Opioids, addiction, and overdose

Bibliography: Reviews/articles on opioids, addiction, and overdose.

**Updated July 2023**

Classic review:

*Paulozzi, L.J. (2012). Prescription drug overdoses: A review. Journal of Safety Research, 43 (4), 283-289. [Cited by]

“Overdoses involving prescription drugs in the United States have reached epidemic proportions over the past 20 years. Host factors include male sex, middle age, non-Hispanic white race, low income, and mental health problems. Agent risk factors include use of opioid analgesics and benzodiazepines, high prescribed dosage for opioid analgesics, multiple prescriptions, and multiple prescribers. Environmental factors include rural residence and high community prescribing rates.”

Featured articles:

*Babu, K. M., Brent, J., & Juurlink, D. N. (2019).  Prevention of Opioid Overdose. The New England Journal of Medicine, 380 (23), 2246-2255. [PDF] [Cited by]

“In the time it takes to read this article, at least one person in the United States will have died from an opioid overdose. From 1999 through 2017, more than 700,000 U.S. residents died from a drug overdose; the majority of these events involved an opioid. Among persons between the ages of 24 and 34 years, one in five deaths is now related to opioid use.”

*Chalhoub, R. M., & Kalivas, P. W. (2020). Non‑Opioid treatments for opioid use disorder: Rationales and data to date. Drugs, 80(15), 1509-1524.  [Cited by]

“Opioid use disorder (OUD) represents a major public health problem that affects millions of people in the USA and worldwide. The relapsing and recurring aspect of OUD, driven by lasting neurobiological adaptations at different reward centres in the brain, represents a major obstacle towards successful long-term remission from opioid use. Currently, three drugs that modulate the function of the opioidergic receptors, methadone, buprenorphine and naltrexone have been approved by the US Food and Drug Administration (FDA) to treat OUD. In this review, we discuss the limitations and challenges associated with the current maintenance and medication-assisted withdrawal strategies commonly used to treat OUD. We further explore the involvement of glutamatergic, endocannabinoid and orexin signaling systems in the development, maintenance and expression of addiction-like behaviors in animal models of opioid addiction, and as potential and novel targets to expand therapeutic options to treat OUD. Despite a growing preclinical literature highlighting the role of these potential targets in animal models of opioid addiction, clinical and translational studies for novel treatments of OUD remain limited and inconclusive. Further preclinical and clinical investigations are needed to expand the arsenal of primary treatment options and adjuncts to maximize efficacy and prevent relapse.”

*Damiescu, R., Banerjee, M., Lee, D.Y.W., Paul, N.W., & Efferth, T. (2021). Health(care) in the crisis: Reflections in science and society on opioid addiction. International Journal of Environmental Research and Public Health, 18(1), 341. [PDF] [Cited by] 

“Opioid abuse and misuse have led to an epidemic which is currently spreading worldwide. Since the number of opioid overdoses is still increasing, it is becoming obvious that current rather unsystematic approaches to tackle this health problem are not effective. This review suggests that fighting the opioid epidemic requires a structured public health approach. Therefore, it is important to consider not only scientific and biomedical perspectives, but societal implications and the lived experience of groups at risk as well. Hence, this review evaluates the risk factors associated with opioid overdoses and investigates the rates of chronic opioid misuse, particularly in the context of chronic pain as well as post-surgery treatments, as the entrance of opioids in people’s lives. Linking pharmaceutical biology to narrative analysis is essential to understand the modulations of the usual themes of addiction and abuse present in the opioid crisis. This paper shows that patient narratives can be an important resource in understanding the complexity of opioid abuse and addiction. In particular, the relationship between chronic pain and social inequality must be considered. The main goal of this review is to demonstrate how a deeper transdisciplinary-enriched understanding can lead to more precise strategies of prevention or treatment of opioid abuse.”

