General Hospital Psychiatry xxx (2014) xxx–xxx
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General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression Jan Jaracz, Ph.D.,M.D. a,⁎, Karolina Gattner, M.D. a, Jerzy Moczko, Ph.D.,M.D. b, Joanna Hauser, Ph.D.,M.D. c a b c
Department of Adult Psychiatry, Poznań University of Medical Sciences, ul. Szpitalna 27/33 60-572 Poznań, Poland Department of Computer Science and Statistics Poznań University of Medical Sciences ul. Dąbrowskiego 79 60-529 Poznań, Poland Department of Psychiatric Genetics, Poznan University of Medical Sciences, ul. Szpitalna 27/33, 60-572 Poznań, Poland
a r t i c l e
i n f o
Article history: Received 22 April 2014 Revised 12 October 2014 Accepted 14 October 2014 Available online xxxx Keywords: Pain Major depression Nortriptyline Escitalopram
a b s t r a c t Objective: Unexplained painful physical symptoms are commonly reported by depressed patients. The evidence suggests that dual-action antidepressants are potent in relieving pain in depression. However, a direct comparison of the effects of selective serotonergic and selective noradrenergic antidepressants on painful symptoms has not been investigated so far. Method: Sixty patients who participated in the Genome-based Therapeutic Drugs for Depression study with a diagnosis of moderate or severe episodes of depression according to the International Classification of Diseases, 10th Revision, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria were involved. All the participants were randomly allocated to receive nortriptyline or escitalopram. The severity of depression was measured using the Montgomery–Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale and the Beck Depression Inventory at weeks 0, 2, 4, 6 and 8. The intensity of pain was measured on the Visual Analog Scale at the same points of the study. Results: At “week 0,” 83.3% of the patients later randomized to treatment with escitalopram and 86.7% of those treated with nortriptyline reported at least one painful symptom. A significant decrease of pain intensity was observed after 2 weeks of treatment. The two groups did not differ in degree of pain reduction at weeks 2, 4, 6 and 8 in comparison to baseline values. A 50% reduction in pain intensity preceded the 50% reduction of depression severity. The intensity of pain at “week 0” did not differ in remitted or nonremitted patients at week 8. Conclusion: Both selective serotonergic and selective noradrenergic antidepressants are equally effective in alleviations of painful physical symptoms of depression. The presence of painful symptoms before the onset of treatment did not determine the final response. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Epidemiological data and clinical experience indicate that a significant proportion of patients with depression report unexplained painful physical symptoms (PPSs) unrelated to any general medical condition. Bair et al. [1], who reviewed 14 studies examining pain in depression, found that the mean prevalence of pain was 65% and ranged from 15% to 100%. Pain complaints were identified in participants of the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study on the basis of one item, somatic pain, of the 30-item Inventory of depressive Symptomatology — Clinical Rating. Pain of at least mild intensity was reported by 77% of subjects [2]. Recent studies have confirmed a high prevalence of pain in depression. Aguera-Ortiz et al. (2011) [3] showed that 59.1% of patients with depression, attended by psychiatrists in their regular practice, reported significant pain, defined as intensity of pain N 40 on the Visual Analogue Scale (VAS) in a range of 0–100. The high prevalence of pain in depression was confirmed in ⁎ Corresponding author. Tel.: +48 61 8491 531. E-mail address: [email protected] (J. Jaracz).
