Pregabalin and lamotrigine in central poststroke pain: A pilot study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_45_16
Source of Support: None, Conflict of Interest: None
Background: Comparative study of Class I drugs in central poststroke pain (CPSP) is lacking.
Keywords: Central poststroke pain, lamotrigine, pain, pregabalin, stroke
Central poststroke pain (CPSP) is a poorly recognized condition despite significant morbidities associated with it. CPSP refers to a pain syndrome resulting from a primary lesion or dysfunction of the central nervous system after a stroke. The prevalence of CPSP is variable in different studies ranging from 8% to 35%.,,, This difference in prevalence may be due to differing inclusion criteria as well as the variation in the study designs. CPSP is often difficult to manage because of a combination of sub-optimal therapeutic response to drugs, high incidence of drug toxicity, and drug interactions in elderly stroke patients. There are only a few Class I studies on the management of CPSP which report efficacy of different drugs like amitriptyline, lamotrigine, pregabalin, intravenous lidocaine, and propofol.,,,,, There is, however, no comparative study evaluating the relative efficacy and safety of the different Class I drugs. This study, therefore, is an attempt to compare the relative efficacy and tolerability of pregabalin vis-a-vis lamotrigine in patients with CPSP.
This is a single-center randomized controlled open-labeled study with crossover design comparing pregabalin and lamotrigine in the patients with CPSP. The protocol was designed by the first and third authors. The study was approved by the Institute Ethics Committee (Research Protocol No. - A11: PGI/IP/IEC/52/19/11/2010) and registered in Clinical Trial Registry of Indian Council of Medical Research (Reg. No. - CTRI/2012/02/002438). No financial support of any kind was obtained for conducting this trial. Written informed consent was obtained from all patients enrolled in this study. The sample size was calculated keeping the Type I error at α = 0.05 and Type II error at β = 0.1 using Z test of proportion. We used absolute risk reduction of 15% for the calculation of sample size. The sample size was calculated as 200 in each arm to enable a power of 90% in this study. The present study, however, is based on 15 patients in each arm who were crossed over after a wash out period of at least 1 month.
The patients with CPSP having pain severity ≥50 mm on Visual Analog Scale (VAS) were included.
The patients with <50 mm pain on VAS, painful peripheral neuropathy, complex regional pain syndrome, psychiatric and post-head injury pain disorders, chronic renal or liver failure, heart failure, cancer, and those with a history of drug allergy were excluded. The patients with dementia and aphasia were also excluded.
All the patients were subjected to medical history and physical examination. The stroke risk factors such as hypertension, diabetes mellitus, smoking, hyperlipidemia, heart disease, and transient ischemic attack were noted. The time from stroke to the onset of CPSP and the duration of CPSP were noted. The distribution, character, aggravating and relieving factors were assessed. The severity of pain was measured on a scale of 0–100 (VAS). Presence of allodynia, its type, and severity were also noted on a scale of 0–10. Cranial nerve palsy, muscle power, tone, reflexes, and cerebellar signs were recorded.
Sensory testing was done first on the normal side before testing the abnormal side. Pinprick and touch sensations were tested. For temperature testing, a cold metal rod, and for vibration testing, a 128 Hz tuning fork was used. Joint position sensation was tested in toes and fingers making 1° deflections. The sensory findings were categorized into normal, reduced, or absent.
Quantitative assessment of central poststroke pain
The severity of CPSP was quantified by a 0–100 VAS, in which a score of 0 indicated no pain while a score of 100 indicated the worst pain. Stimulus-evoked pain was evaluated for mechanical allodynia, dynamic mechanical allodynia, cold allodynia, and cold hyperalgesia. The details of sensory testing have been described in our earlier study. The patients were asked to grade the result of each sensory test on a 0–10 scale. Hospital Anxiety and Depression (HAD) Scale (0–42) was used for rating anxiety and depression.
Blood counts, hemoglobin, erythrocyte sedimentation rate at 1 h, serum chemistry, electrocardiogram and radiograph of chest were done in all patients. Cranial magnetic resonance imaging (MRI) was carried out using 1.5T Signa GE Medical system, Wisconsin, WI, USA. T1-, T2-, and diffusion-weighted T1-images were obtained in all patients. The abnormalities in sensory pathways including parietal cortex, subcortical white matter, internal capsule, thalamus, and brainstem were noted. The MRI abnormalities were classified into either corresponding and noncorresponding lesions with respect to the clinical findings. The presence of multiple lesions was also noted.
