Introduction

Antidepressants are important analgesic adjuncts in the treatment of chronic non‐cancer pain. This chapter is based on systematic reviews of high‐quality randomized clinical trials of antidepressant agents in multiple chronic non‐cancer pain conditions [1–9].

Three classes of antidepressant agents have been widely tested for efficacy in chronic pain: tricyclic antidepressants (TCAs), serotonin‐norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). Currently, several TCAs and SNRIs are FDA‐approved for treatment of chronic pain.

TCAs currently in common clinical use include amitriptyline, nortriptyline, imipramine and desipramine. Additionally, there are also closely‐related tetracyclic antidepressant medications, mirtazapine and maprotiline. The first TCA, imipramine, was approved for treatment of depression in 1959 [10]. Within two years, publications also reported efficacy in myalgia, facial pain and headache. TCAs are now considered first‐line treatment in several chronic pain conditions. TCAs act at multiple molecular targets; they inhibit presynaptic serotonin and norepinephrine reuptake transporters and block additional targets including voltage‐gated sodium channels [11], adrenergic α1 and α2 receptors, histamine H1 receptors and muscarinic receptors [10]. Each of these receptor targets has been associated with increased pain or neuronal hypersensitivity [12], and the non‐selective mechanisms of TCAs may contribute to analgesic efficacy in multiple conditions. However, due to this broad pharmacologic profile, TCAs are often associated with multiple side effects including xerostomia, urinary retention, orthostasis and sedation. Therefore, interest grew in developing antidepressants with fewer side effects.

Emerging evidence on the monoamine hypothesis of depression in the 1960s suggested that low serotonin levels played a role in major depressive disorder [13,14]. Consequently, pharmaceutical companies focused efforts on developing inhibitors of the serotonin reuptake transporter, culminating in the approval of fluoxetine in 1987. Other SSRIs tested in chronic pain include sertraline, paroxetine, citalopram and escitalopram. Several small trials found that SSRIs were more effective than placebo in conditions including diabetic peripheral neuropathy, headache and somatoform disorder; however, a 2016 narrative review concluded that a meta‐analysis of SSRI chronic pain trials was impossible due to trial heterogeneity, quality and risk of bias [15].

Serotonin‐norepinephrine reuptake inhibitors, developed shortly after SSRIs, proved more efficacious in treatment of chronic pain. This pharmacologic class includes the medications duloxetine, venlafaxine, desvenlafaxine and milnacipran. Their most common side effects include nausea, constipation, fatigue and xerostomia. However, these effects often tend to abate with continuing therapy [16].

Pharmacological mechanisms

There is well‐established, complex interplay between pain and emotion. However, trials have clearly demonstrated that the analgesic effects of antidepressants are not solely due to their effects on mood [17]. Additionally, analgesic effects tend to occur more quickly and at lower doses than antidepressant effects [18]. One important analgesic mechanism seems to involve modulation of ascending pain signals by central monoaminergic pathways [12,19,20]. Descending noradrenergic pathways arise from the locus coeruleus and project to the spinal cord. Norepinephrine (NE) binds to multiple subtypes of adrenoreceptors, but inhibitory α2 receptors have been most commonly implicated for pain modulation. Of note, these receptors are also highly expressed in brain regions important for pain processing, including periaqueductal gray, rostral ventromedial medulla (RVM), thalamus, prefrontal cortex and amygdala.

Central serotonergic pain modulation is rather complex. Descending projections from the RVM evoke spinal release of serotonin (5‐HT), which can inhibit or facilitate pain signaling depending on which 5‐HT receptor is activated. Preclinical research suggests that 5‐HT1 receptor subtypes, which are Gi/Go coupled G‐protein coupled receptors (GPCRs), may inhibit nociceptive pathways. Conversely, 5‐HT2 receptors (which are Gq‐coupled GPCRs) and 5‐HT3 receptors (which are cation channels) may facilitate nociceptive pathways.

TCAs share a tricyclic chemical structure and can be divided to secondary amines and tertiary amines, depending the on the number of methyl (‐CH3) groups on the side chain nitrogen. Secondary amine TCAs (nortriptyline, desipramine) result from the demethylation of tertiary amines (amitriptyline and imipramine, respectively), and typically have higher affinity to norepinephrine transporter than to serotonin transporter. In tertiary amines, this ratio is reversed. In addition, secondary amines have lower affinity to muscarinic acetylcholine receptors and thus have a lower likelihood of anticholinergic side effects, especially at low doses. There are some differences among tertiary amine TCAs as well. The affinity of imipramine to block histaminergic H1 receptors, for example, is lower than of amitriptyline [21]; therefore, it might be less sedating.

TCAs are metabolized by the hepatic cytochrome P450 (CYP450) system. Tertiary amine TCAs can be metabolized by multiple CYP450 systems (e.g., CYP1A2, CYP2C19 and CYP2D6). Desipramine and nortriptyline are metabolized almost exclusively by CYP2D6, and thus may be substantially affected by genetic polymorphisms of the CYP2D6 enzyme [21]. All TCAs have excellent oral bioavailability, and have long enough plasma elimination half‐lives to allow once‐daily administration.

The analgesic mechanism of SNRIs is assumed to be similar to that of TCAs in terms of serotonin and norepinephrine reuptake inhibition, but both venlafaxine and duloxetine have very low affinity to cholinergic, adrenergic and histaminergic receptors. In addition, venlafaxine is more selective to the serotonin transporter in lower doses.

Safety profile

Chronic pain conditions