the prospective FINDER (Factors Influencing Depression Endpoints Research) study, and moderate to severe pain was detected in 56% of the patients before initiation of treatment with an antidepressant. One third of the patients continued to experience moderate to severe pain at 6-month follow- up [4]. Several implications of painful symptoms in depression have been suggested. Karp et al. (2005) [5] postulated that a higher level of pain at baseline predicts a longer time to remission and it may therefore be considered as a marker of a more difficult-to-treat depression. Furthermore, painful symptoms in depression are related to poor functional status (higher unemployment and pain-related functional limitations), frequent utilization of health care (at baseline and 1-year follow-up) [6] and a poorer quality of life [7]. There is growing evidence suggesting that the regulation of mood and pain processing may share a common neurobiological mechanism. According to the monoamine theory of the pathogenesis of depression, deficiencies in ascending serotonin and noradrenaline pathways are responsible for core symptoms of depression such as depressed mood, psychomotor retardation, and vegetative symptoms. Descending 5-HT and NA pathways play a crucial role in the modulation of nociceptive
http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005 0163-8343/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
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J. Jaracz et al. / General Hospital Psychiatry xxx (2014) xxx–xxx
signals from the periphery to the higher cerebral centers. Alteration of suppression of ascending sensory input has been implicated in the pathophysiology of painful symptoms in depression [8]. Since both 5HT and NA are involved in descending inhibition of pain impulses, it has been postulated that those antidepressants which block the reuptake of both 5-HT and NA are more effective in reducing pain than drugs acting upon a single neurotransmitter. Considerable research has confirmed the efficacy of venlafaxine, milnacipram and duloxetine in fibromyalgia, neuropathy and other painful conditions [9–13]. These data led to the assumption that analogously dual-action antidepressants are more effective in reducing unexplained pain in depression than selective agents. On the assumption that the analgesic efficacy of different classes of antidepressants is not equivalent, the choice of antidepressant would appear to be an important issue due to the fact that the presence of painful physical symptoms has an impact on several aspects of prognosis in treatment of depression. In recent years, duloxetine, a potent dualreuptake inhibitor of 5-HT and NA, has attracted the attention of investigators in regards to its effect on painful symptoms. Placebo-controlled, randomized studies have shown that duloxetine significantly reduces pain in depressed patients [14–16]. Goldstein et al. [17], on the basis of data from three trials, confirmed that duloxetine is effective in the amelioration of PPSs in depression. However, in one study, paroxetine 20 mg/day appeared to be comparably effective in reducing pain severity to duloxetine 80 mg/day at week 8. The effects of duloxetine have been well documented, but the paucity of data regarding the efficacy of other antidepressants in reducing PPSs of depression is evident. Moreover, it has not been clearly elucidated whether selective serotonin reuptake inhibitors (SSRIs) are noninferior to noradrenaline reuptake inhibitors in reducing painful physical symptoms in depression. PPSs were defined as experience of pain which is unexplained by the presence of general medical conditions. We carried out a randomized controlled noninferiority trial to compare the effects of the SSRI escitalopram and the potent noradrenaline reuptake inhibitor nortriptyline on PPSs in patients treated because of depressive episode. Noninferiority trials are intended to show that the effect of one treatment is not worse than another by a specified margin. 2. Subjects Sixty patients (44 males and 16 females) with the diagnosis of a moderate or severe episode in the course of unipolar major depression were involved in this study. All patients met both the International Classification of Diseases, 10th Revision (World Health Organization, 1992), and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association, 1994), criteria. The diagnosis was confirmed using the Schedules for Human Assessment in Neuropsychiatry v.2.1 (WHO 1999). For 30 patients, it was a first (single) depressive episode and, for others, the second (n = 17) or third (n = 7). All the subjects were participants in the Genome-based Therapeutic Drugs for Depression (GENDEP) study, an open-label, partrandomized multicenter pharmacogenetic study with two active pharmacological treatment arms in one of involved centers [18–20]. Patients with no contradictions were randomly allocated to receive a flexible dosage of nortriptyline (n = 30), a tricyclic antidepressant which inhibits the reuptake of noradrenaline (50–150 mg daily), or escitalopram (n = 30), a selective inhibitor of the serotonin transporter (SSRI) (10–30 mg daily). The following exclusion criteria were established: a family history of schizophrenia; bipolar disorder in first-degree relatives; a personal history of schizophrenia, manic or hypomanic episode, mood incongruent psychotic symptoms, active substance dependence or primary organic disease; current treatment with an antipsychotic or a mood stabilizer; nonresponse to one medication and the presence of serious medical condition interfering with treatment. None of the patients were diagnosed with medical conditions associated with chronic pain. Participants who could not tolerate the initially allocated medication or who did not experience sufficient improvement despite
