Fwd: [RSD-WorldNews] Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type

December 16, 2004

Research article

Randomised controlled trial of gabapentin in Complex Regional Pain

Syndrome type 1 [iSRCTN84121379]

Anton C van de Vusse , Suzanne GM Stomp-van den Berg , Alfons HF

Kessels and Wim EJ Weber

Pain Management and Research Centre, Dept. of Anesthesiology, *Dept.

of Clinical Epidemiology and Medical Technology Assessment, Dept. of

Neurology, University Hospital Maastricht, Maastricht, The Netherlands

BMC Neurology 2004, 4:13 doi:10.1186/1471-2377-4-13

The electronic version of this article is the complete one and can be

found online at: http://www.biomedcentral.com/1471-2377/4/13

This is an open-access article distributed under the terms of the

Creative Commons Attribution License

(http://creativecommons.org/licenses/by/2.0), which permits

unrestricted use, distribution, and reproduction in any medium,

provided the original work is properly cited.

Outline Abstract

Abstract

Background

Methods

Results

Discussion

Conclusions

Competing interests

Authors' contributions

Acknowledgements

References

Pre-publication history

Background

Complex Regional Pain Syndrome type one (CRPS I) or formerly Reflex

Sympathetic Dystrophy (RSD) is a disabling syndrome, in which a

painful limb is accompanied by varying symptoms. Neuropathic pain is a

prominent feature of CRPS I, and is often refractory to treatment.

Since gabapentin is an anticonvulsant with a proven analgesic effect

in various neuropathic pain syndromes, we sought to study the efficacy

of the anticonvulsant gabapentin as treatment for pain in patients

with CRPS I.

Methods

We did a randomized double blind placebo controlled crossover study

with two three-weeks treatment periods with gabapentin and placebo

separated by a two-weeks washout period. Patients started at random

with gabapentin or placebo, which was administered in identical

capsules three times daily. We included 58 patients with CRPS type 1.

Results

Patients reported significant pain relief in favor of gabapentin in

the first period. Therapy effect in the second period was less;

finally resulting in no significant effect combining results of both

periods. The CRPS patients had sensory deficits at baseline. We found

that this sensory deficit was significantly reversed in gabapentin

users in comparison to placebo users.

Conclusions

Gabapentin had a mild effect on pain in CRPS I. It significantly

reduced the sensory deficit in the affected limb. A subpopulation of

CRPS patients may benefit from gabapentin.

Complex Regional Pain Syndrome type one (CRPS I) or formerly Reflex

Sympathetic Dystrophy (RSD) is a disabling syndrome, in which a

painful limb is accompanied by varying symptoms like edema,

hyperhidrosis, hypertrichosis, allodynia, coloring of the skin and,

over time, atrophy of the involved tissue. Spontaneous recovery does

occur and several therapies have been described, but for some patients

CRPS I is a chronic disabling disease[1]. Neuropathic pain is a

prominent feature of CRPS I, occurring in 75% of cases[1], and many

researchers go as far as classifying CRPS I as a neuropathic pain

syndrome [2-6]. Gabapentin (Neurontin®, Pfizer) is an anticonvulsant

with a proven analgesic effect in various neuropathic pain syndromes

[7-15]. Anecdotal reports suggest that gabapentin may also be an

effective analgesic in CRPS patients[3,8,16-27]. To study this

hypothesis, we conducted a double blind, placebo-controlled crossover

trial of gabapentin in 58 patients with Complex Regional Pain Syndrome

type I.

Study population

This study complied with the Declaration of Helsinki regarding

investigations in humans after approval of the protocol by the

Institutional Review Board of the University Hospital Maastricht, the

Netherlands. Patients were recruited from a database with patients

who, in recent years, had been diagnosed with complex regional pain

syndrome type I in our hospital. All patients had been treated in our

pain management and research center (dept. of Anesthesiology,

University Hospital Maastricht, The Netherlands) and had received

sympathetic blocks[28], mannitol infusions[29,30], and transcutaneous

neuromodulation[31]. All participating patients fulfilled the IASP

criteria[32] for the diagnosis of CRPS type I and were included if

they were between 18 – 75 years old and had a score for pain > 3, as

rated on a visual analog score (VAS), where 0 is no pain and 10 is the

worst pain imaginable. Apart from IASP criteria, all patients had

functional loss and pain outside the original traumatized area.

Patients were excluded in case of a possibility of health risk or

confounding by other diseases of syndromes, like e.g., pregnancy,

known kidney and/or severe liver disease, another (2nd) chronic pain

syndrome, known nerve damage in the affected area, active infection or

diabetes mellitus. Patients were participating in 8-week periods from

19-11-1998 until 2-12-1999. Gabapentin was not registered as a drug in

the Netherlands before or during the trial. After the trial the

producing pharmaceutical company supplied gabapentin for compassionate

use if indicated.

