The opium poppy is used for the production of various opioidsAlastair Rae

2017 saw an estimated 72,000 deaths from drug overdoses in the US, of which nearly 48,000 were linked to opioid usage. This exceeded the number of deaths involving road traffic accidents and firearms, which stood at 40,100 and 39,773 respectively. This epidemic is far from confined to North America, however; Nigeria, for example, is witnessing a dramatic rise in misuse of the opioid tramadol. Much of this has been traced back to the legal use of prescription opioids in the treatment of pain. It is the responsibility of government, doctors and healthcare providers to consider the current global crisis and where appropriate, challenge the perceptions, clinical use and supply of opioids in the UK and overseas to guard against a similar crisis.

The term opioid refers to a group of substances which bind to four types of opioid receptors, widely distributed throughout the body, from the nervous system where they exert their analgesic (pain-relieving) effects, to sites such as the digestive system. The diversity of opioid receptors and their location makes opioid drugs more than mere modulators of pain. Stimulation of opioid receptors in the gut slows down its movement and can lead to constipation. Opioids can also affect the immune system and have been linked to increased infection in heroin addicts, a factor of particular relevance for patients with chronic pain, which can itself cause immunosuppression. Further still, opioids can decrease production of a range of hormones including testosterone, cortisol and oestrogen which can induce symptoms ranging from sexual dysfunction to depression.

Explained How do opioids work?

The analgesic and euphoric effects of most widely used opioids are largely mediated by activation of μ opioid receptors (MORs), while opioid receptor blockers are used to treat overdoses and reduce opioid-induced side effects.

MORs are present in areas of the brain such as the periaqueductal gray (PAG) which modulates pain signals from the rest of the body. Opioids are thought to activate central pathways which inhibit the transmission of pain signals, and also modulate the initial responses to painful stimuli in the periphery.

Following the archetypal opioid morphine, further drugs with differing properties have been developed. The pain-relieving effect of codeine is only 20% that of morphine for the same dose. It is also better absorbed when taken orally, making it more suitable for treatment of mild pain. In contrast, the synthetic opioid fentanyl first produced in 1960 is around a hundred times more potent than morphine and has become used widely to control pain in post-operative and cancer patients. Heroin meanwhile has a potency twice that of morphine, into which it is ultimately broken down, but passes more easily into the brain, making it preferred for recreational use.

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More immediately life-threatening, however, are the central nervous system side effects of opioids, which are behind the majority of acute overdose deaths. Breathing is notably depressed with opioid use and can ultimately cease altogether. To make matters worse, the risks associated with opioids increase further in the context of two phenomena: tolerance and addiction.

“The opioid signalling system has a remarkable ability—possibly unequalled by any other receptor system in the body—for tolerance development”

Tolerance describes the decreasing effect of a dose of a drug, especially when given repeatedly. While some patients don’t develop an extensive tolerance, it is common for opioid doses to be increased substantially over the course of treatment in order to achieve the same analgesic effects. These show the greatest degree of tolerance, followed by, commonly, respiratory and peripheral effects in the digestive tract. Known as differential tolerance, this markedly increases the severity of side effects relative to analgesic effects as opioid doses escalate, greatly limiting their long-term efficacy.

In contrast, addiction refers to the compulsive use of a drug. The potent combination of tolerance and addiction makes it difficult for long-term opioid users to abstain, even if the drugs become ineffective in relieving the very pain that they were first prescribed to combat. Due to the consequences of abuse, diamorphine, morphine and fentanyl are all categorised as Class A drugs, with unauthorised possession carrying a potential seven-year prison sentence in the UK. Despite potentially fatal side-effects, these drugs are all licenced by the National Institute of Clinical Excellence (NICE) for medical use. Why is this the case?

Opioids are broadly still the most effective treatment for relieving most types of severe short-term pain. While non-opioids are useful in treating mild pain and in combination with opioids, their independent ability to control moderate to severe pain is often insufficient.

