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. 

In This Article


Several genes are involved in the interindividual variability of the antidepressant response. The best characterized genes encode drug-metabolizing enzymes and drug transporters, such as the CYP superfamily and P-gp. Additionally, few studies have investigated genes involved in antidepressant pharmacodynamics, for example, the serotonin receptor, serotonin transporter, noradrenaline transporter, COMT, MAO and sodium channels.

Polymorphisms Involved in Drug Pharmacokinetics

The majority of the data originated from studies performed in patients treated for depression, and generalization to the pain context was not always possible. Like for antidepressants used for depression, several studies have also indicated a relation between the pain-relieving effect and the serum drug concentration of antidepressants, particularly of tricyclic antidepressants.[18,74–75]

Assuming this relationship, some hypothesis may be discussed.

Cytochrome P450 Enzymes. The CYP superfamily is a large group of enzymes responsible for the oxidation and reduction of 80% of all prescribed drugs. The primary CYP enzymes involved in the antidepressant drug metabolism are CYP1A2, CYP2D6 and CYP2C19[76] (Table 1). Bupropion is metabolized by CYP2ref-6. The metabolic pathways of the most commonly used antidepressants are presented in Table 1, and the drugs that are used as analgesics are indicated.[77] Genetic changes in CYP genes can result in alterations in enzyme activities.

The CYP2D6 system has been extensively studied and is the best characterized to date. The gene encoding CYP2D6 is highly polymorphic, with up to 80 allelic variants currently described.[79] These variants result in differences in enzyme activity ranging from 1 to 200%, which determine its metabolizer status.[61,77] Four phenotypes can be identified: 'ultrarapid metabolizer' (UM), 'extensive metabolizer' (EM), 'intermediate metabolizer' (IM) and 'poor metabolizer' (PM).[77,79–80] The prevalence of CYP2D6 PM, in other words, complete enzyme deficiency, is estimated to be 5–10%[77] in Caucasian populations but is rare – 3% – in other ethnic populations. IMs, which have reduced enzymatic activity, account for 10–15%[77] of Caucasians but up to 50% of Asians. EMs, with normal enzymatic activity, account for 60–70% of Caucasians. UMs, which exhibit increased metabolism, account only for 1–10% of Caucasians but potentially up to 30% of Northern African and Arabian populations.[79,81] Genetic variations of CYP2D6 have been consistently demonstrated to influence the plasma level concentrations of antidepressants with large variations, up to 30–40-fold with similar doses.[45] Because the drug–plasma concentrations influence the response of antidepressants and the occurrence of side effects, antidepressants have been found to exhibit variable efficacy and tolerability. Multiple data have demonstrated that adverse events are related to phenotype differences because more frequent adverse events are found in PMs, even at the usual recommended dosages and the PM genotype is more common in patients reporting tricyclic antidepressant adverse effects.[45–46,82] For efficacy, some data have demonstrated that UM patients present reduced antidepressant efficacy when the drugs are used to treat depression; however, this has not been confirmed in the large STAR*D study population.[83–85] Because CYP2D6 is involved in the endogenous morphine synthesis pathway and because it has been shown that poor metabolizers of CP2D6 may be less tolerant to some pain stimuli, such as tonic pain, than extensive metabolizers independent of analgesic treatment,[86] the findings suggest that the CYP2D6 gene may be a candidate for modulation of the pain sensitivity threshold.[87]

Genetic variations associated with the EM, PM and UM phenotypes have also been described for CYP2C19.[88] The frequency of the PM phenotype is approximately 2–5% in Caucasian populations and approximately 20% in Asian populations.[88] The different phenotypes are also associated with variable plasma concentrations[60,89] and occurrence of side effects.[90] Studies have demonstrated that the plasma concentrations of the antidepressant substrates of CYP2C19 are reduced in UM patients[60] whereas gene deletion (PM) may be associated with a sixfold increase in concentration.[89]

CYP1A2 plays an important role in duloxetine metabolism. There are pronounced interindividual differences in the CYP1A2 activity in humans[91,92] with 15 SNPs having been described in the gene encoding CYP1A2. Furthermore, the most important factor for the variability of CYP1A2 activity is its inducement by the polyaromatic hydrocarbons present in cigarette smoke,[93] which is related to genetic polymorphisms. For example, the -164C>A polymorphism (CYP1A2*1F) in intron 1 confers a high inducibility of CYP1A2 in smokers.[94] Smoking may cause a 50% reduction in the duloxetine plasma concentrations.[95] The influence of these differences in CYP1A2 activity on duloxetine efficacy or tolerance has not been examined in pain management.

Finally, CYP2ref-6 is involved in the metabolism of bupropion. Due to the existence of extensive genetic polymorphism, its activity is also highly variable in the population.

