Anesth Analg 2005;101:220-225
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000152186.89020.36
CRITICAL CARE AND TRAUMA
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
Address correspondence to Chandra Kant Pandey, MD, Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. Address e-mail to ckpandey{at}sgpgi.ac.in. Reprints will not be available from the authors.
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Abstract
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We evaluated the effects of gabapentin and carbamazepine for pain relief in 36 Guillain-Barré syndrome patients. Patients were randomly assigned to receive gabapentin 300 mg, carbamazepine 100 mg, or matching placebo 3 times a day for 7 days. Fentanyl 2 µg/kg was used as a supplementary analgesic on patient demand. The pain score was recorded by using a numeric pain rating scale of 0–10, and sedation was recorded with a Ramsay sedation scale of 1–6 before medications were given and then at 6-h intervals throughout the study period. Total daily fentanyl consumption was recorded each day for each patient. The results of the study demonstrated that patients in the gabapentin group had significantly lower (P < 0.05) median numeric pain rating scale scores (3.5, 2.5, 2.0, 2.0, 2.0, 2.0, and 2.0) compared with patients in the placebo group (6.0, 6.0, 6.0, 6.0, 6.0, 6.0, and 6.0) and the carbamazepine group (6.0, 6.0, 5.0, 4.0, 4.0, 3.5, and 3.0). There was no significant difference in fentanyl consumption between the gabapentin and carbamazepine groups on Day 1 (340.1 ± 34.3 µg and 347.5 ± 38.0 µg, respectively), but consumption was significantly less in these 2 groups compared with the placebo group (590.4 ± 35.0 µg) (P < 0.05). For the rest of the study period, there was a significant difference in fentanyl consumption among all treatment groups, and it was minimal in the gabapentin group (P < 0.05). We conclude that gabapentin is more effective than carbamazepine for decreasing pain and fentanyl consumption.
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Introduction
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Pain occurs in approximately 89% of Guillain-Barré syndrome (GBS) patients during the course of their disease (1). Uncontrolled pain can occur despite compassionate and supportive measures such as the use of air mattresses, careful turning of patients and positioning of limbs, and the use of padding over the elbows and knees to prevent pressure palsies. However, pain in these patients often goes unrecognized and undertreated because most of them remain immobilized, require tracheal intubation, and are unable to communicate their distress (1).
Patients with GBS require aggressive use of analgesics for pain management. Current analgesic therapy is based on two classes of drugs, nonsteroidal antiinflammatory drugs (NSAIDs) and opioids, but these drugs have limited efficacy in some pain states and have unacceptable side effects (2). For example, the use of opioids for pain relief may cause tolerance, dependence, respiratory depression, sedation, and constipation, and the use of NSAIDs may result in gastrointestinal ulceration, bleeding, platelet dysfunction, and renal and hepatic failure (3). This warrants the need for newer drugs with better safety profiles.
Carbamazepine (an anticonvulsant) has been used for pain management in trigeminal and glossopharyngeal neuralgia and in GBS (3). Gabapentin, a newer anticonvulsant, has also demonstrated its efficacy in the treatment of neuropathic pain syndromes, including diabetic neuropathy (4), postherpetic neuralgia (5), multiple sclerosis (6), erythromelalgia (7), trigeminal neuralgia (8), and GBS (9). In addition to having an effect in neuropathic pain syndromes in human and animal models, studies have also demonstrated its effect in nociceptive pain syndromes (10–13). Both carbamazepine and gabapentin have been found to be effective for pain relief of GBS patients; therefore, this clinical study was designed to compare the therapeutic efficacy of gabapentin and carbamazepine for the management of pain in GBS patients in the intensive care unit (ICU).
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Methods
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The institute’s ethics committee approved this randomized, prospective, double-blind, placebo-controlled study for pain management in GBS patients who required assisted ventilation for their ventilatory failure. Written informed consent was obtained from each patient (or from the patient’s surrogate) after the study was explained. Assuming a 20% decrease with 15% variability in fentanyl consumption in treatment groups compared with the placebo group, we required 12 patients in each group for 95% power with an 
of 0.05. The study was conducted over 4 yr. During the study period, 58 patients with GBS were admitted to the ICU. However, 22 patients could not be included in the study. The exclusions were patients who did not require mechanical ventilation, required controlled ventilation, or developed hypoxic respiratory failure during the study period; had a body weight exceeding 20% of the ideal body weight; were aged <12 yr or >60 yr; had uncontrolled concomitant medical diseases (diabetes mellitus or bronchial asthma); had a doubtful clinical diagnosis or involvement of facial nerves; had a clouding of consciousness; had already received medications for pain within 24 h; had a history of hypersensitivity to any drug; were pregnant; had a history of chronic pain syndromes; or had impaired kidney or liver function.
