Effects on Memory After a First-Time Opioid Overdose Compared to Multiple Opioid Overdoses

RESEARCH ANALYSIS

Effects on Memory After a First-Time Opioid Overdose Compared to Multiple Opioid Overdoses

Kayla Yim, BS

Philadelphia College of Osteopathic Medicine

SUMMARY POINTS

-       One of the most concerning side effects of opioid use includes respiratory depression, as it can cause markedly significant hypoxic-ischemic brain injury especially to the CA1 area of the dorsal hippocampus. 

-       One study showed an increase in β-APP and hyperphosphorylated tau proteins in the frontal lobe and hippocampus of chronic opioid-use individuals to be similar to that of the elderly population, despite the mean age of participants being 40 years old, showing evidence that Alzheimer-like pathologies could be the basis of the neurocognitive deficits seen in long-term opioid use.

-       The delayed matching to sample (DMS) experiment tests for working memory and pattern recognition, and studies show that compared to the control group, individuals with a long-term heroin addiction had overall less correct answers and less accuracy.

-       The Tower of London test (TLT) tests for executive function of the frontal lobe, and studies show there is a correlation with longer daily heroin use and worse TLT scores.

-       By comparing the results of a simple memory experiment on participants with one-time, two-time and five-time opioid overdoses, we can begin to understand the potential additive nature of the neurocognitive effects of opioid overdoses. 

ANALYSIS

Background

Opioid use and overdose are largely recognized to cause detrimental neurocognitive effects, including, but not limited to, deficits in executive function and memory (1). It has also been shown that multiple overdoses can lead to cognitive decline and impaired decision-making skills, perpetuating risk-taking and drug dosing behaviors that contribute further to addiction (1). These deficits are due to the markedly significant respiratory depression that occurs following opioid use (2). If severe enough, including in instances of overdose, respiratory depression can cause hypoxic-ischemic brain injury, with the CA1 region of the dorsal hippocampus being the most vulnerable (2). As the hippocampus is also involved in storage and retrieval of memory, it is unsurprising that overdose can profoundly affect memory. Studies have shown that chronic opioid use is associated with long-term memory deficits, even after cessation of the drug (1).

Findings

MRI and post-mortem evaluations of chronic opioid patients have shown increased levels of β-APP in the hippocampus and cerebral white matter, indicating axonal damage and triggering inflammatory marker release that leads to neuroinflammation (3,4). There is also evidence of increased amount and rate of hyperphosphorylated tau positive neuropil thread deposition, like that of early Alzheimer's disease (5). In the Anthony et al. (2010) study investigating the predisposition to Alzheimer-like pathologies in opiate abusers, it was concluded that the level of hyperphosphorylated tau proteins in the hippocampus and the frontal lobe was similar to that of an elderly population, despite the mean age of study participants being 40 years old (5). This study helped shed light on the possibility of Alzheimer-like pathologies being the basis of cognitive impairment and memory deficits associated with long-term opioid use (5).

Figure 1. The correlation of hyperphosphorylated tau deposition in the hippocampus with age of participants, as compared to that of Alzheimer’s disease cases (4).

Despite extensive evidence on the general neurocognitive effects following long-term opioid use, there is also a benefit to understanding how repeated overdoses can affect neurocognition and memory. There are several studies that begin to investigate this question, but none have directly compared the effects of one-time versus multiple overdoses. The delayed matching to sample (DMS) is a neuropsychological test that evaluates working memory and pattern recognition (6). Participants were presented with a complex visual stimulus, and after 0, 4, and 12 seconds, they were asked to select the visual stimulus they were presented with out of four different choices (6). Fishbein et al. (2007) showed that heroin addicts had not only a lower number of correct answers compared to the control group but also increased latency (6).

