Social pain: A systematic review on interventions

1. Introduction

There is growing recognition in the literature of the strong association between social pain, also referred to as social rejection pain, and the exacerbation of physical pain (Zhang, Zhang, & Kong, 2020; Fairhurst et al., 2012; Eisenberger, Lieberman, & Williams, 2003). Studies have indicated that social pain can potentiate physical pain, leading to heightened sensitivity and increased discomfort (Meyer, Williams, & Eisenberger, 2015; Hawkley & Cacioppo, 2010; Kross et al., 2011). Social pain is psychological pain or emotional distress caused by perceived harm or threat to social connections that results in social exclusion, rejection, or loss (Eisenberger, 2015). Building and maintaining close social connections is essential for human survival and has been recognized as a fundamental human drive (Baumeister & Leary, 1995). When these crucial social bonds are threatened, individuals may experience a range of negative emotions (Leary & Springer, 2001). This emotional state is consistently associated with heightened brain activity, particularly in the anterior cingulate cortex (ACC) (Rotge et al., 2014), but also in the insula, the inferior orbitofrontal cortex (OFC), and the middle frontal gyrus (MFG) (Cacioppo et al., 2013; Eisenberger, Lieberman, & Williams, 2003).

Positive and supportive social relationships play a crucial role in maintaining health and well-being, serving as a protective factor against the effects of social stress (Broadhead et al., 1983; Cohen & Wills, 1985). Research has consistently shown that social support has positive effects on the cardiovascular, endocrine, and immune systems (Uchino, Cacioppo, & Kiecolt-Glaser, 1996). On the other hand, experiences of social isolation, exclusion, or rejection can have profound negative consequences. Lack of social support and increased social isolation are associated with a higher risk of mortality, comparable to risk factors such as smoking, obesity, and high blood pressure (Uchino, 2006). The impact of rejection sensitivity may vary among different groups. For example, individuals suffering from borderline personality disorder show higher levels of rejection sensitivity compared to both healthy individuals and other clinical groups, such as those with social anxiety disorder (Bungert et al., 2015; Staebler et al., 2010). Prolonged social rejection is reported to increase the likelihood of psychosomatic and other psychosocial issues such as antisocial behaviors, depression, anxiety, feelings of alienation, and suicidal tendencies (Bungert et al., 2015; Staebler et al., 2010; Uchino, 2006; Jacobs et al., 2000).

The Passion of Jesus Christ highlights quintessential social pain prior to immense physical pain and death. At the Last Suppler, Luke 2:21 accounts that Jesus announced to His disciples that “And yet behold, the hand of the one who is to betray me is with me on the table.” Betrayal is a type of rejection that is often found at the heart of social pain. Jesus not only suffers rejection by Judas Iscariot, but also by his closest friends when they fall asleep in the Garden of Gethsemane. Additionally, Simon-Peter goes on to deny Jesus three times. The crowds, made up largely of Jesus’s own people (“His Tribe”) don’t call for his freedom but instead ask the Roman governor to release a convicted insurrectionist and murderer. Such social pain very well may have been traumatic and worsened Jesus’s physical pain. Interestingly, Jesus offers forgiveness during His crucifixion. Forgiveness is a powerful yet challenging potential solution to alleviate solution pain because it involves intense vulnerability.

Researchers have explored various strategies to mitigate the negative impacts of social pain, including non-pharmacological interventions, such as forgiveness and mindfulness, and pharmacological approaches (Henningsson et al., 2021; Smith, 2009; Toussaint et al., 2010). One pharmacological approach involves the use of oxytocin, a hormone implicated in human social bonding (Henningsson et al., 2021). Studies have shown that plasma oxytocin levels increase during sexual activity (Carmichael et al., 1987), and genetic variations in the oxytocin receptor gene (OXTR) have been linked to the quality of pair bonds (Walum et al., 2012). Research suggests that the impact of intranasal oxytocin on social cognition is influenced by individual differences, such as gender, as well as the social setting (Bartz et al., 2011; Di Simplicio & Harmer, 2016; Olff et al., 2013). Another drug, acetaminophen, typically used to treat physical pain, has also shown effects on social pain. Although the precise mechanisms by which acetaminophen affects physical pain are not entirely clear, it seems to influence central nervous system pathways that play a role in both physical and social pain (Smith, 2009; Toussaint et al., 2010). Research has demonstrated that acetaminophen diminishes individuals’ emotional responses to both social and physical pain experienced by others (Mischkowski, Crocker, & Way, 2016). This systematic review aims to explore some of the interventions that reduce social pain.