*Darcq, E., & Kieffer, B. L. (2018). Opioid receptors: drivers to addiction?  Nature Reviews. Neuroscience, 19 (8), 499-514.  [Cited by]

“Drug addiction is a worldwide societal problem and public health burden, and results from recreational drug use that develops into a complex brain disorder. The opioid system, one of the first discovered neuropeptide systems in the history of neuroscience, is central to addiction. Recently, opioid receptors have been propelled back on stage by the rising opioid epidemics, revolutions in G protein-coupled receptor research and fascinating developments in basic neuroscience. This Review discusses rapidly advancing research into the role of opioid receptors in addiction, and addresses the key questions of whether we can kill pain without addiction using mu-opioid-receptor-targeting opiates, how mu- and kappa-opioid receptors operate within the neurocircuitry of addiction and whether we can bridge human and animal opioid research in the field of drug abuse.

*Emery, M. A., & Akil, H. (2020). Endogenous opioids at the intersection of opioid addiction, pain, and depression: The search for a precision medicine approach. Annual Review of Neuroscience, 43, 355-374. [Cited by] 

“Opioid addiction and overdose are at record levels in the United States. This is driven, in part, by their widespread prescription for the treatment of pain, which also increased opportunity for diversion by sensation-seeking users. Despite considerable research on the neurobiology of addiction, treatment options for opioid abuse remain limited. Mood disorders, particularly depression, are often comorbid with both pain disorders and opioid abuse. The endogenous opioid system, a complex neuromodulatory system, sits at the neurobiological convergence point of these three comorbid disease states. We review evidence for dysregulation of the endogenous opioid system as a mechanism for the development of opioid addiction and/or mood disorder. Specifically, individual differences in opioid system function may underlie differences in vulnerability to opioid addiction and mood disorders. We also review novel research, which promises to provide more detailed understanding of individual differences in endogenous opioid neurobiology and its contribution to opioid addiction susceptibility.”

*Jones, C. M. P., Day, R. O., Koes, B. W., Latimer, J., Maher, C. G., McLachlan, A. J., Billot, L., Shan, S., Lin, C. C., & OPAL, I. C. (2023). Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial. Lancet. [Cited by]  **new**

“Background: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain.

Methods: OPAL was a triple-blinded, placebo-controlled randomized trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone–naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analyzed in all eligible participants who provided at least one post-randomization pain score, by use of a repeated measures linear mixed model. Safety was analyzed in all randomly assigned eligible participants.

Findings: Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI –0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group).

Interpretation: Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions.”

*Rajabi, A., Dehghani, M., Shojaei, A., Farjam, M., & Motevalian, S. A. (2019). Association between tobacco smoking and opioid use: A meta-analysis.  Addictive Behaviors, 92, 225-235.  [Cited by]

“This meta-analysis quantified the association of tobacco use and opioid use and opioid use disorders. Our study indicated that age at onset of smoking (under 14 years old) is associated with opioid use. Almost a third of opioid use and opioid use disorders in the world is attributable to tobacco smoking. Smoking cessation interventions are potentially useful in the reduction of opioid use and opioid use disorders.”

*Volkow, N., Benveniste, H., & McLellan, A. T. (2018). Use and Misuse of Opioids in Chronic Pain.  Annual Review of Medicine, 69, 451-465. [Cited by]

“The prescribing of opioid analgesics for pain management—particularly for management of chronic noncancer pain (CNCP)—has increased more than fourfold in the United States since the mid-1990s. Yet there is mounting evidence that opioids have only limited effectiveness in the management of CNCP, and the increased availability of prescribed opioids has contributed to upsurges in opioid-related addiction cases and overdose deaths. These concerns have led to critical revisiting and modification of prior pain management practices (e.g., guidelines from the Centers for Disease Control and Prevention), but the much-needed changes in clinical practice will be facilitated by a better understanding of the pharmacology and behavioral effects of opioids that underlie both their therapeutic effects (analgesia) and their adverse effects (addiction and overdose). With these goals in mind, this review first presents an overview of the contemporary problems associated with opioid management of CNCP and the related public health issues of opioid diversion, overdose, and addiction. It then discusses the pharmacology underlying the therapeutic and main adverse effects of opioids and its implications for clinical management of CNCP within the framework of recent clinical guidelines for prescribing opioids in the management of CNCP.”

For additional research about opioids, addiction, and overdose, please see the Science Primary Literature database.

Questions?  Please let me know (engelk@grinnell.edu).