Synthetic opioids and their characteristics

There are four main types of synthetic opioid: nitazenes, fentanyl analogues, U-type compounds (‘utopioids’) and brorphine-like opioids. Fentanyls can be divided into two categories: pharmaceutical fentanyls (such as fentanyl, sufentanil, remifentanil and alfentanil) and non-pharmaceutical fentanyls, which are fentanyl analogues or designer fentanyls (such as ocfentanil, butyrfentanyl).

Mode of use

Synthetic opioids are produced in several forms, including powders, tablets (such as standard pills or lozenges), skin patches (transdermal patches) and liquids. They are also sold as benzodiazepines or pain relief medication in blister packs or boxes that look like legitimate pharmaceutical products (European Union Drugs Agency 2024a). They can be taken into the body in many ways: by swallowing, snorting through the nose, smoking, vaping, injecting, applying to the skin, or placing under the tongue, in the vagina or in the rectum. Although not intended for oral ingestion, when a transdermal patch is chewed before being swallowed, the body may absorb more of the drug than it would from swallowing alone. Even after a patch has been worn for treatment, it often still contains a significant amount of the drug. Because of this, people may try to extract the remaining drug from used patches to take it in other ways, such as by injection or snorting.

Traces of clandestinely produced synthetic opioids have been identified on bottle caps and spoons, which demonstrates their misuse as replacements for heroin or other opioids (European Union Drugs Agency 2024a).

Drug effects

Synthetic opioids affect individuals differently depending on the person’s size, body weight and general health. Other factors include the drug’s amount, strength and administration route, and the individual’s degree of tolerance and whether other psychoactive drugs have been taken at the same time. These factors all result in different duration of onset of symptoms and effects. Short-term effects include euphoria, relaxation, pain relief, nausea, vomiting, fever, sweating, hypotension, and slow breathing and heart rate.

As reviewed by Shafi et al (Reference Shafi, Berry and Sumnall2022) and Salle et al (Reference Salle, Bodeau and Dhersin2019), synthetic opioids affect all the major body systems (Box 1). Other effects have also been reported by Kotlińska-Lemieszek (Reference Kotlińska-Lemieszek and Żylicz2022):

• long-term use affects the endocrine system by inhibiting the hypothalamic–pituitary–gonadal axis, resulting in a decrease in testosterone and oestradiol release; this can manifest clinically as loss of libido and impotence in males, amenorrhoea and infertility in females; these symptoms may also lead to reduced energy levels and depression;

• opioids can also inhibit the hypothalamic–pituitary–adrenal axis, which can sometimes present clinically as an adrenal crisis;

• the androgen deficiency promotes osteoporosis, and in chronic use, insulin resistance can appear;

• opioid use can lead to immunosuppression, increasing risk of infections and stimulating gastrointestinal and pulmonary cancer;

• decreased bone density (osteopenia) and increased risk of fractures are well recognised in long-term opioid use;

• opioid use can impair sleep quality and patterns, leading to daytime sleepiness and fatigue;

• opioids can trigger or exacerbate sleep apnoea in predisposed individuals.

Key risk factors for synthetic opioid-related deaths

Reviews and studies have identified a number of risk factors and risk contexts associated with the use of synthetic opioids and the involvement of these drugs in deaths. For example, data from the USA and Europe show that males, compared with females, tend to have higher drug overdose mortality (Butelman Reference Butelman, Huang and Epstein2023; European Union Drugs Agency 2024a, b). In the UK in 2023, there were 127.6 drug-poisoning deaths registered per million population (3645 deaths) among males, compared with 59.8 deaths per million among females (1803 deaths) (OHID 2024a). Although late adolescence and young adulthood are periods of increased risk, the rise of adults aged 55 and older seeking first-time treatment (European Union Drugs Agency 2024a) may indicate an increased risk of death occurring. Low socioeconomic status and marginalisation of some population groups, such as homeless people, have been identified as particular risk factors (Devany Reference Devany2019; Scheibein Reference Scheibein, Wells and Henriques2020); contexts such as prisons are noted as ‘risk environments’ in terms of deaths from synthetic opioid use (Duke Reference Duke, Gleeson and MacGregor2023). People who have a history of problematic drug use and polydrug use are also at greater risk of drug-related mortality (Armoon Reference Armoon, Mohammad and Moghaddam2023).

