Chronic pain can greatly affect a patient's daily functioning and significantly impact health-related quality of life (Pain 2005;119:1-4). Undertreated or untreated chronic pain in children can be especially burdensome to families by disrupting routines, restricting the child's daily activities, and increasing risk of long-term disability (Paediatr Drugs 2002;4:737-46). Therefore, it is not unusual for chronic pain to be highly comorbid with psychiatric disorders. This association is mediated by significant overlap in biological pathways.

First, central and peripheral noradrenergic (NA) and serotoninergic (5-HT) pathways are affected in both pain and mood disorders (Prog Neuropsychopharmacol Biol Psychiatry 2018;87B:290-7; J Psychiatry Neurosci 2001;26:21-9). A pathway involving serotonergic neurons in the dorsal raphe nucleus has been implicated in chronic pain as well as depression (Nat Neurosci 2019;22:1612-4). Both NA and 5-HT brainstem-spinal descending systems suppress nociceptive signals from afferent neurons, and the activation of spinal NA and 5-HT receptors has antinociceptive effects. Second, glutamate signaling, particularly signaling through AMPA receptors, plays a key role in regulating pain, depression, and depression in the context of chronic pain (Neural Plast 2015;2015:504691). In addition to NA, 5HT, and glutamate, endocannabinoid signaling plays important roles in regulating both depression and pain. Pain-induced depression may also have unique physiologic and molecular mechanisms, possibly related to endocannabinoid signaling via the CB2 receptor (Pain 2009;143:206-12). Additionally, neuroplasticity and neuroinflammation are seen in both depression and chronic pain, and the central nervous system undergoes long-term plastic changes associated with chronic pain and depression (Neural Plast 2015;2015:504691). Brain-derived neurotrophic factor, a biomarker of depression (Curr Pharm Des 2017;23:3154-63), is elevated in patients suffering from chronic pain (Neurosci Lett 2019;706:105-9). The same can be said about inflammatory factors like interleukin-6 and C-reactive protein, which are elevated in both depression (Transl Psychiatry 2019;9:127) and fibromyalgia (Cytokine 2016;84:25-8). Lastly, neuroimaging studies have revealed similar structural changes in the amygdala, hippocampus, and limbic structures of patients with chronic pain, depression, and anxiety (Rev Colomb Psiquiatr 2018;47:46-55).

Psychiatric disorders and chronic pain

Studies suggest that youth with psychiatric disorders have higher rates of chronic pain (Headache 2019;59:306-38) and that the prevalence of some psychiatric disorders varies depending on the type of chronic pain. Temporal associations were also found between the onset of mental health disorders and the onset of chronic pain. The greatest association was found when onset of mental disorder preceded onset of pain. However, no significant associations were found when onset of pain preceded onset of mental disorders (J Pain 2015;16:1054-64). Generally speaking, 40% of adolescents admitted with chronic pain have a comorbid mental health condition, primarily mood disorders (28%) and anxiety disorders (18%) (Pediatrics 2013;132:e422-9). Others have estimated that the most common illnesses in the outpatient population are anxiety disorders (J Pain 2015;16:1054-64; Pain Res Manag 2012;17:93-7).

Studies have shown a mutual maintenance of depression in conjunction with pediatric chronic pain (Clin J Pain 2019;35:633-43). Correspondingly, adolescents with chronic pain have a 24.5% lifetime rate of depression, higher than the 14.1% rate of depression without chronic pain (Pain 2016;157:1333-8). Depression is also considered a risk factor for both the development and progression of chronic migraine in youth (Headache 2019;59:306-38). Overall, psychiatric issues such as depression, anxiety, and self-harm are the most common comorbid conditions with migraine in pediatric patients (Pediatr Neurol 2019;97:26-9).

