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. 2025 Jul 22;29(7):e70077. doi: 10.1002/ejp.70077

Differential Effects of Repetitive Transcranial Magnetic Stimulation on Mood and Pain Symptoms in People With Chronic Pain and Major Depressive Disorders—A Review

Daniel Ciampi de Andrade 1,✉, Leandro Valiengo 2,3,4
PMCID: PMC12281609  PMID: 40693547

ABSTRACT

Background and Objective

Chronic pain and major depressive disorder (MDD) are among the most prevalent and disabling conditions globally, often co‐occurring and sharing overlapping symptoms such as fatigue, cognitive dysfunction and mood disturbances. While fibromyalgia, a primary pain syndrome, and MDD have distinct clinical manifestations, their comorbidity presents therapeutic challenges. Repetitive transcranial magnetic stimulation (rTMS), a non‐invasive neuromodulation technique, has shown efficacy in treating both pain and mood disorders when targeted at specific brain regions (motor cortex for pain, dorsolateral prefrontal cortex for mood). This review aimed to investigate whether rTMS interventions for fibromyalgia or MDD improve symptoms across both domains, particularly in comorbid cases.

Databases and Data Treatment

A structured search of PubMed was conducted between January and February 2025. Clinical trials were included if they were randomised, peer‐reviewed, in English and involved ≥ 30 participants. Studies included addressed rTMS effects on pain in MDD or mood in fibromyalgia, or both. Out of 143 identified articles, 36 met the inclusion criteria.

Conclusion

Evidence shows rTMS has target‐ and symptom‐specific effects: Motor cortex stimulation improves pain without reliably affecting mood, while dorsolateral prefrontal cortex stimulation alleviates depressive symptoms but inconsistently influences pain. These outcomes suggest that symptom improvement with rTMS is not global over different symptom clusters, but rather different for specific syndromes and the respective neural networks engaged by therapy. Personalised treatment strategies guided by pre‐treatment connectivity profiles and symptom clusters, already in use for psychiatric disorders, could enhance outcomes in chronic pain management. However, limitations include small sample sizes, low session numbers and potential floor effects in studies involving non‐depressed fibromyalgia patients.

Significance

Noninvasive neuromodulation therapy with repetitive transcranial magnetic stimulation for chronic pain improves pain on fibromyalgia and neuropathic pain but does not improve mood symptoms significantly. Therapy targeting mood symptoms in people with major depressive disorder may have antinociceptive effects in experimental pain models but are not clearly detectable in instances of clinical pain. The relationship between a disease and its associated symptoms is not linear or monotonic and differ between individuals. Unrevealing the associations between individual changes in brain connectivity during disease and the emergence of symptoms is central for the design of personalized and more effective therapeutic interventions.

1. Background and Objective

1.1. The Two Most Impactful Health Conditions Worldwide

Chronic pain affects 18%–26% of the general population (Sá et al. 2019) and is the most prevalent symptomatic disorder worldwide, contributing to the highest disability‐adjusted life years among all symptomatic diseases (GBD 2019 Diseases and Injuries Collaborators 2020; GBD 2021 Diseases and Injuries Collaborators 2024). It is an umbrella term encompassing various pain conditions with distinct risk factors, prognoses and responses to therapy (Rosner et al. 2023). Chronic pain is classified as secondary when it arises as a symptom of an underlying disease or condition, such as neuropathic pain following a stroke, post‐surgical pain, or cancer‐related pain. In contrast, primary pain refers to cases where pain itself is the primary disorder, significantly impacting well‐being and quality of life. Examples include migraine, most cases of non‐specific low back pain and fibromyalgia (Nicholas et al. 2019; Treede et al. 2019). Management of chronic pain depends on its underlying condition and involves both pharmacological and non‐pharmacological approaches. While pain intensity reduction is often the primary outcome in clinical trials, effective pain management extends beyond pain relief and also focuses on improving quality of life and functional abilities (Dworkin et al. 2005; Smith et al. 2020). Furthermore, both primary and secondary pain conditions significantly impact pain‐associated symptom domains such as sleep, motor function, fatigue, cognition and mood (Häuser et al. 2015; Rosner et al. 2023).

