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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 32  |  Issue : 1  |  Page : 40-45

Pregabalin versus oxcarbazepine in painful diabetic neuropathy in elderly population: Efficacy and safety in terms of pain relief, cognitive function, and overall quality of life


1 Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 Department of Anaesthesiology and Critical Care, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
3 Rajiv Gandhi Center for Diabetes and Endocrinology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Date of Web Publication30-Apr-2018

Correspondence Address:
Dr. Hammad Usmani
Consultant Incharge: Pain Unit, Department of Anaesthesiology and Critical Care, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_76_17

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  Abstract 

Background and Aims: The treatment of painful diabetic neuropathy (PDN) in elderly patients is challenging considering the adverse effects associated with long term use of drugs. Pregabalin has been recommended as the first line therapy for relief of neuropathic pain in such patients. However, the occurrence of side effects especially cognitive dysfunction and peripheral edema raised concerns during long term therapy in elderly population. Recently, few studies have highlighted the role of oxcarbazepine, a second generation antiepileptic, in PDN. This prospective, randomized, single-blind, parallel-group study was done to compare pregabaline and oxcarbazepine monotherapy in patients of PDN. Materials and Methods: 150 elderly patients of painful diabetic neuropathy, for at least 6 months of duration with an average baseline pain score ≥ 4 on 11 point numeric rating scale (NRS), were divided into two groups to receive either pregabalin 150 mg/day or oxcarbazepine 600 mg/day. Assessment of pain scores, cognitive functions and quality of life were performed at different time intervals during the course of treatment. Results: Patients in both the study groups showed significant reduction in pain scores from the baseline; however no significant differences in pain scores were noted between the two groups during the course of treatment. The incidence of cognitive dysfunction as measured by BCRS score was significantly more in pregabalin group while no significant changes were noted in oxcarbazepine group. The overall quality of life as demonstrated by SF12 scores was significantly better in both the study groups as compared to baseline. Conclusion: Oxcarbazepine can be used as an alternative to pregabalin in elderly patients with PDN considering the similar degree of pain relief and better cognitive profile.

Keywords: Cognitive function, oxcarbazepine, pain score, painful diabetic neuropathy, pregabalin, quality of life


How to cite this article:
Amir SH, Nasreen F, Usmani H, Siddiqi SS, Hasan M, Tauheed N. Pregabalin versus oxcarbazepine in painful diabetic neuropathy in elderly population: Efficacy and safety in terms of pain relief, cognitive function, and overall quality of life. Indian J Pain 2018;32:40-5

How to cite this URL:
Amir SH, Nasreen F, Usmani H, Siddiqi SS, Hasan M, Tauheed N. Pregabalin versus oxcarbazepine in painful diabetic neuropathy in elderly population: Efficacy and safety in terms of pain relief, cognitive function, and overall quality of life. Indian J Pain [serial online] 2018 [cited 2019 Oct 18];32:40-5. Available from: http://www.indianjpain.org/text.asp?2018/32/1/40/231509


  Introduction Top


Painful diabetic neuropathy (PDN) is a common complication of long-standing diabetes mellitus.[1] The average prevalence of diabetic neuropathy in Indian population is approximately 30%.[2] Of all the risk factors for diabetic neuropathy, chronic hyperglycemia seems to have the most definitive association. The other predisposing factors may include duration of diabetes mellitus, increased age, genetic susceptibility, lipotoxicity and glucotoxicity, inflammation, and oxidative stress.[2],[3],[4]

Although the management of these patients begins with the aim for stable and optimal glycemic control, relief of neuropathic pain forms an essential component of therapy for a better quality of life.[2]

An accelerated decline in cognitive functions in elderly population has generated special interest on the potential cognitive impairment caused by antiepileptic drugs used for the management of neuropathic pain in elderly patients.[5]

Recent controlled clinical trials and systemic reviews have recommended pregabalin, a newer antiepileptic, as a first-line therapy for the management of PDN.[6],[7],[8] However, the negative effect of pregabalin on cognition is an issue of great concern in elderly population. An increased incidence of dizziness, somnolence, and peripheral edema at higher doses could also influence the overall tolerability of the drug during long-term therapy.[1],[9],[10]

Oxcarbazepine is a second-generation antiepileptic, closely related to carbamazepine with a better safety profile and low risk of allergic reactions than carbamazepine.[11],[12] A recent Cochrane review showed significantly higher reduction in pain scores in patients of PDN treated with oxcarbazepine when compared to those treated with placebo.[13] Although studies have shown little evidence of cognitive impairment in general population,[11],[14],[15],[16],[17],[18] the effect on cognition in elderly age group needs further evaluation.

