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  • Team: Georgia Richards, Jeffrey K Aronson, Nicholas DeVito, Ben Goldacre, Carl Heneghan, Richard Hobbs, Constantinos Koshiaris, Kamal R. Mahtani, Tonny Brian Muthee
  • Theme: Communicating evidence
  • Completed projects

Oxford researchers review the evidence of Opioid use through multiple studies and systematic reviews, leading to the identification of 233 opioid drugs, development of The Oxford Catalogue of Opioids and six publications. This project is split into six core areas of research as highlighted below:

Part 1

Oxford Researchers recommend greater action to promote best practice as a new study reveals a rise in prescriptions of opioids for treating chronic pain rise between 1998 and 2018.

Background & METHOD

Recognising a call for greater monitoring of opioid prescribing in the UK, particularly of strong opioids in chronic pain, for which there is little evidence of clinical benefit, Oxford researchers aimed to comprehensively assess trends and variation in opioid prescribing in primary care in England, from 1998 to 2018 and factors associated with high-dose opioid prescribing behaviour in general practices, by conducting a retrospective database study using open data sources on prescribing for all general practices in England.

CONCLUSION

Between 1998 and 2016, opioid prescriptions increased by 34% in England. After correcting for total oral morphine equivalency, the increase was 127%. If every practice prescribed high-dose opioids at the lowest decile rate, 543 000 fewer high-dose prescriptions could have been issued over a period of 6 months. 

Failing to account for opioid strength would substantially underestimate the true increase in opioid prescribing in the National Health Service (NHS) in England. Our findings support calls for greater action to promote best practice in chronic pain prescribing and to reduce geographical variation. This study provides a model for routine monitoring of opioid prescribing to aid targeting of interventions to reduce high-dose prescribing.

This study was published in the Lancet, 20 December, 2018. 

Funding

National Institute for Health Research (NIHR) School of Primary Care Research, NIHR Biomedical Research Centre Oxford, NHS England.

Part 2

Oxford researchers conduct systematic review of observational studies, assessed factors associated with prescribing high-dose #opioids in primary care. 

Background 

The risks of harms from opioids increase substantially at high doses, and high-dose prescribing has increased in primary care. However, little is known about what leads to high-dose prescribing, and studies exploring this have not been synthesized. We, therefore, systematically synthesized factors associated with the prescribing of high-dose opioids in primary care. 

METHOD

A systematic review of observational studies was conducted in high-income countries that used patient-level primary care data and explored any factor(s) in people for whom opioids were prescribed, stratified by oral morphine equivalents (OME). 

Conclusion

High doses of opioids are associated with greater risks of harms. Associated factors such as the co-prescription of benzodiazepines and depression identify priority areas that should be considered when selecting, identifying, and managing people taking high-dose opioids in primary care. Coordinated strategies and services that promote the safe prescribing of opioids are needed.

This research was published in the BMC Medicine, 30 March 2020.

 Part 3 

Oxford researchers produce cross-sectional study assessing 137 national Essential Medicines Lists to determine the numbers and types of opioids in lists & the relation of opioid consumption.

Background

Opioids are deemed essential medicines by the World Health Organization (WHO). However, many countries have inadequate access to them. Whether including opioids in national essential medicines lists (EMLs) influences national opioid consumption has not been evaluated.

Method

The cross-sectional study was conducted to determine whether the listing of opioids in national EMLs was associated with consumption. by quantifying the numbers and types of all opioids included in 137 national EMLs, for comparison with opioids in the WHO’s Model List of Essential Medicines. Using the International Narcotics Control Board (INCB) consumption statistics for 2015–2017, they assessed the relation between annual mean opioid consumption (mg/person) and the numbers of opioids included in EMLs, controlling for region, population, healthcare expenditure, life expectancy, gross domestic product, human development and corruption.

Conclusion

Including opioids in national EMLs was not associated with consumption. National EMLs should be regularly updated to reflect the availability of opioids and the populations’ needs for managing pain.

This study was published in the BMJ Global Health, 10 Nov 2020.

Part 4

An evidence synthesis was conducted of pharmacology databases & resources; quantifying the number of opioids developed and resulting in the creation of the Oxford Catalogue of Opioids. 

Background

The growing demand for analgesia, coupled with an increasing need to treat opioid dependence and overdose, has escalated the development of novel opioids. We aimed to quantify the number of opioid drugs developed and to catalogue them based on their pharmacology.

Method

The systematic search was conducted of seven sources in November 2020, including the WHO's Anatomical Therapeutic Classification index, the British National Formulary, the IUPHAR/BPS Guide to Pharmacology, the International Narcotics Control Board Index of Names of Narcotic Drugs, the WHO's International Nonproprietary Names MedNet service, Martindale's Extra Pharmacopoeia and the Merck Index, to include opioid drugs that targeted or had an effect or coeffect at one or more opioid receptors. We extracted chemical and nonproprietary names, drug stems, molecular formulas, molecular weights, receptor targets, actions at opioid receptors and classes based on their origins. We used descriptive statistics and calculated medians and interquartile ranges where appropriate.

