Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System

Hiroki, Tadanao; Suto, Takashi; Saito, Shigeru; Obata, Hideaki

doi:10.1213/ane.0000000000002352

Cited by 37 publications

(23 citation statements)

References 34 publications

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“…This increase in the withdrawal threshold is reversed by intrathecal injection of idazoxan, an α 2 adrenergic receptor antagonist, and the amount of noradrenaline in the dorsal horn of the spinal cord increases after three daily injections of duloxetine [ 27 ] ( Figure 2 ). In addition, in animals pretreated with a noradrenergic neurotoxin (DSP-4), the antihyperalgesic effect of duloxetine is weakened [ 28 ]. Intraperitoneal administration of amitriptyline, a TCA, over consecutive days gradually increases the withdrawal threshold, but this antihyperalgesic effect is reversed by intrathecal injection of an α 2 -adrenergic antagonist [ 28 ].…”

Section: Noradrenaline Inhibits Neuropathic Pain In the Spinal Cormentioning

confidence: 99%

“…In addition, in animals pretreated with a noradrenergic neurotoxin (DSP-4), the antihyperalgesic effect of duloxetine is weakened [ 28 ]. Intraperitoneal administration of amitriptyline, a TCA, over consecutive days gradually increases the withdrawal threshold, but this antihyperalgesic effect is reversed by intrathecal injection of an α 2 -adrenergic antagonist [ 28 ].…”

Section: Noradrenaline Inhibits Neuropathic Pain In the Spinal Cormentioning

confidence: 99%

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Analgesic Mechanisms of Antidepressants for Neuropathic Pain

Obata

2017

IJMS

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296

203

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Tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors are used to treat chronic pain, such as neuropathic pain. Why antidepressants are effective for treatment of neuropathic pain and the precise mechanisms underlying their effects, however, remain unclear. The inhibitory effects of these antidepressants for neuropathic pain manifest more quickly than their antidepressive effects, suggesting different modes of action. Recent studies of animal models of neuropathic pain revealed that noradrenaline is extremely important for the inhibition of neuropathic pain. First, increasing noradrenaline in the spinal cord by reuptake inhibition directly inhibits neuropathic pain through α2-adrenergic receptors. Second, increasing noradrenaline acts on the locus coeruleus and improves the function of an impaired descending noradrenergic inhibitory system. Serotonin and dopamine may reinforce the noradrenergic effects to inhibit neuropathic pain. The mechanisms of neuropathic pain inhibition by antidepressants based mainly on experimental findings from animal models of neuropathic pain are discussed in this review.

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Section: Noradrenaline Inhibits Neuropathic Pain In the Spinal Cormentioning

confidence: 99%

Section: Noradrenaline Inhibits Neuropathic Pain In the Spinal Cormentioning

confidence: 99%

Analgesic Mechanisms of Antidepressants for Neuropathic Pain

Obata

2017

IJMS

Self Cite

296

203

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“…Based on the curative activity potentials of monoamine reuptake inhibitory drugs on neuropathic pain [ 8 , 9 , 10 , 11 , 12 , 13 ], promising therapeutic efficacy of atomoxetine, a selective noradrenaline reuptake inhibitor drug, on diabetes-induced hyperalgesia was investigated, in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…It is well described that noradrenaline plays an important role in the pain processing and analgesia. Moreover, recent studies pointed out that enhanced level of noradrenaline in the spinal and supraspinal pathways is crucial for the analgesic effects of various drugs on neuropathic pain [ 8 , 9 , 10 , 11 ]. Thus, drugs increasing noradrenaline levels in the central nervous system may have a therapeutic potential for patients suffering from the neuropathic pain disorders.…”

Section: Introductionmentioning

confidence: 99%

Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems

et al. 2018

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Atomoxetine is a selective noradrenaline reuptake inhibitor drug. Based on the knowledge that agents increasing monoamine levels in the central nervous system have therapeutic potential for neuropathic pain, it is planned to investigate the possible efficacy of atomoxetine on diabetes-induced hyperalgesia, in this study. Randall-Selitto (mechanical noxious stimuli) and Hargreaves (thermal noxious stimuli) tests were used to evaluate nociceptive perception of rats. Obtained data indicated that streptozotocin-induced diabetes causes significant decreases in the paw withdrawal threshold and paw withdrawal latency values of the animals, respectively. However, atomoxetine administered at 3 mg/kg/day for 7 and 14 days improved these diabetes-induced hyperalgesia responses. Furthermore, antihyperalgesic activity was antagonized with α-methyl-para-tyrosine methyl ester, phentolamine, propranolol, and sulpiride pre-treatments. The same effect was not reversed, however, by SCH 23390. These findings demonstrated, for the first time, that atomoxetine possesses significant antihyperalgesic activity on diabetes-induced neuropathic pain and this effect seems to be mediated by α- and β-adrenergic and D2/D3 dopaminergic receptors. Results of this present study seem to offer a new indication for an old drug; atomoxetine, but these preclinical data should first be confirmed with further well-designed clinical trials.

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“…14 It is believed that the activities of amitriptyline and its active metabolite, nortriptyline, are primarily but not entirely due to their binding to the noradrenaline and serotonin transporters at central sites. 16 In addition to major depression, amitriptyline was also reported to treat chronic neuropathic pain (pain due to nerve damage), 17,18 fibromyalgia, 19 migraine, and anxiety disorders. 20,21 Although amitriptyline hydrochloride has been widely used in China for several years, only a limited number of reports have studied its efficacy and tolerability during treatment of depressive disorders or other diseases.…”

Section: Introductionmentioning

confidence: 99%

<p>Bioequivalence Study of Amitriptyline Hydrochloride Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions</p>

Zhai

Zheng

et al. 2020

DDDT

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This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug. Materials and Methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC 0-t , AUC 0-∞), the peak plasma concentration (C max), the time to achieve C max (T max), and the elimination half-life (t 1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs). Results: The values of t 1/2 and T max for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of C max , AUC 0-t , and AUC 0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events. Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.

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Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System

Cited by 37 publications

References 34 publications

Analgesic Mechanisms of Antidepressants for Neuropathic Pain

Analgesic Mechanisms of Antidepressants for Neuropathic Pain

Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems

<p>Bioequivalence Study of Amitriptyline Hydrochloride Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions</p>

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