2. Methods

This systematic review was carried out following guidelines published in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 2020 (Page et al., 2021). We used Zenodo.org as an online repository (CC0 license) with the following DOI ( doi.org/10.5281/zenodo.14559893 ) for our Prisma checklist and flow diagram.

3. Results

3.1 Search results

The database yielded a total of 548 articles ( Figure 1), which included 139 from PubMed, 309 from CENTRAL, and 100 from the first 10 pages of Google Scholar. 62 studies were excluded as duplicates, and 461 were excluded during the title and abstract screening. Eleven studies were further excluded during the full-text review for reasons outlined in the flowchart. Ultimately, 14 studies, all of which were randomized controlled trials (RCTs), were included in this review ( Table 2).

Figure 1. PRISMA flow diagram.

An overview of the study selection process for this systematic review on the interventions for Social Pain.

Table 2. Results of Data Extraction.

Study	Participants	Experiment	Control	Outcome measure
Alvares, Hickie, and Guastella (2010)	74 healthy participants, 37 men, mean age of 21.91± 5.93 years	oxytocin (n = 35)	placebo (n = 39)	Fundamental Needs Questionnaire
Dewall et al. (2010)	62 healthy participants	1,000 mg daily of acetaminophen (n = 30)	placebo (n = 32)	Hurt Feelings Scale
Ghavidel-Parsa et al. (2021)	71 fibromyalgia patients	Duloxetine (n=44, mean age of 44.84±9.38 years)	Pregabalin (n=27, mean age of 46.63±7.77 years)	Illness Invalidation Inventory (III), Beck Depression Inventory-II (BDI-II)
Henningsson et al. (2021)	100 participants, 50 male, mean age of 23 ± 4 years	oxytocin (n=50)	placebo (n=50)	VAS scale
Hofman, Wieser, and van der Veen (2021)	72 healthy participants, 24 males, mean age of 21.78±3.57 years	1,000 mg daily of acetaminophen (n=33, 30.6% male, mean age of 20.1 years)	placebo (n=36, 36.1% male, mean age of 22.5 years)	Beck Depression Inventory (BDI-II)
Keng and Tan (2018)	118 participants with high borderline personality (BPD) traits, 36% male, mean age of 21.71± 2.70 years	brief mindfulness and loving-kindness meditation (LKM) (n=79)	no-instruction control (n=39)	5 -item VAS
Koban et al. (2017)	40 right-handed participants, 19 males, mean age of 20.8 years	placebo (n = 20)	control (n = 20)	5 -item VAS
Miller et al. (2014)	48 healthy participants, 16 males, mean age of 20.69 ± 2.17 years	25 g of glucose (n=24)	sucralose placebo (n=24)	5-point scale
Mohr, Kirsch, and Fotopoulou (2017)	93 healthy, right-handed students, 100% female, mean age of 23.13± 2.63 years	oxytocin	placebo	self-reported feelings of rejection
Petereit et al. (2019), Preller et al. (2016)	21 healthy volunteers, 12 males, mean age of 26.48 ± 4.76 years	psilocybin (0.215 mg/kg) (n=21)	placebo, maltose (n=21)	Positive and Negative Affect Schedule (PANAS)
Radke et al. (2020)	43 healthy participants, 100% female, mean age of 22.8 ± 3.1 years	oxytocin (n=22)	placebo (n=21)	self-reported feelings of rejection
Slavich et al. (2019)	42 healthy adults, mean age of 19.48± 1.27 years	1,000 mg of acetaminophen daily (n = 15)	placebo (n = 14) or control i.e. no-pills (n = 13)	Hurt Feelings Scale (HFS), Offense-Specific Forgiveness Measure (OSFM)
Stumpp et al. (2023)	74 participants, 51 females, mean age of 27.27± 11.64 years	placebo (n=38)	no-treatment (n = 36)	9-point Likert-type item
Zhang et al. (2021)	61 healthy participants	oxytocin (n=30)	placebo (n=31)	self-reported pleasantness

* Please note that Petereit et al. (2019) was a follow-up study to Preller et al. (2016). They both reported the same clinical trial.