CYP2ref-6 is one of the most polymorphic CYP genes in humans with over 100 described SNPs.[96] The most common allelic variant CYP2ref-6*6 results in reduced enzyme activity. It is present in 28% of Caucasians and up to 40% of Africans and Chinese. Although the clinical relevance of these mutations in the treatment of chronic pain with bupropion is not known, clinical significance of CYP2ref-6 variants has been implicated in smoking cessation in response to bupropion.[97–100]

Genetic variations of these cytochromes have been consistently demonstrated to influence the plasma level concentrations of antidepressants and the drug–plasma concentrations to influence the response and side effect occurrence.

Because of the well-established data on CYP, the dosage recommendations for 'antidepressive' dosages based on the CYP2D6 and CYP2C19 phenotype/genotype have been developed[70,101] and are easily accessible at the PharmGKB website.[102] These are summarized in Table 2. Admittedly, a reasonable treatment approach is the use of a lower starting dose with dosage adjustments based on the clinical response and plasma concentration in PM individuals and the exclusion of the molecule for UM individuals. The validity of these approaches has not been systematically tested in clinical situations in which antidepressants are used as pain killers, but we can reasonably assume that the use of a lower starting dose with dosage adjustments is suitable for a PM individual, even if very low doses of tricyclic doses are used. For UM subjects, the low dosage warrants the use of the enzyme substrate.

P-gp. P-gp is a plasma membrane transporter encoded by the human ATP-binding cassette ABCref-1 gene, which is expressed in various human tissues, including the placenta, GI tract, kidney and the luminal membranes of endothelial cells in the blood–brain barrier.[103,104] The function of P-gp is to export drugs from cells against a concentration gradient. The absence or inhibition of P-gp function can result in increased exposure to drugs.[105,106] To date, 30 ABCref-1 genetic polymorphisms have been described,[107] and this high number of polymorphisms may explain the interindividual variability in the expression and function of P-gp. For example, ABCB1-knockout mice, which lack the drug-transporting P-gp at the blood–brain barrier, have higher brain concentrations of P-gp substrates. Evidence from several experiments with knockout mice lacking functional P-gp demonstrates that this pump has a significant impact on the analgesic effect of some opioids. In rats treated with a string P-gp inhibitor, a single intravenous morphine injection has a prolonged antinociceptive effect.[108] The previous studies on humans suggest that patients with a lower expression of P-gp require lower doses of morphine and are at greater risk of adverse effects.[109–111] Similarly, the proportion of patients presenting with somnolence and confusion was greater in patients whose P-gp expression was lower.[112] A number of antidepressants are substrates of P-gp (Table 3)[113–115] and a series of studies have investigated the influence of functional polymorphisms of P-gp on the antidepressant drug plasma levels, clinical response and side effect profile and report contradictory findings.[41,49,60,71,116–117] No link between these mutations and antidepressant efficacy or tolerability has been demonstrated to date in depressed or chronic pain patients. But 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, like it has been described for other psychotropic drugs such as the above discussed example of morphine. Exploring P-gp activity should be discussed when CNS adverse effects are intense at a small dosage.

Polymorphisms Involved in Antidepressant Targets

The analgesic properties of antidepressants have been suggested to result from the inhibition of amine, noradrenaline and serotonin reuptake in the CNS, which consequentially leads to increased activity of the antinociceptive descending pathways. The antidepressants may also have an analgesic effect through their action on sodium channel receptors of the primary afferent neurons.

COMT is one of the principal catecholamine metabolic enzymes and acts as a key modulator of dopaminergic and adrenergic/noradrenergic neurotransmission, which are the neurotransmitters implicated in the pathophysiology of chronic pain, but likely also other endogenous substrates. The association between COMT gene variations and pain sensitivity has been reported in various studies. As for CYP2D6, COMT is also a candidate gene that may influence sensitivity to pain and thereby pain management.

The best-described COMT allelic variant is the 158 G>A (rs4680) polymorphism, which results in the Val158Met substitution. The Met/Met variant is associated with fourfold lower COMT activity[118] (Val/Val: Important activity; Val/Met: Intermediate activity; Met/Met: Low activity). The frequencies of the Val/Val, Val/Met and Met/Met genotypes are 21, 47 and 32%, respectively. The lower activity allele results in higher synaptic monoamine concentrations, particularly dopamine levels, ultimately increasing the dopaminergic stimulation of postsynaptic neurons. Dopamine is known to participate in the brain reward system by facilitating the release of enkephalin.[119] However, although a reduction in pain sensitivity may be expected in these patients, it has been demonstrated that Met/Met subjects have a lower tolerance, exhibit more pronounced responses to experimentally induced pain[119] and have an increased sensitivity to pain, specifically non-neuropathic chronic pain.[120,121] Studies performed in fibromyalgia patients demonstrated that Met/Met individuals are also significantly more sensitive to thermal and pressure pain stimuli.[122,123]

