A Theoretical Endogenous Opioid Neurobiological Framework for Co-occurring Pain, Trauma, and Non-suicidal Self-injury

Abstract

Purpose of Review

Individuals with chronic pain are significantly more likely to have experienced overwhelming trauma early and often in key developmental years. There is increasing acknowledgment that childhood trauma disrupts how individuals process and cope with both physical and emotional pain. Emerging studies acknowledge elevated rates of non-suicidal self-injury (NSSI) in chronic pain populations. This review provides a theoretical framework to understand the relationship between NSSI behavior and pain experience in persons with chronic pain and childhood trauma histories. We discuss how NSSI may act to regulate neurobiological (e.g., endogenous opioid systems) and psychological (e.g., heightened negative affect and emotion dysregulation) systems affected by childhood trauma, leading to temporary pain relief and a cycle of negative reinforcement perpetuating NSSI. As these concepts are greatly understudied in pain populations, this review focuses on key areas relevant to chronic pain that may provide a testable, conceptual framework to support hypothesis generation, future empirical investigation, and intervention efforts.

Recent Findings

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Summary

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Introduction

Individuals with chronic pain are significantly more likely to have experienced overwhelming trauma early and often in key developmental years [1–3, 4•, 5•, 6•, 7–10]. Persons exposed to trauma and abuse are approximately three times more likely to develop chronic pain conditions as adults [11]. The co-occurrence of chronic pain and trauma exposure has been associated with increased pain intensity, hyperalgesia, and alterations to neurobiological systems that play a role in physiological self-regulation [3, 4•, 7, 8, 12••]. This comorbidity is also associated with significant affective distress and emotional suffering. Explanatory models propose deficits in emotion regulation as a key factor maintaining the trauma-pain relationship, where emotional distress such as anger or posttraumatic stress symptoms can mediate how a person experiences and copes with pain [5•, 7, 13]. Studies indicate that exposure to earlier and more overwhelming (e.g., childhood and accumulative) trauma leads to even greater deficits in self-regulation ability [14–16]. Such deficits can give rise to maladaptive coping behaviors such as a proclivity for self-harm or non-suicidal self-injury (NSSI) [17–22, 23••, 24–26].

NSSI can be defined as purposeful damage to one’s own body without the intent to die [27]. NSSI is conceptualized as a behavioral strategy used to obtain a number of outcomes, including affect modulation or communication of distress to others [28••]. Acts of NSSI can include self-inflicted cutting, burning, and head-banging. NSSI significantly increases the risk of a future suicide attempt [29]. NSSI is distinct from suicidal self-injurious behavior where the intent to die is present [27, 23••, 34, 35••, 5•]. (For more comprehensive information on NSSI in chronic pain, see [30••].

Studies to date report sobering rates of NSSI among persons with chronic pain, which are reported as at least double that of the general population. Emerging research suggests self-harm rates may be even higher among certain pain conditions such as fibromyalgia (25%; [31]) and in adolescents with persistent pain (30%; [32]). Our recent review focusing specifically on persons with chronic pain suggested 20–50% engage in self-harm behavior and that childhood trauma predicts elevated rates of self-harm among individuals with chronic pain [30••]. In this prior review, one study was identified that explicitly differentiated NSSI from suicidal self-harm, finding that 18.8% of chronic pain patients engaged in NSSI, and that the presence of NSSI was associated with the experience of trauma in childhood [33].

Recent studies have explored various aspects of the relations among trauma, posttraumatic sequelae, chronic (and acute) pain, and NSSI, hypothesizing various links among at least subsets of these clinical phenomena (for recent relevant reviews: [5•, 23••, 34, 35••]). However, no empirically supported, explanatory model exists that articulates the specific associations among these constructs in tandem. Building on the literature identified in our recent systematic review [30••], we posit a conceptual integration of pain experience, trauma, and self-harm in individuals with chronic pain. We aim to provide a theoretical, neurobiological framework for the function that NSSI may serve for people with chronic pain who also have histories of early trauma exposure, including how NSSI may act upon regulatory systems disrupted by early adversity and implicated in chronic pain.