Conclusion

233 opioid drugs were identified and as a result an online resource was created to centralize and disseminate information that could assist researchers, prescribers and the public to improve the safe use of opioids:   www.catalogueofopioids.net. 

There were 10 unique drug stems, and “fentanil” accounted for one-fifth of all opioids. Most of the drugs (n = 133) targeted mu-opioid receptors and the majority (n = 191) were agonists at one or more receptors. 82% were synthetic opioids, 16% were semisynthetic opioids and 3%  alkaloids. 

This work was published in the British Journal of Clinical Pharmacology, 19 Feb 2021

Part 5

A retrospective observational study, examined sales of over-the-counter #codeine products in the UK and 30 other countries using data from IQVIA.

Background

Opioid prescribing trends have been well investigated in many countries. However, the patterns of opioids purchased over-the-counter (OTC) without a prescription are mostly unknown. Codeine is an opioid that is widely available OTC in many countries. We aimed to assess national sales and public expenditure of OTC codeine-containing products purchased in 31 countries between 2013 and 2019.

Method

Oxford researchers conducted a retrospective observational study using electronic point-of-sale data from IQVIA. Countries included Argentina, Belgium, Brazil, Bulgaria, Canada, Croatia, Estonia, Finland, France, Germany, Greece, Ireland, Italy, Japan, Latvia, Lithuania, Mexico, The Netherlands, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, South Africa, Spain, Switzerland, Thailand, the UK, and the USA. They calculated the annual mean volume of sales per 1000 of the population and public expenditure (GBP, £ per 1000) between April 2013 and March 2019. We quantified changes over time and the types of products sold.

Conclusion

31.5 billion units of codeine, costing £2.55 billion, were sold OTC in 31 countries between April 2013 and March 2019. Total sales increased by 3% (3025 units/1000 in 2013 to 3111 in 2019) and public expenditure doubled (£196/1000 in 2013 to £301 in 2019). Sales were not equally distributed across the 31 countries. South Africa accounted for the largest mean volume of sales (31 units/person), followed by Ireland (24 units/person), France (16 units/person), Latvia (15 units/person), and the UK (11 units/person). The types of products (n=569) and formulations (n=12) varied.

In many parts of the world, a substantial number of people may be purchasing and consuming codeine from OTC products. Clinicians should ask patients about their use of OTC products. Public health measures are required to identify and prevent codeine misuse and abuse, increase awareness and education about the harms of codeine, and review medicines legislation to improve the collection of such data.

The results were posted on Medrxiv, 23 April 2021.

Funding

The Primary Care Research Trust of Birmingham and Midlands Research Practices Consortium provided the funds to purchase the sales data from IQVIA. The sponsor was not involved in the study design, collection, analysis or interpretation of data, writing of the manuscript, or decisions on submitting the manuscript for publication.

Part 6

A cross-sectional study examined global, regional & national consumption of #opioids in 214 countries & non-metropolitan territories. 

Background

The consumption of opioids has increased globally since the 1990s. Previous studies of global opioid consumption have concentrated on morphine alone or a subset of opioids, with a focus on cancer pain and palliative care. In this study, we have determined the global, regional, and national consumption of all controlled opioids, including anaesthetics, analgesics, antidiarrheals, opioid substitution therapies, and cough suppressants.

Method

A cross-sectional study was conducted using data from the International Narcotics Control Board (INCB). We calculated mean opioid consumption (mg/person) globally, regionally, and nationally for 2015–2017, where consumption refers to the total amount of controlled opioids distributed for medical purposes and excludes recreational use. The researchers ranked countries by total consumption and quantified the types of opioids consumed globally.

Conclusion

Between 2015 and 2017, 90% of the world’s population consumed only 11% of controlled opioids. An average of 32 mg/person was consumed annually, but this was not equally distributed across the world. Consumption was the highest in Germany (480 mg/person), followed by Iceland (428 mg/person), the United States (398 mg/person) and Canada (333 mg/person). Oxycodone (35%) was the most heavily consumed controlled opioid globally, followed by morphine (15.9%), methadone (15.8%) and tilidine (14%).

Large disparities persist in most of the world in accessing essential opioid medicines. Consumption patterns should continue to be monitored, and collaborative strategies should be developed to promote access and the appropriate prescribing of opioids in all countries and non-metropolitan territories.

This study was published in the British Journal of Pain, 4 May 2021. 

 Final words

Opioids can be overused, underused & cause fatal & non-fatal harms, but are essential medicines that must have a place in modern medicine by being used in the right patient, at the right dosage, formulation & intervals, for the right duration & indication. 

This work led to another project around preventing deaths by reviewing Coroners' concerns to prevent harms and disseminating important lessons that serve patient safety and prevent similar deaths: Preventable Deaths — Centre for Evidence-Based Medicine (CEBM), University of Oxford.