This study was designed to compare pregabalin monotherapy and oxcarbazepine monotherapy in terms of analgesic efficacy, tolerability (particularly their effects on cognitive functions), and overall quality of life in elderly patients with PDN.


  Materials and Methods Top


After taking clearance from the institutional ethics committee, this randomized, single-blind, parallel-group study was conducted in the Pain Clinic of Department of Anaesthesiology, Jawaharlal Nehru Medical College Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India, over a period of 18 months, i.e., from September 2014 to March 2016.

Participants

One-fifty elderly patients (age ≥ 65 years) of either sex with body weight ranging from 40 to 80 kg, with PDN for at least 6 months of duration were enrolled for this trial. After obtaining written informed consent, patients with an average baseline pain score of ≥4 on an 11-point Numerical Rating Scale (NRS) (0 = no pain to 10 = worst pain imaginable) during the 1 week of prerandomization washout period were enrolled for the study. During this period as well as throughout the study, no other analgesic medication except tablet acetaminophen 650 mg (max. dose 4 g/day) was allowed as rescue analgesic. The baseline pain scores, cognitive function, and quality of life of all participants were evaluated at the end of washout period. In addition to complete physical and neurological assessment, all the participants underwent monitoring of complete blood count, metabolic panel, renal function, and electrolytes before the initiation of study and during each follow-up visit.

The exclusion criteria included patients with uncontrolled hyperglycemia (HbA1C ≥ 11%); psychiatric disorders or any clinically significant disease; history of renal insufficiency (creatinine clearance < 30 mL/min) or hyponatremia; history of sensitivity to carbamazepine, oxcarbazepine, or pregabalin; and any drug or alcohol abuse in the past 1 year.

All the subjects were then randomly divided into two groups in a 1:1 ratio to receive either pregabalin (group P) or oxcarbazepine (group O). Randomization was performed using computer-based random number generator, and the allocation was concealed in sealed envelopes, which were not opened until patient consent had been obtained. The treatment period was divided into a titration period of 2 weeks and a maintenance period of 12 weeks.

During the titration period of 2 weeks, pregabalin 50 mg/day and oxcarbazepine 75 mg/day were slowly escalated to 150 mg/day (75 mg twice a day) and 600 mg/day (300 mg twice a day) in group P and group O, respectively. No change in drug dosages was allowed during the 12 weeks of maintenance period.

All the patients were assessed by an investigator blinded to the study groups. A diary was maintained by every patient starting from prerandomization period till the end of study, to record the average daily pain score on NRS, number of doses of rescue analgesic (paracetamol) consumed and incidence of adverse events including any serious adverse effect leading to discontinuation of treatment.

The primary outcome measure was the average pain score at the end of second, sixth, and twelfth week of the treatment period, rated on NRS.

The secondary measures would include changes in cognitive functions using Brief Cognitive Rating Scale (BCRS) and improvement in quality of life of patients using the SF-12 health questionnaire at sixth and twelfth week of study. Time to onset of clinically meaningful pain relief, defined as the first day on which patients showed ≥1-point reduction in mean pain score after the initiation of treatment and the mean dose of study drugs at which the desired effect was achieved, was also recorded.

Statistical Analysis

Continuous variables were summarized as mean and standard deviation and analyzed using paired and unpaired t-test. Data regarding side effects were analyzed using Fisher's exact test using software GraphPad Prism, version 7.03 (GraphPad Software, San Diego, CA). A P-value of <0.05 was taken as significant.

Sample size for the study was calculated on the basis of pilot study conducted on 10 patients in each group. The mean reduction in NRS score after 1 week of therapy was 3.9 in pregabalin group and 2.4 in oxcarbazepine group with standard deviations of 1.2 and 1.1, respectively. The following formula was used for sample size calculation: n = 2(zα+ zβ)2σ2/(Iμ1− μ2I − δ)2, where n is minimum sample size per group; zα is critical value for α, which is 1.645 (one-tailed) at α = 0.05; zβ is critical value for β, which is 0.84 for 80% power; σ is pooled standard deviation, calculated as √(σ1222)/2; μ1 is decrease in mean NRS score after 4 weeks of pregabalin therapy; μ2 is decrease in mean NRS score after 4 weeks of oxcarbazepine therapy; and δ is minimum significant difference for noninferiority of 1.[19]

The sample size was calculated to be 65 patients per group. Assuming a loss to follow-up of 10%–15%, 75 patients were included in each study group. The data of the pilot study were also included in the main study.


