FormalPara Key Summary Points

Why carry out this study?

Chronic pain (CP) and depression frequently coexist as comorbidities that are challenging to treat

Current treatments for depression associated with CP based on tricyclic antidepressants or serotonin noradrenaline reuptake inhibitors are sometimes not effective and/or not well tolerated; therefore, it is important to explore the efficacy and tolerability of novel therapeutic agents

The antidepressant vortioxetine is effective in Major Depressive Disorder (MDD) and presents a new multimodal mechanism of action that could make it a good alternative treatment for patients with MDD and CP

What was learned from the study?

The treatment of vortioxetine and pain medication in patients with MDD and CP alleviates both CP and depressive symptoms, with a good safety profile and improvement in their quality of life

Introduction

Chronic pain (CP) is defined as persistent or recurrent pain lasting > 3 months. This condition is a major source of suffering for patients and therefore requires specific management [1]. CP constitutes a stress state that is a critical factor in determining depression [2]. Thus, depression is considered one of the most frequent psychiatric complications in patients with CP [3, 4].

CP affects 20% of the global population [5]. Depression is one of the most disabling mental disorders worldwide and has been reported to be the third leading cause of the global burden of disease [6, 7]. The prevalence of pain in cohorts of patients with depression and of symptoms of serious depression in cohorts of patients with CP is higher than the prevalence of these two conditions individually [8]. Approximately 65% of patients with depression experience one or more pain complaints, whereas depression can be present in 5–85% of patients with CP, depending on the study setting [8].

Depression in patients with CP is associated with a reduced pain threshold, increased pain perception, greater functional limitations, and worse analgesic response [3]. Likewise, the presence of pain reduces the chance of recovery from depression and is related to more intense symptoms in these patients [8], including impaired sleep, enhanced anxiety, and impaired cognition [9]. Furthermore, in some cases, the presence of depression in patients with CP is a predictor of non-response to antidepressants [10]. Thus, this comorbidity exacerbates the symptoms of both conditions, making treatment more difficult and complicating the management of these patients. Furthermore, CP is considered a predictor of major depression and worsening of anxiety symptoms [11, 12], and the severity of depression and anxiety is also linked to a lack of response to the treatment [13]. Thus, a relationship has been found between the magnitude of pain complaints and the intensity of depressive and anxious manifestations [9, 11].

Of note, the neuronal pathways that are modulated in response to pain and mood disorders involve the same brain regions, including the insular cortex, prefrontal cortex, anterior cingulate, thalamus, hippocampus, and amygdala [14]. Similarly, both pain and depression have been associated with abnormalities in the levels of different substances, including brain-derived neurotrophic factor (BDNF), the neurotransmitters serotonin (5-hydroxytryptamine or 5-HT) and norepinephrine (NE; also known as noradrenaline, NA) [9], and disturbances in noradrenergic and serotonergic neurotransmission in the central nervous system [15]. These observations are consistent with the idea that there is an overlap between the mechanisms that support pain- and depression-induced neuroplasticity, which facilitates the development of CP-induced depression [2].

The mechanism of action of most antidepressants is based on the regulation of the neurotransmitters 5-HT and NE [8, 16]. Tricyclic antidepressants (TCAs) and serotonin noradrenaline reuptake inhibitors (SNRIs) are effective treatment options for patients with depression, anxiety, and other psychosomatic disorders [16]. At the same time, they have also been shown to be useful in the management of concomitant chronic and neuropathic pain [9, 15, 17, 18]. However, in a significant number of patients suffering chronic or neuropathic pain, these treatments have been shown to be ineffective [10, 13, 19]. In addition, some patients have poor tolerability to these two drug classes so, in these cases, selective serotonin reuptake inhibitors (SSRIs) are an alternative to obtain a good antidepressant response [17, 20]. However, SSRIs are not effective in the treatment of neuropathic pain [21].