Randomization and treatment
The patients were randomized using computer-generated random numbers into the pregabalin and lamotrigine groups. The randomization, evaluation, and treatment were done by different investigators. The identity of the drug was not concealed. The dose of lamotrigine was escalated from an initial dose of 25 mg twice daily for 2 weeks to 50 mg twice daily for the next 2 weeks and thereafter 100 mg twice daily for 8 weeks. In the pregabalin group, the starting dose was 75 mg twice daily for 2 weeks followed by 150 mg twice daily for the next 2 weeks and then 300 mg twice daily for 8 weeks. The patients were crossed over to the other study drug in the same manner after a washout period of at least 4 weeks if their pain on VAS score was ≥50 mm. The patients with possible remissions were not crossed over. The underling etiology of stroke was also treated.
The patient's outcome was determined at 3 months after starting the study drug. The primary outcome was defined as ≥50% pain reduction in VAS score. The secondary outcome measures were ≥50% pain reduction in the severity of different allodynia and improvement in HAD score.
The side effects of both the study drugs were noted and severe adverse reactions necessitating hospitalization and/or drug withdrawal were also noted.
The effects of pregabalin and lamotrigine in alleviating pain and allodynia were evaluated by Fisher's exact test. The baseline parameters of the two groups were compared using Fisher's exact test for categorical and independent t-test or Mann–Whitney U-test for the continuous variables. The side effects between the two groups were also compared using parametric and nonparametric tests. The change in severity or allodynia in the same group was compared by paired t-test and between the two groups by independent t-test. Intention-to-treat analysis was done by categorizing the patients with >50% improvement in the pain parameters. The variables were considered significant if P value was <0.05. The statistical analysis was done using the Statistical Package for Social Sciences version 12 (SPSS Inc, Chicago, Ill).
Forty-five patients with CPSP were examined during the study period, 30 of whom were eligible for randomization [Figure 1]. Fifteen patients were excluded; 7 due to <50 mm severity of pain on VAS, 3 due to renal failure, 2 due to associated cognitive impairment, 1 due to coronary artery disease, and 2 patients did not give consent for the study.
Patients' characteristics and recruitment
The median age was 54.5 (25–74) years and there were only 4 (13.3%) female patients in our study. The median duration of CPSP was 165 (3–2190) days. The duration of CPSP from the onset of stroke was variable (median 70; 0–820 days); 8 patients developed CPSP on the day of stroke, 5 within 1 month, 10 between 1 and 6 months, and 7 patients developed CPSP 6 months after the stroke. The risk factors for stroke in our patients included hypertension in 23, smoking in 5, and diabetes in 8 patients. At the time of examination, 13 patients had mild spasticity and 19 had hemiparesis;and, Medical Research Council grade ≥ IV in all except 5 patients who had
Fifteen patients each received pregabalin and lamotrigine. The baseline characteristics were similar in the two groups except for the severity of mechanical static allodynia, and thalamic lesions were more common in the pregabalin group. The details are provided in [Table 1].
At 3 months, both pregabalin (P < 0.0001) and lamotrigine (P < 0.0001) resulted in significant improvement in the VAS score compared to the baseline [Figure 2]. The reduction of pain, however, was not significantly different between the two drugs. About 19 (63.3%) patients in the pregabalin group and 16 (53.3%) in the lamotrigine group had improvement by > 50% on VAS score (P = 0.60). The details are provided in [Table 2].
The severity of allodynia and HAD score improved significantly at 3 months in both the groups compared to the baseline. In the pregabalin group, cold allodynia improved from a baseline severity of 5.2 to 2.2 (P < 0.0001), mechanical static allodynia from 3.3 to 1.6 (P = 0.03), and HAD score from 10.7 to 2.3 (P < 0.0001). The mechanical dynamic allodynia, however, was not significantly different at 3 months compared to the baseline (2.7 ± 1.7 vs. 1.1 ± 1.3 P= 0.05). Similar results were also present in the lamotrigine group. The details are provided in [Figure 3]. In the pregabalin and lamotrigine groups, the improvement in VAS score (19 vs. 16, P= 0.60), static mechanical allodynia (6 vs. 6, P= 1.00), dynamic mechanical allodynia (7 vs. 5, P= 62), cold allodynia (8 vs. 10, P= 0.67), and HAD score (12 vs. 9 P= 1.00) were, however, similar. The details are presented in [Table 2].
The above-mentioned results are based on the combined response of initial randomization and that of the crossover groups. The primary and secondary end points were also similar when the initial and crossover patients were separately analyzed [Table 3].
