The Comparative Evaluation of Gabapentin and Carbamazepine for Pain Management in Guillain-Barre Syndrome Patients in the Intensive Care Unit
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The Comparative Evaluation of Gabapentin and
Carbamazepine for Pain Management in Guillain-Barré
Syndrome Patients in the Intensive Care Unit
Chandra Kant Pandey, MD*, Mehdi Raza, MD*, Mukesh Tripathi, MD*, Deepa V. Navkar, MD*,
Abhishek Kumar, MD*, and Uttam K. Singh, PhD†
*Departments of Anaesthesiology and †Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,
India
We evaluated the effects of gabapentin and carbamaz- and 2.0) compared with patients in the placebo group
epine for pain relief in 36 Guillain-Barré syndrome pa- (6.0, 6.0, 6.0, 6.0, 6.0, 6.0, and 6.0) and the carbamazepine
tients. Patients were randomly assigned to receive group (6.0, 6.0, 5.0, 4.0, 4.0, 3.5, and 3.0). There was no
gabapentin 300 mg, carbamazepine 100 mg, or match- significant difference in fentanyl consumption between
ing placebo 3 times a day for 7 days. Fentanyl 2 g/kg the gabapentin and carbamazepine groups on Day 1
was used as a supplementary analgesic on patient de- (340.1 ⫾ 34.3 g and 347.5 ⫾ 38.0 g, respectively), but
mand. The pain score was recorded by using a numeric consumption was significantly less in these 2 groups
pain rating scale of 0 –10, and sedation was recorded compared with the placebo group (590.4 ⫾ 35.0 g) (P ⬍
with a Ramsay sedation scale of 1– 6 before medications 0.05). For the rest of the study period, there was a signif-
were given and then at 6-h intervals throughout the icant difference in fentanyl consumption among all
study period. Total daily fentanyl consumption was re- treatment groups, and it was minimal in the gabapentin
corded each day for each patient. The results of the group (P ⬍ 0.05). We conclude that gabapentin is more
study demonstrated that patients in the gabapentin effective than carbamazepine for decreasing pain and
group had significantly lower (P ⬍ 0.05) median nu- fentanyl consumption.
meric pain rating scale scores (3.5, 2.5, 2.0, 2.0, 2.0, 2.0, (Anesth Analg 2005;101:220 –5)
P
ain occurs in approximately 89% of Guillain- drugs have limited efficacy in some pain states and
Barré syndrome (GBS) patients during the have unacceptable side effects (2). For example, the
course of their disease (1). Uncontrolled pain can use of opioids for pain relief may cause tolerance,
occur despite compassionate and supportive measures dependence, respiratory depression, sedation, and
such as the use of air mattresses, careful turning of constipation, and the use of NSAIDs may result in
patients and positioning of limbs, and the use of pad- gastrointestinal ulceration, bleeding, platelet dysfunc-
ding over the elbows and knees to prevent pressure tion, and renal and hepatic failure (3). This warrants
palsies. However, pain in these patients often goes the need for newer drugs with better safety profiles.
