In this systematic literature review we identified a range of studies comparing suicidal outcomes
in opioid users and those with opioid abuse/ dependence with outcomes in the general population
and individuals not using opioids. We also identified studies examining the association between
opioid availability and suicides and also suicide attempts. Three general observations emerge
from this analysis: 1) suicide, suicidal ideation and attempts are more common among
individuals with opioid use, opioid abuse/dependence and those receiving higher doses of
opioids compared with the general population; 2) the availability of opioids is associated with
increases in suicidal behavior and suicides; 3) alternative explanations could partially explain the
effects of opioids on suicidal outcomes found in these studies.
Consistently, studies on individuals with opioid abuse/dependence and patients treated for
chronic non-cancer pain provide evidence that the frequent use opioids and use at higher doses is
associated with suicidal ideation/behavior suicide. These findings support the hypothesis of a
causal effect between the frequent use of opioids and suicidal ideation/behavior. However, this
evidence does not provide information about the mechanisms in operation. As theorized, if these
effects are internally valid, it is possible that they operate through individual level mechanisms
influencing the reward system, the distress and negative mood experienced in withdrawal
periods, and also via the adverse experiences that opioid users face (e.g., social discrimination
and financial challenges). In addition, opioids may also increase the risk of suicide among opioid
users by providing a means of suicide; however, the fact that many suicides in these populations
are not opioid-poisoning suicides, suggests that opioids providing a means of suicide is not the
abuse and dependence greatly reduced the prevalence of past-year suicidal ideation and attempts,
which provides additional evidence of the effects of opioids on suicidal outcomes.
Survey studies in adolescents and adults also consistently show evidence that the nonmedical use
of prescription opioids and opioid abuse/ dependence were associated with suicidal ideation (and
attempts in adolescents); although in those with suicidal ideation, opioid use and related abuse/
dependence did not increase the risk of attempts (64). Altogether this evidence supports the
hypothesis that opioid use and abuse/ dependence lead to suicidal ideation, and attempts at least
in adolescents; although no information is presented on the mechanisms at play, they could also
work through the individual level mechanisms described above. Studies on adolescents,
including a longitudinal study (73) following students over time, provide important evidence on
the risk of nonmedical use of opioid at an early age.
Two studies show evidence of an association between the availability of prescription opioids and
suicidal behavior/ suicides. The first study (71) shows that increases in opioid availability are
linked to increases in suicidal behavior. Although opioid availability in a community is a group
level exposure, these effects could have operated at the individual level through the mechanisms
described above. Along with these individual level effects, increases in opioid availability and in
rates of opioid abuse/ dependence and of fatal opioid overdoses could have also resulted in
detriments of group level characteristics, e.g., social capital, that individuals rely on to solve
problems and that give meaning to their lives. Through the erosion of social capital, the opioid
crisis could have influenced feelings of the despair, depression and in turn in suicidal ideation/
potent opioid co-proxamol was associated with reductions in co-proxamol-poisoning suicides,
without increases in suicides by other methods; thus, showing that at least for some individuals
having prescription opioids at hand may increase their risk of suicide. The time between a person
determines to commit suicide and he/ she finds the means to do it can be crucial to reduce
suicidal impulses and prevent suicidal behavior. Because prescription opioids can be readily
accessible, they may not offer this possibility.