Thirteen patients had side effects, 3 in the lamotrigine and 10 in the pregabalin group. In the lamotrigine group, all 3 patients had skin rash necessitating drug withdrawal. In the pregabalin group, the major side effects were sedation in 6, dizziness in 4, pedal edema, tremor, blurred vision, and irritability in 1 patient each; however no patient required drug withdrawal.
In the pregabalin group, the highest dose of 600 mg could be achieved in 9, 300 mg in 19 and 150 mg in 2 patients. In the lamotrigine group, the highest dose of 200 mg could be achieved in 29 patients and 50 mg in one.
In the present study, both pregabalin and lamotrigine were equally effective in reducing the pain and allodynia in patients with CPSP. The intention-to-treat analysis revealed efficacy of 63.3% for pregabalin and 53.3% for lamotrigine. The efficacy of pregabalin and lamotrigine was, however, similar in terms of pain relief and allodynia. There is no head-to-head trial comparing pregabalin and lamotrigine in CPSP. Most of the studies are placebo-controlled., In a recent randomized controlled trial, pregabalin was compared with placebo in patients with CPSP in a dose of 150–600 mg daily. In the pregabalin group, the mean pain score of 6.5 at baseline improved to 4.9 at 12 weeks compared to corresponding values of 6.3 and 5.0 in the placebo group, highlighting the efficacy of pregabalin. Moreover, pregabalin also resulted in improvement in the Medical Outcome Study Sleep Scale, HADS-anxiety scale, and clinician global impression of change.
In another randomized placebo-controlled study with crossover design including 37 patients, lamotrigine in a dose of 200 mg was effective in reducing median daily pain score compared to a placebo at 8 weeks. However, lamotrigine was not effective in lower doses. The median pain score in the last week of treatment reduced to 5 in lamotrigine (200 mg/day) compared to 7 in the placebo group. The side effects were noted in 67% and 60% patients in the lamotrigine and placebo groups respectively. Thirty percent patients needed withdrawal of lamotrigine due to skin rash in this study. In another study including 17 patients, lamotrigine led to improvement in 70.5% patients at 24 weeks. In this study, lamotrigine was effective even at a dose of 100 mg/day in the patients who were refractory to other drugs. Gabapentin, that has a similar action as pregabalin, however, was not found to be effective in neuropathic pain when compared to a placebo. Of note, only 9 patients in this study had CPSP.
In another study with a crossover design, carbamazepine, amitriptyline, and placebo were compared in 15 patients with CPSP. The pain relief was significantly better in the amitriptyline group compared to the placebo group while no difference was found between the carbamazepine and placebo groups.
None of the above-mentioned studies defined improvement using >50% pain reduction. In our study, we have not only used mean reduction in pain but also analyzed the drug effects on the basis of ≥50% pain reduction on VAS. In our study, one patient had complete pain relief at 3 months, and nearly 63.3% patients in the pregabalin and 53.3% patients in the lamotrigine group had more than 50% improvement. Our study revealed that both the drugs were equally effective in terms of pain relief, relief of allodynia, and improvement in anxiety and depression. The benefit of lamotrigine was limited by severe adverse skin reaction necessitating drug withdrawal in one-tenth of the patients (n = 3). Although the number of side effects was more with pregabalin, no patients required drug withdrawal. These side effects could be managed by dose reduction (n = 21). Nine patients tolerated 600 mg daily dose of pregabalin, 19 patients 300 mg daily, and two 150 mg daily. However, lamotrigine was tolerated by the majority in a dose of 200 mg daily, except for one patient. Moreover, we did not use a placebo because of availability of Class I evidence for the treatment of CPSP. Therefore, the use of placebo may not be ethically justified, especially in view of severe pain in our study population.
Our study is limited by a small sample size as this is a single-center experience and we included only the patients with ≥50% pain severity on VAS. Randomization and evaluation were done by different investigators, but the identity of drugs could not be concealed. Both pregabalin and lamotrigine resulted in significant improvement in the VAS score (63.3% vs. 53.3%), allodynia (66.7% vs. 75%), and HADS score (80% vs. 81.8%), compared to the baseline without, however, any significant intergroup differences. Our study has revealed that both pregabalin and lamotrigine are equally effective in CPSP, but pregabalin is safer because lamotrigine had to be withdrawn in three patients due to skin rash.
This study provides Class I Level B evidence of equal efficacy of pregabalin and lamotrigine in CPSP, but pregabalin may be preferred because of a better adverse effect profile.
We acknowledge Mr. Rakesh Kumar Nigam for secretarial help.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]