adequate dosage were offered to change to the other medication. Participants who changed medication were then followed up using the same protocol as for the first antidepressant. Other psychotropic medications were not allowed, with the exception of the occasional use of hypnotics. Before randomization (week 0) and every two weeks (week 2, 4, 6, 8) throughout the study, the severity of depression was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS) [21], the Hamilton Depression Rating Scale (HAMD-17) [22] and the self-report Beck Depression Inventory (BDI) [23]. The mean age of the patients receiving nortriptyline was 38.7 years (S.D.± 11.5), and of those receiving escitalopram, the mean age was 41.3 years (S.D.±12.3). The demographic and clinical characteristics of patients are given in Table 1. At day 0, severity of depression in both groups was much the same, according HAMD (26 vs. 25), MADRS (31.4 vs. 29.8) and BDI (32.9 vs. 29.9). The intensity of pain was measured with the VAS, which has been used in several studies investigating pain in depression. The participants were asked to assess the severity of pain in their head, neck, chest, abdomen and extremities on a range of 0–10 cm and to mark down on VAS every day in the previous 2-week period. During consecutive visits, the mean scores of VAS and the number of painful symptoms were calculated. In the case of multiple pains, the mean VAS scores referring to particular body parts were added up. All the patients gave their written informed consent, and the study protocol was approved by the local ethics board of Poznań University of Medical Sciences. 2.1. Statistical methods The Mann–Whitney and Wilcoxon tests were used to compare pain and depression scores. Data were analyzed with Statistica version 11. This statistical analysis was verified using Hodges-Lehman, Klotz and Lapage tests. On the basis of available data, an equivalence margin of 1.5 cm on the VAS was prespecified [24]. For the purpose of estimation of power of Mann–Whitney test applied for statistical analysis in this study, we administer POWER & SAMPLE SIZE for TWO ORDERED MULTINOMIALS procedure from Cytel Studio Version 10.0.0 (Jan. 16, 2013) software (StatXact suite of statistical tests). Estimations were performed using both exact and asymptomatic methods assuming difference 1.5 cm in pain severity as clinically significant. According to both methods, the power was estimated as 92% and 91%, respectively. 3. Results At “week 0,” 83.3% of the patients randomized afterwards to treatment with escitalopram and 86.7% of those to treatment with nortriptyline reported at least one painful symptom. At this point in the study, the mean VAS score in the escitalopram group was 6.7 (S.D. 7.6), whereas in the nortriptyline group, it was slightly lower at 4.6 (S.D. 4.6). The most common location of pain at day 0 was head (ESC 80%, NOR 77% with headache), chest (ESC 30%, NOR 29%), abdomen (ESC 33%, NOR 30%), upper limbs (ESC and NOR 7%) and lower limbs (ESC and NOR Table 1 Demographic and clinical characteristics of the groups Escitalopram (n = 30)
Age Duration of disease (years) Number of episodes
HAMD MADRS BDI
Nortriptyline (n = 30)
Mean
S.D.
Mean
S.D.
P
41.3 4.23 1 n=12 2–3 n=14 N3 n=4 26 31.4 32.9
12.3 5.36
38.7 4.11 1 n=18 2–3 n=8 N3 n=4 25 29.8 29.9
11.5 5.66
NS NS NS
6.8 8.4 10.6
NS NS NS
4.8 7.2 9.0
Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
J. Jaracz et al. / General Hospital Psychiatry xxx (2014) xxx–xxx
16%). In 26.7% of patients assigned to ESC group and 16.7% to NOR group, pain was reported every day. In similar proportion of patients (ESC 23.3% and NOR 13.3%), painful symptoms were observed 1 day a week or not reported at all (ESC 20%, NOR 33.3%). The remaining patients reported pain 2–6 days a week. In consecutive points of study, a significant decrease in the total VAS score was observed. ESC appeared noninferior to NOR in pain severity and degree of pain reduction at weeks 2, 4, 6 and 8 in comparison to baseline values (Fig. 1). Both antidepressants significantly diminished severity of depression scores measured by HAMD (Fig. 2), MADRS and BDI throughout the study. No significant differences between groups were found when reduction in symptom severity was compared in consecutive weeks of the study. In both groups, a 50% reduction of pain was obtained during the first 2 weeks of treatment, while 50% alleviation of severity of depression according to HAMD was attained between weeks 4 and 6. A clinical response in clinical studies of antidepressants is defined as a N50% reduction of the HAMD score, whereas remission is defined as a score of less than 7 points. At “week 8,” 21 (70%) of patients from the escitalopram group and 18 (60%) of those treated with NOR met these clinical response criteria. Remission was found in four (13%) patients from both groups. The intensity of pain at “week 0” did not differ in nonremitted and remitted patients at “week 8” in the escitalopram group (mean 6.6, S.D. ±6.9 vs 6.9, S.D. ±12.7; P=.31) or the nortriptyline group (mean 4.6, S.D. 4.9 and 4.1, S.D. ±0.9; P=.41). Similarly, the number of painful symptoms at week 0 did not determine the quality of response as assessed at week 8.