Treatment

Since our patient population consisted of chronic CRPS I patients with

a multiple years' duration of pain complaints refractory to various

treatments, we assumed that their pain complaints would be more or

less stable. We therefore undertook a double blind, randomized

crossover study. Randomization of patients took place after baseline

measurements and written informed consent. The assignment scheme was

generated by our hospital pharmacy from a table of random numbers. The

closed envelopes containing the assignments were prenumbered and kept

at the pharmacy. The first treatment group received gabapentin,

followed by a washout period and placebo treatment. The second

treatment group received placebo treatment, which was followed by a

washout period and gabapentin treatment. Each medication period lasted

three weeks separated by the two-weeks washout period. Medication was

stocked and delivered to the patient at the hospital pharmacy. Both

the gabapentin capsules and the identical placebo capsules were

delivered immediately before the start of the two medication periods.

Left over medication was recollected and counted.

The gabapentin (GBP) dose was slowly increased to reduce adverse side

effects:

600 mg's GBP AN once a day on day 1–2

600 mg's GBP b.i.d. on day 3–4

600 mg's GBP t.i.d on day 5–21

Placebo dose was identically titrated. Patients were allowed to take

their usual analgesics and were told preferably not to change the

usual dose.

Follow-up measurements

The patients were reevaluated at the hospital three weeks (T1), five

weeks (T2) and eight weeks (T3) after randomization. During the trial,

the patient noted her/his pain rate of the past 24 hr (VAS) and the

use of additional analgesics in a diary. During each hospital visit

the following assessments were done:

1. Global perceived effect (GPE) on pain indicating: worst ever; much

worse; somewhat worse; not improved/not worse; somewhat improved; much

improved and best ever. GPE on function was scored on an analogous scale.

2. Neuropathic pain scale (NPS), a 10 item qualitative evaluation of

neuropathic pain[33].

3. Sensibility through Von Frey monofilament skin application each on

9 areas corresponding to cutaneous nerve branches and dermatomes of

either both hands or both feet[34]. Stimulus placement of filaments

was as follows: one second for placement, one second for bending and

one second for removal. (handset with resp. 0.0677, 0.4082, 2.052 and

3.632 grams calculated force, North Coast Medical, Inc., San José, USA).

4. Mechanic allodynia test with brush strokes and static pressure with

the finger tip[35], on 9 areas corresponding to cutaneous nerve

branches and dermatomes of either both hands or both feet.

5. Edema, discoloration, and changed skin temperature were scored

after physical examination on a three point scale indicating no, some

or overt presence of each sign, the latter two signs in comparison to

the healthy or healthiest limb. Physical examination in CRPS is well

comparable to instrumental evaluation of signs with volumeter,

infrared thermometer and goniometer[36].

6. Impairment and disability tests: Symptom Checklist-90-Revised

(SCL-90-R)[37], Brief Pain Inventory[38], adapted for CRPS to measure

the influence of CRPS in general on daily life by 0–10 scale ranging

from 0 ('CRPS has not interfered') to 10 ('CRPS completely

interfered'), 'range of motion' as a parameter of limb function.

Side effects during treatment

A blinded independent investigator (STvdB) did sensibility, allodynia

and range of motion tests (see above). A physician (AvdV), who

examined each patient, did all the other measurements throughout the

trial. Patient, investigator and physician were unaware of the

treatment received. We tested blinding by questioning physician and

participants after each medication period.

Statistical analysis

The statistical analysis of VAS-scores was determined per patient

using estimating medication and period effect through linear

regression analyses. Possible relationship of patient characteristics

and outcome was tested by Pearson R's test. Mann-Whitney analyses were

used for monofilament sensitivity on log-transformed data. Three point

scales and seven point scales were dichotomized and like the SCL-90-R,

NPS and CRPS-Brief Inventory questionnaires intra-individual paired

tested (McNemar, t-test, Bonferroni-Holm corrected for multiple

tests). Student t-tests and regression analysis were used to test

treatment effect, which is calculated in crossover studies as

((AT1-AT0)-(AT3-AT2))/2+((BT3-BT2))-BT1-BT0)/2, where A represents

data of placebo starters and B data of gabapentin starters both before

(T0,T2) and after (T1,T3) treatments[39]. Blinding was tested with

Chi-square analyses. Possible related factors to therapy effect were

analyzed with forward stepwise logistic regression. Data analyses

required complete data sets. Patients who were not completing one or

two treatments were excluded for analyses. We tested two-tailed, with

& #945; = 0.05 as a level of significance (Excel 2000, SPSS 10.0 for Windows).