unrecognized and undertreated because most of them Carbamazepine (an anticonvulsant) has been used
remain immobilized, require tracheal intubation, and for pain management in trigeminal and glossopharyn-
are unable to communicate their distress (1). geal neuralgia and in GBS (3). Gabapentin, a newer
Patients with GBS require aggressive use of analge- anticonvulsant, has also demonstrated its efficacy in
the treatment of neuropathic pain syndromes, includ-
sics for pain management. Current analgesic therapy
ing diabetic neuropathy (4), postherpetic neuralgia (5),
is based on two classes of drugs, nonsteroidal antiin-
multiple sclerosis (6), erythromelalgia (7), trigeminal
flammatory drugs (NSAIDs) and opioids, but these
neuralgia (8), and GBS (9). In addition to having an
effect in neuropathic pain syndromes in human and
Accepted for publication November 16, 2004. animal models, studies have also demonstrated its
Address correspondence to Chandra Kant Pandey, MD, Depart- effect in nociceptive pain syndromes (10 –13). Both
ment of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of
Medical Sciences, Lucknow 226014, India. Address e-mail to carbamazepine and gabapentin have been found to be
ckpandey@sgpgi.ac.in. Reprints will not be available from the effective for pain relief of GBS patients; therefore, this
authors. clinical study was designed to compare the therapeu-
DOI: 10.1213/01.ANE.0000152186.89020.36 tic efficacy of gabapentin and carbamazepine for the
©2005 by the International Anesthesia Research Society
220 Anesth Analg 2005;101:220–5 0003-2999/05ANESTH ANALG CRITICAL CARE AND TRAUMA PANDEY ET AL. 221
2005;101:220 –5 CARBAMAZEPINE AND GABAPENTIN IN GUILLAIN-BARRÉ SYNDROME
management of pain in GBS patients in the intensive and tranquil; 3 ⫽ responds to commands; 4 ⫽ asleep
care unit (ICU). but brisk response to light glabellar tap or loud audi-
tory stimulus; 5 ⫽ asleep and sluggish response to
light glabellar tap or loud auditory stimulus; 6 ⫽
asleep and no response) (14). The pain and sedation
Methods scores were recorded at the time of admission to the
The institute’s ethics committee approved this random- ICU, before any medications were given, and were
ized, prospective, double-blind, placebo-controlled labeled as pain and sedation at 0 h. Then, throughout
study for pain management in GBS patients who re- the study period, pain and sedation scores were re-
quired assisted ventilation for their ventilatory failure. corded at 6-h intervals. The total daily supplementary
Written informed consent was obtained from each pa- analgesic requirement was recorded for each patient.
tient (or from the patient’s surrogate) after the study was The observer also inquired about giddiness, headache,
explained. Assuming a 20% decrease with 15% variabil- light-headedness, diplopia, hallucinations, nausea, fa-
ity in fentanyl consumption in treatment groups com- tigue, and bowel irregularities (diarrhea for more than
pared with the placebo group, we required 12 patients in two motions per day and constipation [no motion for
each group for 95% power with an ␣ of 0.05. The study 2 days]); observed the patient for nystagmus and
was conducted over 4 yr. During the study period, 58 tremor; and recorded the data.
patients with GBS were admitted to the ICU. However, General supportive measures in the form of enteral
22 patients could not be included in the study. The nutrition, appropriate antibiotics, passive and active
exclusions were patients who did not require mechanical physiotherapy of the upper and lower limbs, chest
ventilation, required controlled ventilation, or developed physiotherapy, gastric acid prophylaxis (ranitidine
hypoxic respiratory failure during the study period; had 150 mg twice a day), and low-molecular-weight hep-
a body weight exceeding 20% of the ideal body weight; arin for prophylaxis against deep vein thrombosis
were aged ⬍12 yr or ⬎60 yr; had uncontrolled concom- were continued during the patient’s stay in the ICU.
itant medical diseases (diabetes mellitus or bronchial After completion of the study, medications were de-
asthma); had a doubtful clinical diagnosis or involve- coded, and patients were divided into three groups:
ment of facial nerves; had a clouding of consciousness; Group 1 (n ⫽ 12), patients who received gabapentin;
had already received medications for pain within 24 h; Group 2 (n ⫽ 12), patients who received carbamaz-
had a history of hypersensitivity to any drug; were preg- epine; and Group 3 (n ⫽ 12), patients who received
nant; had a history of chronic pain syndromes; or had placebo.
impaired kidney or liver function. The data were entered into the statistical software
Patients were asked to communicate their pain package SPSS 9.0 (SPSS Inc., Chicago, IL). The non-
score by blinking their eyes a specific number of times, parametric Mann-Whitney U-test was used to com-
corresponding to a numeric pain rating scale (NPRS) pare the pain and sedation scores (at 0 h and from Day
of 0 –10. Patients were also trained to demand analge- 1 to Day 7) in different groups (median and interquar-
sia whenever they felt pain by holding their breath tile range). One-way analysis of variance was used to
(for 12 s) to initiate the apnea alarm of the ventilator. calculate and compare the mean of total fentanyl dose
The apnea alarm of the ventilator was set at 12 s. The consumed by patients on each day in each group.
patients were randomly assigned to 3 equal groups to Demographic data were compared by using Student’s
receive gabapentin (300 mg 3 times a day), carbamaz- t-test. A P value ⬍0.05 was considered statistically
epine (100 mg 3 times a day), or matching placebo (3 significant.
