A randomized active controlled trial to assess efficacy, effect on heart rate variability and safety of pregabalin- nortriptyline and pregabalin-duloxetine combination in patients with diabetic neuropathy

Diabetes is one of the commonest metabolic disorders and Diabetic neuropathy (DiN) is a prevalent complication of diabetes and is characterized as the manifestation of symptoms of peripheral nerve impairment[1]. DiN has been found to present with discomfort, hyperalgesia, allodynia, tingling, aching, and burning sensations, as well as varied degrees of limb weakening. The pain in DiN has varied presentation such as intense, persistent, deep-seated, or intense pain that worsens at night [2]. The major classes of drugs that are used are Gabapentinoids like Gabapentin and Pregabalin, Tricyclic antidepressants (TCAs) like Amitriptyline, Serotonin–norepinephrine reuptake inhibitors (SNRI) like Duloxetine and Venlafaxine and Opioids like Tramadol and Tapentadol[3,4]. Cardiovascular autonomic neuropathy is one of the major consequences of diabetes and leads to impairment and injury to the heart’s autonomic nerve fibres innervating the myocardium and coronaries, causing anomalies in vascular dynamics and heart rate regulation[5,6,7]. To assess the cardiac autonomic neuropathy, one of the crucial tests is assessment of heart rate variability (HRV). The HRV refers to the fluctuation between two successive cardiac beats; an increased variance indicates heightened parasympathetic activity[8]. A high HRV indicates a person’s ability to consistently adjust to various minimal environmental alteration, stress and capacity to swiftly adjust to the physical or psychological exigencies of the environment and a reduced HRV is an indicator of enhanced cardiovascular risk [8,9]. A study by Jiang et al. reported that pregabalin improves HRV apart from providing relief in diabetic neuropathy[10]. A study conducted on non-diabetic individuals for four weeks concluded that both pregabalin and amitriptyline have the property to significantly increased HRV in the patients of neuropathic pain[11]. No similar evidence could be traced with low dose duloxetine and its effect on HRV in patients of DiN.

Given that pregabalin, duloxetine and nortriptyline are well-known neuropathic pain relievers, there shouldn’t be many new side effects. The established side effects with pregabalin are dizziness, somnolence, dry mouth, weight gain, and mostly related to trouble concentrating [12]. Likewise the common adverse events with duloxetine are nausea, dry mouth, somnolence, fatigue, constipation, decreased appetite, and hyperhidrosis[13]. Nortriptyline is also associated with similar adverse events like fatigue, sedation, dry mouth, constipation, nausea and headache[14].

Majority of the studies conducted on DiN have compared any two gabapetinoids or a gabapentinoid with SNRI like amitriptyline for their effectiveness in the management of DiN. However, there is a paucity of research among the widely used fixed dose combinations of gabapentinoids and TCA or gabapentinoids and SNRI available in the market. Hence, we planned this study to compare fixed dose combination of pregabalin and nortriptyline, pregabalin and low dose duloxetine for their effectiveness and tolerability in the management of diabetic neuropathy.

1.      Hypothesis:

H0: The pregabalin-nortriptyline and pregabalin-low dose duloxetine fixed dose combination is equi-efficacious and safe in reducing pain in diabetic neuropathy

H1: Either of pregabalin-nortriptyline or pregabalin-low dose duloxetine fixed dose combination is more effective or safer

2.      Research questions:

Which of the two fixed dose combination namely pregabalin-nortriptyline and pregabalin-low dose duloxetine is more effective and safer in patients of diabetic neuropathy

Primary outcome

1.     To assess the efficacy of pregabalin-nortriptyline and pregabalin-low dose duloxetine fixed dose combination in reducing pain in diabetic neuropathy

Secondary objective

1.     To assess the alterations in heart rate variability in participants on either interventional medication

2.     To detect all the adverse events associated with the medications and assess the causality, type and severity of the noted adverse events

references

**1.**Yang Z, Chen R, Zhang Y, et al. Scoring systems to screen for diabetic peripheral neuropathy. Cochrane Database Syst Rev. 2018;2018(7). doi: 10.1002/14651858.CD010974.pub2

**2.**Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol. 2021 Jul;17(7):400-20. doi: 10.1038/s41574-021-00496-z.

**3.**Cavalli E, Mammana S, Nicoletti F, et al. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. 2019;33:2058738419838383. doi: 10.1177/2058738419838383.

**4.**Einhorn LM, Hudon J, Ingelmo P. The Pharmacological Treatment of Neuropathic Pain in Children. Curr Neuropharmacol. 2024;22(1):38-52. doi: 10.2174/1570159x21666230804110858

**5.**Maser RE, Mitchell BD, Vinik AI, et al. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care. 2003 Jun;26(6):1895-901. doi: 10.2337/diacare.26.6.1895. PubMed PMID: 12766130; eng.

**6.**Vinik AI, Maser RE, Mitchell BD, et al. Diabetic autonomic neuropathy. Diabetes Care. 2003 May;26(5):1553-79. doi: 10.2337/diacare.26.5.1553. PubMed PMID: 12716821; eng.

**7.**Vinik AI, Ziegler D. Diabetic Cardiovascular Autonomic Neuropathy. 2007;115(3):387-97.

**8.**Benichou T, Pereira B, Mermillod M, et al. Heart rate variability in type 2 diabetes mellitus: A systematic review and meta-analysis. PLoS One. 2018;13(4):e0195166. doi: 10.1371/journal.pone.0195166.

9.      Boudet G, Walther G, Courteix D, et al. Paradoxical dissociation between heart rate and heart rate variability following different modalities of exercise in individuals with metabolic syndrome: The RESOLVE study. Eur J Prev Cardiol. 2017 Feb;24(3):281-96. doi: 10.1177/2047487316679523.

10.   Jiang W, Ladd S, Martsberger C, et al. Effects of pregabalin on heart rate variability in patients with painful diabetic neuropathy. J Clin Psychopharmacol. 2011 Apr;31(2):207-13. doi: 10.1097/JCP.0b013e31820f4f57. PubMed PMID: 21346609; eng.

11.   Srivastava R, Kantharia ND. Evaluation of effect of amitriptyline and pregabalin on heart rate variability in neuropathic pain in non-diabetic patients. International Journal of Research in Medical Sciences. 2022 04/26;10(5):1145-50.

12.   HIGHLIGHTS OF PRESCRIBING INFORMATION- (pregabalin 2018 [Sept 29, 2024]. Available from: https://www.accessdata.fda.gov/drugsatfda\_docs/label/2018/021446s035,022488s013lbl.pdf

13.   FDA. HIGHLIGHTS OF PRESCRIBING INFORMATION-duloxetine hydrochloride 2010 [Sept 29, 2024]. Available from: https://www.accessdata.fda.gov/drugsatfda\_docs/label/2010/022516lbl.pdf

Medscape L. nortriptyline 2024 [cited 2024 Sept, 27, 2024]. Available from: https://reference.medscape.com/drug/pamelor-nortriptyline-342944#0