Prevalence of synthetic opioid-related deaths

The European Union Drugs Agency estimated that there were around 6400 drug-induced deaths in the EU in 2022, with considerable variation between countries (European Union Drugs Agency 2024a): this represents a mortality rate of 22.5 deaths per million population aged 15 to 64. The report noted the growing concern over deaths linked to synthetic opioids but, with a few exceptions, these drugs are not routinely monitored or reported at EU level. It is likely, therefore, that deaths linked to synthetic opioids are under-reported.

The UK has one of the highest rates of drug-related deaths among European countries. Global markets are rapidly evolving, reflecting growing alarm that the UK may potentially face a similar ‘opioid epidemic’ as in the USA. Data published by the Office for National Statistics reveal that there were 5448 drug-related deaths in England and Wales in 2023 (Office for National Statistics 2024).

The UK’s first nitazene death was recorded in 2019 and a big influx in the summer of 2024 has seen nitazenes detected all over the country. The OHID and the National Crime Agency confirmed that there were 179 deaths involving one or more nitazenes between 1 June 2023 and 31 May 2024 in England (OHID 2024a). Over this period, nitazenes were present in all deaths involving illicit fentanyl or analogues of fentanyl. However, from available information, it is not always possible to determine whether fentanyl involved in a death was illicit or pharmaceutical. Table 1 shows the number of these deaths associated with different nitazene compounds identified by laboratory tests. In 17 out of the total 179 deaths, there was no confirmation of the specific compounds involved.

TABLE 1

Deaths (n = 179) associated with nitazene use in England, 1 June 2023 to 31 May 2024

a. More than one nitazene was detected in some deaths, so the sum of detections is greater than the total nitazene deaths.

Source: Office for Health Improvement and Disparities (2024a).

Deaths involving nitazenes have been recorded in every region of England, with notable differences across the regions. For example, of the 179 deaths between June 2023 and May 2024, the region with the highest rate was the East of England, with 33 deaths, followed by the East Midlands with 29 deaths. Only 3 deaths were recorded in the North East, with a range of 12 to 25 deaths occurring in the remaining six regions (OHID 2024a). We found no research examining the reasons for these regional differences in England. However, analyses of differences in drug-related deaths between England and Scotland, and between Europe, the USA and the UK, suggest that a complex range of factors is at play, including drug availability, an ageing cohort, the number of people not in drug treatment and the nature of available treatment services in an area (Pierce Reference Pierce, van Amsterdam and Kalkman2021; van Amsterdam Reference van Amsterdam, van den Brink and Pierce2021).

Synthetic opioids: a looming crisis?

The rise of synthetic opioids in Europe, particularly those linked to fatal overdoses and acute poisonings, has alarmed health services and law enforcement agencies.

Some potential reasons why synthetic opioid use has become so pervasive have been postulated to include lower production costs, stronger or longer-lasting highs and increasingly efficient synthesis by manufacturers (Ciccarone Reference Ciccarone2021; Kline Reference Kline, Mattern and Cooperman2021).

These substances are easily transported and hidden, and they can be produced in small quantities to yield large numbers of street-level doses. Although Europe’s opioid crisis is not as severe as the US fentanyl crisis, it is still a significant public health concern (European Union Drugs Agency 2024b).

The European Union Agency for Law Enforcement Cooperation (Europol) has identified 49 synthetic opioids in the European drug market since 2009, with 34 being fentanyl derivatives. In 2018 alone, six new opioid derivatives emerged. Synthetic opioids are now the fourth most commonly monitored substance group in Europe, following synthetic cannabinoids, cathinones and phenethylamines. Fentanyl derivatives accounted for over 70% of synthetic opioid seizures in Europe in 2017 (European Union Drugs Agency 2024b).

The harms associated with opioid use and the importance of addressing unmet needs in opiate dependence to avoid overdose have been well documented in the literature (Herlinger Reference Herlinger and Lingford-Hughes2021).