The Role of Trauma in Self-regulation

Early psychological trauma disrupts numerous core domains of self-regulation, both at the neurobiological and psychological levels. Regarding neurobiological disruption, early exposure to trauma is associated with long-term alterations to the stress response via inhibited hypothalamic-pituitary-adrenocortical axis (HPA) functioning and increased basal cortisol levels [36]. Although (minor) acute stress may evoke temporary analgesia [37•], chronic trauma exposure may alter the body’s natural ability to respond to pain through reductions in the release of endogenous opioids (detailed further below). Psychologically, exposure to early trauma can also increase the likelihood of dissociation in response to stress, increase situational anxiety, and contribute to chronic emotional dysregulation [12••, 38–42]. Further, psychological disorders such as major depressive disorder and posttraumatic stress can emerge over time. These factors cumulatively influence how a person may respond to the experience of pain.

In addition, experimental research suggests that individuals with trauma histories have heightened sensitivity to pain. In studies examining responses to standardized evoked pain stimuli, trauma exposure has been directly linked to indicators of hyperalgesia, such as reduced pain thresholds, heightened temporal summation, and increased pain sensitivity (e.g., [25, 43–45]). This suggests that trauma exposure may alter nociceptive processing broadly, intensifying acute pain responsiveness and increasing vulnerability to the development of chronic pain. Furthermore, psychological trauma appears to be associated with a hypersensitivity to pain that often is generalized throughout the body [6•, 7], likely via centrally mediated increases in pain transmission (i.e., central sensitization) [46]. Thus, while individuals with chronic pain may normally experience hyperalgesia in parts of the body associated with their pain condition, those with psychological trauma experience widespread pain sensitivity throughout the body [6•, 7, 47]. Sensitivity to pain stimuli is in part mediated by a person’s affective and coping responses. Trauma exposure is associated with increased pain catastrophizing, depression, and posttraumatic stress symptoms, all of which are known mediating factors increasing a person’s perception of pain [7, 48–51]. Hence, trauma appears to lead to altered sensory processing of pain stimuli, affect dysregulation, and ineffective coping, all of which increase a person’s responsiveness to pain and contribute to difficulty with self-regulation.

Common neurobiological mediators may underlie both the chronic physical and emotional pain endorsed by victims of early childhood trauma. Although early trauma may exacerbate physical and psychological pain in distinct ways (“multifinality”), a growing body of neuroanatomical evidence suggests that the underlying networks that give rise to physical pain and psychological pain overlap substantially (e.g., within insular, cingulate, and secondary somatosensory cortices) [28••, 35••, 52–54]. There is also evidence that emotional distress and physical pain exacerbate each other through a process of “mutual maintenance” [55, 56], suggesting that attempts to self-regulate, such as through NSSI, may both be multiply determined (i.e., driven by either physical or emotional pain) and may have multiple benefits (i.e., providing relief from either form of pain). However, the underlying functional mechanisms of NSSI or other means of self-regulation remain less clearly understood.

The Role of the Endogenous Opioid System in Pain Regulation

One candidate neurobiological system that likely contributes to posttraumatic hyperalgesia is the endogenous opioid (EO) system. EOs are naturally produced neuropeptides (e.g., β-endorphin and met-enkephalin) that bind to opioid receptors and produce analgesia and diminished negative affect similar to administration of exogenous opioid medications [57–59]. Exposure to acute stress typically leads to analgesia, a phenomenon known as stress-induced analgesia [60••]. Studies indicate that stress-induced analgesia in humans can be blocked by administration of opioid receptor antagonists (e.g., naltrexone), indicating that EOs contribute to stress adaptation and stress-induced analgesia [37•, 61–64]. Animal models further suggest that trauma reminders or cues [43] and contextual factors associated with stressful experiences (e.g., locations and harmless cues associated with the stressor) both may evoke EO-mediated analgesia similar to that observed with actual stressor exposure [42, 65, 66]. EOs may serve to reduce the emotional activation associated with stress and trauma [42, 67], thereby functioning as an emotional-regulatory mechanism by which the body adapts to trauma.