Anxiety and other disorders

Anxiety also is associated with higher rates of pain (Pediatr Neurol 2019;97:26-9), and adolescents with chronic pain have higher lifetime rates of anxiety. This association exhibits a sex bias. Girls with anxiety have a 2.6 times greater prevalence of headaches, a 100 times greater prevalence of stomach aches and headaches together, and a 3.4 times greater prevalence of musculoskeletal pain than girls without an anxiety disorder (J Am Acad Child Adolesc Psychiatry 1999;38:852-60). In contrast, boys show no association between anxiety and somatic complaint. However, boys with oppositional defiant disorder or attention deficit hyperactivity disorder were more likely to have stomach aches, and boys with conduct disorder were more likely to have headaches (J Am Acad Child Adolesc Psychiatry 1999;38:852-60).

Another study reported that functional neurological disorder and other somatization disorders were present in 6% of children admitted with chronic pain and that 2.4% of those children had post-traumatic stress disorder (Pediatrics 2013;132:e422-9). Also, a cohort study found higher levels of post-traumatic stress disorder symptoms in both youth with chronic pain and their parents (Pain 2016;157:2277-84).

Chronic pain can also cause changes in the eating habits of adolescents, causing comorbid eating disorders in some cases. However, eating disorders can also precede the development of chronic pain (J Pediatr Health Care 2017;31:67-74). Interestingly, a search of the literature did not identify any articles describing comorbidity between chronic pain and psychotic disorders in pediatric and adolescent populations.

One non-negligible comorbidity of chronic pain is suicide. Chronic pain is undoubtedly a risk factor for suicide in adults (Aging Ment Health 2016;20:166-94); however, the data are inconclusive in youth. A 2017 study of 186 adolescents found that the occurrence of suicidal ideation was similar among youth with and without chronic pain (Clin J Pain 2017;33:21-7). However, in 2011, a much larger study of 9,970 adolescents reported that rates of suicide ideation and attempts were higher among youth who had chronic pain than among those who did not (J Pain 2011;12:1032-9). Interestingly, Lewcun et al. (Psychol Serv 2018;15:309-15) found that most types of pain were predictive of developing suicidal ideation and that a longer duration of amplified pain could be a risk factor for suicidal ideation. Notably, the comorbidity between suicidality and chronic pain could be mediated by depressive symptoms.

Guiding principles for treatment

Given the close association between psychiatric disorders and chronic pain, it is critical to screen and treat these disorders concomitantly to achieve positive outcomes. A few principles guide the treatment for children suffering from both psychiatric disorders and chronic pain. The treatment of choice remains a multidisciplinary approach that addresses pain with biological, psychological, and social aspects (Am Psychol 2014;69:119-30). The disciplines contributing to this approach are psychiatry and psychology for mental health disorders; surgery and rheumatology for injections and surgical interventions; anesthesiology for pharmacological and interventional analgesia; and physical and occupational therapy to increase functionality (Am Psychol 2014;69:119-30; Med Clin North Am 2016;100:55-64; Rheumatol Int 2017;37:29-42). Involvement of these disciplines has proven to be superior to usual care for increasing functionality and decreasing pain and disability in patients with chronic pain (BMJ 2015;350:h444).

From a risk assessment perspective, it is imperative to screen for suicidal ideation in this population. From a pharmacological perspective, it is recommended that practitioners use the “start low and go slow” approach because most treatment modalities have been extrapolated from adults with few guidelines for the pediatric population. Moreover, several medications used to treat the target symptoms may increase suicidal ideation. In recent years, the opioid crisis shed light on the need for adequate non-opioid treatment options. Thus, several non-opioid psychiatric drugs could be used off-label to treat pain and psychiatric disorders simultaneously.

“Given the close association between psychiatric disorders and chronic pain, it is critical to screen and treat these disorders concomitantly to achieve positive outcomes.”

