Opioid use disorder is a serious illness that affects approximately 26 to 36 million people across the globe (2). Not only does this illness affect the individual in multiple aspects of their lives, it places a great economic burden on healthcare systems (56). We have recently seen a dramatic increase in the number of people misusing opioids, a significant proportion of whom misuse prescription opioids specifically. While this crisis has global impacts, North America has experienced the majority of the burden of illness. The United States alone consumes 80% of the global supply of prescription opioids, and it is estimated that their use has increased by 300% since 1991 (57). Research has suggested that those prescribed an opioid prescription for chronic pain have a risk of up to 60% of misusing prescriptions (58). It is critically important to investigate the emerging cohort of patients who were introduced to opioids by legitimate prescriptions to see whether they fare differently in MAT compared to those who were introduced to opioids recreationally. To our knowledge, this is the first systematic review to synthesize the literature examining this question.

Our meta-analysis found that those that were introduced to opioids through a legitimate prescription were less likely to use illicit opioids while in treatment than those that were introduced to opioids through recreational means (OR 0.70, 95% CI 0.50, 0.99, p-value 0.04). Our findings also revealed that the prescription introduction to opioids cohort were less likely to have used cocaine (OR 0.50, 95% CI 0.29, 0.85, p-value 0.01), alcohol (OR 0.75, 95% CI 0.59, 0.95, p-value 0.02), cannabis (OR 0.54, 95% CI 0.32, 0.89, p-value 0.02), and injection drugs (OR 0.25, 95% CI 0.14, 0.43, p-value <0.001). There was no association found between the source of introduction to opioids and benzodiazepine use (OR 0.82, 95% CI 0.54, 1.26, p-value 0.37).

Those introduced to opioids through prescriptions were found to be less likely to continue using opioids during treatment than those whose first introduction was through recreation. This suggests that first introduction to opioids through illegal means predicts continued use during treatment, and that the first introduction may explain trends in subsequent opioid use. Brands et al. demonstrated that patients in MMT who used only prescription opioids had significantly less experience with sharing opioid injection equipment in comparison to those patients who used heroin only or initially (59). While this study did not ask patients about their first introduction to prescription opioids, most patients using prescription opioids only (86%) or initially (61.9%) indicated that their initial reason for using opioids was to manage pain. They conclude that those who were likely introduced to opioids through prescription as a means of treating pain tend to engage in less risk-taking behavior, and are less likely to continue using opioids during treatment in comparison to those not using opioid drugs to manage pain (59). Further, in another study of patients in treatment for OUD, those using only prescription opioids had a higher treatment retention, fewer opioid-positive urine samples, and were more likely to complete treatment than those patients using a combination of heroin and prescription opioids or those using heroin exclusively (35). Taken together, first introduction and reason for use, perhaps mediated by risk-taking behaviors, may predict future opioid use and explain our finding that those who were not first introduced to opioids through a prescription have an increased likelihood of continued use in treatment. People whose opioid use was first initiated through prescription also tend to be demonstrate lower risk-taking behavior, further supporting the observation that those who initiate opioid use from a prescription tend to be less likely to continue use during treatment. Prescription-introduced opioid users are more likely to be female, generally have an older age of opioid use onset, and are more like to have completed a post-secondary education (53). These factors likely influence the level of continued use of illicit opioids in treatment as women in general are less likely to use opioids (60) and are shown to engage in fewer risks than men in terms of both everyday risk-taking behaviors (61) as well as in financial, recreational, ethical, and recreational domains (62). Risk-taking attitudes are found to be reduced with age (62), and older adults are also less likely to partake in risk-taking behavior and illegal opioid use while in treatment. A study of treatment outcomes for opioid use found that 61% of older adults had no positive urine screens for opioids, compared to 35% in younger adults after initiating treatment (63).