Vortioxetine (approved for marketing in Europe in 2013 and marketed as Brintellix®) is an antidepressant with a multimodal mechanism of action indicated for major depressive disorder (MDD) in adults. Its clinical efficacy has been demonstrated in the short and long term, with beneficial effects on affective [22], physical [23], and anxiety symptoms [24,25,26] and remarkable efficacy in improving cognitive dysfunction associated with unipolar depression [22, 27,28,29,30] and dementia [28]. Furthermore, vortioxetine has shown a good safety and tolerability profile, and unlike other antidepressants, it does not produce cardiovascular alterations, significant weight gain, or sexual dysfunction [31, 32]. However, its combination with opioids is not recommended to avoid the possibility of serotonergic syndromes. [33]. Likewise, several preclinical and clinical studies have recently demonstrated the effectiveness of vortioxetine in managing CP [15, 34,35,36,37], although more evidence is needed.

Vortioxetine inhibits the release of GABA, the main inhibitory neurotransmitter in the organism, through stimulation of the 5-HT1A receptors, and this secondarily triggers the release of dopamine (DA), noradrenaline (NA), histamine (HA), and acetylcholine (Ach) in the prefrontal cortex.

Vortioxetine binds with high affinity to the serotonin transporter (SERT, Ki 1.6 nM), thereby inhibiting its activity and increasing 5-HT levels. This is believed to be the principal mechanism underlying the antidepressant effects of vortioxetine and numerous other antidepressants [38]. Evidence suggests that serotonergic pathways are involved in the inhibitory control of pain, although the effect of 5HT on pain modulation in the spinal cord may be inhibitory or facilitatory, depending on which receptor subtypes are preferentially activated [3]. Vortiotexine also regulates multiple 5-HT receptor subtypes related to pain transmission at the same time: it exerts agonist action at 5-HT1A receptors (Ki = 15 nM), hastening its desensitization and making 5-HT release occur faster [39]; partial agonist action at 5-HT1B receptors (Ki = 33 nM) and antagonist action at 5-HT1D (Ki = 54 nM) and 5HT7 (Ki = 19 nM) receptors, inhibiting the serotonin release brake [39]; and antagonist action at 5HT3 (Ki = 3.7 nM) receptor, involved in 5HT-induced hyperalgesia [39, 40]. The multiple sites of action of vortioxetine also result in increased levels of dopamine (DA), NA, histamine (HA), and acetylcholine (Ach) [3]. In addition, pharmacological studies have shown that 5-HT7 receptors are involved in 5HT-induced analgesia, while 5-HT3 receptors are involved in hyperalgesia [41]. Thus, vortioxetine is a serotonergic transmission enhancer and powerful inhibitor of 5-HT3 receptors. SSRIs are ineffective in treating neuropathic pain because they induce the disinhibition of serotoninergic neurons, which may result in maladaptive changes in the descending serotonin pathways, resulting in nociceptive sensitization and chronic pain [42,43,44]. Considering that 5-HT3 receptors are involved in 5HT-induced hyperalgesia, the ability of vortioxetine to inhibit 5-HT3 receptors and other 5-HT receptors, modulating rather than only promoting serotoninergic transmission [39], makes it an interesting candidate for CP treatment [3, 34].

Considering all previous findings, this observational study aimed to investigate, in the context of common clinical practice, improvements in depressive symptoms and pain in patients with MDD and CP treated with vortioxetine.

Methods

Study design and patients

This was a 3-month, multicenter, prospective, open-label, non-interventional pharmacoepidemiologic study conducted at four centers in Barcelona, Spain, from November 5, 2020, to February 23, 2023. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Fundació Unio Catalana Hospitals local ethics committee approved the study (code CEI 19/33), and it was accepted by all the sites. All patients provided written informed consent before study participation.

Eligible participants were those who attended pain units on an outpatient basis, showed an ineffective response to the long-lasting medication for depression they were receiving at that time, and/or had considerable adverse effects to the antidepressants. The inclusion criteria were male or female participants, aged ≥ 18 years, already diagnosed with MDD, with a 9-item Patient Health Questionnaire (PHQ-9) score ≥ 15, with an associated CP condition (visual analogic scale [VAS] score ≥ 4), and having concomitant medication to treat habitual pain, with no changes during the study. This analgesic medication consists of minor opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and/or metamizole (any of them inducing undesirable effects such as drowsiness, dry mouth, constipation, and disorientation). Patients were required to read and understand the Patient Information sheet and sign an Informed Consent form. Patients with any contraindications specified in the Vortioxetine SPC, cognitive impairment that mades it impossible for them to sign the informed consent form, or suffering from significant acute or unstable disease or unstable medical condition that could compromise their participation in the study according to the investigator's judgment were ineligible for study participation. Patients who were members of the staff involved in the study or their immediate family, or a subordinate (or an immediate family member of a subordinate) of the staff involved in the study, who were previously enrolled in this study, or who participated in another ongoing clinical trial were also excluded. In addition, patients who had been receiving treatment with major opioids or, in the opinion of the investigator, were unable to comply with the study protocol were not considered.