4. Discussion The aim of this study was to compare the impact of the SSRI escitalopram and of nortriptyline, a tricyclic antidepressant inhibiting the noradrenaline transporter, on PPSs in patients with a diagnosis of unipolar major depression of at least moderate severity. A significant proportion of the patients included at the screening visit (83.3%) reported at least one PPS. The prevalence of pain was similar to that observed by Husain et al. [2] but higher than in two other studies where a more rigorous cutoff for intensity of pain was applied [3,4]. Our findings suggest that both drugs had a comparable effect on reduction of severity of pain throughout the study. A significant reduction of pain was observed as early as 2 weeks after the onset of treatment. Improvements in depression severity were also similar for both ESC and NOR. For the extensive GENDEP study (n = 811 initially), no differences in the efficacy of the two drugs were found when total scores of HAMD, MADRAS and BDI were compared. However, when the effect on three symptom dimensions, namely, mood, cognitive symptoms and neurovegetative symptoms, was evaluated, differences were detected. The mood and cognitive symptoms improved more in escitalopramNS
7
NS
NS
NS
0-6
0-8
6 5 4 3 2 1 0 weeks
0-2
0-4 ESCIT
NOR
Fig. 1. The comparison of differences of pain severity between week 0 (ESCIT mean 6.7, NOR mean 4.6) and consecutive points of the study in patients treated with escitalopram (n=30) and nortryptyline (n=30) (Mann–Whitney test).
16
NS
3 NS
NS
NS
0-4
0-6
0-8
14 12 10 8 6 4 2 0 0-2
ESCIT
NOR
Fig. 2. Comparison of differences of depression severity according HAMD between week 0 and consecutive points of the study (baseline ESCIT 26, NOR 25) (Mann–Whitney test).
treated participants, but the neurovegetative symptoms improved more in the patients receiving nortriptyline [25]. The relationship between reduction of pain severity and improvement in depressive symptoms was the focus of interest of investigators of duloxetine. Fava et al. (2004) [14] argue that 50% of the improvement in pain severity with the use of this drug was independent of the amelioration of depressive symptoms. In depressed patients who responded to duloxetine, self-rated pain reduction of N 50% was observed slightly earlier (mean 6.3 days) than self-rated time to 50% mood response (7.6 days), suggesting earlier conscious perception of pain than mood changes [26]. The results of our study suggest that 50% reduction of pain was obtained during the first 2 weeks of treatment with escitalopram and nortriptyline, whereas a 50% alleviation of severity of depression was only attained later. This may suggest that the effects of antidepressants on pain and depression are partially independent. This observation is consistent with the results of the study of Marangell et al. [27] who investigated the effect of duloxetine on pain and depression in patients with fibromyalgia and major depression. The authors calculated that 69% of the improvement in pain was a direct effect of treatment, while improvement in mood accounted for 31% of pain response. They finally concluded that both direct and indirect analgesic and antidepressant properties appear to be relevant for the treatment of these comorbid patients. It has not been clearly elucidated whether 5-HT and NA neurons in descending pathways have an equipotential impact on suppression of pain. The results of several recent studies emphasize an important role for noradrenergic pathways in analgesia in animal models of pain [28,29]. Interestingly, inhibition of norepinephrine reuptake along with mu-opioid agonism is considered a mechanism of action of the novel analgesic drug tapentadol [30]. However, increase of NA in the spinal cord and the related antihyperalgesic effect were found after the administration not only of maprotyline, a selective NA reuptake inhibitor, but also of the SSRI paroxetine [29]. There is evidence to suggest that paroxetine has beneficial effect on pain symptoms in physical illness as comorbid with depression and anxiety. It has been postulated that the impact of paroxetine on pain symptoms is probably related to its high affinity for the 5-HT transporter and inhibition of noradrenaline transporter [31]. However, the higly selective SSRI escitalopram was superior to a placebo in reducing pain symptoms in patients with multisomatoform disorders, suggesting that selective enhancement of serotonergic neurotransmition has an influence on pain perception [32]. Recently, Mazza et al. [33] demonstrated that escitalopram was comparably effective to duloxetine in reducing chronic low back pain. The authors concluded that the pain response was mediated by a direct analgesic effect of both medicines. Finally, some limitations of our study should be pointed out. First, the sample size is relatively small, and results should be confirmed in further research involving larger study samples. Second, it is usually difficult to differentiate medically unexplained pains from pains of other etiology in depressed patients. This might have implications for interpretation of results and account for limitation of the study. To reduce this
Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
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confounding effect, patients were asked to report only pains attributable to present depressive episode. Third, noninferiority trials have a number of inherent weaknesses: no single conservative analysis approach, lack of protection from blinding difficulty (for instance, escitalopram and nortriptyline have differing side effects that can lead to problems with blinding) and difficulty in specifying the noninferiority margin. The results of this study suggest that serotonergic antidepressant is noninferior to noradrenergic in reduction of severity of unexplained painful physical symptoms in depression.
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Acknowledgments The authors thank prof. Geoffrey Shaw for his linguistic consultation of the text.