3.2 Results of quality assessment

Most of the studies exhibited some concerns regarding study bias, with only three classified as having a high risk of bias, while four were considered to have a low risk of bias ( Figure 2). The domains of randomization and deviation from intended interventions were areas of concern. Overall, the studies demonstrated a low risk of bias with some concerns, indicating that they were of moderate to high quality ( Figure 3).

Figure 2. Risk of bias graph.

D1: Risk of bias arising from the randomization process, D2: Risk of bias due to deviations from the intended interventions (effect of assignment to intervention), D3: Missing outcome data, D4: Risk of bias in measurement of the outcome; D5: Risk of bias in selection of the reported result.

Figure 3. Risk of bias summary.

A depiction of the bias in the included studies.

4. Discussion

This systematic review included 14 RCTs with varying pharmacologic interventions, with the objective of determining which of them leads to a more effective/greater reduction in social pain. Given the complexity of pain management, understanding the relationship between social pain and physical pain has important implications for clinical practice (Ryans et al., 2024). Healthcare professionals should consider the psychosocial aspects of pain management and incorporate interventions targeting social support and coping strategies into treatment plans for individuals experiencing chronic pain (Brooks et al., 2023). By addressing both the emotional distress associated with social pain and the physical discomfort of chronic pain, clinicians can provide more holistic care and improve overall well-being for their patients (Brooks et al., 2023). Additionally, interventions aimed at reducing social stressors and fostering supportive social environments may help mitigate the impact of social pain on physical health outcomes, ultimately leading to better treatment outcomes and enhanced quality of life for individuals dealing with both social and physical pain (Williams, 2007).

A systematic review with meta-analysis examining the experiences of children and adolescents have shown that early exposure to social rejection and peer victimization can significantly impact health outcomes later in life (Moore et al., 2017). Psychosocial factors play a significant role in mediating the relationship between social and physical pain. Feelings of loneliness, social isolation, and perceived lack of social support have been associated with increased vulnerability to both social and physical pain (Kross et al., 2011). Chronic exposure to social stressors, such as bullying or interpersonal conflict, can exacerbate physical pain conditions over time, highlighting the detrimental impact of prolonged social pain on physical well-being (Hawkley & Cacioppo, 2010). Studies have shown that experiencing social rejection triggers the activation of the body’s stress response system, leading to the release of stress hormones such as cortisol and adrenaline (MacDonald & Leary, 2005; Rosen et al., 2012; Fairhurst et al., 2012; Chen et al., 2008). These hormones not only modulate emotional responses to social pain but also influence pain perception and sensitivity to physical stimuli (Zhang, Zhang, & Kong, 2020; Eisenberger, 2015; Kross et al., 2011).

Acetaminophen, both deceptive and open-label placebos, mindfulness training, and psilocybin were found to reduce social pain. However, oxytocin, fibromyalgia drugs (duloxetine and pregabalin), and glucose were reported to have no impact. Understanding the mechanisms behind these outcomes, particularly how the pain relievers were able to reduce social pain, is crucial. The ability of acetaminophen to alleviate social distress is supported by a growing body of literature indicating that certain brain regions are involved in both social and physical pain (Eisenberger & Lieberman, 2004; Panksepp, 2005). Neuroimaging studies focusing on the emotional or distressing aspects of physical pain often investigate brain regions such as the dorsal anterior cingulate cortex (dACC) and anterior insula (Apkarian et al., 2005; Peyron, Laurent, & García-Larrea, 2000). Individuals with damage to these brain regions often report a lack of distress from physical pain, despite still being able to feel it (Berthier, Starkstein, & Leiguarda, 1988). Furthermore, research has shown that these same neural regions are involved in processing experiences of social rejection or loss in humans (Eisenberger, Lieberman, & Williams, 2003; O’Connor et al., 2008). Given this overlap in neural systems, it is reasonable to assume that factors reducing physical pain would also affect social pain. Studies using acetaminophen, also known as paracetamol, a well-known painkiller, have demonstrated this effect (Dewall et al., 2010). While the specific mechanisms by which acetaminophen relieves pain are not fully understood, it is generally accepted that acetaminophen acts on the central nervous system rather than the peripheral nervous system (Anderson, 2008; Smith, 2009). Therefore, acetaminophen may reduce the perception of social pain by reducing neural activity in brain regions involved in both physical and social pain processing, such as the dorsal anterior cingulate cortex (dACC) and the anterior insula.

