What is The Opioid Problem all about?


You’ve probably heard about the "opioid problem" in the news before, but how did it arise in the first place?


Opioids have proven to be a feasible and readily available option for acute pain management due to their incredible effectiveness [1]. However, long-term exposure to opioid-derived drugs can lead to relapsing use, such that patients who no longer require medical, therapeutic intervention become addicted, seeking cheaper illicit substitutes for extra-medical and recreational purposes, like heroin [2]. As a result, narcotic painkillers have paved the way for a multitude of societal conundrums across the Western world. Understanding how complex opioid drugs work in the central nervous system (CNS) is critical to mediating or solving the “opioid problem”.



The Neuroscience of Opioid-Induced Pain Relief and Addiction

In 2018, the global opioid market was valued at AUD$35.5 billion, [3] highlighting the lucrative nature of the modern-day pharmaceutical industry. Opioid pharmaceuticals can either be harvested from the Papaver somniferum, the opium poppy, or synthetically manufactured in a laboratory. Opioid drugs work in the body by interacting with mu, delta and kappa opioid receptors found on cell membranes in many regions of the nervous system [4]. Different receptor subtypes are coupled to intracellular mechanisms via G-proteins. Different opioids have varying affinity for different opioid receptors, [5] with specific receptor activations generating different effects within the body. [6] Generally, opioids provide pain relief by inhibiting the release of certain neurotransmitters which are responsible for transmitting pain signals. More specifically, opioids reduce Ca2+ entry, increase K+ outward movement and block the action of adenylate cyclase in cells. [7] As a result, the activity of the CNS slows down, the body’s perception of pain is muffled, and sedative feelings of pleasure and euphoria are induced.


What about the neurobiology underlying opioid tolerance and addictions? This phenomenon mainly stems from the increased binding of opioid drugs with mu opioid receptors (MORs) on neurons in the brain, which has two key effects. Firstly, the opioids will cause decreased noradrenaline (NA) release in the locus coeruleus (LC), which will in turn result in sedation and shallower breathing. [8] However, the body will try to compensate for these changes by increasing the raw materials used to produce NA, such that normal levels of alertness and respiration are restored. Thus, with repeated use, the same dose of opioids will have less severe effects on the individual, resulting in drug tolerance. The binding of opioids to MORS also triggers increased dopamine (DA) release by cells in the ventral tegmental area (VTA) into the nucleus accumbens (NAc). Such excessive amounts of DA in the brain will prompt the body to restore balance by decreasing baseline or “resting state” levels of DA release. Therefore, although the initial flood of DA following opioid use results in euphoria, once the drug’s effects wear off, the user’s now lowered baseline DA levels will cause dysphoria and other withdrawal symptoms. These unpleasant states can motivate the user to engage in further opioid use as a means of escape, thus perpetuating the addiction cycle. [9]



Figure 1. Key Areas in Opioid Tolerance and Dependence. The figure shows the ventral tengmental area (VTA), nucleus accumbens (NAc) which produce and receive dopamine collectively. Also shown is the locus ceruleus (LC) and prefrontal cortex (PFC). Collectively, these areas are part of the mesolimbic reward system. Image from [9].



The Social Costs of Opioid Abuse

Opioids have a significant place in medicine, but the problem often stems from legitimate use that grows into abusive patterns in patients, which could be potentially attributed to its over-prescription. So happens when an opioid prescription expires for a patient undergoing chronic or short term pain management who no longer needs one? Users end up “doctor shopping”, the process of seeing a different physician to obtain a new prescription to support their likely developed opioid habit. Every day in Australia, nearly 150 opioid-harm related hospitalisations occur and 3 people die from opioid abuse. [10] The inexpensive nature of opioids in Australia has most certainly contributed to its overuse, over-prescription and subsequent problems.


Addiction is not the only problem resulting from opioid abuse. A lesser-known phenomenon is that patients in palliative care are often uneasy with being administered opioids due to a perceived risk of developing addiction and drug-seeking behaviours. In reality, there is evidence to suggest that opioids are not addictive when used in acute pain settings. This highlights how the opioid crisis calls for a balance between distribution and regulation, where much needed reform is required in order to ensure the safety of patients is prioritised above the exponential profitability of the pharmaceutical industry.



Opioid Dilemmas in Australia & the USA

Australia has faced significant challenges regarding its opioid dilemma. Although opioids cannot be bought over-the-counter here, the Pharmaceutical Benefit Scheme (PBS) makes these drugs affordable for anyone who can obtain a prescription. [11] In other words, if someone with an opioid addiction can get a prescription for such drugs, then the PBS makes their drug habit relatively cheap to maintain. This may be cause for concern, especially given that almost 15 million opioid prescriptions were dispensed in 2015. [12]


However, in 2020, the PBS in collaboration with the Therapeutic Goods of Australia (TGA) announced a policy of single quantity, no repeat opioid prescriptions for all non-chronic pain management. [13] This is a step in the right direction in response to the aforementioned high number of deaths and hospitalisations in Australia, mainly caused by legal, prescription opioids, rather than illegally-sourced opioids. [14]



Figure 2: Trends in Opioid Overdose Deaths, 2001-2012 amongst Australians 15-74 years. 58% of opioid overdose deaths were classified as pharmaceutical opioid overdose deaths during this period. Image from [15].