Patients were asked to communicate their pain score by blinking their eyes a specific number of times, corresponding to a numeric pain rating scale (NPRS) of 0–10. Patients were also trained to demand analgesia whenever they felt pain by holding their breath (for 12 s) to initiate the apnea alarm of the ventilator. The apnea alarm of the ventilator was set at 12 s. The patients were randomly assigned to 3 equal groups to receive gabapentin (300 mg 3 times a day), carbamazepine (100 mg 3 times a day), or matching placebo (3 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) was dissolved in 10 mL of water and administered through the Ryle’s tube. The Ryle’s tube was flushed with 10 mL of water after the medicine administration. The duration of the study was 7 days. Analgesia was provided with IV fentanyl 2 µg/kg on patient demand, given over 2 min.
Data were recorded by a senior resident who was not aware of the type of medication administered. Pain was recorded on a NPRS scale of 0–10 (0 = no pain and 10 = worst pain), and sedation was measured with a Ramsay sedation score of 1–6 (1 = anxious, agitated, or restless; 2 = cooperative, oriented, and tranquil; 3 = responds to commands; 4 = asleep but brisk response to light glabellar tap or loud auditory stimulus; 5 = asleep and sluggish response to light glabellar tap or loud auditory stimulus; 6 = asleep and no response) (14). The pain and sedation scores were recorded at the time of admission to the ICU, before any medications were given, and were labeled as pain and sedation at 0 h. Then, throughout the study period, pain and sedation scores were recorded at 6-h intervals. The total daily supplementary analgesic requirement was recorded for each patient. The observer also inquired about giddiness, headache, light-headedness, diplopia, hallucinations, nausea, fatigue, and bowel irregularities (diarrhea for more than two motions per day and constipation [no motion for 2 days]); observed the patient for nystagmus and tremor; and recorded the data.
General supportive measures in the form of enteral nutrition, appropriate antibiotics, passive and active physiotherapy of the upper and lower limbs, chest physiotherapy, gastric acid prophylaxis (ranitidine 150 mg twice a day), and low-molecular-weight heparin for prophylaxis against deep vein thrombosis were continued during the patient’s stay in the ICU. After completion of the study, medications were decoded, and patients were divided into three groups: Group 1 (n = 12), patients who received gabapentin; Group 2 (n = 12), patients who received carbamazepine; and Group 3 (n = 12), patients who received placebo.
The data were entered into the statistical software package SPSS 9.0 (SPSS Inc., Chicago, IL). The nonparametric Mann-Whitney U-test was used to compare the pain and sedation scores (at 0 h and from Day 1 to Day 7) in different groups (median and interquartile range). One-way analysis of variance was used to calculate and compare the mean of total fentanyl dose consumed by patients on each day in each group. Demographic data were compared by using Student’s t-test. A P value <0.05 was considered statistically significant.
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Results
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There were no demographic differences among the three study groups (Table 1). At 0 h there was no significant difference in median NPRS among the gabapentin, carbamazepine, and placebo groups (Table 2). Patients in the gabapentin group had significantly lower median NPRS (3.5, 2.5, 2.0, 2.0, 2.0, 2.0, and 2.0) on all treatment days in comparison to the placebo (6.0, 6.0, 6.0, 6.0, 6.0, 6.0, and 6.0) and carbamazepine (6.0, 6.0, 5.0, 4.0, 4.0, 3.5, and 3.0) groups (P < 0.05) (Table 2). There was no statistically significant difference in the median NPRS between the carbamazepine and placebo groups from Day 1 to Day 3 (3.0, 3.0, and 3.0 vs 4.0, 4.0, and 4.0), but from Day 4 until the end of the study, significantly lower median NPRS scores were noted in the carbamazepine groups (4.0, 4.0, 3.5, and 3.0) compared with placebo (6.0, 6.0, 6.0, and 6.0) (P < 0.05) (Table 2). No statistically significant difference was noted in sedation scores at 0 h among the gabapentin, carbamazepine, and placebo groups (2.0, 2.0, and 1.0, respectively).
