In recent times, a growing number of epidemiological and clinical studies have shown the existence of complex relationships between cancer pain and mood disorders 12. The treatment of anxiety and depression in patients with pain is therefore a must: basically, complete control of pain cannot be achieved without concomitant control of related emotional disturbances 3. Depressive mood reduces the pain threshold and increases, emotionally and cognitively, the pain perception, while chronic pain induces depression. Similar biological mechanisms underlie both pathologies: first of all, a neurotransmitter reduction, mainly concerning serotonin (5HT) and norepinephrine (NE); secondly, a cytokine imbalance, with an increase of pro-inflammatory agents and a modification of neurotrophic factors, can intervene in such mutual involvement 4.

Depression is the most prevalent psychological disorder among cancer patients and has a negative impact on quality of life and treatment adherence 5.

A meta-analysis of studies that assessed pain in patients with cancer estimated its prevalence at 53%. 67.

Data suggest that the most effective treatment approaches to the treatment of depression and cancer pain include the combination of psychotherapeutic and pharmacological interventions 89. Antidepressants (ADs) demonstrate important effects on mood but also on pain. Serotonin and norepinephrine reuptake inhibitors (SNRIs such as venlafaxine, duloxetine, milnacipran) showed greater efficacy on painful physical symptoms of depression 1011. Among SNRIs, venlafaxine shows peculiar pharmacodynamic and kinetic properties that suggest its use in oncological patients 1213.

Consistent evidence supports the efficacy of psychological interventions for alleviating pain related to depression when added to pharmacological treatment. Studies with varying results on the effects of Cognitive Behavioural therapy (CBT) for cancer-related emotional distress and pain have been published 141516. Psychotherapies can act by modifying pain intensity and the pain affective component 1718. Conversely, only minimal data are available for psychological interventions other than Cognitive-Behavioural Therapy and, in particular, few studies have been carried out on psychodynamic psychotherapy 19202122. Moreover there are not any clinical trials on Brief-Adlerian Psychodynamic Psychotherapy (B-APP) applied to oncological patients with pain.

The main object of the study was to evaluate the effects of adding a psychotherapeutic intervention, Brief Adlerian Psychodynamic Psychotherapy (B-APP) to venlafaxine (VLF) related to pain and depressive symptoms compared with usual care plus venlafaxine on depressed oncological patients with pain.

This is a randomized, controlled trial comparing B-APP plus venlafaxine versus VLF plus usual care. Randomization by a table of random number was centralized. Nine hundred and ninety five patients with cancer, of both sexes, from 18 to 75 years old, receiving ambulatory care at the Oncology Center of Citta’della Salute e della Scienza Hospital of Turin were screened for depression and pain.

Inclusion criteria were: a life expectancy ≥1 year, a Karnofsky Performance Status ≥70, a mood disorder according to DSM-IV-TR criteria, depression score (HADS-D ≥8) and concomitant relevant pain (VAS ≥5).

Exclusion criteria were: any mood disorders concomitant with pain, metastatic disease, some drugs interacting with venlafaxine such as tramadol, psychotic disorder, bipolar disorder, acute suicide risk and concurrent psychotherapy.

Of a total of 995 patients, 885 did not meet inclusion criteria, 10 did not meet SCID criteria for a depressive disorder or declined to participate. A total of 100 subjects were enrolled and randomly assigned to receive combined therapy (COM: VLF associated with B-APP) (n=51) or (VLF: venlafaxine plus usual care) (n=49).

Patients were evaluated by an expert psychiatrist of the Psycho-Oncology Unit (LA), Department of Neurosciences, University of Turin. The main baseline demographic and clinical characteristics are summarized in Table 1.