times a day) in a blinded fashion. The nursing staff
was given a 7-day supply of medicine in powder
packs coded by patient number, and the medicine
(gabapentin, carbamazepine, or matching placebo) Results
was dissolved in 10 mL of water and administered There were no demographic differences among the
through the Ryle’s tube. The Ryle’s tube was flushed three study groups (Table 1). At 0 h there was no
with 10 mL of water after the medicine administration. significant difference in median NPRS among the
The duration of the study was 7 days. Analgesia was gabapentin, carbamazepine, and placebo groups (Ta-
provided with IV fentanyl 2 g/kg on patient de- ble 2). Patients in the gabapentin group had signifi-
mand, given over 2 min. cantly lower median NPRS (3.5, 2.5, 2.0, 2.0, 2.0, 2.0,
Data were recorded by a senior resident who was and 2.0) on all treatment days in comparison to the
not aware of the type of medication administered. placebo (6.0, 6.0, 6.0, 6.0, 6.0, 6.0, and 6.0) and carbam-
Pain was recorded on a NPRS scale of 0 –10 (0 ⫽ no azepine (6.0, 6.0, 5.0, 4.0, 4.0, 3.5, and 3.0) groups (P ⬍
pain and 10 ⫽ worst pain), and sedation was mea- 0.05) (Table 2). There was no statistically significant
sured with a Ramsay sedation score of 1– 6 (1 ⫽ anx- difference in the median NPRS between the carbam-
ious, agitated, or restless; 2 ⫽ cooperative, oriented, azepine and placebo groups from Day 1 to Day 3 (3.0,222 CRITICAL CARE AND TRAUMA PANDEY ET AL. ANESTH ANALG
CARBAMAZEPINE AND GABAPENTIN IN GUILLAIN-BARRÉ SYNDROME 2005;101:220 –5
Table 1. Demographic Data
Group
Variable Gabapentin Carbamazepine Placebo
No. patients 12 12 12
Age, yr (mean ⫾ sd) 31.0 ⫾ 15.1 34.7 ⫾ 8.2 30.9 ⫾ 13.4
Weight, kg (mean ⫾ sd) 55.8 ⫾ 12.6 54.7 ⫾ 14.0 58.7 ⫾ 8.1
Male/female 8/4 8/4 6/6
Table 2. Pain Scores on a Numeric Pain Rating Scale of 0 –10 (Median and Interquartile Range) in Different Groups
Group 0h Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Gabapentin 8 3.5* 2.5* 2.0* 2.0* 2.0* 2.0* 2.0*
(n ⫽ 12) (1.0) (2.5) (1.0) (1.8) (1.0) (1.0) (0.8) (0.8)
Carbamazepine 8.0 6.0 6.0 5.0 4.0† 4.0† 3.5† 3.0†
(n ⫽ 12) (1.0) (0.8) (0.0) (1.0) (0.8) (1.0) (1.0) (1.0)
Placebo 8 6.0 6.0 6.0 6.0 6.0 6.0 6.0
(n ⫽ 12) (1.0) (1.0) (0.8) (1.8) (1.8) (1.8) (1.8) (1.8)
* P ⬍ 0.05 (gabapentin versus carbamazepine and placebo).
† P ⬍ 0.05 (carbamazepine versus placebo).