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Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression Jan Jaracz, Ph.D.,M.D. a,⁎, Karolina Gattner, M.D. a, Jerzy Moczko, Ph.D.,M.D. b, Joanna Hauser, Ph.D.,M.D. c a b c
Department of Adult Psychiatry, Poznań University of Medical Sciences, ul. Szpitalna 27/33 60-572 Poznań, Poland Department of Computer Science and Statistics Poznań University of Medical Sciences ul. Dąbrowskiego 79 60-529 Poznań, Poland Department of Psychiatric Genetics, Poznan University of Medical Sciences, ul. Szpitalna 27/33, 60-572 Poznań, Poland
a r t i c l e
i n f o
Article history: Received 22 April 2014 Revised 12 October 2014 Accepted 14 October 2014 Available online xxxx Keywords: Pain Major depression Nortriptyline Escitalopram
a b s t r a c t Objective: Unexplained painful physical symptoms are commonly reported by depressed patients. The evidence suggests that dual-action antidepressants are potent in relieving pain in depression. However, a direct comparison of the effects of selective serotonergic and selective noradrenergic antidepressants on painful symptoms has not been investigated so far. Method: Sixty patients who participated in the Genome-based Therapeutic Drugs for Depression study with a diagnosis of moderate or severe episodes of depression according to the International Classification of Diseases, 10th Revision, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria were involved. All the participants were randomly allocated to receive nortriptyline or escitalopram. The severity of depression was measured using the Montgomery–Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale and the Beck Depression Inventory at weeks 0, 2, 4, 6 and 8. The intensity of pain was measured on the Visual Analog Scale at the same points of the study. Results: At “week 0,” 83.3% of the patients later randomized to treatment with escitalopram and 86.7% of those treated with nortriptyline reported at least one painful symptom. A significant decrease of pain intensity was observed after 2 weeks of treatment. The two groups did not differ in degree of pain reduction at weeks 2, 4, 6 and 8 in comparison to baseline values. A 50% reduction in pain intensity preceded the 50% reduction of depression severity. The intensity of pain at “week 0” did not differ in remitted or nonremitted patients at week 8. Conclusion: Both selective serotonergic and selective noradrenergic antidepressants are equally effective in alleviations of painful physical symptoms of depression. The presence of painful symptoms before the onset of treatment did not determine the final response. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Epidemiological data and clinical experience indicate that a significant proportion of patients with depression report unexplained painful physical symptoms (PPSs) unrelated to any general medical condition. Bair et al. [1], who reviewed 14 studies examining pain in depression, found that the mean prevalence of pain was 65% and ranged from 15% to 100%. Pain complaints were identified in participants of the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study on the basis of one item, somatic pain, of the 30-item Inventory of depressive Symptomatology — Clinical Rating. Pain of at least mild intensity was reported by 77% of subjects [2]. Recent studies have confirmed a high prevalence of pain in depression. Aguera-Ortiz et al. (2011) [3] showed that 59.1% of patients with depression, attended by psychiatrists in their regular practice, reported significant pain, defined as intensity of pain N 40 on the Visual Analogue Scale (VAS) in a range of 0–100. The high prevalence of pain in depression was confirmed in ⁎ Corresponding author. Tel.: +48 61 8491 531. E-mail address: [email protected] (J. Jaracz).