Such a response may be adaptive when faced with acute stress or pain. However, when stressful experiences are overwhelming or chronic, as in the case of sexual and physical trauma and neglect, chronic physiological and neurobiological overactivation occurs. In this case, the body’s natural activation of stress responses systems such as the HPA axis [36, 68, 69] and the EO system becomes impaired. Specifically, due to overactivation of the EO system, trauma appears to produce chronically reduced levels of EOs in the body [42, 70–77]. Although much of this human literature is cross-sectional, an experimental manipulation of trauma among rats has found evidence of reduced basal enkephalin in striatal regions in response to maternal separation [77] though see also Ploj et al. [78], consistent with the hypothesis that overwhelming or chronic stress in humans leads to low levels of endogenous opiates in the brain. In addition, trauma may disrupt the body’s ability to naturally respond to stress with analgesia, disrupting activity of various neurobiological regions [42] implicated in stress-induced analgesia (e.g., anterior cingulate cortex; [79]), leaving the individual more vulnerable to heightened negative affect in the context of stress and pain. This stress state may demand novel attempts to self-regulate, as parallel lines of evidence suggest that individuals with low EO activity Bruehl et al. [80–82] and with a childhood trauma history [71] both show greater analgesic and positive subjective responses (e.g., greater drug liking and desire to take the drug again) to administration of exogenous opiates such as morphine. Taken together, findings suggest the possibility that hypersensitivity to the effects of opioid analgesic administration among individuals who have experienced childhood trauma may be due in part to low EO system function.

The EO system may also contribute to the affective and behavioral dysregulation subsequent to childhood trauma, such as mood alterations and dissociation in posttraumatic stress disorder (PTSD). A recent review highlights the role of EOs in mediating affective dysregulation and dissociation in PTSD among trauma victims [12••]. This review suggests that during a dissociative stress response, the EO system releases κ-opioids, which both modulate emotions in response to stress and produce analgesia. One comparative study with rats found that only “PTSD-phenotype” rats (i.e., those with an elevated acoustic startle to predator-scent stress) displayed lower levels of EOs in hippocampal regions compared to either control (non-traumatized rats) or rats with minimal behavioral response to the stressor (i.e., “non-PTSD-phenotype” rats) [83]. Although not trauma-specific, evidence in humans indicates that an expressive style of anger regulation (i.e., individuals who tend to “blow up” when angry), often a feature of PTSD, is linked to reduced EO activity [13, 84–86]. It is notable however that despite low basal EO activity in these “high anger-out” individuals, they do appear to elicit effective EO analgesia under specific anger-triggering conditions [13].

Taken together, the work described above suggests that chronic pain patients with a childhood trauma history may exhibit deficient pain inhibition and impaired regulation of negative emotions that both are related to reduced EO inhibitory function. As a result, we hypothesize that they may resort to additional or external means by which to regulate distressing and painful experiences.

Non-suicidal Self-injury as Self-regulation

A large body of work has explored the emotion regulating function of NSSI. Although a number of reasons for NSSI have been put forth, which have been categorized along dimensions of interpersonal vs intrapersonal purposes and positive vs negative reinforcement [87, 88], individuals tend to overwhelmingly endorse negatively reinforcing intrapersonal motivations for NSSI behavior (e.g., to reduce negative emotions) [89–93]. In other words, NSSI functions to alleviate acute negative affective states, and may do so through various means, such as via redirection of attention [4•] or by causing dissociation [94, 95]. Consistent evidence exists that NSSI is also associated with attenuated acute physical pain. Many of those who self-harm report little to no pain while harming themselves, which has been corroborated by numerous experimental studies finding that individuals who self-harm exhibit lower pain intensity and higher pain threshold and tolerance when exposed to evoked pain stimuli than those who do not self-harm or who have stopped self-harm [28••, 34, 35••, 96–98, 99•].