  Results Top


Sixty-eight patients in pregabalin group (group P) and 70 patients in oxcarbazepine group (group O) completed the study successfully [Figure 1]. Three patients (4%) of group P and two patients (2.6%) of group O were lost during the follow-up period of study. Four patients (5.3%) in group P withdrew due to excessive dizziness and somnolence whereas three patients (4%) in group O withdrew due to intractable nausea and vomiting. Majority of withdrawals were seen during the titration period of study in both the study groups (4% in group P vs. 2.6% in group O). Both the treatment groups were similar with respect to demographic characteristics and baseline pain scores [Table 1] and [Table 2].
Figure 1: Profile of randomized control trial

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Table 1: Demographic data of the study groups

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Table 2: NRS scores in the study groups before and after treatment

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There was significant reduction in mean pain scores (NRS) at second, sixth, and twelfth weeks when compared to baseline values in both the study groups [Table 2]. The onset of therapeutic effect in group P was significantly early as compared to group O (P< 0.001) [Figure 2]. Mean doses of drugs at which patient first reported ≥1 point reduction in NRS scores were 80 ± 25.8 mg/day for group P whereas 231.8 ± 78.3 mg/day for group O [Table 3]. The requirement of rescue analgesic was also comparable in both the study groups at different time intervals [Table 3]. Incidence of cognitive dysfunction as measured by BCRS score was significantly more in pregabalin group at sixth and twelfth weeks as compared to baseline whereas no significant change in cognitive function was observed in oxcarbazepine group during the study period. However, a trend toward improvement in cognitive function was noted at twelfth week in pregabalin group [Table 4].
Figure 2: Time to onset# of clinically meaningful pain relief (*P < 0.001) #Defined as number of days after which patients showed ≤1 point reduction in mean pain score after initiation of treatment

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Table 3: Requirement of rescue analgesics in the two study groups

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Table 4: BCRS scores of the study groups before and after treatment

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The improvement in overall quality of life as showed by SF-12 score was significantly better in both the treatment groups at sixth and twelfth weeks as compared to baseline. Although on intergroup comparison, no significant difference in SF-12 scores was noted at different time intervals between the two study groups [Table 5]. The commonly reported side effects in group P were dizziness (22%), somnolence (17.6%), peripheral edema (11.7%), and nausea (2%) whereas those in group O were nausea (20%), dizziness (7.1%), vomiting (5.7%), and somnolence (5.7%) [Table 6]. However, no life-threatening adverse effects were observed in either group throughout the study period. Laboratory parameters and electrographic monitoring showed no significant changes from baseline in either group during the course of study.
Table 5: SF-12 scores in the study groups before and after treatment

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Table 6: Incidence of side effects in the two study groups

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  Discussion Top


This randomized, single-blind, parallel-group trial showed that both oxcarbazepine 600 mg/day and pregabalin 150 mg/day provided significant degree of pain relief in peripheral diabetic neuropathy in elderly population. Although patients on pregabalin therapy showed an early onset of therapeutic effect as compared to oxcarbazepine, the efficacy of the two drugs was found comparable during 12 weeks of follow-up period of study.

The results of a recent Cochrane review of three multicenter randomized trials investigating the role of oxcarbazepine in patients of PDN showed significantly higher reduction in pain scores in patients of PDN treated with oxcarbazepine when compared to those treated with placebo; however, this result was based on data only from the trial conducted by Beydoun et al. because data from other two trials were not included in meta-analysis.[13] Beydoun et al.[17] conducted a dose-response study to evaluate the efficacy and tolerability of three daily doses of oxcarbazepine monotherapy in patients of PDN. They reported a strong statistical trend favoring oxcarbazepine 1800 and 1200 mg/day in patients of PDN but not for 600 mg/day. Another study conducted by Dogra et al.[20] showed that oxcarbazepine monotherapy at 1800 mg/day provided significant reduction in pain score from baseline in patients treated with oxcarbazepine as compared to placebo following 16 weeks of therapy. However, the higher doses of oxcarbazepine therapy in both the studies were associated with increased incidence of serious adverse effects and a higher rate of premature discontinuation from the study.[17],[20]

In this study, we have chosen relatively lower doses of oxcarbazepine (600 mg) and pregabalin (150 mg) monotherapy for elderly patients of PDN, taking into consideration the fact that elderly population showed an increased sensitivity to drugs and a corresponding increase in the incidence of adverse effects. The lower body mass index of Asians and their slower drug metabolism could be the other possible reasons for obtaining significant pain relief in PDN at relatively lower doses of drug therapy in this study.[21],[22]

Commonly reported adverse effects in oxcarbazepine (600 mg/day) group in this study were nausea (20%), dizziness (7.1%), and somnolence (5.7%). The rate of premature discontinuation due to adverse effects (intractable nausea and vomiting) in oxcarbazepine group was only 4.0% in our study whereas Beydoun et al.[17] reported premature withdrawals following adverse effects in 11% of patients on similar doses of oxcarbazepine therapy. The lower rate of discontinuation in this study could be due to a flexible titration schedule of 2 weeks with lower initial doses (75 mg) of oxcarbazepine therapy as compared to rigid titration period of 5 days only with higher initial doses (300 mg) of oxcarbazepine therapy in the study of Beydoun et al. Majority of withdrawals in our study were reported during the titration period, which is similar to the pattern of withdrawal observed by Beydoun et al.[17] and Dogra et al.[20]