To reduce the risk of selection bias, the following measures were implemented: (1) patients were consecutively included in the study; (2) investigators were trained to respect the protocol and remain neutral during the evaluation of the patients to be included in the study; (3) several centers were included to reflect the diverse range of practices, which was expected to reduce bias linked to systematic errors; (4) a very specific sample was chosen with little variability in baseline characteristics.

Vortioxetine baseline treatment was 10 mg/day. Fifteen days after the first dose, patients received a phone call to evaluate their clinical evolution, and the dose could be increased to the maximum therapeutic dose (20 mg/day) or decreased to 5 mg/day based on individual patient response at the investigator’s judgment. All patients continued with pain medication during the study, as per common clinical practice. Study assessments and follow-ups were performed at three visits: at baseline, 1 month (± 2 weeks), and 3 months (± 2 weeks) of vortioxetine treatment (visits 1, 2, and 3, respectively).

Study Assessments

The primary objective was to assess the improvement in depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9). PHQ-9 consists of nine items with Likert-type responses ranging from 0 to 3, relative to the last two weeks. A total score between 0 and 27 is obtained:1–4, 5–9, 10–14, 15–19, and 20–27 represent minimal, mild, moderate, moderately severe, and severe depression, respectively [45].

Secondary objectives were to assess improvement in pain and treatment satisfaction in the patients. To this aim we used the following tests:

Visual analogic scale (VAS) [46] helps determine the intensity of pain to be measured with maximum reproducibility between observers. It consists of a 10-cm horizontal line, the ends of which are the extreme expressions of a symptom. The left end shows the absence of pain or lowest intensity, and the right end shows the highest intensity. The patient is asked to mark the point on the line indicating the intensity, which is measured with a millimeter ruler in centimeters or millimeters. Thus, a total measure between 0 and 10 is obtained: 0–3, 4–7, and 8–10 represent mild, moderate, and severe pain, respectively. Patients with a VAS score  < 4 suffer from mild pain, which thus should not lead to major depression. Consequently, they were excluded from this study.

Brief Pain Inventory (BPI) [47] consists of 10 items. It is a multidimensional pain assessment instrument that provides information on pain intensity and its interference with activities of daily living. It also assesses the description, location, and level of pain relief associated with the treatment.

The Chronic Pain Coping Inventory (in Spanish, “Cuestionario de Afrontamiento del Dolor” [CAD]) [48] is a questionnaire on strategies to cope with pain, built using an entirely Spanish sample of patients with CP. It consists of 31 items grouped into six dimensions: self-affirmation, readiness to find information, religion, distraction, catharsis, and mental self-control. Religion and catharsis dimensions are grouped into “passive” pain coping and the remaining dimensions into “active” pain coping. The items are assessed on a 5-point agree/disagree scale.

Clinical Global Impression (CGI) Scale [49] was used to assess the overall disease severity and clinical improvement. In the current study, the Improvement (CGI-I) clinician-rated subscale was used. The Patient Global Impression Improvement (PGI-I) scale [50] consists of a single question asking the patient to rate the relief obtained with treatment. Both scales range from 1 (very much improved) to 7 (very much worse).

Satisfaction with Medicines Questionnaire (SATMED-Q) [51] is a 17-item questionnaire with six dimensions: treatment effectiveness, convenience of use, impact on daily activities, medical care, global satisfaction, and undesirable side effects. It measures the level of patient satisfaction with health care and treatment.

Adverse events (AEs) associated with vortioxetine were described during treatment. The summary included the dates of start and end, outcome, causality relationship, and severity criteria.

BPI scale and PHQ-9, CAD, and SATMED-Q questionnaires were administered at baseline and at 3 months and VAS, CGI, and PGI scales at baseline and at 1 and 3 months.