There is emerging evidence that acute relief from physical pain or pain numbing during NSSI is mediated by EO function, similar to stress-induced analgesia, which results in acute relief from physical and emotional pain. Several studies have found reduced basal EO levels among individuals who engage in NSSI [99•, 100]. Further, “homeo-Stasis” models have posited that NSSI serves, in part, to upregulate the EO system particularly in the context of stress [28••, 100, 101]. These models are consistent with findings that NSSI can be reduced through administration of drugs that block EO activity [102], consistent with what would be expected if EO release was maintaining NSSI via negative reinforcement processes (see below). To our knowledge, only one study has explored the temporal sequence of EO activity and NSSI. Störkel et al. [93] measured salivary β-endorphin levels across 15 days among women with a history of NSSI, finding that momentary levels of β-endorphins within the roughly 10 min prior to NSSI were lower than β-endorphin levels for the 30 min after NSSI. Although correspondence between salivary β-endorphin levels and central EO function is unknown, these findings suggest that NSSI may directly contribute to increased EO levels. Importantly, basal β-endorphin levels were lower than usual on days in which participants engaged in NSSI (prior to self-harm), suggesting that NSSI was engaged in response to deficient EO activity, consistent with the homeostasis model of NSSI [100]. Indeed, NSSI appears to be unique from other types of self-harm (e.g., suicide attempts) in its association with low basal EO [100]. By stimulating EO responses, NSSI would thus provide acute relief from both physical and mental pain [103]. In addition, we posit that individuals with chronic pain and co-occurring childhood trauma may be at particularly high risk for short-term regulatory behaviors such as self-harm, given both deficits in EOs and a lack of sufficient adaptive emotion regulation skills, both of which are notable outcomes of childhood trauma.

The Reinforcing Cycle of Temporary, NSSI-Induced Relief

An operant reinforcement framework helps to understand how NSSI may be maintained over time. Individuals who engage in NSSI report this behavior being prompted by acute negative emotional states [100, 104], which has been corroborated by a number of studies using ecological momentary assessment of individuals who self-harm [105]. The relief from distress and negative feelings produced by NSSI (likely mediated in part by triggering of EO release) provides a powerful negative reinforcer of the behavior, as has been articulated in behavioral models of NSSI (e.g., [106]). In addition, multiple studies suggest that reduced positive affect may precipitate NSSI [105], and NSSI may also serve, then, to increase positive affect (which may also be mediated in part by EO function; [103]). Evidence also finds that more rapid reductions in pain produce greater experience of relief compared to slower reductions in pain (e.g., waiting for a flare up of a chronic pain condition to subside) even if the reduction is the same in degree [107].

While NSSI may induce short-term analgesia, longer-term, it may exacerbate chronic pain itself, as repeated intradermal injury or pain induction may elicit central nociceptive sensitization [46]. Some have also argued that opiate administration that exceeds that which is needed to appropriately alleviate pain may have the effect of shifting the normal benefit produced by opiates and simultaneously heighten the triggering experiences of physical and emotional pain [108]. Theoretically, self-harm may function similarly in the brain, suddenly flooding it with endogenous opioids (particularly in a brain with hypersensitized opioid receptors due to childhood trauma [71]), providing brief, immediate relief, but long-term pain and hypersensitization to pain. NSSI also has distal effects of increasing negative affect (particularly guilt and shame [109, 110]). The emotional sequelae of self-harm also likely increases the experience of chronic pain [7, 48, 50, 51], leading to states in which self-harm or other (maladaptive) affect regulating strategies that operate via opioid function (e.g., opiate abuse; for a thorough review, see [111]) are more likely.