Besides patients had to meet at least one of the two following criteria in order to be eligible for the study: 1) the fixed-dose opioid had to be at least an equianalgesic daily dose of 60 mg of oral morphine and the patients were not expected to gain further therapeutic benefit by further increasing of the dose of the opioid therapy; 2) they were experiencing or had previously experienced intolerable side effects when increasing the dose of opioid therapy. In addition, in order to assess the antalgic add-on efficacy of venlafaxine, during the 10 weeks of this study, no change in the basic therapeutic regimen with analgesics was allowed. However, when pain breakthrough conditions were present, all analgesic adjunctive takings were recorded. The ten-week duration was decided in order to: a) verify the antidepressant response and the antalgic response to venlafaxine in the short-medium term; b) allow an adequate brief psychotherapy intervention, as stated in our previous study 22.

This study was carried out according to the “Declaration of Helsinki” (2002) and approved by the Citta’della Salute e della Scienza Hospital and University International Ethics Committee. The nature of the study and all procedures were fully explained to the patients and written informed consent to treatment was obtained from each patient.

SPSS version 21.0 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY, USA) was used for analysis and an intent-to-treat approach, i.e. including all enrolled patients taking at least one dose of medication and with at least one follow-up assessment, was used for the primary end-point analysis. Cardinal variables were described by using the mean and standard deviation. The Paired-Samples t-Test was used to evaluate significant differences within each group between assessments at baseline (T0) and after 10 weeks (T1). Significant differences were calculated between COM and VLF groups by the Independent-Samples t-Test. As for ordinal variables, significant differences within each group between T0 and T1 were calculated using the Wilcoxon Signed Ranks Test; whereas the Mann Whitney U Test was used to evaluate significant differences between the COM and VLF groups.

Of 995 patients consecutively evaluated in Citta’della Salute e della Scienza Hospital, 106 patients fulfilled the study selection criteria. One hundred depressed patients with cancer pain agreed to participate in this study, the others refused for various reasons (2 insufficient motivation, 3 burden of cancer, 1 other reasons). Sample demographic, psychiatric and oncological characteristics are described in Table 1. All the patients were treated with a fixed daily dose of venlafaxine 75 mg extended release (XR). All patients of the COM group attended the individual sessions of psychotherapy.

Ninety-four patients (94%) completed the study, five dropped out because of drug-related side effects (tachycardia, agitation, hypertension, headache) and one died at home because of the progression of oncological pathology.

The statistical analysis shows homogeneous demographic and clinical characteristics while the comparison between groups at T0 highlighted no significant difference on all rating scales.

This study represents the first randomized, controlled clinical trial which assesses the effectiveness of B-APP plus venlafaxine compared with venlafaxine related to pain and depressive symptoms among Italian patients with non-metastatic cancer who met depression diagnostic criteria according to DSM-IV-TR. In addition, this study represents the first one in which B-APP for cancer patients has been used.

The first important outcome measure of the study was the reduction of pain perception. At the end of the study, cancer pain perception in the sample decreased and the intensity of pain is <5 at VAS but the COM group showed a more significant improvement (p<0.01) than the VLF group (p<0.05). Our study showed that the efficacy of pharmacotherapy on depressed oncological patients with pain, should be positively reinforced by brief psychotherapy, according to previous data 394041. Psychological intervention, together with pharmacological treatment, modified patients’ interpretations, expectations and meaning of oncological pain, reducing pain perception and improving their quality of life 42 more than pharmacological treatment alone. Besides an essential component needed for efficacy of a psychotherapy for pain reduction seems to include enhancement of self-efficacy or confidence in one’s ability to manage pain 4344.

Mood improvement was demonstrated by a significant reduction, from baseline to the 10 weeks endpoint, in the self-rated Hospital Anxiety and Depression Scale (HADS) in both groups, although it was more significant in the COM group (p<0.01) than the VLF group (p<0.05). According with previous studies, we found that cancer patients with higher level of depression and pain showed a worst quality of lifeand also that the combined intervention could preserve a better sense of well-being and could support participants appraising positively their stressful and threatening disease94546. B-APP associated with venlafaxine could allow patients to explore their feelings, needs and to interpret their experience with a supportive and facilitating therapist. In fact, the theraphist focuses on the integration and interpretation of the material brought by the patient, in order to facilitate him/her insight into its origin and bring about emotional and cognitive changes.