A significant difference in the median sedation scores was recorded during the study period in the gabapentin (2.0, 2.0, 2.0, 2.0, 2.0, 2.0, 2.0, and 2.0), carbamazepine (2.0, 3.0, 3.0, 3.0, 3.5, 3.0, 3.0, and 3.0) and placebo (1.0, 4.0, 4.0, 4.0, 4.0, 4.0, 4.0, and 4.0) groups. During the study period, patients in the gabapentin and carbamazepine groups had significantly lower sedation scores compared with placebo (P < 0.05) (Table 3). There was no significant difference in fentanyl consumption between the gabapentin group and the carbamazepine group on Day 1 (340.1 ± 34.3 and 347.5 ± 38.0, respectively), but consumption was significantly less in these 2 groups compared with placebo (590.4 ± 35.0) (P < 0.05; power of test, >95%) (Table 4). During the rest of the study period (Day 2 and onward), there was a significant difference in fentanyl consumption among all the groups, and it was significantly less in the gabapentin group (power of test, >95%) (Table 4). None of our patients reported any side effects during the study period.
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Discussion
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Our study demonstrated a significant analgesic benefit from the use of 300 mg of gabapentin 3 times a day and 100 mg of carbamazepine 3 times a day in GBS patients who were having pain in the course of their disease. Patients who were given gabapentin for pain management reported significantly lower NPRS compared with carbamazepine and placebo during the study period, whereas patients who received carbamazepine reported significantly lower median NPRS compared with placebo from Day 4 onward (Table 2). Median sedation scores were significantly lower in the gabapentin group compared with the carbamazepine and placebo groups, and patients in the carbamazepine group also had significantly lower median sedation scores compared with the placebo group (Table 3). There was no significant difference in fentanyl consumption between the gabapentin and carbamazepine groups (340.1 ± 34.3 and 347.5 ± 38.0, respectively) on Day 1. However, there was a significant decrease in fentanyl consumption in the gabapentin group compared with the carbamazepine and placebo groups from Day 2 to Day 7. In the carbamazepine group as well, fentanyl consumption was significantly less than in the placebo group during the study period.
The effect of gabapentin and carbamazepine on fentanyl and pethidine requirements for pain management in GBS has been studied in previous crossover clinical trials. Gabapentin significantly decreased fentanyl consumption compared with placebo when it was administered at 15 mg · kg–1 · d–1 in 3 divided doses, whereas carbamazepine 100 mg 3 times a day significantly decreased the pethidine requirement in GBS without any adverse effects (3,9). Similar to previous investigations, this study demonstrated significantly decreased supplementary analgesic consumption in the treatment groups. During our study, we did not encounter any adverse effects of gabapentin or carbamazepine.
The pain in GBS has two different origins. The most common is deep pain in the back and lower extremities, correlating with the distribution of motor loss there and, less often, with motor loss in the upper extremities. This is associated with tenderness and pain during passive movement of the affected muscles (15). This pain might be related to inflammation and entrapment of nerve roots (15). The second type of pain is paresthesia or causalgia with hyperesthesia and a constant burning sensation. This peripheral neuralgia-like pain is related to alteration in function or spontaneous discharge in demyelinated sensory nerves (16). Despite the identification of two different clinical types of pain in GBS, the mechanism of the pain is not well known. The possible mechanisms include 1) radicular pain related to inflammation and entrapment of nerve roots and 2) peripheral neuralgia related to alteration in function as a result of demyelination (the larger myelinated fibers exert an inhibitory influence, and smaller unmyelinated fibers exert an excitatory influence). The demyelination of peripheral nerves in GBS alters the balance of sensory input from myelinated and unmyelinated fibers to the dorsal horn of the spinal column, and this results in the perception of pain (3,16). Thus, because of its dual nature, GBS pain may not respond to systemic opioids or NSAIDs and may require combination therapy, especially if the pain is related to spontaneous neuronal discharges resulting from demyelination (3).