Synthetic opioid exposure has been demonstrated to confer nearly twice the risk of fatal overdose relative to prescription opioids or heroin (Florence Reference Florence, Luo and Rice2021; Manchikanti Reference Manchikanti, Singh and Staats2022). The combination of minimal production costs and extraordinary potency renders fentanyl particularly suitable for admixture with heroin and other illicit substances (Volkow Reference Volkow and Blanco2021). In addition, fentanyl and related analogues are frequently encountered in counterfeit formulations designed to mimic the appearance of widely prescribed opioids and benzodiazepines, colloquially termed ‘pressed pills’ (Armenian Reference Armenian, Vo and Barr-Walker2018).

According to the US Drug Enforcement Administration (2021), synthetic opioid-related deaths are frequently attributable to their use as low-cost adulterants, although intentional consumption also occurs. The inadvertent exposure of users to fentanyl and its analogues, now routinely detected in cocaine, methamphetamine, heroin and falsified pharmaceuticals, is regarded as a principal driver of drug-related overdose deaths (Han Reference Han, Yan and Zheng2019).

The heightened overdose risk associated with synthetic opioids compared with heroin stems from their far greater potency and availability within the drug supply (Skolnick Reference Skolnick2022). A dose that might be ‘normal’ for heroin can be fatal without immediate medical intervention if replaced with fentanyl or carfentanil. In addition, while a heroin overdose may take 20–30 min to become deadly, fentanyl can cause severe, life-threatening respiratory arrest within just 2–5 min (Skolnick Reference Skolnick2022).

In addition, fentanyl derivatives have significant risk of addiction and can have adverse effects on health and social problems commonly associated with opioid use. Fentanyl analogues are a major cause of poisonings, fatal or not, in the USA and in Northern Europe. In other countries, their presence is less visible.

Addressing the harms of opioid misuse

In the following sections, we consider prevention approaches that address the wider public health aspects of the use of opioids and synthetic opioids, before discussing what can be done in treatment settings to identify, assess and manage synthetic opioid use and related harms.

Management of an overdose

Risk factors for opioid overdose are listed in Box 4. Many of these generally apply to synthetic opioid overdose as well. However, some factors may be more pronounced with synthetic opioids, owing to their potency and unpredictable nature (Box 5).

The administration of naloxone is key in the management of opioid and synthetic opioid overdose, and Box 6 provides information and advice its use.

Challenges and barriers

Synthetic opioids, like other novel psychoactive substance groups, constantly evolve. Therefore, surveillance and monitoring programmes are essential to keep up with the associated public health challenges. As mentioned above, the OHID (part of the Department of Health and Social Care) has been working with the National Crime Agency to monitor deaths associated with illicit use of potent synthetic opioids in the UK (OHID 2024a).

The information they provide is necessary to prioritise synthetic opioids for international review and eventual scheduling and regulation. It is imperative to implement regional testing of drug samples and establish forensic services where they do not exist. In addition, laboratories must modify their current methods or develop new forensic and toxicological analytical methods to detect emerging drugs. This can be challenging as data on the emergence of synthetic opioids differ between regions and become rapidly outdated (OHID 2024a).

Testing of drug samples should be more regularly carried out in primary and secondary care settings as well as in the criminal justice system.

The global spread of synthetic opioids is a serious issue that requires coordinated international responses. These substances are widely accessible on the dark web, easy to hide and can be delivered through standard or express mail services. Clinicians should be aware that commonly used detection/analysis kits may not identify fentanyl analogues or newer synthetic opioids, and they must remain vigilant for signs of opioid use, such as slow or shallow breathing, bluish skin (cyanosis) and pinpoint pupils (miosis). In such cases, naloxone remains the first-line treatment for opioid intoxication. Naloxone is widely recognised as an effective intervention for reversing opioid-induced respiratory depression and has saved countless lives (Albores-García Reference Albores-García and Cruz2023).

Because fentanyl and other synthetic opioids are extremely potent, multiple doses of naloxone – or repeated administrations of the nasal spray where available – may be required, along with an extended monitoring period. Naloxone works by binding to opioid receptors without activating them, thereby displacing opioid drugs and reversing the life-threatening respiratory depression caused by heroin, fentanyl and other synthetic opioids (Albores-García Reference Albores-García and Cruz2023).