Table 1. An excerpt of results of Fishbein et al. (2007) DMS experiment⁶

The Tower of London test (TLT) is another neuropsychological test that has been commonly used in diagnosing Alzheimer’s disease and other neurocognitive impairment disorders (7). It has been previously proposed that the neurocognitive impairments from long-term opioid use can be due to early Alzheimer-like pathologies, so the TLT can also be used to test the frontal lobe’s executive planning function for chronic opioid users (7). Since the frontal lobe is also involved in memory, it is possible that the results of the TLT test can also shed light on the deficits in memory. The study led by Bruin et al. (2024) showed there was a relationship between TLT scores and length of daily heroin use (8). More specifically, it was found that participants with longer daily heroin use had worse TLT scores and frontal lobe deficits (8). Since longer daily heroin use is also associated with an increased risk of unintentional overdoses, there may also be an association between the increased number of unintentional overdoses and the worsening frontal lobe deficits (9). Further evaluation of this topic would explore whether multiple opioid overdoses can cause compounding frontal lobe deficits, or whether lower TLT scores are independent of the effects of overdose.

Figure 2. A difficult TLT level, in which participants are presented with the different sized rings in a disorganized order and asked to correctly stack the rings by moving one at a time (7).

Discussion

There is a lack of literature directly comparing the neurocognitive deficits of patients with one-time and multiple opioid overdoses. The vast and severe neurocognitive effects that are associated with both long-term opioid use and opioid overdose are well understood, but more information on the potential additive nature of these deficits is an important question to explore. By gathering willing participants that have experienced one, two, and five opioid overdoses in their lifetime and presenting them with a simple memory experiment, we may be able to better understand the compounding effects of multiple overdoses. This information can be used to further educate patients on the detrimental effects on long-term opioid use and multiple overdoses.

REFERENCES

1.     Voronkov M, Ataiants J, Cocchiaro B, Stock JB, Lankenau SE. A vicious cycle of neuropathological, cognitive and behavioural sequelae of repeated opioid overdose. Int J Drug Policy. 2021;97:103362. doi:10.1016/j.drugpo.2021.103362

2. Hong JS, Moran MT, Eaton LA, Grafton LM. Neurologic, Cognitive, and Behavioral Consequences of Opioid Overdose: a Review. Curr Phys Med Rehabil Rep 7, 2019;7:305–313 doi:10.1007/s40141-019-00247-2

3. Büttner A, Rohrmoser K, Mall G, Penning R, and Weis S. Widespread axonal damage in the brain of drug abusers as evidenced by accumulation of β-amyloid precursor protein (β-APP): an immunohistochemical investigation. Addiction. 2006;101(9): 1339-1346. doi:10.1111/j.1360-0443.2006.01505.x

4. Morrison H, Young K, Qureshi M, Rowe RK, Lifshitz J. Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury. Sci Rep 7. Oct 2017: 13211. doi:10.1038/s41598-017-13581-z

5. Anthony IC. Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers. Brain. 2010;133(12):3685-3698. doi:10.1093/brain/awq263

6. Fishbein DH, Krupitsky E, Flannery BA, et al. Neurocognitive characterizations of Russian heroin addicts without a significant history of other drug use. Drug Alcohol Depend. 2007;90(1):25-38. doi:10.1016/j.drugalcdep.2007.02.015

7. Davydov DM, Polunina AG. Heroin abusers' performance on the Tower of London Test relates to the baseline EEG alpha2 mean frequency shifts. Prog.Neuro-Psychopharmacol.Biol.Psychiatry. 2004;28(7). doi:10.1016/j.pnpbp.2004.06.006

8. Briun EA, Gekht AB, Polunina AG, Davydov DM, Gusev EI. Neuropsychological deficit in chronic heroin abusers. Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova. 2001;101(3):10-19. Accessed June 20, 2024. https://europepmc.org/article/med/11490442

9. Miller M, Barber CW, Leatherman S, et al. Prescription Opioid Duration of Action and the Risk of Unintentional Overdose Among Patients Receiving Opioid Therapy. JAMA Intern Med. 2015;175(4