Statistical Analysis

The sample size was calculated based on the primary variable of the study: the change from baseline to month 3 in the PHQ-9 total score. With an SD of 5, the objective was to recruit 100 patients to obtain a 95% confidence interval (95% CI) with an accuracy error of ≤ 1.

The evaluable population comprised all eligible patients who had taken at least one dose of vortioxetine and had at least one post-baseline datum on the primary endpoints, including those patients with protocol violations or who discontinued the study. The safety population included all patients who received at least one dose of the study treatment.

Descriptive statistical analyses were performed for all variables. Continuous variables were described by the number of valid cases, mean, standard deviation (SD), median, 25th and 75th percentiles (P25-P75), and minimum and maximum. On the other hand, categorical variables were described by absolute and relative frequencies of each category over the total number of valid values (N). In case of missing values, the number per group was described. Comparisons of categorical variables were made using ANOVA, chi-square test, or Fisher's exact test, as applicable. For continuous variables, the Student t-test for paired data or the Mann-Whitney U-test was used depending on the type of data. A bilateral statistical significance level of 0.05 was used for all comparisons.

Statistical analysis was performed following the principles specified in the ICH E9 guidelines as well as in the standards of good clinical practice. Statistical analysis was performed using SAS (Statistical Analysis System), version 9.4, on a Windows platform.

Results

Study Population

Much of the study was conducted under the health restrictions imposed by the SARS-CoV-2 pandemic. Therefore, only four of the seven centers initially included participated in the recruitment, and only 64 patients out of the 100 initially planned were enrolled in the study. All (64 patients, 100%) signed the informed consent form. The 64 participants (100%) completed the study.

Baseline demographics and disease characteristics are shown in Table 1. The mean age of the participants was 63.6 years, and most were women (81.3%). Only two participants (3.1%) were on medical leave. Most patients (92.2%) reported at least one comorbidity (the most frequent being hypertension and osteoporosis), and all were previously receiving several analgesics (with paracetamol, NSAIDs, and tramadol being the most common) and treatment for depression (escitalopram [32.8%] and duloxetine [18.8%] in most cases) (see Table 1).

Table 1 Patients baseline demographics, previous treatments, and disease characteristics
Full size table

All patients were diagnosed with MDD. Most patients (92.2%) suffered from severe pain, with a mean intensity of pain (SD) of 7.64 (0.68) (lasting > 3 months and < 12 months in 40.6% and between 2 and 5 years for 25%). Patients had already developed a coping strategy to deal with pain, with readiness to find information and catharsis being the most frequent (see Table S1 in the Electronic Supplementary Material for details). Pain was located in the lower extremities and lower back in 68.8% and 67.2% of the participants, respectively, and the type of pain most commonly suffered was mixed (92.2%). Pain was mainly caused by lumbosciatica (45.3%), osteoarthritis (32.8%), and degenerative spinal problems (35.9%). Patients’ baseline clinical assessments are presented in Table 2 and showed moderate to severe pain with interference with daily life activities and moderately severe to severe depressive symptoms.

Table 2 Patients’ PHQ-9 and VAS baseline clinical assessments
Full size table

None of the participants had previously received vortioxetine treatment. The starting dose was 10 mg/day for all patients and was increased up to 20 mg/day at visit 2 in six patients. Mean (SD) vortioxetine dose was 10.00 (0.0) mg/day at baseline and 10.94 (2.94) mg/day at 3 months (Table 3).

Table 3 Dosage of vortioxetine
Full size table

Effect of Vortioxetine Depressive Symptoms

Statistically significant clinical improvement in the severity of depressive symptoms, as measured by the PHQ-9 score, was observed at 3 months (P < 0.0001) (Fig. 1). The PHQ-9 score changed from a mean (SD) of 16.63 (1.47) at baseline to 7.30 (2.60) at 3 months (Fig. 1a), with most patients reporting mild depression (n = 50, 78.1%), followed by moderate (n = 10, 15.6%) and minimal (n = 4, 6.3%) depression (Fig. 1b). At 3 months, the PHQ-9 score was < 15 for all patients, indicating a general improvement in depressive symptoms.