Figures

Figure 1

Selection of patients participating in the trial

Figure 2

VAS for pain in both groups at start (T0), three weeks (T1), five

weeks (T2), and eight weeks (T3) after randomization

Figure 3

Global perceived pain relief (on a seven-point scale) as reported by

patients

Tables

Table 1

Patient characteristics

Table 2

Basic characteristics of participating patients on neuropathic pain

scale (NPS), CRPS brief inventory and SCL-90-R. Data are mean with (±

standard deviation).

Table 3

Patients (%) with global perceived effect on pain in the four arms of

treatment and totals for the two treatments.

Table 4

Mann-Whitney scores of monofilament application in CRPS patients

testing cutaneous sensibility thresholds

Demographics

After randomization 58 patients were enrolled, with a mean age of 44.0

(range 24–75) resulting in 29 patients in the gabapentin-placebo arm

and 29 patients in the placebo-gabapentin arm; 49 patients completed

the gabapentin period, 50 patients the placebo period, 46 patients

completed both periods and were used for further within-patient paired

analysis (Fig. 1). Twelve patients discontinued treatment of which 6

during the placebo treatment, 2 during washout and 4 during GBP

treatment. Three of these four GBP users discontinued due to side

effects (Fig. 1). Between randomization and start of (placebo)

medication one patient withdrew after rereading the information letter

about possible side effects. These patients were excluded from

analysis, since intra-individual testing was necessary for most of the

data-analyses. Patients, who could not be used for analysis, did not

differ in their characteristics from the total group nor comparing

between the two arms of treatment (Tables 1 and 2). When comparing the

placebo-GBP arm and GBP-placebo arm on sexes, age and pain level

before period 1 or 2, duration of illness, SCL-90-R score, we could

not find a difference between the two arms (Tables 1 and 2). SCL-90-R

score revealed increased values on any subscale comparing to standard

norms, indicating personal distress (Table 2). We found relative

higher scores on somatic and sleeping complaints. The SCL-90-R scores

were identical to control chronic pain patients (N = 143), besides

higher score on sleeping complaints (T. Forouzanfar, data not

published). Trial medication was returned and counted afterwards, but

revealed no lack of compliance in any patient.

Blinding

After each medication period both patient and physician were asked

about their ideas concerning study medication in the past period. The

treating physician guessed the used medication correctly more often

after both phases than can be explained by coincidence (p = 0.000).

Blinding for patients was sufficient in the first phase, but not

anymore after the second phase (p = 0.2 versus p = 0.000).

Response to treatment

Pain

Comparing gabapentin and placebo users in terms of pain relief, there

was a significant pain relief in favor of gabapentin in the first

period. Therapy effect in the second period was less, finally

resulting in no significant effect combining results of both periods.

There was an unexpected increase of pain level above baseline in the

washout period for both the gabapentin starters and placebo starters

(Figure 2).

Global perceived pain relief as measured by the seven-point scale

showed a significant effect for gabapentin, and also more pronounced

in the first period. This measurement also found a significant effect

in the second period, with an effect being defined as a patient

scoring 'much improvement'. Statistical analysis of global perceived

effect showed significant more treatment effect (p = 0.002) with 43 %

versus 17 % reported pain relief respectively during gabapentin

compared to placebo treatment. 13 % of patients reported aggravation

of pain during gabapentin vs. 9 % during placebo treatment (Figure 3

and table 3). Stepwise forward logistic regression analysis of

baseline value of pain level, age, sex, duration of illness, location

of illness, mono- or bilateral CRPS, trial arm and all items of

CRPS-BI, NPS and SCL-90-R was performed. Only the level of self care

was related to perceived pain relief during GBP. The neuropathic pain

scale, indicating different aspect of pain, improved significantly in

terms of less hot and more comfortable, but not when corrected for

multiple tests (Bonferroni-Holm correction). We found that during

gabapentin use, patients reported equal use of co-medication comparing

to baseline assessment and placebo-use with a non-significant trend

towards less medication during GBP use.

Sensory tests

Each participant was tested throughout the study on response to

mechanical stimuli with von Frey filaments. The CRPS patients had

sensory deficits at baseline. Application of smaller filaments was not

felt in multiple skin areas. We found, with Mann-Whitney analyses,

that this sensory deficit was significantly reversed in gabapentin

users in comparison to placebo users (p = 0.027). This difference was

found in patients with upper and lower extremity CRPS, but was still

significant in the subgroup of lower extremity CRPS (p = 0.011) as

seen in table 4.

Mechanical allodynia to static and dynamic stimuli (soft touch and

brush) was measured by a mean of 11-point scales (range 0–10) of 9

areas of the hand/feet corresponding to cutaneous nerve branches. We

found no effect of gabapentin on allodynia in comparison to placebo.

Other symptoms

No difference was found on the parameters edema, discoloration, range

of motion of wrist/ankle and fingers/toes between placebo and GBP. 10

patients out of 45 improved in relative skin temperature during

placebo use compared to 18 patients out of 45 in gabapentin, which is

two sided tested not significantly different (McNemar analysis, p =

0.096).

