Comparative Study of Safety and Efficacy of Gabapentin Versus Amitriptyline in Patients With Painful Diabetic Peripheral Neuropathy , A Randomized open Label Parallel Group Study

The study was aimed to compare the safety and efficacy of Gabapentin vs amitriptyline in patients with painful diabetic peripheral neuropathy. Study was conducted in Chennai during the period from October 2014 to May 2015 were a total of 100 patients were randomized to two treatment groups in 1:1 ratio. Gabapentin 600 mg per day and increased upto a maximum of 1800 mg per day, at bed time. Amitriptyline 25 mg per day and increased upto a maximum of 75 mg per day, at bed time. There were four scheduled visits during the study. All study participants were given a diary and necessary scales (Visual analog scale and sleep interference scale). Categorical variables are analysed using Chi square test and Paired Students‘t’ test. With similar baseline for both groups, Gabapentin produced significant improvement versus amitriptyline for mean pain scores (P<0.05); mean sleep interference scores (P<0.05). Additional statistically significant (P<0.05) differences favouring gabapentin treatment were observed in measures of quality of life (Global Impression of Change in both Patient and Clinician perspective). Gabapentin group showed more number of adverse events like increased appetite, somnolence and liver function test increase, while amitriptyline group had increased micturition and dizziness. The study revealed that gabapentin is safer and efficacious compared to amitriptyline in patients with painful diabetic peripheral neuropathy


INTRODUCTION
In type 2 diabetes, DPN is one of the commonest causes of foot complications leading to pain, loss of sensation, foot ulcers and amputation leading to a reduced functional capacity of an individual 1 .In a study to determine the prevalence of foot ulcers and the incidence of amputations in patients with type 2 diabetes, Bruun C et al observed that after 19 years of diagnosis of type 2 diabetes, the incidence of amputations was still high in type 2 diabetes population 2 .
It is clear that metabolism of nerve cells is altered by increased glucose level in blood.This results from the loss or damage to the sensory nerve fibres.The initial problem is loss of sensation for pain and this increases the likelihood of foot ulcers in the diabetic population.This also accounts for recurrent hospitalization than other complications of type 2 diabetes and is also the most common cause of non traumatic amputations.In addition to this, diabetic peripheral neuropathy (DPN) patient's encounters problems with balance while standing and walking, reduced work capacity and pain in the legs, thus reducing their overall functional output leading to poor quality of life.
Glycemic control is the only currently known therapy to delay the development and progression of Diabetic peripheral neuropathy.Once a patient has been diagnosed with DPN, treatment options focus on symptom control.Previously there had been many studies focusing on drug related prophylaxis for population suffering from DPN such as antidepressants, anticonvulsants, oral hypoglycemic agents but either they have a major side -effect or cannot be continued for long term trials for patients 3 .Antidepressants are a common group of drugs used for neuropathic pain.Tricyclic Antidepressants (TCAs), Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Norepinephrine Reuptake Inhibitors (SNRIs) have been tested for off-label uses in pain management 4 .Amitriptyline was the first and most frequently studied TCA to show a significant improvement in pain scores.Later, other TCAs, such as desipramine and nortriptyline proved to have beneficial effects, still the most common and least tolerated adverse effects with tricyclic antidepressant are the anticholinergic effects, which include dry mouth, blurred vision, constipation, urinary retention and cognitive impairment.Other serious side effects associated with these agents relate to cardiovascular toxicity and include orthostatic hypotension, tachycardia and changes in atrioventricular conduction 4 .

