Early reduction in painful physical symptoms is associated with improvements in long-term depression outcomes in patients treated with duloxetine

Depressive patients frequently report somatic symptoms including painful physical symptoms (PPS) accompanying their depression (mean prevalence 65%) [1]. The causal relationship between pain and depression remains unclear [2–4]. Pain can be a symptom, a cause, or a consequence of depression [2]. Neurobiological evidence suggests that mood and chronic pain are connected via the serotonin and noradrenalin neurotransmitter pathways. A malfunctioning of the descending serotonergic and noradrenergic pathways could allow routine sensory input to be interpreted as uncomfortable or even painful [5, 6]. Studies investigating the direction of the association between pain and depression suggest that it is the stress of living with chronic pain that causes depression [7], but there is also evidence that pain develops secondary to depression through increases in pain sensitivity and that high depression scores result in a greater risk of developing chronic pain [8].

In 69% of depressed patients, painful or non-painful physical symptoms were the only presenting complaints in general practice [9]. This can lead to a lack of awareness of depression, missed diagnosis [10, 11] and inappropriate treatment [12]. Conversely, failure to treat PPS in depressed patients may adversely impact depression treatment outcomes [13, 14]. Recognizing and optimizing the management of pain that commonly coexists with depression may be important in enhancing depression response and remission rates [15]. The presence of severe pain at start of depression treatment has been associated with non-response to antidepressants [16], and a lower overall pain severity score at baseline was associated with higher odds of achieving remission [17].

In a naturalistic clinical trial addressing long-term treatment of PPS and emotional depressive symptoms [18], it was found that the effect of selective serotonin reuptake inhibitors (SSRIs) on PPS was less pronounced than on the emotional symptoms. However, this trial was restricted to SSRIs, and it is argued that for an adequate pain response, substances affecting both serotonin and noradrenaline are necessary [19].

Extensive data support the efficacy of tricyclic antidepressants (TCAs) for the alleviation of pain in chronic pain patients [20], and also the newer serotonin and noradrenaline reuptake inhibitors (SNRIs) duloxetine [14], venlafaxine [21] and milnacipran [22] have shown efficacy in the treatment of pain and depression. Duloxetine is a SNRI with proven efficacy for PPS of depression [14, 23, 24]. Analyses from short-term trials demonstrated that a greater reduction in pain was associated with a higher probability of remission [14, 25]. Furthermore, the efficacy of duloxetine has been also proven for the treatment of painful diabetic neuropathy [26].

The primary research objective of the present 6-month, observational study with duloxetine ('PADRE') was to investigate the association of an early improvement in PPS with long-term changes in depressive symptoms, which could be used as a predictor of long-term treatment outcomes in depression. Such a predictor could be helpful for an early adjustment of treatment to the individual patient [27].

In the PADRE study, 80% of the depressed patients had moderate to severe overall pain at baseline. For all patients, the mean overall pain VAS score was 55.0 mm. This high pain intensity could partly result from the fact that depressed patients with pain syndromes could be overrepresented in this study because of the proven analgesic efficacy of duloxetine [14, 23]. However, the observed prevalence of pain in depressed patients in the PADRE study is in line with the literature reporting prevalence rates of 56% [33], 65% [1] and 88% [34].

For 72.1% of the PADRE population, concomitant somatic diseases were documented most frequently 'muscle and skeleton diseases' (33.7%). The high prevalence of patients suffering from pain conditions may raise concern that common depression rating scales overestimate depressive symptoms in these patients, as they may score higher on somatic items because of their pain rather than because of their mood. However, Poole et al. [35] showed a good correlation of a commonly used depression rating scale that includes somatic items (Beck Depression Inventory-II) with a structured clinical interview for DSM-IV Axis Disorders (SCID) which represents a gold standard for assessment of depressive symptomatology.

The main finding of our study is that early change in pain severity was strongly associated with a long-term reduction of depressive symptoms according to the mean KUSTA score. Pain responders also had a higher chance of achieving a 50% reduction in the IDS-C total score after 6 months.

This association of an early improvement in pain with long term depression outcomes was already seen after 2 weeks, albeit, to a smaller extent than after 4 weeks. This is remarkable, considering that 72.9% of the patients started duloxetine treatment with a dose of 30 mg/day, which is lower than the recommended starting and maintenance dose.

Patients with a VAS pain reduction of ≥ 50% after 2 and 4 weeks, showed also higher remission rates after 6 months than patients without a ≥ 50% pain reduction (Figure 2).

For clinicians, it is of interest whether or not early improvement of pain is a better predictor of the long-term outcome to antidepressant treatment than early improvement of depressive symptoms. Therefore, post-hoc analyses were performed including early response in depressive symptoms after 2 and 4 weeks (as measured with IDS-C total score). Results showed that an early pain response had similar predictive value compared to early depression response for long term depressive outcomes as measured with the KUSTA scale.

The main results of the PADRE study are in contrast to a recent publication [36], reporting a very low predictive association between analgesic and antidepressant responses in six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder. However, the studies used in these post-hoc meta-analyses were not designed to assess the relationship between antidepressant and analgesic response, and there were only few data points available for early response assessment.

Other studies support the association between early improvement in pain and long-term antidepressant response [15, 37]. Pooled data from two 9-week randomized, double-blind duloxetine studies showed that the remission rate for pain responders (improvement in VAS overall pain from baseline to last observation ≥ 50%) was twice that observed for pain non-responders (36.2% vs. 17.8%, p < 0.001). Improvements in pain severity were also related to improved quality of life and improved clinician- and patient-rated global health outcomes [14]. A secondary analysis of a 12-week open-label trial with duloxetine in 249 patients [25] found similar results. Patients who experienced clinically important pain reduction in the first week of duloxetine treatment were significantly more likely to reach remission at endpoint than the patients without this pain reduction (64.0% vs. 35.6%, p < 0.001).

The results of the PADRE study are of interest in the context of other recent research [27, 38–42]. Evidence was provided questioning the belief that antidepressant response usually appears with a delay of several weeks, and new evidence continues to accumulate that individual improvement within the first 2 weeks is a key predictor of treatment response. Lack of early response in depression symptom subscales was highly predictive of a lack of sustained remission [41]. A lack of improvement during the first 2 weeks of therapy may indicate that changes in depression management should be considered earlier than conventionally thought [32]. Results from PADRE also suggest that early improvements in concomitant PPS measured with simple VAS scales should be considered in treatment decisions during the initial 2-4 weeks of a new antidepressive treatment. The results of PADRE could also be important for patients with generalized anxiety disorder with or without comorbid MDD, as the clinical relevance of PPS and resulting functional impairment has been reported [43, 44].

As this was a large observational study in daily clinical practice, several methodological limitations such as the absence of monitoring or a high number of patients lost to follow-up were unavoidable and may lead to concerns with regard to data quality. However, this non-interventional approach reflects current treatment of patients with MDD by office-based psychiatrists and should therefore allow generalization of our results to clinical practice. Perhaps the most serious shortcoming of non-interventional trials is selection bias because of absence of randomization. Another limitation of the study is the lack of a control group, as only duloxetine-treated patients were included.

Pain is a frequent and often severe concomitant symptom in depressive patients in clinical practice. Pain reduction after 2 and 4 weeks can be used to estimate long-term outcomes regarding successful antidepressive treatment with duloxetine.

The present results emphasize the importance of PPS associated with depression because of their potential role in predicting and achieving depressive symptom remission.