbalance (n=3).

*

Discontinuation

Not reported

Warner Lambert (Parke-Davis Pharmaceuticals)
1

Titration incremented in 300mg increases over 4 weeks

Titration incremented in 300mg increases over 4 weeks

From: Evidence Tables

Cover of Type 2 Diabetes
Type 2 Diabetes: National Clinical Guideline for Management in Primary and Secondary Care (Update).
NICE Clinical Guidelines, No. 66.
National Collaborating Centre for Chronic Conditions (UK).
Copyright © 2008, Royal College of Physicians of London.

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