“Almost half of patients with advanced cancer are under-treated for their pain, largely because clinicians are reluctant to use strong opioids”

The efficacy of opioids in controlling severe acute pain and cancer pain is high, and addiction rates are remarkably low. As such, over half of cancer patients in the last three months of their life are given opioids which play a crucial role in palliative care. Fear of addiction can, however, lead to clinicians being inappropriately cautious in prescribing opioids.

Modern pharmacological control of pain also rarely uses one drug in isolation. The efficacy of opioids can be augmented, or even replaced in many cases, by a number of other classes. A group of researchers at the University of Cambridge recently published a report outlining the role of the pregenual anterior cingulate cortex (a part of the brain) in controlling the body’s own pain relief pathways. The group hopes that understanding of the system that controls perception of pain in different circumstances will allow the development of new drugs and better use of current classes. Despite this, it is wishful thinking to believe that non-opioid analgesics represent entirely safe alternatives or adjuncts. By one estimate, non-steroidal anti-inflammatory drugs such as ibuprofen were responsible for more deaths in the UK in 2011 than road traffic accidents, mainly due to gastrointestinal bleeding and cardiovascular disease. Effectively controlling the opioid crisis therefore requires prescribing practices that ensure all analgesics are only used when evidence shows their benefits to outweigh their harm.

“Opioids are ineffective in much chronic pain beyond modest effects in the short term”

A review in 2017 estimated the incidence of chronic pain, defined as that lasting for more than 12 weeks to be 43% in the UK, with estimates rising  due to an ageing population. Lack of effective treatment for chronic pain can lead to unsuitable prescriptions of opioids and ensuing addiction, with little clinical benefit. In addition to being ineffective, inappropriate opioid use is intrinsically dangerous. GPs, however, with few alternatives, often prescribe opioids for fear of turning patients away without pain medication. Primary care is in need of more effective support in these scenarios.

Rises in opioid use and misuse are well-documented in the UK. In 2017 there were 24m prescriptions for opioids issued by the NHS, though less than half the number per person prescribed in the US. In the last 15 years the proportion of UK patients prescribed opioids has doubled while US prescription rates have been falling since a peak in 2012.  Public Health England is due to publish a report in early 2019 examining dependence on and withdrawal from prescribed medicines, including opioids. This is expected to go further in linking prescribing practices and opioid addiction.

On the other hand, the nature of the UK healthcare system has rendered it more resistant to irresponsible prescription. The vast majority of opioids are prescribed by the NHS, allowing better monitoring of the practices of hospitals, regions and individual doctors. Patients are also less able to shop around for alternative opinions when access to opioids is controlled or refused on clinical grounds. As such, the UK is not likely to witness a prescription opioid crisis of the same magnitude as that seen in the US.


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Yet the issue runs deeper than simply prescribing practices. Studies in the US suggest that simply cutting the supply of prescription opioids is insufficient when demand itself is not controlled. While the opioid crisis was largely initiated by legal use, illegal trade has the potential to fill the void left by a reflexive tightening of prescribing practices. With its high potency, fentanyl is easier and more lucrative to trade, with a single kilogram potentially fetching in excess of £1m on the black market. To complicate matters, an estimated 7.5% of adults in the UK aged 16-59 admitted to having taken prescription-only painkillers not prescribed to them, in doing so bypassing a crucial clinical checkpoint designed to prevent inappropriate use. There is also an extensive social stratification of this problem, which cannot be ignored any longer.

It is clear that controlling the opioid crisis will therefore require a combination of measures from patient education to improved classification and treatment of addiction and control over illicit supplies. There is evidently huge demand for better management of long-term pain with combinations of opioid and non-opioid drugs in addition to non-pharmacological measures. What links these changes is the need for an evidence-based approach which appreciates the complexity of the current crisis. It is not only doctors that should have a role to play if the UK is to effectively mitigate against and control an opioid epidemic. Nevertheless, appropriate challenges to opioid use in many circumstances should not hinder the use of opioids in scenarios where their effectiveness is well-supported.

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