Pain is an acknowledged feature of Guillain-Barré Syndrome (GBS) and occurs in approximately 89% of patients during the course of the disease. However, it often goes unrecognized and is undertreated (1). The pain syndromes in GBS, which include back and leg pain, dysesthetic extremity pain, myalgic- rheumatic extremity pain, visceral pain, pressure palsies, and dysautonomic headache, suggest its neuropathic as well as nociceptive origin (1).
The recognition of pain syndromes in GBS is important because most of the patients remain immobilized, require tracheal intubation, and are unable to communicate their distress (2). The use of opioids for pain relief may cause tolerance, dependence, respiratory depression, sedation, and constipation. The use of nonsteroidal antiinflammatory drugs 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.
Anticonvulsants have been effective for treating neuropathic pain, and gabapentin is a recent addition to this class of drugs (3–5). Its efficacy in the treatment of neuropathic pain syndromes, including diabetic neuropathy (6) and postherpetic neuralgia (7), has been demonstrated. There are clinical case reports of multiple sclerosis (8), postpoliomyelitis neuropathy (9), erythromelalgia (10), trigeminal neuralgia (11), and reflex sympathetic dystrophy (12) in which gabapentin had been used successfully for the management of pain. In addition to having an effect in neuropathic pain in human and animal models, studies have also demonstrated the effectiveness of gabapentin in nociceptive pain syndromes (13–15). Because of the bimodal nature of pain in GBS and the capability of gabapentin to relieve pain in both nociceptive and neuropathic models, this clinical study was designed to evaluate the therapeutic efficacy of gabapentin in relieving pain in GBS patients in the intensive care unit (ICU).
Approval for the clinical study was obtained from the Ethical Committee of the institute. Informed consent was obtained from all patients (or from their legitimate guardians) after explanation of the nature of the study. Patients were told to communicate their pain score by blinking their eyes a specific number of times (on a numeric pain rating scale of 0–10). They 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 reset at 12 s. The study was conducted over a period of 1 yr. Numeric pain score, Ramsay sedation score, and requirement for a rescue analgesic (fentanyl) were specified as primary response variables. During the study period, 23 patients with GBS were admitted to the ICU; however, 5 patients could not be included in the study (exclusion criteria included extremes of ages, i.e., <12 yr or >80 yr; associated concomitant medical diseases; doubtful clinical diagnosis; clouding of consciousness; already receiving medications for pain; or a numeric pain score of <3 on the 0–10 scale).
The study was a double-blinded, placebo-controlled, crossover study of 18 patients with GBS who were admitted to the ICU for ventilatory support. Patients were randomly assigned in equal numbers to receive either gabapentin or placebo in a blinded fashion as the initial medication. The nursing staff was given a 7-day supply of medicine in patient number-specific coded powder packs, and the medicine (gabapentin and matching placebo) was dissolved in 5 mL of water and administered through a Ryle’s tube. Each time, the Ryle’s tube was flushed with 10 mL of water after the administration of drug. The initial phase of study was for 7 days, followed by 2 days of washout, when no medication (gabapentin or matching placebo) was given. Those who received gabapentin were initiated on a dose of 15 mg · kg−1 · d−1 (on the basis of a previous randomized controlled trial) in 3 divided doses (15). At the end of the washout period, those who previously received gabapentin received placebo, and those receiving placebo received gabapentin in a fashion similar to the initial phase of 7 days. A senior resident who was not aware of the type of medication administered recorded the data.
A numeric pain rating scale of 0–10 (0, no pain; 10, worst pain) and the Ramsay sedation score of 1–6 (1, anxious, agitated, or restless; 2, cooperative, oriented, and tranquil; 3, responds to commands; 4, asleep but has a brisk response to a light glabellar tap or loud auditory stimulus; 5, asleep, has a sluggish response to a light glabellar tap or loud auditory stimulus; 6, asleep, no response) were used to record the pain and sedation (16). The pain and sedation scores were recorded at the time of admission of the patient to ICU, before medications were given, and the noted pain score was labeled as pain at 0 h. Throughout the study period, pain and sedation were recorded at 6-h intervals. The rescue analgesic, fentanyl 2 μg/kg, was administered on patient demand or when the pain score was >5. The total daily rescue analgesic requirement was recorded for each patient. The observer also inquired about giddiness, headache, diplopia, hallucinations, nauseated feelings, fatigue, and bowel irregularities (diarrhea, more than two motions per day; constipation, no motion for 2 days); observed for nystagmus and tremor; and recorded the data.
