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.

Abstract and Introduction

Abstract

Antidepressants are widely administered to chronic pain patients, but there is large interindividual variability in their efficacy and adverse effect rates that may be attributed to genetic factors. Studies have attempted to determine the impact of genetic polymorphisms in enzymes and transporters that are involved in antidepressant pharmacokinetics, for example, cytochrome P450 and P-gp. The impacts of genetic polymorphisms in the targets of antidepressants, such as the serotonin receptor or transporter, the noradrenaline transporter and the COMT and monoamine oxydase enzymes, have also been described. This manuscript discusses the current knowledge of the influence of genetic factors on the plasma concentrations, efficacy and adverse effects of the major antidepressants used in pain management.

Introduction

The management of chronic pain is a major issue in clinical practice. Several non-opioid based therapies can be useful for managing pain. The current evidence-based guidelines recommend the use of antidepressants, particularly tricyclics and serotonin-noradrenaline reuptake inhibitor antidepressants (SNRIs), for the treatment of various types of chronic pain, including neuropathic pain,^[1,2] musculoskeletal pain, such as low back pain, central pain syndrome and fibromyalgia.^[3,4]

Chronic pain and depression are closely linked and are part of the most frequent reasons to seek medical care. The prevalence of chronic pain is high in the general population and ranges from 2 to 60% depending on the reference definition.^[5,6] Between 40 and 60% of patients with chronic pain also experience depression.^[7–9] The link between depression and chronic pain may be psychological, but it may also be biological due to common pathways. Because the biological mechanism for depression relies mostly on the dysregulation of the neurotransmitters serotonin (5-HT), noradrenaline (NA) and dopamine, NA and 5-HT have also been implicated in the pathophysiology of chronic pain.

Thus, antidepressants are not only used in pain management because depression is often a comorbidity of chronic pain. Experimental and clinical data suggest that antidepressants have analgesic effects that differ from their classical action on mood. Indeed, studies have shown that analgesia is often achieved with lower doses than those required for depression and that the effect onset may be faster than that obtained in depression. For example, in diabetic polyneuropathy, 60 mg of duloxetine demonstrated an improvement in the 24-h average pain severity score with a rapid onset of action with separation from the placebo beginning at 1 week.^[10] Moreover, the analgesic effect may be present without an effect on mood.

This effect seems independent of the antidepressant effect. The antinociceptive activity of antidepressants is demonstrated in a large amount of preclinical^[11] and clinical^[12] experimental studies. Ongeha et al.^[13] clearly revealed this analgesic effect in nondepressed pain patients, in their meta-analysis of 39 placebo-controlled studies.

However, the precise analgesic mechanism of action of antidepressant drugs remains debated. The commonly accepted hypothesis is a central action mediated by descending pain control pathways via an inhibition of the presynaptic reuptake of noradrenaline and serotonin,^[14,15] but effects at the peripheral site, that are independent from the mood effect, have also been described: particularly the blockade of sodium channel.

The efficacy of the tricyclic antidepressants amitriptyline, clomipramine, imipramine, desipramine, nortriptyline and doxepin on the treatment of chronic and neuropathic pain has been demonstrated in numerous studies.^[16–21] However, new antidepressants are also effective for other chronic pain conditions and are increasingly used in chronic pain patients because of their improved tolerability. These belong to the group of SNRIs, for example, venlafaxine, duloxetine and milnacipran,^[22,23] and the atypical antidepressant group, such as bupropion^[24] and mirtazapine.^[25] The superiority of tricyclics, particularly clomipramine and amitriptyline, in the management of pain may be explained by their additional action on sodium channels blockade,^[26–29] which is an action that SNRIs do not exhibit. Venlafaxine has a similar chemical structure to the opioid derivative tramadol, has the tertiary amine functional group necessary for μ-opioid receptor recognition, and may indeed act also partly as an agonist to the μ-opioid receptor.^[30] This type of opioidergic profile may explain their efficacy for pain management. The analgesic efficacy of selective serotonin reuptake inhibitors (SSRIs) remains undoubtedly less important.^[31,32]

Successful pain management has to provide adequate analgesia without excessive adverse effects. The management of pain with antidepressants is complicated by the large interindividual response variability to therapy. No response, a partial response and an unbearable side effect have been reported following the same conventional drug dosing, which may affect the treatment adherence.

The high frequency of poor adherence in chronic pain conditions was confirmed in a recent prospective study^[33] and a meta-analysis^[34] that investigated medication adherence in patients with chronic, nonmalignant pain. These studies determined that nonadherence to medication is common in 40–60% and 30% of patients, respectively. Another study demonstrated that patient adherence to a newly initiated antidepressant treatment varied significantly across the medical conditions for which it was prescribed. The duloxetine adherence rate was thus lower in patients with chronic pain conditions (29.9%) than in patients with major depressive disorder (37.3%).^[35]

Poor adherence is likely the most important factor contributing to treatment failure, but factors such as age, gender, co-medication, smoking habits, treatment duration and/or inadequate dosages^[36,37] and genetic variations should also be considered. Because genetic factors appear to be the most stable and predictable elements, a pharmacogenetic approach may aid the individualization of treatment.

During recent years, the possible influence of a set of genetic polymorphisms and the response to antidepressants in the treatment of depression were examined in genome-wide association studies (GWAS)^[38–40] and clinical studies.^[41–51] They include the CYP superfamily, the P-gp, the COMT, the MAO, the serotonin transporter, the noradrenaline transporter and variants in the serotonin receptors.

Because tricyclic antidepressants and SNRIs are now an integral part in the management of chronic and neuropathic pain, this paper discusses the potential role of these polymorphisms in the specific context of pain management.

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Abstract and Introduction
Method
Discussion
Future Perspective
References
Sidebar

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.