Adolescent Pain, Anxiety, and Depressive Problems

A Twin Study of Their Co-occurrence and The Relationship to Substance Use

Simona Scaini; Giorgia Michelini; Stefano De Francesco; Corrado Fagnani; Emanuela Medda; Maria Antonietta Stazi; Marco Battaglia


Pain. 2022;163(3):e488-e494. 

In This Article

Abstract and Introduction


Data on the etiological factors underlying the co-occurrence of common adolescent pain with anxiety and depression symptoms are very limited. Opioid prescriptions for adolescent pain problems are on the rise in North America and constitute a risk factor for diversion, misuse, and substance use. In this study, we aimed to investigate the phenotypic and etiological association among pain, depression, and anxiety and to test their link to substance use in adolescents. By taking advantage of the Italian National Twin Registry and of the relatively low incidence of opioid prescriptions in Italy, we applied multivariate modelling analyses to 748 Italian adolescent twins (374 pairs, mean age 16 ± 1.24 years). Twins' responses to the Achenbach Youth Self-Report questionnaire were used to build a composite adolescent pain index and to measure anxiety, depression, and substance use. All monozygotic within-pair correlations were higher than the dizygotic correlations, indicating genetic influences for adolescent pain, anxiety, and depressive problems. A common latent liability factor influenced by genetic and environmental elements shared among pain, depression, and anxiety provided the best fit to explain the co-occurrence of adolescent pain, anxiety, and depression problems. A common phenotypic factor capturing all 3 phenotypes was positively associated (β = 0.19, P < 0.001, confidence interval: 0.10–0.27) with substance use. These findings indicate that several intertwined mechanisms, including genetic factors, can explain a shared liability to common adolescent pain, anxiety, and depression problems. Their association with substance use remains traceable even in societies with relatively low prevalence of opioid prescriptions.


Chronic pain affects between 8% and 12% of adolescents aged 11 to 17 years and 16% to 20% of youth or young adults in North America and Europe.[12,19,38,46,50] Adolescent pain is often persistent,[5,12,19] and mostly occurs without a recognisable relationship to a medical condition.[19] There is also growing epidemiological evidence of the association of childhood or adolescent pain problems with anxiety and depressive (also known as "internalizing") symptoms.[6,34,41,44] These data echo similar findings in adults,[24] and because of the temporal continuity between adolescent and adult pain, they warrant further investigation.

At least 2, urgent and clinically relevant questions arise from the apparent connection between common persistent pain problems and mental health among the population's younger strata. The first is etiological in nature, asking why common pain problems are associated with internalizing symptoms. This is essential knowledge to inform best treatment practices. Although some clinicians may be more prone to attribute causal justifications (eg, pain causes anxiety or vice-versa) to such comorbidity (see Ref. 42 for a critical appraisal), empirical epidemiological approaches incorporate shared elements of risk as possible, competing explanations for the co-occurrence of 2 or more distinct clinical images. Studies of identical (monozygotic [MZ]) and fraternal (dizygotic [DZ]) twins constitute a special example of such an empirical approach, as they seek to clarify the sources of individual differences for a variety of phenotypes and their co-occurrence. Twin studies reported moderate genetic effects for some specific adult chronic pain problems and nociception[31,32,39] and for some specific adolescent pain (neck pain and headache) problems.[45,53] Genetic overlap between specific (ie, back pain) adult pain problems and anxiety or depression has also been reported by a few studies.[35,39,45,53] A recent systematic review reported that most twin studies found substantial covariation of genetic and/or environmental factors to explain the co-occurrence of chronic pain and anxiety or depression, with a minority of studies supporting the likelihood of phenotypic causation.[18] The same review also underscored the dearth of children or adolescent twin studies of pain and internalizing disorders, a noticeable gap, given the early onset of chronic pain problems in the population.[12,19,38,46] A successive longitudinal Canadian twin study[5] yielded genetic factors and nonshared environmental factors as the best-fitting model to explain the co-occurrence of anxiety and persistent adolescent pain problems. Yet, that study[5] did not encompass depression in the model. Clarifying the nature of the adolescent pain–internalizing problems association is critical to understand etiology, reformulate diagnosis, and shape early intervention.[20,33,34,42]

The second question addresses the relationship between adolescent pain, anxiety, depressive problems, and substance use. For instance, adolescents who experience more frequent pain are also more likely to smoke, drink alcohol, and report feelings of anxiety and depression.[15] The connection between adolescent pain, internalising symptoms, and substance use or abuse has wide societal and public health implications that encompass pathways to the current opioid crisis (see Figure S1, available as supplemental digital content at Opioid prescriptions remain relatively common among U.S. adolescents.[11] They are also significantly more common (odds ratio >4) among Canadian adolescents in a trajectory of high and persisting pain problems compared with those in a trajectory of no-to-minimal pain problems.[5] Moreover, 6% of Canadian adolescents endorse abusing prescribed opioid pain relievers "to get high."[48] Although adolescents compose a lesser part of the yearly deadly toll of the U.S. opioid crisis, many of these fatalities can be directly attributed to prescription of opioids during adolescence and onwards.[43] Furthermore, among U.S. adolescents, internalizing disorders and benzodiazepine prescriptions are strong predictors of transitioning from a first opioid prescription to long-term opioid treatment.[37] Together, these data suggest that adolescent persistent pain and internalizing disorders may constitute a gateway to premature, more prolonged, and more hazardous opioid prescription. This, in turn, can lead to substance diversion, abuse, and possibly overdose,[7,55] at least in North American settings that maintain relatively liberal attitudes towards opioid pain relievers prescriptions for the young. Consistent with these data, the first national U.S. longitudinal examination of prescription drug misuses showed that opiates prescriptions in adolescence predict trajectories of substance use and abuse.[22]

This evidence points to prescriptions for pain and internalizing problems as a recognised risk factor for diversion, misuse, and substance abuse. However, this risk pathway is inextricably nested into the specific sociocultural environment of North America, which includes prescribing habits. By estimating the risk for substance use predicted by pain, anxiety, and depression problems in cultures with low prevalence of opioid prescriptions, one can partially attenuate this confounder. Because of the availability of a National Twin Registry,[26] and the low incidence of opioid prescriptions[14] compared with North American standards,[10] Italy offers an appropriate comparative context to address these topics. As a reference parameter, the defined daily doses/1000 population for Oxycodone was 13 for the Canadian population[10] in 2017 and 0.1 for the Italian population in 2019.[14]

We tackled the aforementioned matters by addressing 2 main questions in a cross-sectional study of a population-based Italian twin cohort of adolescents. First, to what extent genetic and environmental factors contribute to the co-occurrence among adolescent pain, anxiety, and depression? Second, to what extent is the shared proclivity for adolescent pain problems, anxiety, and depression associated with substance use, once this is measured in a societal context of opioid prescription that is, more conservative than the U.S. and Canadian opioid prescription context?