Our finding that those introduced to opioids through recreational means are more likely to engage in using other substances such as alcohol, marijuana, and cocaine, is also congruent with the literature. Studies have found that the nonmedical use of opioids was significantly associated with the use of other illicit substances (56). Specifically, there is research that suggests that there are differences in polysubstance use between prescription users and recreational users, and that this poly-substance use in recreational opioid users may be associated with risk-taking behaviors. A study investigating HIV risk-taking behavior found that men who are recreational, poly-substance drug users were more likely to engage in risky behaviors such as the sharing of needles and sex without protection (64). Morely et al. took a closer look at recreational drug users and found that different mental disorders and behavior patterns are predictive of the type and degree of polysubstance use a recreational user engages in (65). Depression and anxiety disorders were found to be predictive of medication and cannabis use, whereas violent and risky behavior suggested the use of illicit or all drugs. In contrast, participants in the non-polysubstance class were more likely to be female, have a lower desire to use drugs, and were less likely to have a diagnosis of anxiety or depression, or engage in violent risk-taking behaviors. Thus, risk-taking behavior and the presence of mental illness may be predictive of polysubstance use in recreational drug users, which would explain our finding that recreational drug users have a higher likelihood of misusing more than one illicit substance. A study reported that respondents who had experienced at least one major depressive episode in the past year were more likely to engage in non-medical use of prescription pain relievers (66). Providing support and resources for comorbid mental health concerns within this population may be an area that clinicians and policy makers should consider implementing within OUD treatment plans.

With the increased availability of prescription opioids contributing to the opioid epidemic, countries across the globe have taken initiatives to control access and prescribing patters of opioids. Some of these initiatives include legislative changes through guideline recommendations in opioid prescribing for chronic, non-cancer pain, acute pain conditions, and prescription monitoring programs (42, 67). Research examining these changes have suggested that there is a decrease in opioid prescribing with these measures in place such as using the recommendation of nonsteroidal anti-inflammatory drugs (NSAIDs) over opioids for acute pain (28, 67–70). These findings in combination with the ever-changing synthetic opioids drug market would suggest that is important to continue to tailor recommendations to fit the ever-changing opioid user.

These findings are important as they can help develop tailored MAT programs for patients. It may be important to consider comorbid medical conditions such as pain that may have led to being introduced to opioid by prescription or concurrent substance use when creating a treatment plan. This systematic review has highlighted that those introduced to opioids by prescription means are less likely to use other substances including opioids. This cohort of individual are most likely people that did not intend to engage in risk-taking behavior. They ended up dependent to opioids because of the associated addictive properties. They may benefit from being treated in different settings and with the use of different approaches to addiction philosophy. Addiction specialists should consider addressing harm reduction strategies such as hepatitis C treatment awareness and provision of clean needles to those still engaging is IV drug use while in treatment. Pain specialists and pharmacists may want to consider including a brief educational component and treatment plan to mitigate problematic use potential surrounding opioids when prescribing opioids to a patient is necessary. Additionally, those who were introduced through recreational means likely have a different set of problems to address than those whose use began with prescriptions. Perhaps there should be additional support provided for patients that desire to stop using additional substances alongside illicit opioids. The current lack of data present on poly-drug use, the associated risks and individual goals is limited and should be expanded on in order to develop personalized support for poly-drug users. Some research has predicted that the increased strictness of prescribing opioids will not have a huge impact on the number of opioid overdoses and deaths (71). Targeting illicit opioid use in treatment is where focus should also be. Policy makers may want to provide different treatment settings for OUD patients and, by identifying patients with high risk behavior patterns who were introduced to opioids recreationally, can take advantage of opportunities for interventions to reduce patients’ hazardous use of other substances. It is also important to address the lack of information on the emergence of novel opioid substances and their apparent popularity with illicit opioid users as it limits the level of insight current literature can provide to drug addiction services and clinicians. Due to the lack of information on current opioid related changes future directions may include updating this paper to possibly highlight novel data on poly-drug use and opioid derivatives. Furthermore, due to the extended focus on North American and Australian data present in this paper future studies could explore ethnic and socioeconomic differences present in method of introduction to opioids.