the prospective FINDER (Factors Influencing Depression Endpoints Research) study, and moderate to severe pain was detected in 56% of the patients before initiation of treatment with an antidepressant. One third of the patients continued to experience moderate to severe pain at 6-month follow- up [4]. Several implications of painful symptoms in depression have been suggested. Karp et al. (2005) [5] postulated that a higher level of pain at baseline predicts a longer time to remission and it may therefore be considered as a marker of a more difficult-to-treat depression. Furthermore, painful symptoms in depression are related to poor functional status (higher unemployment and pain-related functional limitations), frequent utilization of health care (at baseline and 1-year follow-up) [6] and a poorer quality of life [7]. There is growing evidence suggesting that the regulation of mood and pain processing may share a common neurobiological mechanism. According to the monoamine theory of the pathogenesis of depression, deficiencies in ascending serotonin and noradrenaline pathways are responsible for core symptoms of depression such as depressed mood, psychomotor retardation, and vegetative symptoms. Descending 5-HT and NA pathways play a crucial role in the modulation of nociceptive
http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005 0163-8343/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
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signals from the periphery to the higher cerebral centers. Alteration of suppression of ascending sensory input has been implicated in the pathophysiology of painful symptoms in depression [8]. Since both 5HT and NA are involved in descending inhibition of pain impulses, it has been postulated that those antidepressants which block the reuptake of both 5-HT and NA are more effective in reducing pain than drugs acting upon a single neurotransmitter. Considerable research has confirmed the efficacy of venlafaxine, milnacipram and duloxetine in fibromyalgia, neuropathy and other painful conditions [9–13]. These data led to the assumption that analogously dual-action antidepressants are more effective in reducing unexplained pain in depression than selective agents. On the assumption that the analgesic efficacy of different classes of antidepressants is not equivalent, the choice of antidepressant would appear to be an important issue due to the fact that the presence of painful physical symptoms has an impact on several aspects of prognosis in treatment of depression. In recent years, duloxetine, a potent dualreuptake inhibitor of 5-HT and NA, has attracted the attention of investigators in regards to its effect on painful symptoms. Placebo-controlled, randomized studies have shown that duloxetine significantly reduces pain in depressed patients [14–16]. Goldstein et al. [17], on the basis of data from three trials, confirmed that duloxetine is effective in the amelioration of PPSs in depression. However, in one study, paroxetine 20 mg/day appeared to be comparably effective in reducing pain severity to duloxetine 80 mg/day at week 8. The effects of duloxetine have been well documented, but the paucity of data regarding the efficacy of other antidepressants in reducing PPSs of depression is evident. Moreover, it has not been clearly elucidated whether selective serotonin reuptake inhibitors (SSRIs) are noninferior to noradrenaline reuptake inhibitors in reducing painful physical symptoms in depression. PPSs were defined as experience of pain which is unexplained by the presence of general medical conditions. We carried out a randomized controlled noninferiority trial to compare the effects of the SSRI escitalopram and the potent noradrenaline reuptake inhibitor nortriptyline on PPSs in patients treated because of depressive episode. Noninferiority trials are intended to show that the effect of one treatment is not worse than another by a specified margin. 2. Subjects Sixty patients (44 males and 16 females) with the diagnosis of a moderate or severe episode in the course of unipolar major depression were involved in this study. All patients met both the International Classification of Diseases, 10th Revision (World Health Organization, 1992), and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (American Psychiatric Association, 1994), criteria. The diagnosis was confirmed using the Schedules for Human Assessment in Neuropsychiatry v.2.1 (WHO 1999). For 30 patients, it was a first (single) depressive episode and, for others, the second (n = 17) or third (n = 7). All the subjects were participants in the Genome-based Therapeutic Drugs for Depression (GENDEP) study, an open-label, partrandomized multicenter pharmacogenetic study with two active pharmacological treatment arms in one of involved centers [18–20]. Patients with no contradictions were randomly allocated to receive a flexible dosage of nortriptyline (n = 30), a tricyclic antidepressant which inhibits the reuptake of noradrenaline (50–150 mg daily), or escitalopram (n = 30), a selective inhibitor of the serotonin transporter (SSRI) (10–30 mg daily). The following exclusion criteria were established: a family history of schizophrenia; bipolar disorder in first-degree relatives; a personal history of schizophrenia, manic or hypomanic episode, mood incongruent psychotic symptoms, active substance dependence or primary organic disease; current treatment with an antipsychotic or a mood stabilizer; nonresponse to one medication and the presence of serious medical condition interfering with treatment. None of the patients were diagnosed with medical conditions associated with chronic pain. Participants who could not tolerate the initially allocated medication or who did not experience sufficient improvement despite