However, it has been shown that cancer patients carrying the Met/Met mutation require significantly lower daily morphine than heterozygous and noncarriers[124,125] and that the Met/Met genotype is associated with higher regional density of μ-opioid receptors.[119] Another study demonstrated differences in the morphine side effects, such as drowsiness, confusion and hallucinations, associated with certain COMT variants, which influenced how well the patients tolerated morphine.[112] Experimental evidence points to a link with CNS endogenous opioid dysfunction. The enhanced monoaminergic activity may upregulate opioid receptors by decreasing the level of endorphin, and the abnormal endogenous control of nociceptive pain pathways could lead to an overexcitability of the dorsal neurons in the spinal cord, a decrease in nociceptive thresholds and an increase in spontaneous pain. Although the results remain conflicting, it has been shown that a polymorphism in the COMT gene, namely, Val158Met, influences pain sensitivity in human experimental pain and the efficacy of morphine in cancer pain treatment. Due to the role of COMT as modulators of the intrasynaptic catecholamine concentrations, a potential role of the COMT gene in the antidepressant response is supported. The influence of the Met/Met variant on the therapeutic efficacy of antidepressants has been studied only in patients with depression but not in pain. The results are contradictory, some of the studies showing a weaker and slower response in Met/Met patients,[43,126] some the contrary.[127,128] However, all these studies indicate a possible role of the COMT gene in the response to antidepressants.

Regarding other candidate genes, several studies have demonstrated the existence of numbers of polymorphisms of the MAO, serotonin transporter and receptors and noradrenaline transporter genes. The clinical consequence of these mutations on antidepressant treatment when used for depression is not clear. The main polymorphisms and their impact on enzyme function are listed in Table 4. Given that one of the putative mechanisms of action of antidepressants in the treatment of pain involves a balanced increase in noradrenaline and serotonin transmission, we can assume that a decrease in the expression of the MAO and/or noradrenaline transporter (SLC6A2) leads to a higher efficacy but also a higher risk of the monoaminergic side effects. Because the antidepressant analgesic effect relies not only on monoaminergic transmission and because there are multiple determinants of pain, the clinical relevance of this assumption should be formally further assessed. The evidence for the efficacy of SSRIs in the treatment of pain is anecdotal, suggesting that the dual reuptake inhibition of both monoamines is necessary for the analgesic activity of antidepressants. The influence of gene mutations of the serotonin transporter and receptors, which are well described in the setting of depressive disorders, should therefore have less impact in the context of pain management.

Voltage-gated sodium channels are multimeric complexes encoded by multiples genes. They are key regulators of the membrane potential in excitable tissues, such as sensory neurons. Nine isoforms of voltage-gated sodium channels (Nav 1.1–Nav 1.9) have been identified. The cellular and tissue expressions of individual isoforms are quite specific. Subunit Nav 1.7 is preferentially expressed in nociceptive neurons and plays a major role in nociception and neuropathic pain. It is encoded by the SCN9A gene. A large number of polymorphisms have already been discovered.[145,146] Studies in mice have emphasized their role in neuropathic, inflammatory, mechanical and thermal acute pain thresholds.[147,148] In humans, mutations in the SNC9A gene cause overexpression and hyperexcitability of Nav 1.7. It has been implicated in several painful states, such as idiopathic erythermalgia and paroxysmal extreme pain disorder.[149,150] Conversely, a null mutation of Nav 1.7 induces the loss of channel function and a lack of propagation of nociceptive signals. It is linked to a rare condition, namely, the congenital insensitivity to pain syndrome, in which normal individuals have impaired perception of pain.[151,152] As stated above, part of the analgesic effect of tricyclic antidepressants is due to the blockade of this sodium channel; many tricyclics, including fluoxetine and paroxetine, inhibit Nav 1.7 with different potencies. These all interact, predominantly in a state- and use-dependent manner, with the inactivated state of the channel. It has been shown that the potencies of amitriptyline, nortriptyline, imipramine, desipramine and maprotiline to block the inactivated state are in the range of the therapeutic plasma concentrations used for the treatment of neuropathic pain, whereas SSRI are blockers only in supratherapeutic dosages.[11] The link between the overexpression of Nav 1.7 and the variability of the response to treatment with amitriptyline has not been clearly demonstrated, but a relationship between the level of expression of the SNC9A gene and the effect of amitriptyline may be postulated.