The scale of the opioid epidemic in the U.S. is alarming. According to the U.S. Centers for Disease Control, more than 200,000 people died as a result of opioid overdose between 1999 and 2016, roughly 46 people a day.

Europeans consider this failure of care a uniquely American phenomenon intrinsic to the way pharmaceuticals are marketed and prescribed in that country; this could never happen in Europe is the standard response. To the contrary however, all evidence shows the assumption is flawed. Canada, for example, which has a very different healthcare system to the U.S. is also suffering a prescription opioid crisis. In 2016, nearly 3,000 opioid-related deaths were recorded according to Health Canada; this in a population one-tenth the size of its Southern neighbor. Australia too has its problems. Levels of prescription opioid overdose, including accidental overdose are at record levels and deaths from prescription opioids now exceed those from heroin use by a significant margin.^1,2

Bolting the stable door
The U.S. and Canada are now, belatedly, adopting wide ranging strategies to curb their epidemics. These include enhanced physician training, controls on prescribing, increasing treatment and rehabilitation options, and importantly the introduction of abuse deterrent opioid medications. Early research suggests good progress is being made and that the introduction of abuse deterrent products and tablets significantly reduce opioid overdoes.^3,4,5  

In Europe, while prescription opioid consumption is still lower than in the U.S., it is growing exponentially. If such growth is not to result in a European epidemic it is vital that European authorities learn from the American experience and put prospective measures in place to mitigate abuse.

The continued need for opioid analgesics
Opioid analgesics, despite their dangers are still a vital therapeutic resource and for many they are the most effective way of treating their pain. Given the current lack of effective alternatives, it is likely that they will remain a necessity for many years to come and that over time, their use will grow.

For example, approximately 20% of European adults suffer from chronic pain conditions with those of middle age or greater suffering most frequently. Given the continent’s ageing population, this percentage will only increase.^6,7 In addition, as the population ages more surgical procedures are being conducted in Europe.⁸ This is reflected in the increasing use of opioid analgesics for postoperative pain⁹ while the growing incidence of diseases like cancer¹⁰ is also increasing the number of opioid pain medicines being prescribed.

In short, opioids are effective at controlling pain and older people need more pain control. This fact of life accounts, at least in part for the general increase in opioid prescribing across the European Union that have occurred in recent years.^{11,12,13,14,15}

Increased use, increased risk
Whether in America, Canada, Europe or Australia, there is a well-established link between the number of opioid sales and deaths from their abuse.¹⁶ In this respect, opioid medications are no different from an illicit narcotic.

Similarly the pathway from patient to abuser to overdose victim is also well documented and understood. The typical process begins with swallowing multiple tablets to achieve euphoria, followed by increased tolerance and then addiction. Once addicted, an opioid abuser is more likely to indulge in behaviors to accelerate their high, such as crushing or chewing tablets, snorting crushed tablets (insufflation) and finally, most dangerous of all, injecting crushed tablet solutions.

Prevention
It has been shown that technologies that prevent medications from being chewed, snorted or injected can significantly reduce the extent of opioid diversion and consequently the number of overdose deaths.¹⁷ Simply put, such abuse deterrent formulations, or ADFs, are an ideal way of preventing tablets from being manipulated, making it harder for overdose to occur.

Currently, there are two basic ADF strategies that have been shown to work. Firstly there are ADF technologies that possess physiochemical barriers to abuse. For example, simply making a tablet very hard makes it more resistant to chewing, crushing or grinding. Causing tablets to form a viscous gel if tampered with, reducing the possibility for injection, can further enhance ADF properties. Examples of barrier technologies include the HTR (Heat Treatment Recrystalization) platform used for OxyContin (Purdue Pharma), the Deterx platform employed by Collegium Pharma and the Intellitab platform developed by Altus Formulation.

The other common ADF approach is based on the use of agonist antagonist combination technologies. In such formulations a sequestered opioid antagonist is included in the tablet or capsule to counteract the effects of the opioid should the tablet be abused. Examples of products favoring this approach include Embeda from Pfizer, comprising morphine with the opioid antagonist naltrexone and Targiniq from Purdue Pharma which comprises hydrocodone and naloxone. While agonist antagonist combinations do not prevent abuse in the way barrier technologies can, they may dissuade abusers by mitigating the high they are looking for when snorting or injecting crushed tablets.

ADFs: Pluses and Minuses
The introduction of ADF technologies to the European market has advantages as well as pitfalls that must be avoided.

For patients, and society as a whole, ADFs offer an effective preventative measure to reduce the harm that opioids will cause if abused or misused. They are easy to use by patients and for pharmaceutical companies development is relatively straightforward incurring manufacturing costs no greater than those for non-ADF products.

In contrast, cost is an issue. In North America today all ADFs are branded products and they are significantly more expensive than non-ADF formulations, in some cases adding an additional $20 per tablet; the stress such prices place on already overstretched healthcare budgets makes their introduction in Europe unlikely to the detriment of patients and society.

To address this common problem, the U.S. FDA is championing the development of generic ADF products.^18,19 These are products that are no less effective or abuse deterrent than their branded counterparts but which can be provided to patients at a fraction of the cost. Generic ADFs therefore offer the best of both worlds, safer to use products accessible to all.  European regulators should heed the pioneering approach of the FDA. By putting in place pathways for the introduction of generic ADF now, before an epidemic emerges, Regulators can ensure patients have access to the safest products while also ensuring the societal impact and costs of drug abuse are minimized.