There are also potential limitations in studies included in this review. Although the associations
between opioid use and opioid abuse/ dependence and suicide outcomes described in studies can
be causal, they could also arise from alternative explanations, including confounding. In studies
examining patients receiving treatment for opioid abuse/ dependence, it is often found that these
patients not only have higher prevalences of suicidal outcomes than the general population, but
also higher levels of distress and harsh events in their life (74). They often report having
experienced child maltreatment, having a rough child environment such as living in poverty,
living with a parent with drug or alcohol addiction or attempting suicide, and also having
psychiatric disorders, including depression, anxiety disorders, antisocial and borderline
personality disorders (49, 52, 74-76) It is likely that these prior events are drivers of both suicidal
ideation/ behavior (77-83) and also initiation and continuous use of substances that can serve as
an alternative to cope with negative emotions (78-80, 84-87). Also, most studies used the general
population as comparison group; however, using a control group that more closely resembles
those in treatment for opioid dependence (e.g., in regards to child maltreatment, psychiatric
disorders and family history of attempted suicide) (50) may provide better estimates of the effect
may be an important factor predicting treatment seeking among opioid users. Because of this and
given that these studies are based on populations of opioid users in treatment, associations
between opioid abuse/ dependence and suicidal outcomes may be the result of selection bias. In
this regard, one study on opioid users not in treatment (59) and therefore not affected by this type
of selection bias, still shows that the prevalence of suicidal ideation was high in this group,
suggesting that selection bias may only partially explain associations.
Confounding may also be an issue in survey studies, as models are often not adjusted by other
important confounders of these associations, such as traumatic childhood experiences or prior
psychiatric disorders occurring prior to onset of prescription opioid use, mostly because there are
no measures of these constructs in survey data. In addition, reverse causation could be an
alternative explanation for these findings, as studies use cross sectional data with opioid use and
suicidal outcomes measures occurring during the same time period. Because of this, there is less
certainty about the directionality of these associations. Individuals with prior psychiatric
diagnoses or having previously attempted suicide are also at greater risk of long-term opioid use
and of nonmedical use of prescription opioids (88-90), suggesting that the directionality may be
reciprocal. Longitudinal studies, such as the study by Guo et al., (69) provide stronger support
for these effects as findings are less likely explained by reverse causation.
In studies on patients with chronic non-cancer pain, confounding by indication may alternatively
explain these associations (30, 60-63). Moderate/severe pain is an important factor that can lead
to higher opioid dosage and to suicide risk, and therefore identifying the causal effect of opioid
60, 62, 63). However, separating the effects of opioid use from levels of pain is challenging,
particularly because the continuous use of opioids may also lead to hyperalgesia (91), a path
through which opioids can cause suicidal outcomes. Hyperalgesia can lead to loss of control over
opioid use, to depressive states (23, 29), and eventually to suicidal ideation and behavior. Despite
the fact that pain could explain the effects of prescription opioids on suicidal outcomes in
patients with chronic pain, the findings in these studies show the importance of screening for
suicidal ideation/ attempts, and the need for greater monitoring and alternative treatment options
for patients with suicidal ideation/ behavior.
Finally, there are also potential limitations in studies examining effects of the availability of
prescription opioids on suicide behavior. No adjustment for potential confounders and lack of
information on estimates provided in results limit the conclusions that can be obtained from the
study showing the effects of opioid prescriptions on suicide calls (71). Also the lack of a control
group in the study on co-proxamol withdrawal (72) is problematic given that other laws,
programs or events occurring around the same time could have explained the reductions in
suicides.
Limitations of this systematic literature review must be also noted. Although two independent
reviewers selected studies to be included, only one researcher extracted the data and identified
potential limitations in the included studies, which could lead to lower sensitivity to detect
potential limitations or to wrongfully list limitations in some studies. Also, due to the substantial
However we tried to summarize findings from studies in a clear a succinct way for a better
understanding of this evidence.
To conclude, we show evidence from national and international studies supporting our
hypothesis of effects of opioid use and opioid abuse/dependence on suicidal outcomes. However,
characteristics of populations studied and potential limitations in studies, including the use of
inappropriate comparison groups and reverse causation in many of these studies, could partially
explain these findings. Nevertheless studies included here show the importance of screening for
suicidal ideation/ attempts, and the need for greater monitoring and treatment options for
individuals using opioids, whether they use them for medical or non-medical purposes. Further
studies with individual longitudinal data and addressing some of the limitations discussed here
(e.g., adjusting for other potential confounders), will provide additional and stronger evidence
supporting or refuting the hypothesis of effects of opioid use on suicidal outcomes. Also, group
level studies using control groups and examining effects at a more granular level (e.g., state or
counties) may also provide support for individual and also group level effects happening during