Limb dysfunction and quality of life

The reported function improvement was, with 10 positive responders

during GBP versus 7 positive responders during placebo, not

significantly different (N = 46) between the two treatments. The

SCL-90 showed no significantly better scores during gabapentin

treatment. CRPS-BI showed improvement of sleep between placebo

treatment and gabapentin treatment., but this effect disappeared after

Bonferroni-Holm correction.

Adverse effects

Dizziness, somnolence and lethargy were significantly more often

reported during gabapentin use than during placebo. Before washout 95

% of patients (n = 21) reported side effects during gabapentin use

versus 58 % in placebo treatment (n = 14). After washout this was

respectively 63% (n = 15) in GBP and 32% (n = 7) in placebo use. For

more details on side effects see table 6. Since a high incidence of

side effects can produce a stronger placebo effect, we analyzed the

possible correlation between side effects and pain relief. There was a

small relation between perceived side effects and pain relief in

placebo users in period 2 (p = 0.04, Pearson's R value is 0.4), but,

whether in period 1 or period 2, no relationship was found during the

use of gabapentin (p = 0.2 in period 1, P = 0.4 in period 2).

To evaluate gabapentin treatment as a treatment for pain in CRPS, we

conducted a placebo-controlled crossover study. We conclude from our

trial that overall, gabapentin did not relieve pain as compared to

placebo on pain visual analogue scores, our primary outcome measure.

Gabapentin relieved pain in a subgroup of patients and gave a

significant global perceived pain relief. The effect was mild and

there was no patient in which gabapentin completely eliminated pain.

Moreover, the frequency of side effects as dizziness, somnolence and

lethargy was higher during gabapentin treatment than with placebo.

These side effects probably also account for the relative lack of

blinding we observed in our study. This does not mean that the study

was biased: our population was chronic CRPS patients who all had

undergone numerous unsuccessful treatments, and clearly wanted the

drug to work. Any possible bias would therefore have been positive

towards gabapentin.

Although we did not find a significant pain reducing effect when

analyzing the complete trial, we did find a significant effect in the

first half of the trial. In fact, the difference in outcome between

the two trial halves is striking. There was a reverse carry-over

effect resulting in increasing pain above baseline after the washout

period for both gabapentin and placebo starters. The increase of pain

intensity above baseline level in the second period (before the start

of placebo treatment) cannot be explained pharmacologically.

Gabapentin has no known biological dependency or tolerance mechanism.

It can be a period effect, although this would more likely result in a

regression to the middle instead of increasing pain. Perhaps this is a

reversed placebo effect in which the expectation and/or the actual

perception of not receiving gabapentin anymore might increase pain

intensity. Kemler and de Vet found that treatment allocation in a

trial could influence pain intensity in CRPS[40]. The decreasing

therapy effect after washout is found in other crossover pain

trials[41]. Expectation and attention have been shown to be powerful

influences on pain pathways in the brain[42], and perhaps a crossover

design is not suited to study treatments in chronic pain patients.

We found a decreased sensory deficit in gabapentin users compared to

placebo users. We did not expect this, but found in the literature

several cases in which gabapentin decreased the area of hypesthesia in

neuropathic pain syndromes[43]. This has, to our knowledge, never been

described for any other medication. Numbness or mechanical hypesthesia

is a frequently found complaint for approximately 75 % of CRPS

patients, which can improve in time spontaneously and after placebo

treatment[44]. It is possible that the somatosensory findings and pain

outside the original area of trauma can be attributed to referred pain

mechanisms. Gabapentin has been reported to alleviate referred

pain[45]. Since many CRPS patients have mechanical hypesthesia, we

hypothesize that gabapentin influences some common neural pathway for

'referred' sensations, whether mechanical sensation or pain.

Conclusions

Gabapentin had a mild effect on pain in patients CRPS I. It

significantly reduced the sensory deficit in the affected limb. A

subpopulation of CRPS patients may benefit from gabapentin, but then

for each individual patient the benefit has to be weighed against the

frequently occurring side effects.

Competing interests

Parke- (now a Warner-Lambert/Pfizer division) supplied gabapentin

and matching placebo capsules for this trial. Drs. Van de Vusse and

Weber have received financial support from Parke- to attend one

congress. Parke- has had no role in the writing of this manuscript

Tables

Table 5

Side effects as mentioned after treatment

AvdV initiated the trial and wrote, with WEJW and AHFK, the protocol.

The study and its data management was done by AvdV and SS-vdB. AHFK

did the statistical analyses. AvdV wrote the first draft of the

manuscript, which was finished in its final form by WEJW.

Acknowledgements

We would like to thank Inge Lamé for her support in data management,

Drs. Brad Galer and Mark Jensen for the NPS and CRPS-Brief Pain Inventory.

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