Mood symptoms, including depressive symptoms and anxiety, are omnipresent in people with chronic pain and are considered an inherent dimension of the experience of pain. Mood symptoms may be more or less prominent in different pain syndromes and across different people. This does not necessarily mean all patients with chronic pain have major depression. Major depressive disorder (MDD) is characterised by a persistent and pervasive depressed mood, significant loss of interest or pleasure in most activities (anhedonia) and a range of cognitive and physical symptoms (Otte et al. 2016). MDD presents with a constellation of symptoms, including profound sadness, feelings of hopelessness and a diminished ability to experience pleasure. Cognitive symptoms involve impaired concentration, indecisiveness and recurrent thoughts of worthlessness or death. Physical symptoms may include disturbances in appetite, body weight, sleep patterns, psychomotor agitation or retardation and fatigue (Marx et al. 2023; Uher et al. 2014). To meet diagnostic criteria, these symptoms must cause clinically significant distress or impairment in social, occupational or other essential areas of functioning and must not be attributable to substance use or another medical condition. MDD is among the most prevalent health disorders worldwide and ranks as a leading cause of disability‐adjusted life years, second only to low back pain (GBD 2021 Diseases and Injuries Collaborators 2024; Greenberg et al. 2021). It is more common in women than in men, peaks in prevalence between the ages of 55 and 59 years (Rong et al. 2025) and is disproportionately more frequent in areas of low sociodemographic development (Greenberg et al. 2021; Yan et al. 2024). MDD is associated with increased pain sensitivity, lower pain thresholds and a high prevalence of comorbid chronic pain (Hermesdorf et al. 2016).

The interaction between pain and pain‐associated symptoms is complex and probably multidirectional. For example, it has been shown that depression can mediate the effects of neuropathic pain on quality of life in some patients (Lu et al. 2019). Relatedly, there is evidence supporting that both pharmacological and non‐pharmacological therapy may have differential inter‐individual effects on the different associated symptoms in people with chronic pain (Bhai et al. 2022; Perrot and Russell 2014). This raises a critical challenge for patients and healthcare providers: which symptom or functional domain should be prioritised when designing a treatment plan to achieve optimal functional improvement? Addressing this question requires an understanding of how different interventions influence various aspects of pain and its associated symptoms.

In this context, here we will explore the effects of a widely used non‐invasive neuromodulation technique—repetitive transcranial magnetic stimulation (rTMS)—in chronic pain management, with a particular focus on its impact on depressive symptoms. We will also describe the current data on the effects of rTMS, primarily used for the management of MDD, on associated pain symptoms. When an electric current flows through a TMS coil, it generates a strong but brief electromagnetic pulse, which induces a localised, low‐intensity electric current within the brain parenchyma (Ciampi de Andrade and García‐Larrea 2023; Faraday and Day 1999). This allows for the non‐invasive modulation of neural activity, bypassing the intense discomfort and pain typically associated with direct electrical stimulation of the scalp, which is densely innervated with nociceptive fibres. Since 2008, the U.S. Food and Drug Administration (FDA) has approved rTMS for the treatment of MDD, and it is now widely available in many countries, though accessibility varies across regions (Foy 2011). More recently, in 2025, the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (IASP) officially recommended rTMS as a therapy for neuropathic pain for the first time (Soliman et al. 2025). Recently, a large international randomised double‐blind study confirmed (Silva et al. 2025) results from earlier studies (Mhalla et al. 2011) on the efficacy of rTMS for fibromyalgia as an add‐on intervention to best medical therapy for fibromyalgia. The effects of rTMS on pain versus mood symptoms in fibromyalgia provide a valuable model for disentangling the interplay between mood improvement, MDD treatment efficacy and pain relief (Lapa et al. 2025). This is because rTMS protocols differ based on the primary therapeutic goal: for mood regulation in MDD, rTMS is typically applied at the dorsolateral prefrontal cortex (dlPFC). For pain management, rTMS is usually directed at the primary motor cortex (M1), often at lower intensities than those used in MDD (Attal et al. 2021; Pascual‐Leone et al. 1996). This dual application of the technique also provides an opportunity to examine how depression treatment influences pain perception in individuals with comorbid chronic pain and MDD, while also allowing for the exploration of how the use of rTMS, primarily prescribed for pain relief, can affect mood symptoms. This information may be useful in designing therapies aiming at jointly controlling various symptom clusters caused by a single health care condition and may inform personalised therapeutic strategies based on an individual's combination of pain‐associated symptoms. This later approach is already used in neuromodulation for Parkinson's disease and dystonia and has been shown to be a useful method to individualise treatment choice (Berényi et al. 2012; Beuter et al. 2014; Caspers et al. 2021; Rajamani et al. 2024).