Fig. 1
figure 1

Effect of treatment with vortioxetine in the PHQ-9 score of patients at baseline and 3 months expressed as a mean PHQ-9 score ± SD and b number and percentage of patients according to the severity of depression at each timepoint. ***p < 0.0001 with respect to baseline. SD standard deviation

Full size image

Effect of Vortioxetine on Pain and Overall Disease Severity

The VAS score showed a sustained improvement in patients' pain during the 3 months of treatment, with significant changes from baseline at 1 and 3 months (mean [SD] 7.42 [0.69], 6.31 [0.81], and 5.09 [1.6], respectively [P < 0.0001]) (Fig. 2a). At baseline, patients had moderate to severe pain (54.7% and 45.3%, respectively); at 1 month, most of them had moderate pain (96.9%); at 3 months, they had mild to moderate pain (9.4% and 89.1%, respectively) (Fig. 2b), indicating a decrease in the intensity of the pain. Only one patient (1.6%) reported severe pain at 3 months. Similar results were obtained with the BPI scale (Fig. 2c), which showed a significant decrease in the severity of pain in patients at 3 months from baseline (mean [SD] 6.20 (0.80) at baseline and 4.73 (0.98) at 3 months [P < 0.0001]). Furthermore, this improvement was accompanied by a significant decrease in pain interference with daily activities (Fig. 2d), with a change in the BPI score mean [SD] that ranged from 7.02 (0.85) at baseline to 4.79 (1.23) at 3 months (P < 0.0001).

Fig. 2
figure 2

Pain variations from baseline to 3 months measured by VAS (a and b) and BPI (c and d) scores: a mean VAS score ± SD; b number and percentage of patients according to intensity of pain, based on VAS score at each timepoint; c intensity of pain and d interference of pain in daily activities, according to BPI scale ± SD at each time point. ***p < 0.0001 with respect to the baseline. BPI Brief Pain Inventory; SD standard deviation; VAS visual analogue scale

Full size image

An overall significant (P < 0.0001) improvement in patient condition was observed with the CGI score from baseline to 1 and 3 months (P < 0.0001 at all time points) (Fig. 3a and b). While at baseline the mean (SD) was 3.00 (0.00), it was 2.05 (0.21) at 1 month and 1.91 (0.39) at 3 months. At 3 months, 84.4% of patients were perceived as better and 12.5% as much better. According to the PGI (Fig. 3c and d), at baseline, the mean (SD) was 3.00 (0.00), showing a significant (P < 0.0001) improvement at both 1 month (2.44 [0.64]) and 3 months (1.98 [0.33]). At 3 months, 89.1% of the patients reported feeling better, and 6.3% reported feeling much better.

Fig. 3
figure 3

Improvement of the patients from baseline to 1 and 3 months according to CGI (a and b) and PGI (c and d) scores: a mean CGI score ± SD; b number and percentage of patients according to the improvement of the patient observed by the clinician at each time point; c mean PGI score ± SD; d number and percentage of patients who reported an improvement at each timepoint. ***p < 0.0001 with respect to the baseline. CGI clinical global impression; PGI patient global impression; SD standard deviation

Full size image

Safety, Tolerability, and Acceptance

Vortioxetine was well tolerated, and only 18.8% and 17.2% of patients showed AEs at 1 and 3 months, respectively (See Table S2 in the electronic supplementary material). Three types of AEs were reported and ranked, at both times, as follows: drowsiness (10 patients [15.6%] and 6 patients [9.4%], respectively), dry mouth (2 patients [3.1%] and 4 patients [6.3%], respectively), and nausea (1 patient [1.6%] at week 2). All AEs were mild. No other AEs were reported.

The results from the SATMED-Q questionnaire showed that patients were satisfied with vortioxetine treatment, and no safety concerns were detected (See Table S3 in the electronic supplementary material for details).

Discussion

Comorbid medical conditions, particularly chronic systemic disorders, are often found in patients with major depression, with CP being frequently reported in depression and anxiety [2, 3, 9]. Discrimination between these conditions is difficult, and treating them individually is inconvenient owing to the low efficacy of this approach [8]. Although TCAs and SNRIs are the first-line treatment options for this comorbid condition [9, 15, 17], they have been shown to be ineffective in a significant number of patients [10, 13, 19]. As there is little evidence that SSRIs are useful in CP [21], new treatment alternatives are needed for this comorbidity.