General supportive therapy, 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 of deep vein thrombosis were continued during the patient’s stay in the ICU.
After completion of the study, medications were decoded. Because the same 18 patients received gabapentin and placebo at different time intervals, the data were presented as period of treatment with gabapentin (PTG) or period of treatment with placebo (PTP).
All the data were entered into the statistical software package SPSS 9.0 (SPSS Inc., Chicago, IL). The mean and sd of sedation and pain for all patients in both groups were calculated at 0, 6, 12, and 24 h for all 7 days. The mean for each day of pain and sedation for all 7 days was calculated from the means of 6, 12, 18, and 24 h. Similarly, the total dose of rescue analgesic required by patients each day in each group was also compared. Data for pain and sedation were analyzed by application of repeated-measures analysis of variance. Post hoc testing (Student-Newman-Keuls test) was applied for observing the effectiveness of therapy in relation to days. A two-tailed Student’s t-test was applied to compare the results between the two study periods (PTP and PTG). P < 0.05 was considered statistically significant.
The two study periods (PTG and PTP) were similar in demographic data, because the same patients received gabapentin and placebo. The mean age and weight was 31.05 ± 15.15 yr and 54.80 ± 12.60 kg, respectively, and the male/female ratio was 13:5 (Table 1).
In the observed variables for pain and sedation, the value at 0 h was considered the control value for subsequent comparison (Tables 2 and 3). There was no difference in the pain scores at 0 h. During the PTG, mean pain scores decreased from 7.22 ± 0.83 to 2.06 ± 0.63 on the seventh day (power >99%) (P < 0.001); however, the decrease in pain scores in PTP was not significant (7.83 ± 0.78 to 5.67 ± 0.91) (Table 2). The carryover effect of gabapentin was excluded by comparing the pain scores of patients who received placebo initially (and gabapentin later) with those who received gabapentin initially and placebo later (P = 0.68). The baseline rescue analgesic requirement on Day 1 in both groups was used as a control value to compare the intra- and intergroup rescue analgesia requirements (P < 0.001) (power >99%) (Table 4). A total of six adverse events were noted: one during PTG and five during PTP. Nausea occurred in three patients: one during PTG and two during PTP. Constipation occurred in three patients during PTP only (Table 5).
This study revealed a significant analgesic benefit from the use of gabapentin in GBS patients who were having pain in the course of their disease. Patients who were given gabapentin for pain management reported significantly lower pain and sedation scores, decreased analgesic consumption, and fewer side effects in comparison to the patients who received placebo.
In a previous report, gabapentin 100 mg thrice daily and 200 mg twice daily has been used without adverse effects for the management of pain in GBS (1). Fisher et al. (17) also reported its use in partial seizures, with a frequent incidence of adverse effects when rapid initiation of therapy (900 mg/day) was used in comparison with slow initiation. However, we used a weight-related dose regimen of 15 mg · kg−1 · d−1 in 3 divided doses, and no significant side effects were observed. In our series, 6 patients (16.66%), 1 during PTG and 5 during PTP (5.5% versus 27.7%), developed side effects (Table 5). Nausea was observed in one case during PTG and two during PTP. Three patients developed constipation during PTP. The increased incidence of side effects during PTP was probably because these patients required larger doses of fentanyl as a rescue analgesic. Fentanyl probably contributed to constipation and nausea in the patients who received placebo. Somnolence, dizziness, nystagmus, headache, tremor, diplopia, vomiting, and rhinitis were not present in any of the patients in our series.
