Pharmacogenetics and Analgesic Effects of Antidepressants in Chronic Pain Management

Frédérique Rodieux; Valérie Piguet; Patricia Berney; Jules Desmeules; Marie Besson

Personalized Medicine. 2015;12(2):163-175.

Method

Relevant articles in the PubMed and EMBASE databases were identified using the following keywords: 'pain', 'neuropathy', 'depression', 'antidepressants', 'resistance' and/or 'pharmacogenetics.' We limited our search to English language studies published in peer-reviewed journals. Additional publications were identified from review articles.^[52–73]

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Table 1. Antidepressant metabolic pathways.
Antidepressants	Cytochrome
Agomelatine	1A2, 2C9, 2C19
Amitriptyline^†	1A2, 2C9, 2C19, 2D6, 3A
Bupropion^†	2B6
Citalopram	2C19, 2D6, 3A
Duloxetine^†	1A2, 2D6
Fluoxetine	2C9, 2C19, 2D6, 3A
Fluvoxamine	1A2, 2D6
Imipramine^†	1A2, 2C19, 2D6, 3A
Maprotiline^†	2D6
Mirtazapine^†	1A2, 2D6, 3A
Paroxetine	2D6
Reboxetine	3A
Sertraline	2B6, 2C9, 2C19, 2D6, 3A
Trazodone	2D6, 3A
Trimipramine^†	2C9, 2C19, 2D6
Venlafaxine^†	2D6, 3A

^†Antidepressants used for the treatment of chronic pain at the University Hospitals of Geneva [78].

Table 2. Dosage guidelines for amitriptyline and, by analogy, tricyclics according to the CYP2C19 and CYP2D6 phenotype.
CPY2C19	CYP2D6
CPY2C19	UM	EM	IM	PM
UM	• Avoid use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments	• Avoid use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments	• Avoid use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments	• Avoid use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments
EM	• Avoid use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments	• Initiate therapy with recommended starting dose	• Consider a 25% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments	• Avoid use of tricyclic drugs • If a tricyclic is warranted, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments
IM	• Avoid use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments	• Initiate therapy with the recommended starting dose	• Consider a 25% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments	• Avoid use of tricyclic drugs • If a tricyclic is warranted, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments
PM	• Avoid the use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments	• Decrease the usual dose by 50% and adjust according to therapeutic monitoring	• Avoid the use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustment	• Avoid the use of tricyclic drugs • If a tricyclic is warranted, utilize therapeutic drug monitoring to guide dose adjustments

EM: Extensive metabolizer; IM: Intermediate metabolizer; PM: Poor metabolizer; UM: Ultrarapid metabolizer.
Adapted with permission from [70] © Macmillan Publishers Ltd (2013).

Table 3. Antidepressant substrates of P-gp.
Antidepressants	P-gp
Agomelatine
Amitriptyline^†	x
Bupropion^†
Citalopram	x
Duloxetine^†
Fluoxetine
Fluvoxamine
Imipramine^†	x
Maprotiline
Mirtazapine^†
Paroxetine
Reboxetine
Sertraline
Trazodone
Trimipramine^†	x
Venlafaxine^†	x

^†Antidepressants used for the treatment of chronic pain at the University Hospitals of Geneva [78].

Table 4. Polymorphisms of enzymes involved in antidepressant pharmacodynamics.
Protein	Function	Main SNP	Enzymatic activity	Clinical impact	Ref.
Monoamine oxidase (MAO)	Serotonin and noradrenaline metabolism	VNTR polymorphism of the promoter region (S and L)	L: associated with increased expression and activity of MAO up to 10×	Conflicting results, no proven associations	[129–132]
Serotonin transporter (SERT)	Regulation of the concentration of serotonin in the synaptic cleft by the presynaptic reuptake level	Promoter (5-HTTLPR) (S and L)	S: associated with increased transcription and serotonin reuptake (up to 2- to 2.5-times)	L: better response to fluvoxamine, fluoxetine, paroxetine, mirtazapine, sertraline, escitalopram and citalopram treatments	[51,57,133]
				Homozygotes SS: more side effects with fluoxetine, citalopram and escitalopram treatments
		VNTR of intron 2 (STIN2)		Conflicting results, no proven associations	[134–137]
Noradrenaline transporter SLC6A2	Regulation of the concentration of noradrenaline in the synaptic cleft by presynaptic reuptake	Several polymorphisms		Conflicting results, no proven associations	[132,138–140]
Serotonin receptor 5HT1A	Postsynaptic + presynaptic localization modulation of serotonin release	G>C 1019 promoter C1019G (rs6295)		G>C: Poorer response to fluvoxamine, fluoxetine and citalopram treatment, no proven associations	[42,132,139–142]
Serotonin receptor 5HT2A	Postsynaptic localization modulation of serotonin release	T>C 102 (rs6313) A>G 1438 (rs6311)		No proven associations No proven associations	[78,132,143–144]