Another challenge within specialist addiction treatment services is to adopt proactive outreach approaches targeting high-risk populations and thus expand the cohort receiving OST. Current local clinical guidance on prescribing of OST needs to be updated, given the increased use of buprenorphine and associated practices mentioned earlier.

In both primary and secondary care, clinicians need to be aware of the risks of iatrogenic addiction to opioids prescribed for pain management, especially chronic pain, and training and education should address this.

Several of the above challenges might be overcome by the integration of ongoing research and evidence-based treatment into protocols for managing synthetic opioid misuse, and by collaboration between addiction specialists, colleagues in other specialties and general practitioners (Morris Reference Morris2021).

What do we need to do?

Although it is not within the scope of this article, more attention needs to be given to pain management and opioid use disorder (OUD). Understanding pain is important to further understand the neurobiology of OUD and to help develop more effective prevention and treatment.

In the meantime, five areas are central to reversing the opioid crisis: (a) improving treatments for chronic pain and improving opioid prescription practices; (b) expanding access to medications for OUD; (c) expanding the availability of naloxone and developing models to link patients who experience overdose to OUD treatment; (d) improving prevention by focusing on the risk factors for opioid misuse and OUD; and (e) raising awareness among healthcare providers, patients and the general public about the dangers of synthetic opioids, including their potency, addictive nature and potential for overdose.

Achieving these goals requires reversing the stigma attached to medications for OUD, removing infrastructural barriers to their adoption, and expanding the engagement of healthcare professionals, including psychiatrists and those in criminal justice settings, in OUD treatment. Against this background, strategies to address the psychosocial factors that lead people to use opioids and other drugs are necessary.

Overdose prevention centres where people can use their own drugs in a monitored and safe space with professionals on hand to intervene in the event of an overdose need to be set up throughout the UK. These were first established in Switzerland more than 20 years ago and if they are resourced properly the evidence base for them is substantial. They also provide an invaluable opportunity to give additional support to the most marginalised people, who can be offered referrals to relevant social, health and drug treatment services. The Faculty of Public Health (a membership organisation for public health professionals) has led calls from more than 100 public health, medical, academic, drug treatment and advocacy organisations calling for overdose prevention centres in the UK. The first such centre opened in Glasgow on 13 January 2025, with support from the Scottish Government.

Drug checking services, where the public can submit substances for testing to find out what is in them, give healthcare professionals and drug workers an opportunity to offer advice and referrals to other support if needed. If people have access to these services, they can check whether their substances contain nitazenes or other dangerous drugs and avoid inadvertently consuming them.

The stigma faced by people who use drugs is a key barrier stopping them from engaging with services that would otherwise help them keep themselves safe, and it must be challenged. People with the most harmful patterns of drug use often experience other problems, such as socioeconomic deprivation, homelessness and trauma, which have led to or exacerbated harmful relationships with drugs. Stigma only makes their lives harder and may aggravate the factors that led them to develop problems with drugs in the first place (Volkow Reference Volkow, Jones and Einstein2019).

Key implications and recommendations for practising psychiatrists

Key implications of this overview are listed in Box 7. The increasing challenges posed by the rise in the availability and use of synthetic opioids indicate the following recommendations for psychiatrists.

• Educate patients: discuss the risks associated with illicit drug use, including the potential presence of fentanyl and other synthetic opioids.

• Assess for risk: screen patients for OUD and assess their risk of overdose.

• Adopt harm reduction strategies:

  1. (i) discuss safer use practices, such as avoiding mixing opioids with other substances and not using alone;

  2. (ii) provide information on naloxone and encourage patients to carry it;

  3. (iii) connect patients with harm reduction services, such as needle exchange programmes and overdose prevention training;

  4. (iv) offer support for substance use treatment, including OST, and encourage wider use of buprenorphine with rapid prescribing practices.

• Advocate for policy changes: support policies that address the opioid crisis, such as increased access to treatment, harm reduction programmes and overdose prevention initiatives (Lovrecic Reference Lovrecic, Lovrecic and Gabrovec2019).