In this perspective, the review will mainly focus on primary pain conditions, as: (i) they are highly prevalent and among the most burdensome and costly healthcare conditions worldwide (e.g., non‐specific low back pain, primary headaches, fibromyalgia) (GBD 2019 Diseases and Injuries Collaborators 2020); (ii) they are not influenced by structural, mechanistic, or systemic confounders linked to secondary diseases (Nicholas et al. 2019); (iii) they allow for a more direct comparison to psychiatric conditions like MDD, which is also classified as a primary disorder. Among various primary pain syndromes, we will centre the discussion around fibromyalgia. Fibromyalgia, like MDD, has a higher impact on women, a higher prevalence among working‐age adults and it has significant mood‐related symptoms as a part of its core features (Abeles et al. 2007; Wolfe et al. 2018; Häuser and Fitzcharles 2018; Vidal et al. 2021). Fibromyalgia has been studied in several rTMS studies, including international multicentre trials, and can be comorbid with major depression, allowing for the assessment of the differential effects of therapy on pain and mood symptoms.

1.2. The Interplay Between Mood Symptoms, Major Depressive Disorder and Fibromyalgia

Although fibromyalgia is categorised as a pain syndrome, patients often report that non‐painful symptoms, such as mood disturbances, cognitive dysfunction and fatigue, are the most debilitating aspects affecting their quality of life (Mellace et al. 2024; Weinstein et al. 2024). Fibromyalgia can occur as an isolated syndrome or alongside other diseases, such as systemic lupus erythematosus, MDD, or hormone therapy for breast cancer. In these latter cases, it is called comorbid fibromyalgia (Wolfe et al. 2018). Comorbidity does not imply causality, as it is purely a descriptive term to indicate the coincidence of two conditions (Häuser and Fitzcharles 2018; Perrot and Russell 2014). Fibromyalgia disproportionately affects women and is present in 2%–8% of the general population (Häuser et al. 2015; Perrot 2019). Mood disturbances are an inherent feature of fibromyalgia, with over 80% of patients reporting symptoms of anxiety or depression (Consoli et al. 2012; Häuser et al. 2015). However, despite this overlap, the co‐occurrence of MDD and fibromyalgia is not the rule. Only about one‐fourth of individuals with MDD meet fibromyalgia criteria, and conversely, approximately 25% of those with fibromyalgia fulfil the diagnostic criteria for MDD (Løge‐Hagen et al. 2019). MDD and fibromyalgia share many pathophysiological mechanisms, including (i) dysfunction in serotonergic projections from brainstem nuclei to cortical, subcortical and spinal targets, which contributes to both mood regulation and pain processing (Mann 2013; Schneck et al. 2021; Stahl 2009; Üçeyler et al. 2022), (ii) defective intracortical inhibition, a neurophysiological marker observed in both conditions, which correlates with symptom severity (Kaziyama et al. 2020; Levinson et al. 2010; Mhalla et al. 2010, 2011). However, despite these shared features, major depression and fibromyalgia present a wide number of distinct systemic, neurophysiological and clinical underpinnings. Their core clinical manifestations diverge, and comorbidity between these two conditions occurs in a minority of instances (Marx et al. 2023; Otte et al. 2016).

2. Databases and Data Treatment

A structured review of the PubMed databases for clinical trials in humans was conducted from January to February 2025 using: ((‘fibromyalgia’[MeSH Terms] OR ‘fibromyalgia’[Title/Abstract]) AND (‘repetitive transcranial magnetic stimulation’[MeSH Terms] OR ‘rTMS’[Title/Abstract] OR ‘repetitive transcranial magnetic stimulation’[Title/Abstract]) AND (‘anxiety’[MeSH Terms] OR ‘depression’[MeSH Terms] OR ‘mood’[Title/Abstract] OR ‘anxiety’[Title/Abstract] OR ‘depression’[Title/Abstract] OR ‘mood’[MeSH Terms])) OR ((‘major depressive disorder’[MeSH Terms] OR ‘major depressive disorder’[Title/Abstract]) AND (‘repetitive transcranial magnetic stimulation’[MeSH Terms] OR ‘rTMS’[Title/Abstract] OR ‘repetitive transcranial magnetic stimulation’[Title/Abstract])) and a clinical trial filter. Selection of the relevant reports was based on the following inclusion and exclusion criteria. Inclusion: (1) randomised controlled trial (RCT) reporting on the effects of mood outcomes in fibromyalgia rTMS trials; or (2) RCT on the effects of pain outcomes in rTMS trials primarily for MDD therapy; or (3) RCT reporting effects of rTMS on mood in people with MDD; and (4) articles in English. Exclusion: (1) studies that report on pain or mood using validated outcome measurements, (2) non‐peer‐reviewed articles, editorials and opinion pieces, and (3) studies with < 30 included participants. We divided the articles based on fibromyalgia with a diagnosis of MDD (based on inclusion and exclusion criteria and depression scales at baseline).