First, antidepressants are often used for analgesic, antidepressant, and anxiolytic effects (Prog Neuropsychopharmacol Biol Psychiatry 2018;87B:290-7). Tricyclic antidepressants (TCAs) and selective serotonin and noradrenaline reuptake inhibitors (SNRIs) are considered first-line treatments, whereas selective serotonin reuptake inhibitors (SSRIs) are considered second-line treatment and bupropion third-line (Eur J Neurol 2010;17:1113-e88). It is important to note that analgesia is achieved at lower doses than those needed to address depression (Am Psychol 2014;69:119-30). TCAs are also ineffective for depression in youth (Prog Neuropsychopharmacol Biol Psychiatry 2018;87B:290-7). Duloxetine, which has been approved by the Food and Drug Administration for anxiety in youth, is the most-reported drug prescription in the pediatric pain population and in one study was found to be particularly effective for treating isolated peripheral neuralgia with associated depression in teenagers (Paediatr Anaesth 2014;24:608-13).

Second, antiepileptics, which are widely used for pain, are also effective for some psychiatric disorders. Gabapentin is particularly useful in generalized anxiety disorder (GAD) with social anxiety disorder and alcohol withdrawal symptoms (Front Psychiatry 2019;10:228), and pregabalin is somewhat efficacious for GAD (Ann Pharmacother 2012;46:424-9). Valproate and topiramate, two known mood stabilizers, are also used, especially in the management of chronic daily headache. Benzodiazepines have a well-established role in managing anxiety disorders associated with chronic pain and may be considered for short-term therapy in patients with concurrent anxiety disorders and low back pain (Prog Neuropsychopharmacol Biol Psychiatry 2018;87 B:290-7).

Third, cannabis is used mainly in palliative settings in the U.S.

Non-psychopharmacological interventions include therapies such as physical therapy, cognitive-behavioral therapy (CBT), biofeedback, yoga (PM R 2015;7:S295-S315), and mindfulness. CBT effectively decreases the intensity of chronic pain in youth while also reducing distress and the interference of pain in day-to-day activities (Pain 2010;148:387-97). CBT is also beneficial for anxiety and depression in adolescents with comorbid inflammatory bowel disease (J Am Acad Child Adolesc Psychiatry 2007;46:1290-8).

In conclusion, psychiatric disorders are a non-negligible comorbidity of chronic pain. This association can be explained in part by shared neurobiological pathways between chronic pain and psychiatric diseases and also by the negative physical and psychosocial sequelae of chronic pain. Depression is one of the most common psychiatric comorbidities of chronic pain and is the most common in the inpatient population. In contrast, anxiety is the most common comorbidity for outpatient community youth. This distinction may be explained by the fact that admitted patients have more severe illness and higher disability, making depression a more likely comorbidity. The risk of suicide should be evaluated in all patients. Treatment approaches for youth with chronic pain and psychiatric disorders have been extrapolated from adults; therefore, additional research with randomized controlled trials is required to inform treatment in youth. Finally, addressing comorbid mental health illnesses in patients with chronic pain syndromes will have a positive effect on both the pain and patients' ability to manage their pain, and is integral to improving treatment outcome.

Souraya Torbey, MD, Assistant Professor, Johns Hopkins University/Kennedy Krieger Institute, Baltimore.

Souraya Torbey, MD, Assistant Professor, Johns Hopkins University/Kennedy Krieger Institute, Baltimore.

Gaëlle Rached, MD, MSc, Faculté de Médecine, Université Saint Joseph, Beirut, Lebanon.

Gaëlle Rached, MD, MSc, Faculté de Médecine, Université Saint Joseph, Beirut, Lebanon.

Dimitri Fiani, Medical student, Université Saint Joseph, Beirut, Lebanon.

Dimitri Fiani, Medical student, Université Saint Joseph, Beirut, Lebanon.

M-Irfan Suleman, MD, FAAP, FASA, Assistant Professor, Founding Director, Pediatric Interventional Pain Program, Johns Hopkins Children's Center, and Founding Medical Director, Multidisciplinary Pediatric Chronic Pain Rehabilitation Program, Kennedy Krieger Institute, Baltimore.

M-Irfan Suleman, MD, FAAP, FASA, Assistant Professor, Founding Director, Pediatric Interventional Pain Program, Johns Hopkins Children's Center, and Founding Medical Director, Multidisciplinary Pediatric Chronic Pain Rehabilitation Program, Kennedy Krieger Institute, Baltimore.