Study procedure
After baseline laboratory investigations all the 100 patients selected were randomized and allotted a treatment group.Gabapentin was initiated at 600 mg per day and increased upto a maximum of 1800 mg per day once daily at bed time and Amitriptyline initiated at 25 mg per day and increased upto a maximum of 75 mg per day, once daily at bed time.Baseline laboratory investigations were done.There were four scheduled visits during the study, baseline visit, after 1 st month, then after 2 nd month and at the 3 rd month (end of study visit).Increase in dosage is determined during each visit after examination.
All study participants were given a diary and necessary scales (Primary endpoint: 11 point Visual analog scale and Secondary endpoint: 11 point sleep interference scale).Other secondary endpoints with the following 7 point scale system is used to assess the effectiveness of treatment during the follow-up visits, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally  Atli A et al studied the improvement of pain in diabetic neuropathy in a placebo based randomized control study and found that the measurement of Visual analog scale when used correctly is a validated procedure for evaluation of pain in neuropathy 7 .KC Yuen et al in a double blind placebo controlled cross over study used visual analog score as mean to measure the pain in diabetic neuropathy 8 .Assessment of Visual analog scale showed a significant reduction in pain in both treatment groups (p<0.05).But the extent of the benefit is analysed by comparing the score during the final end point showed gabapentin (67.72±16.93 to 29.51±16.90)has significant reduction in pain compared to amitriptyline (65.92±12.89 to 36.85±14.14).Treatment effect was seen bit earlier on patient group taking Gabapentin.This may be a valid option for patients requiring immediate reduction in pain intensity. .
One of the main characteristics of neuropathic pain is, it interferes with daily sleep.Zelman DC et al conducted a sleep data analysis in patients with diabetic peripheral neuropathy and has found that it is considerably associated with sleep impairment 11 .Also a meta-analytic study conducted by Roth T, provided evidence from data of 2399 patients, that there is a significant improvement in sleep quality from medications for peripheral neuropathy in diabetes 12 .Daily sleep interference score analysis in our study has been performed.Both treatment group showed a great deal of potential in improving the sleep (p<0.05).But Gabapentin showed a very high significance in sleep improvement at a very early stage (6.72±1.91 to 4.74±2.03within four weeks compared to amitriptyline, 5.96±2.09 to 5.61±2.13).Both these drugs are candidates in causing sleep related adverse effects that had proven to be beneficial in this condition but reports suggested that residual sleep was present in some subjects, two in amitriptyline group and four in gabapentin group.This was more in amitriptyline.
Any chronic illness always have a tendency to take toll on the quality of life and diabetic neuropathy is no exception.Benbow SJ et al observed the effect of this disease affecting the quality of life and urged to have intensive research for effective management 13 .Amanda Boyd et al validated a questionnaire for measuring the quality of life in diabetic neuropathy 14 .AE Bunner et al used global impression of change as a scale to analyse the quality of life in diabetic neuropathy patients 15 .Global impression of change was obtained in both perspectives (patient and clinician).While the results of clinician's global impression of change improved significantly (p<0.05) from the initial value, they didn't find any significant difference in both treatment groups.But patient's global impression of change suggested that patients in gabapentin group (4.10±1.36 to 2.16±1.45)experienced an increased sense of wellbeing compared with that of amitriptyline group (3.90±1.20 to 3.11±1.2) and both group showed significant improvement in wellbeing.
The main drawback of treating a complication of chronic disease is the dose limiting adverse drug reaction.This happened in our study also.Tolerability data available from our study is consistent with previous similar studies.Tricyclic antidepressants is usually limited with highly intolerable adverse effects like increased sedation, retention of urine, postural hypotension, or cardiac arrhythmias as evident from Moore R.A et al 16 .But drug tolerance was never a factor for discontinuation or treatment non-compliance in our study.Even though adverse events has been reported in our study, there were no need of any study discontinuation.Some patients in gabapentin group experienced side effect like weight gain.But amitriptyline group patients experienced day time drowsiness and increased frequency of micturition.Both study drugs increased the mean liver function test compared to baseline but only gabapentin group (two patients) showed a clinically significant increase in liver function tests (p<0.05).
In both study groups there has been no change in the glycated haemoglobin value from baseline, this suggest that the beneficial effects in neuropathic pain can be completely attributed to the study drugs and not to pharmacotherapy of diabetes mellitus.
Although this study has given us an understanding the benefits and shortcomings of both the drugs we had our own limitations, primarily based on the design, this is an open label study and no cross-over was done.Educated patients may be prone for bias due to the amount of content available on the World Wide Web.Also we couldn't use a placebo arm in this study due to the obvious logistics issue.Future study may extend the present therapy and include an add-on therapy such as topical applications and verify the benefit and any dose reduction of the main therapy.

CONCLUSION
This study revealed that gabapentin is safer and efficacious compared to amitriptyline in patients with painful diabetic peripheral neuropathy.Both treatment group provided clinically meaningful relief of pain with tolerable side effects.But the induction of pain relief was very much superior in gabapentin when compared with amitriptyline.The same holds for the improvement in quality of sleep and for day to day quality of life.The incidence and severity of adverse effect is less in gabapentin compared with amitriptyline To conclude newer therapy based on the actions of gabapentin provide a promising role in reducing pain and improving the quality of life in such chronic painful condition.

Fig. 2 :
Fig. 2: Comparison of change in visual analog score during treatment duration