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.
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P. The Pharmacological Treatment of Neuropathic Pain in Children. Curr
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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
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AI, Ziegler D. Diabetic Cardiovascular Autonomic Neuropathy.
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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
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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
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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 |