Dizziness, somnolence, and peripheral edema were the most common adverse effects reported with pregabalin therapy in this study. Four patients (5.3%) in pregabalin group withdrew from this study due to excessive dizziness and somnolence. Freeman et al.[23] conducted a pooled analysis of seven randomized, controlled trials on the efficacy, safety, and tolerability of pregabalin therapy for patients of PDN. They observed a dose-dependent reduction in pain scores in patients of PDN, with maximum efficacy observed at pregabalin 600 mg/day and the lowest effective dose was pregabalin 150 mg/day. However, with increased doses of pregabalin therapy, there was a simultaneous increase in the incidence of adverse effects, as well as the rate of premature discontinuation due to adverse effects (4% with pregabalin 150 mg/day, 9.8% with pregabalin 300 mg/day, and 14.6% with pregabalin 600 mg/day). Dizziness, somnolence, and peripheral edema were the most common adverse effects reported with pregabalin therapy in their analysis. A post hoc analysis of pooled data from 11 placebo-controlled trials on the efficacy of pregabalin in patients of peripheral diabetic neuropathy reported that dizziness, somnolence, and peripheral edema were the most common adverse effects in pregabalin-treated patients of diabetic peripheral neuropathy.[24]

The potential for cognitive dysfunction is an issue of great concern during long-term pregabalin therapy in elderly population as it is found to be the strongest determinant of impaired health-related quality of life in people taking antiepileptic drugs.[25] Zaccara et al.[26] reviewed the adverse event profile of pregabalin therapy through meta-analysis of available randomized, placebo-controlled, double-blind trials in adults with different neurologic and psychiatric disorders. They observed that the risk of dizziness, somnolence, ataxia, and peripheral edema was higher at pregabalin 150 mg/day dose whereas balance disorder, incoordination, blurred vision, and disturbance in attention were reported at higher doses of pregabalin therapy. A dose-response relationship was particularly observed between pregabalin therapy and cognitive dysfunctions, which were more evident on higher doses of pregabalin therapy.

A significant impairment of cognitive functions was reported even at pregabalin 150 mg/day dose in elderly population in our study. Because diabetes mellitus in itself is associated with an accelerated decline in cognitive function in old age, the negative cognitive effects of pregabalin even at lower doses could be an issue of great concern in this particular age group of patients.

Peripheral edema due to pregabalin therapy is an important concern in elderly population due to the presence of underlying comorbid conditions leading to edema of extremities. An analysis on efficacy, safety, and tolerability of pregabalin in patients of PDN showed a dose-dependent increase in the incidence of peripheral edema without any evidence of derangements of cardiovascular, renal, or hepatic functions.[23] In this study, despite the use of relatively lower doses of pregabalin, approximately 10% of the patients developed peripheral edema at the end of the study period, whereas none of the patients in oxcarbazepine group had this complication.

Decreased serum sodium levels have been reported with the use of oxcarbazepine in elderly people. A review by Schmidt et al.[27] showed that the incidence of hyponatremia (serum sodium < 125 mmol/L) was 7.3% in patients on oxcarbazepine therapy aged more than 65 years, although it was more commonly seen in patients on concomitant medications known to lower serum sodium levels. In our study, laboratory assessments showed no significant change in mean sodium levels from baseline following treatment with oxcarbazepine at 600 mg/day doses.

Quality of life of patients in both the groups was significantly improved from baseline at sixth and twelfth week of study. Although mean SF-12 scores were comparable between the two study groups at sixth and twelfth weeks, however, it was observed that improvement in physical activities was somewhat limited in pregabalin group due to higher incidence of somnolence and dizziness while the emotional components were better controlled as compared to oxcarbazepine group.

Major limitations of this study worth mentioning were short-term follow-up of only 12 weeks and a smaller sample size, calculated at α = 0.05 and power 80%. Sample size calculated using a power of 90% would have resulted in better precision and accuracy. Long-term follow-up would have better ascertained the safety profile and potential adverse effects of drugs, which might not be apparent during relatively short study period. Moreover, the inability to achieve uniform coding of study drugs could have introduced bias in this single-blind study.


  Conclusion Top


Findings of this study suggest that oxcarbazepine can be used as an alternative drug therapy to pregabalin in PDN in elderly patients, owing to its similar analgesic efficacy and lesser incidence of cognitive dysfunction. However, further large, multicenter studies are needed to establish its efficacy and safety in elderly population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

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