Our patients showed a significant decrease in pain scores after gabapentin therapy. The pain scores at the time of admission (zero hours) were comparable in both study periods, and no significant difference was noted either in the pain score or in the consumption of analgesics (Table 4). The sedation score increased significantly after the initiation of gabapentin therapy but remained low during the therapy in comparison to placebo (Table 3). There was a significant decrease in the need for rescue analgesics during PTG from Day 2 to Day 7 (Table 4) (211.11 ± 21.38 μg on Day 1, which decreased to 68.65 ± 20.60 on Day 2 and was 65.55 ± 16.17 on Day 7). During PTP (Table 4), the analgesic consumption was unchanged at Day 7.
Gabapentin is an analog of gamma-amino-butyric acid (GABA), which is an inhibitory neurotransmitter expected to cause sedation, but during PTG, it had a lower sedation score on Day 1 through to Day 7 in comparison to the same period during PTP (the probable cause may have been the larger requirement of fentanyl as a rescue analgesic) (Tables 3 and 4).
The conventional pain management in GBS revolves around the use of opioids and nonsteroidal antiinflammatory drugs, but it is not always successful. The other treatment modalities (quinine, phenytoin, carbamazepine, and systemic and epidural opioids) have been tried with variable success (2–5,18). In ventilated patients with primarily lower- back and leg pain, epidural opioids may be used in small doses to produce profound analgesia without motor, sensory, or autonomic effects. However, this may be ineffective in other pain syndromes of GBS (18,19).
Gabapentin has been successfully used in many neuropathic painful conditions (6–9), and its efficacy and safety have been demonstrated in the reduction of nociceptive pain in animal and human models (13–15). GBS is an acute postinfective polyneuropathy characterized by demyelination of the peripheral nervous system and rapidly progressing paralysis. Pain can occur in GBS despite compassionate and supportive measures such as the use of an air mattress, careful turning of patients and positioning of limbs, and the use of padding over the elbows and knees. Pain in GBS is of two distinct clinical types. One is a deep pain common in the back and lower extremity, less often involving the upper extremities and correlating with the distribution of motor loss. This pain is associated with tenderness on active and passive movement of the affected muscle groups. The second type of pain is a continuous burning sensation in the extremities, as is reported in neuropathic pain states. Because neuropathic pain responds poorly to opioids, this supports a distinction between the two types of pain, suggesting different mechanisms for each (2,20,21).
Despite the identification of two different clinical types of pain in GBS, the mechanism of pain is not well known. The possible mechanisms include radicular pain related to inflammation and entrapment of nerve roots, peripheral neuralgia related to alterations in function as a result of demyelination, and an imbalance in neuronal input to the dorsal horn of the spinal cord (2,12). The larger myelinated fibers exert an inhibitory influence on cells in the substantia gelatinosa, whereas 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, accompanied by the perception of pain (22). The excitotoxic events both peripherally and within the spinal cord horn are possibly mediated by excitatory amino acid activity at receptors that may lead to increased calcium permeability (23). A gabapentin-specific binding site α-2-δ subunit of voltage-dependent calcium channels has been identified in the central nervous system. By binding to this site, gabapentin may be effective in reducing hyperalgesia (24).
When gabapentin is given systemically, it does not change the pain threshold to either mechanical or thermal stimulation, but both tactile and cold allodynia are reduced. It readily crosses the blood-brain barrier and gains a 10-fold larger intracellular than extracellular concentration (25). It neither interacts with GABA receptors nor inhibits the reuptake or metabolism of synaptic GABA (23). The increased total concentration of GABA in the brain may be responsible for the modulation of central pain pathways, including decreased synthesis of glutamate in afferent or descending nociceptive fibers (26). Animal studies have shown that although gabapentin does not affect the nociceptive threshold, it is effective in reducing both allodynia and hyperalgesia, suggesting that it has a selective effect on the nociceptive process involved in central sensitization (23,26).
We conclude that gabapentin 15 mg · kg−1 · d−1 in 3 divided doses as a sole drug is effective in relieving pain in GBS. The rapid initiation of gabapentin with 15 mg · kg−1 · d−1 does not cause untoward side effects, and the optimal antihyperalgesic effects appear on the second day. It causes minimal sedation in comparison to placebo. The drug is safe and well tolerated and has minimal side effects in GBS. Thus, gabapentin may be considered important for managing pain in GBS.
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© 2002 International Anesthesia Research Society
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