L: Long form; S: Short form.

Sidebar

Executive Summary

Use of antidepressants in chronic pain management

The current evidence-based guidelines recommend the use of antidepressants, particularly tricyclics and serotonin-noradrenaline reuptake inhibitors, for the treatment of various types of chronic pain.
The analgesic properties of antidepressants have been suggested to result from the inhibition of amine, noradrenaline and serotonin reuptake in the CNS, which leads to increased activity of the antinociceptive descending pathways, but effects at the peripheral site, that are independent from the effect on the mood, have also been described.

Important interindividual variability in antidepressant drug response

The management of pain with antidepressants has been found to exhibit variable efficacy and tolerability, that may be attributed to genetic factors.
Numerous studies and reviews have described the influence of pharmacogenetics on the efficacy and tolerance of antidepressants in the treatment of depression. We now discuss the potential role of these polymorphisms in the specific context of pain management.

Polymorphisms involved in drug pharmacokinetics

Antidepressant drugs are mainly metabolized through the cytochrome P450 superfamily.
CYP2D6 is highly polymorphic, with up to 80 allelic variants described. Genetic variations of CYP2D6 have been demonstrated to influence the plasma level concentrations of antidepressants. More frequent adverse events are found in PM and data suggest that UM patients present reduced efficacy.
Genetic variations have also been described for CYP2C19 and the different phenotypes are also associated with variable plasma concentrations and occurrence of side effects.
Because of the well-established data on CYP2D6 and CYP2C19 showing the link between the genetic variations, the drug–plasma concentrations, the response of antidepressants and the occurrence of side effects, dosage recommendations based on the CYP2D6 and CYP2C19 phenotype/genotype have been done for 'antidepressive' dosages and can be extrapolated for 'analgesic' dosages.

P-gp

A number of antidepressants are substrates of P-gp. To date, no link between mutations of ABCref-1 gene and antidepressant efficacy or tolerability has been demonstrated. It is reasonable to believe that an increased CNS exposure to antidepressants, due to a low P-gp activity, would increase the risk of adverse effects.

Polymorphisms involved in antidepressant targets

COMT is one of the principal key modulator of dopaminergic and adrenergic/noradrenergic neurotransmission, suggesting a possible role of the COMT gene in the response to antidepressants. The association between COMT gene variations and pain sensitivity has been reported in various studies but the influence on the therapeutic efficacy of antidepressants remains contradictory.
Part of the analgesic effect of tricyclic antidepressants is due to the blockade of the voltage-gated sodium channels key regulators of the membrane potential in excitable tissues, such as sensory neurons. A link between the overexpression of the subtype Nav 1.7 and the variability of the response to treatment with amitriptyline is postulated.

Future perspective

Because half of the patients treated for chronic pain are not relieved and a substantial proportion exhibits side effects that lead to treatment discontinuation, the exploration of the reason of this variability should be more systematically conducted.
The identification of genetic biomarkers that can predict the antidepressant treatment response and genetically guide the prescription of drugs could definitively improve clinical practice.
Genotypic and phenotypic tests have become more accessible and are the first steps toward individualized prescription medicine, particularly in an area where many objective tests are not available to help guide the treatment.
However antidepressants interact with several molecular targets and the pharmacogenetics of antidepressants in the context of pain management remains a field with a high amount of missing information.
Further studies are needed before the pharmacogenetics can be integrated into an individualized prescription.