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

Abstract and Introduction


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.


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.