To summarize, the relief produced by NSSI likely reinforces subsequent use of this strategy over others, despite longer-term physical, emotional, and social costs associated with self-harm. At the same time, individuals who self-harm, and particularly those with a history of trauma, may have fewer barriers (e.g., a stable self-image [112]) that normally inhibit NSSI use [28••]. Hence, we suggest that a cycle unfolds such that:

1. Childhood trauma confers chronic risk for both chronic pain and coping via NSSI due to:

   1. Deficient basal EO function, and
   2. Increased chronic negative affect and poor emotion regulation skills;

2. Childhood trauma is linked to fewer natural barriers to engaging in NSSI, such as positive self-esteem and social support;

3. NSSI proximally produces acute, rapid relief from stress, negative affect, and chronic pain symptoms;

4. Repeated NSSI distally produces both long-term nociceptive sensitization and increased negative affect;

5. NSSI becomes a preferred and repeated strategy to produce acute relief from moments of high stress, negative affect, or chronic pain symptoms via reinforcement mechanisms (Fig. 1).

Fig. 1.

Chronic-pain-maintaining reinforcement cycle of non-suicidal self-injury among individuals with childhood trauma

This cycle explains the attenuated acute pain (e.g., experimentally induced) endorsed by individuals who engage in NSSI (i.e., through acute relief via EO release) [34, 96, 113–115] and the simultaneous increased prevalence of chronic pain conditions among the same individuals (i.e., negative reinforcement loop associated with NSSI use), a phenomenon referred to as “the pain paradox” [116, 117]. In addition, this cycle is consistent with evidence that chronic pain itself does not chronically stimulate the EO system (thus chronic pain is not self-attenuating) but acute pain does [107]. Finally, this reinforcement cycle also explains findings that only chronic and ongoing self-harm evokes acute analgesia, as evidence suggests that among those who discontinue self-harm behavior, pain tolerance/sensitivity appears to normalize [98, 118, 119].

Clinical Implications and Recommendations

Our review suggests a number of ways in which clinical care can be enhanced for chronic pain patients. As we have argued elsewhere (e.g., [7, 30••]), providers treating chronic pain should assess not only for adult physical trauma (which is often routine in chronic pain evaluation) but also for childhood trauma of various types (e.g., sexual abuse and emotional neglect). We encourage providers to interview for both trauma exposure and, when present, trauma-related symptoms (e.g., hyperarousal to trauma-related cues and avoidance of certain people or situations). In addition, particularly among patients who display poor coping or heightened emotional dysregulation, or those who display evidence of self-harm (e.g., forearm scars or burn marks and damaged skin around extremities), clinicians ought to carefully inquire of patients whether they have previously or are currently experiencing urges to harm themselves in any way. Such line of inquiry can be intertwined with standardized risk assessment, such as when assessing for suicidal ideation or intent. Self-harm behaviors remain highly stigmatized among both the wider community and within the healthcare system itself [120], requiring clinicians to take a gentle but straightforward approach to assessing for such behaviors as well as a demeanor of caring curiosity—rather than criticism or panic—when patients endorse self-injurious urges or behaviors.

When NSSI is present, conveying an understanding of the potential function (e.g., emotional relief) as well as the stigma surrounding the behavior is important and can be validating for patients. At the same time, psychoeducation may also be provided to patients regarding the impact NSSI may have on heightening both negative affect and long-term pain, despite the acute relief it may bring. Most importantly, appropriate resources to address NSSI directly, including the risk for suicide it confers, are warranted. Although, to date, no comprehensive empirically supported treatment exists for NSSI among patients with chronic pain, treatments that integrate concepts for working with chronic pain in the context of childhood trauma (e.g., Emotional Awareness and Expression Therapy [121, 122]) with those tailored to NSSI and emotion dysregulation (e.g., dialectical behavior therapy; [123]) may be particularly helpful as either primary or adjunctive treatments for chronic pain patients who have experienced childhood trauma and who engage in—or endorse risk for—NSSI.

In addition, our review provides implications for pharmaceutical care of patients with chronic pain. Although opiate abuse is outside of the scope of this review, our review suggests that chronic pain patients with a history of trauma may experience greater analgesia with and desire for opiate medications. This may prompt both overreliance on opiates and a risk for opiate abuse in this group, which itself is linked with increased suicide risk [108, 124]. Opiate abuse may, like NSSI, interfere with adaptive coping strategies and may exacerbate chronic pain in the long-term.