Compared to Australia, the USA’s own opioid problem has far more distressing economic and social ramifications. In 2007, it was estimated that societal costs to the USA of prescription-based opioid abuse was USD$55.7 billion, spent on health care, workplace and criminal justice expenses. [15] This is more than the current value of the global opioid pharmaceutical industry! A specific example of opioid abuse is oxycodone, which was initially marketed as a non-addictive drug and frequently used in the USA. This drug eventually revealed itself to be one of the primary contributors to their opioid crisis.


Additionally, there is a strong correlation between key social determinants and the increase in opioid overdose mortality, such that young adults and people from poor socioeconomic backgrounds are most affected and at risk. [16]. In the USA, unlike in Australia, the lack of a viable public healthcare system and PBS makes health costs incredibly expensive. The costs of treatment, whether it be for overcoming opioid addiction or obtaining opioids for genuine pain-management needs, can put help out of reach for many individuals.


Overall, this opioid crisis has escalated into a devastating issue, threatening the wellbeing of patients who become addicts. The variety of mental and behavioural problems from opioid exposure has led to a myriad of negativities, as opposed to its intended, medicinal good. Fortunately, in Australia, the inexpensive costs of the drugs have been balanced by a revised regulatory framework to better control when and how patients can obtain prescription opioids. On the other hand, without an equivalent PBS in place in America, former patients turn to cheaper, street equivalent, opioid-derived recreational drugs, accounting for the USA’s exceedingly high opioid-associated mortality rate. [15] Therefore, greater awareness is required to deal with the “opioid problem” and deconstruct the tribulations associated with opioid pharmaceuticals.



References:

[1] Rosenblum A, Marsch LA, Joseph H, Portenoy RK. Opioids and the treatment of chronic pain: Controversies, current status, and future directions. Experimental and Clinical Psychopharmacology [Internet]. 2008;16(5):405–16. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711509/11.


[2] Stoicea N, Costa A, Periel L, Uribe A, Weaver T, Bergese SD. Current perspectives on the opioid crisis in the US healthcare system. Medicine. 2019 May;98(20):


[3] Opioids Market Size, Share & Trends Analysis Report By Product (IR/ Short-acting, ER/Long-acting), By Application (Pain Relief, Anesthesia), By Region, And Segment Forecasts, 2019 - 2026 [Internet]. Grand View Research. 2019. Available from: https://www.grandviewresearch.com/industry-analysis/opioids-market


[4] Krieger C. What are opioids and why are they dangerous? [Internet]. Mayo Clinic. ; 2018. Available from: https://www.mayoclinic.org/diseases-conditions/prescription-drug-abuse/expert-answers/what-are-opioids/faq-2038127010.


[5] Valentino RJ, Volkow ND. Untangling the complexity of opioid receptor function. Neuropsychopharmacology. 2018 Sep 24;43(13):2514–20.


[6] Senese NB, Kandasamy R, Kochan KE, Traynor JR. Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management. Frontiers in Molecular Neuroscience. 2020 Jan 24;13.


[7] Chahl L. Experimental and Clinical Pharmacology: Opioids - mechanisms of action. Australian Prescriber. 1996;19(3):63-65.


[8] Kosten T, George T. The Neurobiology of Opioid Dependence: Implications for Treatment. Science & Practice Perspectives. 2002;1(1):13-20.


[9] Kosten T, George T. The Neurobiology of Opioid Dependence: Implications for Treatment. Science & Practice Perspectives. 2002;1(1):13-20.


[10] Australian Institute of Health and Welfare (AIHW). Opioid harm in Australia: and comparisons between Australia and Canada. 2018 Nov p. 1–89.


[11] National Centre for Education and Training on Addiction (NCETA), Nicholas R. Pharmaceutical opioids in Australia: A double-edged sword. Adelaide: Flinders University; 2019 p. 1–51.9.


[12] Campbell G, Lintzeris N, Gisev N, Larance B, Pearson S, Degenhardt L. Regulatory and other responses to the pharmaceutical opioid problem. Medical Journal of Australia. 2018 Dec 12;210(1):6.


[13] Department of Health. Revised opioids PBS listings for the management of severe disabling pain. Australian Government; 2020 p. 1-2.


[14] Australian Institute of Health and Welfare (AIHW). Opioid harm in Australia: and comparisons between Australia and Canada. 2018 Nov p. 1–89.


[15] Meyer R, Patel AM, Rattana SK, Quock TP, Mody SH. Prescription Opioid Abuse: A Literature Review of the Clinical and Economic Burden in the United States. Population Health Management. 2014 Dec;17(6):372–87.


[16] Senese NB, Kandasamy R, Kochan KE, Traynor JR. Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management. Frontiers in Molecular Neuroscience. 2020 Jan 24;13.


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