Hofman, Wieser, and van der Veen (2021) conducted a novel experiment using a social judgment paradigm (SJP) to investigate the effects of acetaminophen on social pain. Participants were either unexpectedly accepted or rejected 15 minutes after taking a single dose of acetaminophen. This approach differed from Dewall et al. (2010), who used a cyberball paradigm and administered acetaminophen over three weeks. Over time, the placebo group reported decreasing expectations of acceptance, indicating learning from negative feedback. In contrast, the acetaminophen group consistently reported similar levels of acceptance. This unexpected impact of acetaminophen on predictive behavior suggests its potential role in altering perceptions of social pain. The results imply that when individuals consume acetaminophen, the typical learning effect related to social pain may disappear, indicating a reduced perception of pain following acetaminophen ingestion.

The study conducted by Slavich et al. (2019) examined how daily forgiveness, when combined with a daily dose of acetaminophen, influenced the level of social pain experienced the following day. The study found that while acetaminophen alone reduced feelings of social pain, those who reported higher levels of forgiveness experienced even greater reductions in social pain. This suggests a new perspective on the impact of acetaminophen in reducing social pain, indicating that a daily combination of acetaminophen and forgiveness is more effective than acetaminophen alone. Importantly, the effectiveness of acetaminophen was still evident, as participants in the placebo group who reported high levels of forgiveness did not experience similar reductions in social pain. These results align with previous research suggesting that both forgiveness and acetaminophen independently reduce the experience of social pain resulting from negative interpersonal interactions (Akhtar and Barlow, 2016; Dewall et al., 2010). However, this study goes further to demonstrate that the combination of acetaminophen and forgiveness is more effective than either intervention alone.

It has been suggested that the effects of oxytocin (OT) depend heavily on the context (Declerck et al., 2010). For example, research indicates that OT’s impact on cooperative behavior is only significant when there has been prior social contact (Alvares, Hickie, & Guastella, 2010). In situations where the interaction partner is anonymous, OT does not seem to have an effect (Declerck et al., 2010). Ostracism, as a form of social rejection, is a clear and overt social stressor that lacks ambiguity or positive social cues. In Alvares, Hickie, and Guastella (2010), participants engaged in a computer-based task in a laboratory setting where no rewards, social interactions other than with the experimenter, or social encouragement were available to those who were ostracized. In situations where there is a lack of social information or where a social approach is unlikely to lead to a positive outcome, oxytocin does not appear to influence behavior or emotions.