adequate dosage were offered to change to the other medication. Participants who changed medication were then followed up using the same protocol as for the first antidepressant. Other psychotropic medications were not allowed, with the exception of the occasional use of hypnotics. Before randomization (week 0) and every two weeks (week 2, 4, 6, 8) throughout the study, the severity of depression was measured using the Montgomery–Åsberg Depression Rating Scale (MADRS) [21], the Hamilton Depression Rating Scale (HAMD-17) [22] and the self-report Beck Depression Inventory (BDI) [23]. The mean age of the patients receiving nortriptyline was 38.7 years (S.D.± 11.5), and of those receiving escitalopram, the mean age was 41.3 years (S.D.±12.3). The demographic and clinical characteristics of patients are given in Table 1. At day 0, severity of depression in both groups was much the same, according HAMD (26 vs. 25), MADRS (31.4 vs. 29.8) and BDI (32.9 vs. 29.9). The intensity of pain was measured with the VAS, which has been used in several studies investigating pain in depression. The participants were asked to assess the severity of pain in their head, neck, chest, abdomen and extremities on a range of 0–10 cm and to mark down on VAS every day in the previous 2-week period. During consecutive visits, the mean scores of VAS and the number of painful symptoms were calculated. In the case of multiple pains, the mean VAS scores referring to particular body parts were added up. All the patients gave their written informed consent, and the study protocol was approved by the local ethics board of Poznań University of Medical Sciences. 2.1. Statistical methods The Mann–Whitney and Wilcoxon tests were used to compare pain and depression scores. Data were analyzed with Statistica version 11. This statistical analysis was verified using Hodges-Lehman, Klotz and Lapage tests. On the basis of available data, an equivalence margin of 1.5 cm on the VAS was prespecified [24]. For the purpose of estimation of power of Mann–Whitney test applied for statistical analysis in this study, we administer POWER & SAMPLE SIZE for TWO ORDERED MULTINOMIALS procedure from Cytel Studio Version 10.0.0 (Jan. 16, 2013) software (StatXact suite of statistical tests). Estimations were performed using both exact and asymptomatic methods assuming difference 1.5 cm in pain severity as clinically significant. According to both methods, the power was estimated as 92% and 91%, respectively. 3. Results At “week 0,” 83.3% of the patients randomized afterwards to treatment with escitalopram and 86.7% of those to treatment with nortriptyline reported at least one painful symptom. At this point in the study, the mean VAS score in the escitalopram group was 6.7 (S.D. 7.6), whereas in the nortriptyline group, it was slightly lower at 4.6 (S.D. 4.6). The most common location of pain at day 0 was head (ESC 80%, NOR 77% with headache), chest (ESC 30%, NOR 29%), abdomen (ESC 33%, NOR 30%), upper limbs (ESC and NOR 7%) and lower limbs (ESC and NOR Table 1 Demographic and clinical characteristics of the groups Escitalopram (n = 30)
Age Duration of disease (years) Number of episodes
HAMD MADRS BDI
Nortriptyline (n = 30)
Mean
S.D.
Mean
S.D.
P
41.3 4.23 1 n=12 2–3 n=14 N3 n=4 26 31.4 32.9
12.3 5.36
38.7 4.11 1 n=18 2–3 n=8 N3 n=4 25 29.8 29.9
11.5 5.66
NS NS NS
6.8 8.4 10.6
NS NS NS
4.8 7.2 9.0
Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
J. Jaracz et al. / General Hospital Psychiatry xxx (2014) xxx–xxx
16%). In 26.7% of patients assigned to ESC group and 16.7% to NOR group, pain was reported every day. In similar proportion of patients (ESC 23.3% and NOR 13.3%), painful symptoms were observed 1 day a week or not reported at all (ESC 20%, NOR 33.3%). The remaining patients reported pain 2–6 days a week. In consecutive points of study, a significant decrease in the total VAS score was observed. ESC appeared noninferior to NOR in pain severity and degree of pain reduction at weeks 2, 4, 6 and 8 in comparison to baseline values (Fig. 1). Both antidepressants significantly diminished severity of depression scores measured by HAMD (Fig. 2), MADRS and BDI throughout the study. No significant differences between groups were found when reduction in symptom severity was compared in consecutive weeks of the study. In both groups, a 50% reduction of pain was obtained during the first 2 weeks of treatment, while 50% alleviation of severity of depression according to HAMD was attained between weeks 4 and 6. A clinical response in clinical studies of antidepressants is defined as a N50% reduction of the HAMD score, whereas remission is defined as a score of less than 7 points. At “week 8,” 21 (70%) of patients from the escitalopram group and 18 (60%) of those treated with NOR met these clinical response criteria. Remission was found in four (13%) patients from both groups. The intensity of pain at “week 0” did not differ in nonremitted and remitted patients at “week 8” in the escitalopram group (mean 6.6, S.D. ±6.9 vs 6.9, S.D. ±12.7; P=.31) or the nortriptyline group (mean 4.6, S.D. 4.9 and 4.1, S.D. ±0.9; P=.41). Similarly, the number of painful symptoms at week 0 did not determine the quality of response as assessed at week 8.