3.0, and 3.0 vs 4.0, 4.0, and 4.0), but from Day 4 until carbamazepine and placebo during the study period,
the end of the study, significantly lower median NPRS whereas patients who received carbamazepine reported
scores were noted in the carbamazepine groups (4.0, significantly lower median NPRS compared with pla-
4.0, 3.5, and 3.0) compared with placebo (6.0, 6.0, 6.0, cebo from Day 4 onward (Table 2). Median sedation
and 6.0) (P ⬍ 0.05) (Table 2). No statistically significant scores were significantly lower in the gabapentin group
difference was noted in sedation scores at 0 h among compared with the carbamazepine and placebo groups,
the gabapentin, carbamazepine, and placebo groups and patients in the carbamazepine group also had sig-
(2.0, 2.0, and 1.0, respectively). nificantly lower median sedation scores compared with
A significant difference in the median sedation scores the placebo group (Table 3). There was no significant
was recorded during the study period in the gabapentin difference in fentanyl consumption between the gabap-
(2.0, 2.0, 2.0, 2.0, 2.0, 2.0, 2.0, and 2.0), carbamazepine entin and carbamazepine groups (340.1 ⫾ 34.3 and 347.5
(2.0, 3.0, 3.0, 3.0, 3.5, 3.0, 3.0, and 3.0) and placebo (1.0, 4.0,
⫾ 38.0, respectively) on Day 1. However, there was a
4.0, 4.0, 4.0, 4.0, 4.0, and 4.0) groups. During the study
significant decrease in fentanyl consumption in the gaba-
period, patients in the gabapentin and carbamazepine
pentin group compared with the carbamazepine and
groups had significantly lower sedation scores com-
placebo groups from Day 2 to Day 7. In the carbamaz-
pared with placebo (P ⬍ 0.05) (Table 3). There was no
significant difference in fentanyl consumption between epine group as well, fentanyl consumption was signifi-
the gabapentin group and the carbamazepine group on cantly less than in the placebo group during the study
Day 1 (340.1 ⫾ 34.3 and 347.5 ⫾ 38.0, respectively), but period.
consumption was significantly less in these 2 groups The effect of gabapentin and carbamazepine on fen-
compared with placebo (590.4 ⫾ 35.0) (P ⬍ 0.05; power tanyl and pethidine requirements for pain manage-
of test, ⬎95%) (Table 4). During the rest of the study ment in GBS has been studied in previous crossover
period (Day 2 and onward), there was a significant dif- clinical trials. Gabapentin significantly decreased fen-
ference in fentanyl consumption among all the groups, tanyl consumption compared with placebo when it
and it was significantly less in the gabapentin group was administered at 15 mg · kg⫺1 · d⫺1 in 3 divided
(power of test, ⬎95%) (Table 4). None of our patients doses, whereas carbamazepine 100 mg 3 times a day
reported any side effects during the study period. significantly decreased the pethidine requirement in
GBS without any adverse effects (3,9). Similar to pre-
vious investigations, this study demonstrated signifi-
Discussion cantly decreased supplementary analgesic consump-
Our study demonstrated a significant analgesic benefit tion in the treatment groups. During our study, we did
from the use of 300 mg of gabapentin 3 times a day and not encounter any adverse effects of gabapentin or
100 mg of carbamazepine 3 times a day in GBS patients carbamazepine.
who were having pain in the course of their disease. The pain in GBS has two different origins. The most
Patients who were given gabapentin for pain manage- common is deep pain in the back and lower extremi-
ment reported significantly lower NPRS compared with ties, correlating with the distribution of motor lossANESTH ANALG CRITICAL CARE AND TRAUMA PANDEY ET AL. 223
2005;101:220 –5 CARBAMAZEPINE AND GABAPENTIN IN GUILLAIN-BARRÉ SYNDROME
Table 3. Sedation Scores on a Ramsay Sedation Scale of 1– 6 (Median and Interquartile Range) in Different Groups
Group 0h Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Gabapentin 2.0 2.0* 2.0* 2.0* 2.0* 2.0* 2.0* 2.0*
(1.0) (1.0) (1.0) (1.0) (1.0) (0.8) (0.0) (0.0)
Carbamazepine 2.0 3.0† 3.0† 3.0† 3.5† 3.0† 3.0† 3.0†
(1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0)
Placebo 1.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0
(1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0)
* P ⬍ 0.05 (gabapentin versus carbamazepine and placebo).
† P ⬍ 0.05 (carbamazepine versus placebo).
Table 4. Fentanyl Consumption in Different Groups (g) (Mean ⫾ sd)
Group Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Gabapentin 340.1 ⫾ 34.3* 182.0 ⫾ 28.6* 148.9 ⫾ 27.6* 130.8 ⫾ 31.4* 128.0 ⫾ 32.4* 120.1 ⫾ 26.4* 126.0 ⫾ 26.2*
Carbamazepine 347.5 ⫾ 38.0 277.5 ⫾ 36.5† 212.0 ⫾ 30.2† 198.5 ⫾ 39.8† 180.5 ⫾ 48.0† 174.5 ⫾ 30.5† 174.5 ⫾ 30.0†
Placebo 590.4 ⫾ 35.0‡ 421.1 ⫾ 31.3‡ 379.4 ⫾ 36.0‡ 348.2 ⫾ 42.2‡ 355.6 ⫾ 28.1‡ 368.3 ⫾ 35.7‡ 350.7 ⫾ 34.2‡
Power of test, ⬎90%.