Furthermore these data could support the relation between emotional disorders and physical symptoms, because patients with these disorders were more likely to report moderate to mild degree of global suffering 47. In fact, chronic pain, is often related to depression and depression in itself should induce a reduction of the pain threshold, with an amplification of painful symptomatology and a worsening quality of life 48. These findings support the importance of screening for, monitoring and treating both pain and depressive symptoms concurrently in patients with cancer.

The hetero-evaluated Montgomery Asberg Depression Rating Scale (MADRS) total scale confirmed a significant statistical reduction in both groups, again more significant in the COM group (p<0.01) than the VLF group (p<0.05). So venlafaxine shows efficacy not only with somatic but also with emotional and cognitive symptoms, as confirmed by MADRS scores, as shown in Figure 2, according to Hotopf et al. (2002) 49. Our data demonstrated that the association of psychotherapy with antidepressants increases the effectiveness of venlafaxine on several depressive clusters, as also observed by De Maat’s study (2008) 50. In fact the statistical analysis emphasized a greater reduction of Pessimistic Thoughts subitem in the COM group than in the VLF group, suggesting that the supportive role of psychotherapy strengthened the therapeutic action of the antidepressant.

A further interesting finding of this study is that psychological treatment was associated with significant changes in measures of coping strategies 51. Greater improvements were found in some subscales of the Mini-MAC in patients treated with venlafaxine combined with B-APP: particularly an increase of Fighting Spirit and a decrease of Fatalism, Anxious Preoccupation and Avoidance coping styles. In this context, brief psychotherapy is used to improve adaptive coping styles and to maintain adherence with the therapeutic program of oncological patients with pain: when depression and pain are comorbid, the patients’ adherence with treatments was reduced 52.

In this study, patients’ quality of life, evaluated with EORTC-QLQ-C30, improved over time in both groups, together with a significant reduction in scores for pain and depression symptoms. These improvements were observed both with physical symptoms and functional scales. The COM group, particularly, showed a higher significant response in emotional and cognitive functioning, global physical condition and global quality of life. These results support the notion that combined treatment compared with usual care improves significantly patient’s quality of life 9.

These findings suggest that patients with an higher level of a sense of well-being, were more capable of confronting the reality of the situation and this implied that also most of the participants attempted to develop effective coping strategies in order to maintain their better psychosocial well-being 53. Analyzing the VSSS-54, the subjects were satisfied with the treatment they had received as long as the intervention was effective. In particular, it was observed that brief psychotherapy, when associated with venlafaxine, showed greater improvements in prevention (p<0.01), social relations (p<0.01), working capacity (p<0.01) and self-care (p<0.01). In fact combined therapy, allows to confront the impact of pain on patients’social and existential concerns and to listen the needs of the patients, may be considered very relevant in determining their quality of life 54.

This study provides data supporting the effectiveness of B-APP used in combination with venlafaxine in reducing cancer pain and depression.

This study presents several limitations: the small number of patients recruited, may reflect the difficulties in recruiting patients with strict criteria, the use of an open-label design was caused by deontological aspects in patients with persistent pain. The use of restricted and limited Statistical tools could be another limitation 555657. The use of a non-manualised type of psychotherapy (B-APP) could be a limitation, even though some studies have demonstrated that non-manualised treatments are as effective as manualised therapies. The final limitation is that our analysis was restricted to the short-term effects of time-limited treatments. Further controlled trials on the synergistic activity of psychotherapies and pharmacotherapies in oncological patients are needed.

This is a spontaneous study without pharmaceutical grant sponsorisation. The authors of this manuscript have no financial or other relationships that might lead to a conflict of interests.