The Need for Surveillance
Tracking abuse is key to assessing the efficacy of any anti-abuse strategies. It is also a means of identifying new drugs that could benefit from the addition of ADF technologies. For example, products like gabapentinoids and benzodiazapines also have potential for abuse.

In the U.S., a system of pre- and post-marketing surveillance is employed. The approach has resulted in the approval of new, safer products and the removal from the market of older problem products. 

In Europe, such monitoring systems are not established, which means geographically relevant, product-specific information is not available. As a result, it is harder to monitor the extent of drug abuse and only with these systems in place will the true extent of opioid abuse in Europe become evident; it’s hard to say a problem doesn’t exist if you are not looking.

Ideally, multiple input surveillance systems comprising data from criminal justice systems, treatment professionals as well as information on susceptible patient populations and acute health events should be introduced. 

Conclusion
Europe is not immune to opioid abuse. The continent’s aging population, combined with the increasing incidence of disease is increasing the use of opioid medications prescribed in Europe which, in turn, increases the opportunity for abuse of such medicines.

It is vital Europe learns from efforts to tackle the opioid abuse epidemic in North America and encourages the adoption of measures to prevent similar problems from developing. ADF technologies incorporated in generic ADF products offer a cost-effective preventative measure, which, when linked to an effective surveillance system, can minimize the human and societal costs of abuse.

References
1. https://ajp.com.au/columns/opinion/how-can-australia-stop-the-opioid-epidemic-before-its-too-late/
2. https://www.tga.gov.au/consultation/consultation-prescription-strong-schedule-8-opioid-use-and-misuse-australia-options-regulatory-response
3. Dart RC, Surratt HL, Cicero TJ, Parrino MW, Severtson SG, Bucher-Bartelson B, Green JL.  Trends in opioid analgesic abuse and mortality in the United States.  N Engl J Med 2015;372:241-8
4. Dart RC, Iwanicki JL, Dasgupta N, Cicero TJ, Schnoll SH. Do abuse deterrent opioid formulations work J Opioid Manag. 2017;13(6):365-378. doi: 10.5055/jom.2017.0415.
5. Severtsen, G.S., Ellis,M.S., Kurtz, S,P. et al  Sustained reduction of diversion and abuse after introduction of an abuse deterrent formulation of extended release oxycodone. Drug and Alcohol Dependence 168 (2016) 219–229
6. O. van Hecke, N. Torrance and B. H. Smith*Chronic pain epidemiology and its clinical relevance. British Journal of Anaesthesia 111 (1): 13–18 (2013)
7. https://www.cdc.gov/aging/pdf/state-aging-health-in-america-2013.pdf
8. T. E. F. Abbott A. J. Fowler T. D. Dobbs E. M. Harrison M. A. Gillies R. M. Pearse Frequency of surgical treatment and related hospital procedures in the UK: BJA: British Journal of Anaesthesia, Volume 119, Issue 2, 1 August 2017, Pages 249–257,
9. A Feizerfan G Sheh Continuing Education in Anaesthesia Critical Care & Pain, Volume 15, Issue 2, 1 April 2015, Pages 98–102,
10. GW Hanks, F de Conno, N Cherny Morphine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of Cancer (2001) 84(5), 587–593
11. Ruscitto, A., Smith, B.H. and Guthrie, B. (2015). Changes in opioid and other analgesic use 1995–2010: Repeated cross-sectional analysis of dispensed prescribing for a large geographical population in Scotland. European Journal of Pain, 19: 59–66. doi: 10.1002/ejp.520
12. Zin, C.S., Chen, L.-C. and Knaggs, R.D. (2014). Changes in trends and pattern of strong opioid prescribing in primary care. European Journal of Pain, 18: 1343–1351. doi: 10.1002/j.1532-2149.2014.496.x
13. https://www.bma.org.uk/collective-voice/policy-and-research/public-and-population-health/analgesics-use
14. Karima Hider-Mlynarz , Philippe Cavalié and Patrick Maison Trends in analgesic consumption in France over the last 10 years and comparison of patterns across Europe. Br J Clin Pharmacol (2018) in press
15. Will the UK face an opioid abuse epidemic? https://onlinelibrary.wiley.com/doi/pdf/10.1002/psb.1604
16. Kate M Dunn , Kathleen W Saunders, , Carolyn M Rutter, Overdose and prescribed opioids: Associations among chronic non-cancer pain patients Ann Intern Med. 2010 January 19; 152(2): 85–92.
17. Green JL, Bucher Bartelson B, Le Lait MC, Roland CL, Masters ET, Mardekian J, Bailey JE, Dart RC. Medical outcomes associated with prescription drug abuse via oral and non-oral routes of administration. Drug Alcohol Depend 2017;175:14-145.
18. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm586117.htm
19. https://www.fda.gov/downloads/Drugs/…/Guidances/UCM492172.pdf
20. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm562401.htm

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Damon Smith founded and is chief executive officer of Altus Formulation, a company set up to develop and commercialize safer to use value added medicines incorporating INTELLITAB and other technologies.

Richard Dart is executive director of the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS) System. RADARS System is a surveillance system that collects product- and geographically-specific data on abuse, misuse, and diversion of prescription drugs in the Europe and North America.

Christopher Hirst is head of RPH Pharmaceuticals AB, a subsidiary of Recipharm AB. Recipharm is a leading CDMO in the pharmaceutical industry offering manufacturing services of pharmaceuticals in various dosage forms, production of clinical trial material and APIs, and pharmaceutical product development.