3. Results

Combining the search results yielded a total of 143 articles. Of these, only 36 articles fit the inclusion criteria.

4. Discussion

4.1. Effects of rTMS for Pain and Mood Symptoms in Fibromyalgia and Major Depressive Disorder

One might expect that many treatments for MDD would also alleviate depressive symptoms in individuals with fibromyalgia. Conversely, therapies approved for fibromyalgia could be expected to relieve at least pain symptoms in patients with fibromyalgia comorbid with MDD. These assumptions are supported by numerous studies demonstrating that antidepressants such as duloxetine can reduce pain in individuals with MDD and improve depressive symptoms in those with comorbid major depression and fibromyalgia (Häuser et al. 2009). Non‐pharmacological interventions for fibromyalgia management have also been shown to alleviate depressive symptoms (Kundakci et al. 2022). However, therapeutic effects on pain and mood are not uniformly observed across all patients and appear to be influenced by distinct mechanisms and temporal patterns. For example, the pain‐relieving effects of duloxetine in fibromyalgia patients are not entirely dependent on mood improvement. Instead, most patients who experience pain relief from duloxetine benefit from a direct analgesic effect that is independent of changes in depressive symptoms (Marangell et al. 2011). Additionally, evidence suggests that pain relief from duloxetine may manifest more quickly than its antidepressant effects (Harada et al. 2016).

MDD therapy with rTMS targeting dlPFC improves mood symptoms and has an estimated effect size of up to −0.725 (Hedges' g) (Hsu et al. 2024). Few studies have explored the effects that this approach has on concomitant chronic pain. While initial studies reported the analgesic effect of rTMS prescribed for mood improvement in people with MDD and chronic pain (Che et al. 2021; Petelin et al. 2023), the available data do not provide information on whether pain was directly related to MDD, on whether pain was chronic, or on the types of pain syndromes that were assessed (Petelin et al. 2023). Recently, it has been acknowledged that the cooccurrence of chronic pain with MDD may be more relevant only for some specific pain syndromes (Zhou et al. 2024) and could even be a marker of lower propensity to respond to the antidepressive effects of rTMS for MDD (Corlier et al. 2023) (Figure 1).

FIGURE 1.

FIGURE 1

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Summary of the main findings of trials treating major depressive disorder, and fibromyalgia with repetititve transcranial magnetic stimulation.

Studies on the use of rTMS for fibromyalgia can provide further insights into the effects of pain therapy on different symptom clusters. Studies exploring rTMS in fibromyalgia using the strict stimulation protocols recommended for neuropathic pain (Attal et al. 2021) in patients without comorbid MDD have consistently shown positive results on pain relief. These were single (Baudic et al. 2013; Mhalla et al. 2011; Passard et al. 2007) and multicentre international trials (Silva et al. 2025). Induction sessions were delivered daily for 5 or 10 days, and maintenance sessions were performed weekly, fortnightly and monthly up to 25 weeks. In these studies, pain intensity was significantly reduced in the active compared with the sham arms, which was accompanied by varying degrees of fibromyalgia symptoms reduction (Silva et al. 2025), improvements in aspects of quality of life (Tekin et al. 2014) in pain interference with daily life and catastrophising scores (Mhalla et al. 2011). However, in none of these positive studies was rTMS ever effective in improving mood symptoms of fibromyalgia. This could be related to a lack of selective effect of M1 stimulation on brain networks relevant for mood modulation.

While dlPFC rTMS is effective for mood symptoms in people with MDD, studies targeting the dlPFC in people with fibromyalgia without associated MDD showed varying results (Bilir et al. 2021; Fitzgibbon et al. 2018; Tanwar et al. 2020). In one of the few head‐to‐head studies comparing M1, dlPFC and sham stimulation on people with fibromyalgia without comorbid MDD, neither target improved mood symptoms, while only M1 stimulation had significant analgesic effects compared with sham (Altas et al. 2019). Studies targeting the dlPFC in people with comorbid fibromyalgia and MDD showed contradictory results and have small sample sizes (Carretero et al. 2009; Short et al. 2011; Tiwari et al. 2024) (Figure 1). The negative effects of dlPFC rTMS for pain relief in fibromyalgia and other chronic pain syndromes may be because, for MDD therapy, the stimulation intensity is about 30% higher than that used in most chronic pain trials. Additionally, the number of therapeutic sessions (associated as a marker of response in rTMS) was systematically higher for MDD therapy (30 to 50) than for chronic pain studies (usually below 15 sessions) (Lefaucheur et al. 2020; McClintock et al. 2018).