On the other hand, if the EO system is central to repetitive self-injury, then treatment with a long-acting opioid antagonist could block the reward associated with EO release triggered by such behaviors and subsequently lead to their extinction [52, 102]. Indeed, a number of studies have found that naloxone or naltrexone is useful in diminishing NSSI [102]. Additionally, examining the efficacy of buprenorphine, a partial μ-opioid agonist/κ- and δ-opioid antagonist, for NSSI may be a promising avenue of research [100, 125–127].

Avenues for Future Research

Although growing research implicates the EO system in the relations among childhood trauma, chronic pain, and NSSI, there remain a number of avenues for further research. We posit causal links among these phenomena, yet the direction of effects between EO system disruption and trauma remains unclear [23••]. For instance, though evidence appears to suggest EO system disruption subsequent to trauma, no research has explored whether or not prior EO dysregulation puts one at risk for trauma itself or posttraumatic sequelae. For instance, [128] found that posttraumatic pain after motor vehicle accident was influenced by a μ-opioid receptor gene polymorphism, though the effect of genotype was moderated by both gender and peritraumatic distress, suggesting a complex interaction between preexisting genetic liability and the psychological experience of trauma on pain outcomes. In the same vein, it is possible that repeated NSSI causes—rather than results from [93]—low basal levels of EO [98, 129], or perhaps a reciprocal relationship unfolds between EO and NSSI overtime. Clearly, future longitudinal research is needed to corroborate the direction of effects posited in our theoretical framework.

There is also a need to explore the potentially diverging developmental and functional trajectories of NSSI among men and women with co-occurring trauma and chronic pain. Several key experimental studies cited in our review either only recruited women [43, 97] or only found significant evidence of the regulating function of NSSI among women [95], leaving largely unknown how overarching patterns among these phenomena may manifest differently based on gender. Men and women not only utilize NSSI at different rates but the form of NSSI they select differs [130]; it is possible that different types of NSSI (e.g., cutting vs burning) may be more or less likely based on sex-moderated differences in endogenous opioid release and/or dissociative response (e.g., [34, 128]). Gender differences in NSSI and chronic pain may also be associated, in part, with gender differences in abuse rates and/or types of abuse [131]. Additionally, which specific type(s) of childhood trauma may confer the most risk for pain-related outcomes remains unclear [5•, 11].

There are also methodological limitations surrounding assessment of EO that limit the extant research. For instance, a number of studies have used gross EO measures that do not capture opioid receptor sensitivity (e.g., salivary, plasma, or cerebrospinal fluid assay; e.g., [93, 100]), while only some have used placebo-controlled opioid blockade (e.g., [103]). The latter, alongside positron emission tomography (PET) scan with radio-labelled opioid ligands, are more nuanced and appropriate ways to capture EO system function.

Although our review focuses on NSSI, NSSI is likely not the only form of opiate regulating behavior utilized by individuals with chronic pain. For instance, other psychological mechanisms (e.g., dissociation [12••]; anger expression [80]) as well as behavioral mechanisms (e.g., opiate abuse; [132]) may also serve to upregulate low basal EO levels via acute opiate activity and may function similarly to NSSI as a self-regulation strategy.

Conclusion

Our review supports a theoretical, neurobiological framework in which childhood trauma elicits risk for chronic pain and promotes non-suicidal self-injury as a self-regulating strategy to deal with acute emotional and physical distress. We argue that endogenous opioid dysfunction is a primary mechanism linking childhood trauma, chronic pain manifestation, and NSSI. We suggest that future research explore various components of this model, and we provide specific recommendations for practitioners, including assessing childhood trauma and PTSD, as well as self-harm behaviors, and providing appropriate referrals for specialized treatment for patients who display concurrent chronic pain, childhood trauma, and self-injury.