* P ⬍ 0.05 (gabapentin versus placebo).
† P ⬍ 0.05 (gabapentin versus carbamazepine).
‡ P ⬍ 0.05 (carbamazepine versus placebo).
there and, less often, with motor loss in the upper opioids may be used in small doses to produce pro-
extremities. This is associated with tenderness and found analgesia without motor, sensory, and auto-
pain during passive movement of the affected muscles nomic effects. However, this may be ineffective for
(15). This pain might be related to inflammation and other GBS pain syndromes (17). Carbamazepine has
entrapment of nerve roots (15). The second type of been effective in reducing stimulus-induced dis-
pain is paresthesia or causalgia with hyperesthesia charges in the amygdala of kindled rats and in block-
and a constant burning sensation. This peripheral ing pentylenetetrazol-induced seizures (18). Its action
neuralgia-like pain is related to alteration in function is on the sodium channels, and it inhibits high-
or spontaneous discharge in demyelinated sensory frequency discharges in and around epileptic foci,
nerves (16). Despite the identification of two different with minimal disruption of normal neuronal traffic
clinical types of pain in GBS, the mechanism of the (19). Pain in GBS is very similar to neuralgia, and this
pain is not well known. The possible mechanisms is why carbamazepine has been effective in relieving
include 1) radicular pain related to inflammation and pain and thereby decreasing the demand for opioids,
entrapment of nerve roots and 2) peripheral neuralgia as in our series.
related to alteration in function as a result of demyeli- Gabapentin is an anticonvulsant and is structurally
nation (the larger myelinated fibers exert an inhibitory related to ␥-aminobutyric acid (20). It is not effective in
influence, and smaller unmyelinated fibers exert an reducing immediate pain from injury, but it reduces
excitatory influence). The demyelination of peripheral abnormal hypersensitivity induced by inflammatory
nerves in GBS alters the balance of sensory input from response or nerve injury (21). Evidence from experi-
myelinated and unmyelinated fibers to the dorsal mental and clinical models of neuropathic and inflam-
horn of the spinal column, and this results in the matory hyperalgesia has suggested that gabapentin
perception of pain (3,16). Thus, because of its dual has an effective antinociceptive and antihyperalgesic
nature, GBS pain may not respond to systemic opioids action in addition to being an anticonvulsant (20). The
or NSAIDs and may require combination therapy, mechanism of action of gabapentin is not well under-
especially if the pain is related to spontaneous neuro- stood. A highly specific gabapentin binding site in the
nal discharges resulting from demyelination (3). brain has been described that is identified as the ␣2-
The current analgesic therapy in GBS is primarily ␦-subunit of calcium channels (22). In addition, labo-
based on two classes of drugs, opioids and NSAIDs, ratory studies have demonstrated that gabapentin
but both of these classes have limited efficacy and treatment may involve glutamate metabolism and its
unacceptable side effects. Other treatments, such as release (22). Gabapentin has also been shown to act
quinine, phenytoin, and systemic and epidural opi- within the spinal cord or brain to reduce the sensiti-
oids, have been tried with variable success for pain zation of dorsal horn neurons, but how it exerts its
management in GBS patients (1,3). For GBS patients effect on spinal and peripheral neurotransmitter re-
who primarily have lower back and leg pain, epidural lease is unclear (20). The proposed mechanism is that224 CRITICAL CARE AND TRAUMA PANDEY ET AL. ANESTH ANALG
CARBAMAZEPINE AND GABAPENTIN IN GUILLAIN-BARRÉ SYNDROME 2005;101:220 –5
gabapentin might decrease the synthesis of the neuro- management in GBS patients. It offers the benefits of
transmitter and excitotoxin glutamate (23). Because better pain control, less sedation, and fewer supple-
intracellular calcium accumulation is important for the mentary analgesics.
spread of epileptic discharges, an effect of gabapentin
on voltage-gated calcium channels is possible (21).
Although gabapentin binds to the ␣2-␦-subunit of
voltage-dependent calcium channels, the functional References
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