The evidence reviewed above suggests that the effects of rTMS are dependent not only on the target of stimulation but also on the clinical outcome being assessed. It has been hypothesised that symptoms from neuropsychiatric diseases such as major depression, Parkinson's disease and dystonia would occur due to abnormal connectivity between brain areas secondary to abnormal neuronal oscillatory patterns (Buzsáki 2010; Buzsáki and Draguhn 2004; Caspers et al. 2021; Rajamani et al. 2024). It has been proposed that specific symptom clusters would depend on distinct abnormal oscillatory activity present on specific networks, and that therapeutic interventions such as medications or deep brain stimulation would have their effects dependent on the attenuation of such abnormal activity. In this framework, different patients with the same disease would have different clusters of symptoms depending on the networks affected by the disease‐related abnormal oscillatory activity (Fan et al. 2019; Li et al. 2018; Liu et al. 2021). And importantly, personalised therapeutic interventions would allow for targeting network‐specific abnormal oscillatory patterns (Filippi et al. 2021; Horn et al. 2017, 2019; De Micco et al. 2021). One could hypothesise that M1 stimulation would improve pain intensity and pain‐associated symptoms in people with fibromyalgia, but not mood symptoms, due to different connectivity abnormalities associated with each of these two symptom clusters. It has been suggested that within the motor homunculus in M1, there are areas highly connected to cognitive, interoceptive and pain control networks, that would constitute gateways connecting M1 with non‐motor networks that are important for allostasis and behaviour (Gordon et al. 2023). Indeed, during acute pain, probing M1 influenced phase‐based connectivity in the alpha‐band in parieto‐occipital areas, which correlated with an individual's sensitivity to pain, which was not present when the dlPFC was probed (De Martino, Casali, Casarotto, et al. 2024). It has also been shown that rTMS delivered to M1 exclusively affected M1‐based connectivity with amplitude and phase reset changes in beta frequency around the stimulation target, but had no effects on dlPFC‐dependent connectivity (De Martino, Casali, Nascimento Couto, et al. 2024). Taken together, the current evidence suggests that improvement after rTMS is not only target‐dependent but also symptom‐dependent, where improvements are not global and non‐specific, being rather centred around discrete symptom clusters. For example, one rTMS for MDD study showed that targeting dlPFC with different methodologies (using the EEG 10–20 system or the ‘5.5 cm anterior from M1 rule’) had equal antidepressive response but different effects on anxiety symptoms (Trapp et al. 2023). This implies that the assessment of the pre‐treatment ‘connectivity state’ of the potential rTMS target to be used in therapy (and its related symptom profiles) would be decisive in response to therapy and could guide treatment decision‐making. In these same lines, recent studies have suggested that specific symptom combinations such as severe mood symptoms at baseline can predict the efficacy of M1 rTMS in neuropathic pain (Attal et al. 2024), and that cortical excitability and alpha wave peak can predict persistent symptoms after long‐lasting experimental pain models (Chowdhury et al. 2025). Phase‐based connectivity state has also been shown to be feasible in guiding rTMS target choice for chronic pain therapy (De Martino et al. 2025). In fact, connectivity‐based targeting of the dlPFC has been proven to be effective for the management of MDD to personalise targeting to each individual patient (Cole et al. 2020).

In summary, the current data suggest that rTMS therapy does not lead to non‐specific improvements in symptoms. Instead, the effects depend on the cortical targets being aimed at and on the symptoms presented by patients. Pain relief does not grant mood improvement, and it has been hypothesised that targeting abnormal oscillatory networks would be key in obtaining symptom‐specific effects and more personalised treatments. Such an approach has already been proven to be efficacious in the field of psychiatry and could potentially benefit chronic pain patients.

Author Contributions

Daniel Ciampi de Andrade and Leandro Valiengo contributed equally to data retrieval, synthesis and manuscript writing.

Conflicts of Interest

The authors declare no conflicts of interest.

Ciampi de Andrade, D. , and Valiengo L.. 2025. “Differential Effects of Repetitive Transcranial Magnetic Stimulation on Mood and Pain Symptoms in People With Chronic Pain and Major Depressive Disorders—A Review.” European Journal of Pain 29, no. 7: e70077. 10.1002/ejp.70077.

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