The current analgesic therapy in GBS is primarily based on two classes of drugs, opioids and NSAIDs, but both of these classes have limited efficacy and unacceptable side effects. Other treatments, such as quinine, phenytoin, and systemic and epidural opioids, have been tried with variable success for pain management in GBS patients (1,3). For GBS patients who primarily have lower back and leg pain, epidural opioids may be used in small doses to produce profound analgesia without motor, sensory, and autonomic effects. However, this may be ineffective for other GBS pain syndromes (17). Carbamazepine has been effective in reducing stimulus-induced discharges in the amygdala of kindled rats and in blocking pentylenetetrazol-induced seizures (18). Its action is on the sodium channels, and it inhibits high-frequency discharges in and around epileptic foci, with minimal disruption of normal neuronal traffic (19). Pain in GBS is very similar to neuralgia, and this is why carbamazepine has been effective in relieving pain and thereby decreasing the demand for opioids, as in our series.
Gabapentin is an anticonvulsant and is structurally related to 
-aminobutyric acid (20). It is not effective in reducing immediate pain from injury, but it reduces abnormal hypersensitivity induced by inflammatory response or nerve injury (21). Evidence from experimental and clinical models of neuropathic and inflammatory hyperalgesia has suggested that gabapentin has an effective antinociceptive and antihyperalgesic action in addition to being an anticonvulsant (20). The mechanism of action of gabapentin is not well understood. A highly specific gabapentin binding site in the brain has been described that is identified as the 2-
-subunit of calcium channels (22). In addition, laboratory studies have demonstrated that gabapentin treatment may involve glutamate metabolism and its release (22). Gabapentin has also been shown to act within the spinal cord or brain to reduce the sensitization of dorsal horn neurons, but how it exerts its effect on spinal and peripheral neurotransmitter release is unclear (20). The proposed mechanism is that gabapentin might decrease the synthesis of the neurotransmitter and excitotoxin glutamate (23). Because intracellular calcium accumulation is important for the 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 significance of this action is controversial (24). Gabapentin reduces calcium influx into glutamatergic terminals, thus inhibiting the potassium-induced release of endogenous aspartate and glutamate (25). The inhibition of excitatory amino acid release conceivably leads to reduced postsynaptic excitability, and this provides one reasonable explanation for the antinociceptive efficacy of gabapentin (26). However, evidence shows that the antiglutamatergic properties of gabapentin are due to inhibition of cytosolic branched-chain aminotransferase, an enzyme that synthesizes glutamate in the brain (26). Gabapentin has been effective in clinical inflammatory and neuropathic pain syndromes, and the significantly decreased demand for fentanyl in the gabapentin group compared with the carbamazepine and placebo groups in this study also demonstrates that it is effective in suppressing the dual nature of GBS pain and is an effective treatment option for pain in clinical conditions in which neuropathic and inflammatory pain coexist.
We did not encounter side effects with either gabapentin or carbamazepine in our study but side effects, such as vertigo, diplopia, nausea, vomiting, and ataxia, have been reported with both drugs. In addition, potentially life-threatening complications, such as aplastic anemia, thrombocytopenia, hepatocellular and cholestatic jaundice, oliguria, hypertension, cardiac dysrhythmias, and chronic suppression of white blood cell counts, are associated with the use of carbamazepine. They necessitate monitoring of hepatic, cardiac, and renal function, as well as bone marrow examinations, during treatment (27). The most serious adverse effects reported with gabapentin treatment are convulsions (28). Thus, in terms of side effects, gabapentin seems to have a better drug-safety profile than carbamazepine.
Although neither the mechanism of action of gabapentin and carbamazepine in pain relief nor the mechanism of pain in GBS is well known, our study has demonstrated a significant analgesic benefit from the use of gabapentin and carbamazepine in GBS patients. The analgesic effects of gabapentin were noted from Day 1, whereas analgesia was delayed until Day 4 in patients who received carbamazepine. Gabapentin decreased fentanyl consumption more effectively than carbamazepine, and it did not increase sedation. Both drugs appeared safe and were tolerated well by the GBS patients.
On the basis of our study, we suggest that gabapentin is a better adjuvant than carbamazepine for pain management in GBS patients. It offers the benefits of better pain control, less sedation, and fewer supplementary analgesics.
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Footnotes
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Accepted for publication November 16, 2004.
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Abstract
Introduction