Vortioxetine has shown clinical efficacy in the treatment of MDD in adults and recently in relieving pain and depression in patients with burning mouth syndrome [36, 37]. These properties, together with its good safety profile and fewer side effects, make it an interesting alternative for treating patients with MDD and CP.

The population in the current study comprised outpatients attending pain units diagnosed with MDD, experiencing any kind of associated CP (Table 1), and receiving concomitant medication to treat pain but never treated before with vortioxetine. Vortioxetine was administered at the same doses approved for MDD (10–20 mg/daily) [33]. Although of the 100 patients initially planned only 64 were finally included because of pandemic sanitary restrictions, this number of patients allowed us to obtain statistically significant data. The results showed a good safety profile and efficacy of this drug in patients with this comorbid condition in terms of pain relief and depressive symptoms. At baseline, patients suffered from moderately severe to severe depressive symptoms, accompanied by severe pain with interference in daily life activities, and had already developed a pain coping strategy. Nevertheless, at 3 months, most patients reported an improvement in depressive symptoms and pain, with a reduction in clinical parameters. Improvement in depressive symptoms with vortioxetine has been reported previously [27, 28, 30, 37, 52], and as expected, all patients showed an improvement in the PHQ-9 questionnaire mean score from baseline to 3 months of approximately 9 points, which was < 15 for depressive symptoms in all patients. These results are interesting, as a greater effectiveness of vortioxetine in reducing depressive symptoms was observed in these patients compared to the depression medication they were previously taking. Thus, vortioxetine appears to be effective in the treatment of depression with inadequate response to previous antidepressants, which is comorbid with chronic pain, similar to that noted in patients without coexisting pain disorders [53, 54].

Regarding pain relief, a 2-point reduction in the VAS score for pain severity was observed, as previously reported [36, 37]. This means that patients experienced a change in the category of pain they felt, which implies an improvement. Thus, while at baseline patients reported moderate to severe pain (54.7% and 45.3%, respectively), at 1 month, most had moderate pain (96.9%), and at 3 months, they had mild to moderate pain (9.4% and 89.1%, respectively). Similarly, the BPI scale showed an improvement in the mean score from baseline to 3 months of approximately 1.5 and 2.25 points, respectively. This change implies that the intensity of the pain experienced by the patient has decreased and is having less interference with daily activities. These results suggest that vortioxetine could be effective in reducing pain in patients with depression. Furthermore, clinical efficacy was evaluated using both the CGI and PGI scales, showing a decrease in the scores, indicating the improvement of the participants perceived by both clinicians and patients in overall disease severity and in the impact on global functioning. The use of the two scales, which show both the physician's and the patient's perspectives, is a methodological strength that reinforces the results obtained in the clinical improvement of the patients. Improvements in CGI score have already been observed in studies on vortioxetine pain treatment [37].

Considering the above, we must also consider that before being included in the study, the participants were already on medication consisting of an antidepressant plus pain medication. The results obtained with the change in their depression treatment, thus accompanying their pain medication with vortioxetine instead of other antidepressants, seem to imply that vortioxetine could play a role in relieving the pain and depression symptoms of patients. Furthermore, it was accompanied by a general improvement in the participants, perceived by both clinicians and patients, and with general satisfaction with the treatment reported by the subjects, which could improve their quality of life. Taken together, these results reinforce the hypothesis that vortioxetine could be an interesting alternative to other antidepressants for treating pain in patients with depression. However, it would be interesting to conduct longer clinical studies to check whether the measured parameters continue to improve or remain unchanged over time.

Limitations

The limitations of the study are that it is a single-arm, with no control group, non-randomized study with a small sample of patients and a short duration. However, this study of real clinical practice showed very good results in the treatment of pain in patients with comorbid medical conditions, including MDD and CP.

Conclusion

This observational study, performed in the context of clinical practice, has shown that the treatment of vortioxetine and pain medication in patients with MDD and CP can improve both depressive symptoms and CP, with a good efficacy and safety profile and patient satisfaction. This also shows that vortioxetine may be an interesting treatment for the management of CP, not only for depression.

Although further research is needed, this study opens the door to new, longer clinical trials in which the efficacy of vortioxetine in relieving CP can be compared with that of antidepressants already indicated for patients with MDD and CP.