4. Discussion The aim of this study was to compare the impact of the SSRI escitalopram and of nortriptyline, a tricyclic antidepressant inhibiting the noradrenaline transporter, on PPSs in patients with a diagnosis of unipolar major depression of at least moderate severity. A significant proportion of the patients included at the screening visit (83.3%) reported at least one PPS. The prevalence of pain was similar to that observed by Husain et al. [2] but higher than in two other studies where a more rigorous cutoff for intensity of pain was applied [3,4]. Our findings suggest that both drugs had a comparable effect on reduction of severity of pain throughout the study. A significant reduction of pain was observed as early as 2 weeks after the onset of treatment. Improvements in depression severity were also similar for both ESC and NOR. For the extensive GENDEP study (n = 811 initially), no differences in the efficacy of the two drugs were found when total scores of HAMD, MADRAS and BDI were compared. However, when the effect on three symptom dimensions, namely, mood, cognitive symptoms and neurovegetative symptoms, was evaluated, differences were detected. The mood and cognitive symptoms improved more in escitalopramNS
7
NS
NS
NS
0-6
0-8
6 5 4 3 2 1 0 weeks
0-2
0-4 ESCIT
NOR
Fig. 1. The comparison of differences of pain severity between week 0 (ESCIT mean 6.7, NOR mean 4.6) and consecutive points of the study in patients treated with escitalopram (n=30) and nortryptyline (n=30) (Mann–Whitney test).
16
NS
3 NS
NS
NS
0-4
0-6
0-8
14 12 10 8 6 4 2 0 0-2
ESCIT
NOR
Fig. 2. Comparison of differences of depression severity according HAMD between week 0 and consecutive points of the study (baseline ESCIT 26, NOR 25) (Mann–Whitney test).
treated participants, but the neurovegetative symptoms improved more in the patients receiving nortriptyline [25]. The relationship between reduction of pain severity and improvement in depressive symptoms was the focus of interest of investigators of duloxetine. Fava et al. (2004) [14] argue that 50% of the improvement in pain severity with the use of this drug was independent of the amelioration of depressive symptoms. In depressed patients who responded to duloxetine, self-rated pain reduction of N 50% was observed slightly earlier (mean 6.3 days) than self-rated time to 50% mood response (7.6 days), suggesting earlier conscious perception of pain than mood changes [26]. The results of our study suggest that 50% reduction of pain was obtained during the first 2 weeks of treatment with escitalopram and nortriptyline, whereas a 50% alleviation of severity of depression was only attained later. This may suggest that the effects of antidepressants on pain and depression are partially independent. This observation is consistent with the results of the study of Marangell et al. [27] who investigated the effect of duloxetine on pain and depression in patients with fibromyalgia and major depression. The authors calculated that 69% of the improvement in pain was a direct effect of treatment, while improvement in mood accounted for 31% of pain response. They finally concluded that both direct and indirect analgesic and antidepressant properties appear to be relevant for the treatment of these comorbid patients. It has not been clearly elucidated whether 5-HT and NA neurons in descending pathways have an equipotential impact on suppression of pain. The results of several recent studies emphasize an important role for noradrenergic pathways in analgesia in animal models of pain [28,29]. Interestingly, inhibition of norepinephrine reuptake along with mu-opioid agonism is considered a mechanism of action of the novel analgesic drug tapentadol [30]. However, increase of NA in the spinal cord and the related antihyperalgesic effect were found after the administration not only of maprotyline, a selective NA reuptake inhibitor, but also of the SSRI paroxetine [29]. There is evidence to suggest that paroxetine has beneficial effect on pain symptoms in physical illness as comorbid with depression and anxiety. It has been postulated that the impact of paroxetine on pain symptoms is probably related to its high affinity for the 5-HT transporter and inhibition of noradrenaline transporter [31]. However, the higly selective SSRI escitalopram was superior to a placebo in reducing pain symptoms in patients with multisomatoform disorders, suggesting that selective enhancement of serotonergic neurotransmition has an influence on pain perception [32]. Recently, Mazza et al. [33] demonstrated that escitalopram was comparably effective to duloxetine in reducing chronic low back pain. The authors concluded that the pain response was mediated by a direct analgesic effect of both medicines. Finally, some limitations of our study should be pointed out. First, the sample size is relatively small, and results should be confirmed in further research involving larger study samples. Second, it is usually difficult to differentiate medically unexplained pains from pains of other etiology in depressed patients. This might have implications for interpretation of results and account for limitation of the study. To reduce this
Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
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confounding effect, patients were asked to report only pains attributable to present depressive episode. Third, noninferiority trials have a number of inherent weaknesses: no single conservative analysis approach, lack of protection from blinding difficulty (for instance, escitalopram and nortriptyline have differing side effects that can lead to problems with blinding) and difficulty in specifying the noninferiority margin. The results of this study suggest that serotonergic antidepressant is noninferior to noradrenergic in reduction of severity of unexplained painful physical symptoms in depression.
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Acknowledgments The authors thank prof. Geoffrey Shaw for his linguistic consultation of the text.
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Please cite this article as: Jaracz J., et al, Comparison of the effects of escitalopram and nortriptyline on painful symptoms in patients with major depression, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.10.005