Placebos are therapeutic interventions that, based on the underlying therapeutic theory, are not intended to have any effect on the treated condition (Grünbaum, 1986). Open-label placebo pills have been found to alleviate symptoms in conditions such as migraine attacks (Kam-Hansen et al. 2014), irritable bowel syndrome (IBS) (Kaptchuk et al., 2010), cancer-related fatigue (Hoenemeyer et al. 2018), and allergic rhinitis (Schaefer, Harke, & Denke, 2016). Moreover, placebos have been shown to effectively reduce physical pain. Therefore, Koban et al. (2017) and Stumpp et al. (2023) sought to investigate whether placebo pills could also alleviate social pain. Koban et al. (2017) used deceptive placebos, while Stumpp et al. (2023) used open-label placebos, meaning that participants were clearly informed that they were receiving a placebo. Both studies reported positive outcomes, specifically a reduction in social pain. The effects of the placebo can be explained through three proposed mechanisms: pharmacological memory, the influence of a treatment rationale, and “embodied” consciousness (Colloca & Howick, 2018; Kaptchuk, 2018; Locher et al., 2017). Pharmacological memory suggests that taking any pill, even if known to be a placebo, triggers associations with taking an active drug, leading to a conditioned response (Colloca & Howick, 2018). The treatment rationale, provided by the experimenter in a friendly and trustworthy manner, can enhance placebo effects by boosting positive expectations (Locher et al., 2017; Gaab et al., 2019). Embodied cognition theory posits that physical interactions with the world affect cognitions (Borghi & Caruana, 2015), and placebo effects may arise from bodily sensations shaping pain perceptions and triggering the production of pain-relieving substances (Colloca & Howick, 2018; Kaptchuk, 2018; Schienle, Unger, & Schwab, 2022). These mechanisms are likely interconnected, with placebo effects depending on the combined influence of all three (Colloca & Howick, 2018).

The findings of Keng and Tan (2018) suggest that brief mindfulness training accelerates emotional recovery from negative feelings following social rejection, in comparison to a control condition. This is consistent with previous research indicating that brief mindfulness training can alleviate dysphoric mood and negative affect in response to adverse stimuli (Arch & Craske, 2006; Broderick, 2005; Sauer & Baer, 2012). Keng and Tan (2018) also suggest that mindfulness practice can help moderate emotional responses to social rejection, a stressor that individuals with BPD are particularly sensitive to. Individuals with BPD often engage in avoidance behaviors or excessive rumination on negative thoughts and emotions (Selby et al., 2009). Mindfulness training was found to assist these individuals in disengaging from avoidance or rumination, enabling them to approach difficult emotions with mindfulness and without judgment, potentially leading to more effective emotion regulation.

The idea that consuming glucose could reduce social pain by enhancing motivation, persistence, and executive control through dopaminergic activity, specifically D1 receptor activation, as suggested by Granon et al. (2000), Touzani, Bodnar, and Sclafani (2010), and Williams (2009), was not supported by Miller et al. (2014). According to their findings, glucose’s rewarding effects rely on D1, not D2, receptor activation in the prefrontal cortex, and D1 agonists can improve executive function. This implies that if D2 activation is necessary to alleviate social pain, glucose may not be effective (Touzani, Bodnar, & Sclafani, 2010). The lack of social pain relief through D1 activation is consistent with other studies that have explored similar interventions.

Petereit et al. (2019) found that psilocybin administration led to a decrease in activity in the dorsal anterior cingulate cortex (dACC), which did not correspond to a reduction in feelings of social exclusion. This reduced neural response in the dACC was notably associated with changes in self-awareness induced by psilocybin and a decrease in aspartate (Asp) levels. In summary, the stimulation of 5-HT2A/1A receptors with psilocybin appears to reduce the processing of social pain, aligning with changes in self-perception (Carhart-Harris et al., 2014).

5. Conclusions

Acetaminophen, both deceptive and open-label placebos, mindfulness training, and psilocybin were found to reduce social pain (Dewall et al., 2010; Hofman, Wieser, & van der Veen, 2021; Keng & Tan, 2018; Koban et al., 2017; Petereit et al., 2019; Preller et al., 2016; Slavich et al., 2019; Stumpp et al., 2023). In contrast to interventions that leverage the neural connection between physical and social pain, mindfulness training focused on developing conscious emotional responses to social exclusion. Additionally, a combination of acetaminophen and forgiveness yielded superior results compared to either acetaminophen or forgiveness alone (Slavich et al., 2019). However, interventions such as oxytocin, duloxetine, pregabalin, and glucose did not show an impact on social pain (Alvares, Hickie, & Guastella, 2010; Ghavidel-Parsa et al., 2021; Henningsson et al., 2021; Miller et al., 2014; Mohr, Kirsch, & Fotopoulou, 2017; Radke et al., 2020; Zhang et al., 2021).

Ethics and consent

Ethics and consent were not required.