Chapter 2: Prescribing and administration of drugs and the deaths that resulted
Overview of drugs used at the hospital
Opioid analgesics are a large group of drugs used to treat moderate to severe pain, most commonly in trauma, myocardial infarction (heart attack) or other acute pain, and palliative care of people with cancer or other end of life conditions. They are also widely used in anaesthetic practice. The terms ‘opioid’ and ‘opiate’ are often used interchangeably and this is of no clinical significance.
Strictly speaking, opiates are the drugs that occur naturally in opium – mainly morphine and codeine – while opioids include a much wider group of synthetic or semi-synthetic drugs such as diamorphine, pethidine, fentanyl and tramadol. They were formerly also known as narcotic analgesics, reflecting their powerful sedative, as well as analgesic, effects. The British National Formulary (BNF), the authoritative national compendium of advice on drug therapy, uses the term opioid, which the Panel has adopted throughout this Report.
Opium is the dried juice of the seed capsule of the opium poppy. It contains 10–12% morphine and has been used medicinally since prehistoric times. Laudanum was a tincture (alcoholic solution) of opium containing about 1% morphine, which was widely used in the UK for pain and cough and, until the early 20th century, was freely available without prescription.
Opioids remain central to the management of acute and chronic pain. Whether naturally occurring like morphine, or more recent synthetic or semi-synthetic drugs like diamorphine and fentanyl, they all act in the same way. The newer opioids began to emerge in the 19th century with the development of the modern chemical industry. For example, diamorphine is a semi-synthetic drug first derived from morphine in 1874. It was marketed under the trade name heroin – incredibly in the light of what we now know of its addictive properties – as an over-the-counter, non-addictive analgesic.
The history of opioid chemistry is in fact one of repeated but doomed attempts to produce a non-addictive strong painkiller. This is exemplified most recently by tramadol, which was initially thought to be safer and less addictive than other opioids when introduced in the UK. However, it is now known to be widely misused and to cause widespread dependency and increasing numbers of deaths through accidental or deliberate overdose. Following a government consultation, it was therefore reclassified as a controlled drug in 2014.1 ,2 Pethidine is a totally synthetic drug introduced in 1939 and widely used in obstetrics for many years. Fentanyl, a highly potent synthetic opioid which is also active via the skin so can be used in dermal patches, was introduced in 1960.
Opioids are of immense value in the management of acute and chronic pain and in anaesthetic practice:
“Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.” Thomas Sydenham, physician, 1680
Opioids are used to help manage the acute pain of trauma and myocardial infarction, in maintaining pain control in anaesthesia, and in the management of post-operative pain. Their appropriate and expert use in palliative care can transform patients’ comfort and well-being at the end of life.
All opioids work by acting on specific sites in the central nervous system (receptors) with which the drug combines. Opioid receptors carry pain messages to the brain and the drugs block or reduce the perception of pain. Endorphins – ‘the brain’s own morphine’ – produce their effects in the body by acting on the same receptors, thereby helping to control pain. Because of this very specific action, opioids are also one of the few groups of drugs for which there are specific antidotes (for example, naloxone), which are used to reverse the toxic effects of overdose and poisoning.
Although they vary in potency and in the range and severity of their side effects, all opioids produce profound analgesia, sedation and euphoria. This combination of effects is particularly valuable in treating traumatic or other acute pain. At higher doses, all opioids depress respiration, and this is their major dose-limiting side effect. Death from opioid overdose is invariably due to respiratory arrest. All opioids produce tolerance; that is to say, with continued use larger doses are needed to achieve the same effect. They can all produce dependency (addiction) with continued use. Their therapeutic value is therefore accompanied by huge potential for harm, either by careless use or deliberate misuse. Massive research efforts have been unable to disaggregate these properties of opioids.
Opioids have what pharmacologists call a narrow therapeutic index. That is, the ratio between a therapeutic dose and a harmful dose is small. For example, in an opioid-naïve person, a single dose of 5–10 milligrams (mg) diamorphine would provide profound pain relief but 30 mg could be lethal. Few drugs exhibit this phenomenon and most have a wider margin of safety. This means that accidental death can occur from relatively low doses if, for example, an inexperienced or over-tired out-of-hours doctor inadvertently overdoses a patient by selecting from the emergency bag a dose of 30 mg or more rather than a 5 or 10 mg ampoule of diamorphine, leading to death from respiratory arrest.3 ,4
In the criminal sphere, a striking feature of the murders committed by Harold Shipman is that, although he is known to have used much higher doses, he killed many of his victims with no more than a single 30 mg dose of diamorphine. As they were invariably opioid naïve, this was sufficient to cause death by respiratory arrest. In the report of her Inquiry into his crimes, Dame Janet Smith wrote: 5
“It is now clear that, during 1993, Shipman was using 30mg ampoules of diamorphine to kill and was replenishing his stock as and when necessary … With the 14 ampoules he obtained between February and August 1993, Shipman killed 13 patients during the same period.”
Paradoxically, while relatively small doses can be lethal in people who are opioid naïve, the development of tolerance means that those taking opioids over a prolonged period – whether for chronic pain or because of addiction – can survive doses that would otherwise be rapidly fatal. It is not uncommon for a person taking long-term morphine to need very large daily doses. The BNF states that following initial dose titration, patients with pain in palliative care may require oral morphine at doses of up to 1,200 mg per 24 hours.6
Getting the dose of opioids right is particularly important in people with severe pain in terminal illness. While large doses are often needed, these increase the risk of respiratory arrest. Safe adjustment of the dose (titration) requires skill and an understanding of the pharmacology of these drugs. The current medico-legal position is that, where it is necessary to control otherwise intolerable pain, appropriate escalation of the dose where there may be a concomitant risk of respiratory arrest is both lawful and ethical. Increasing the dose simply to end life is unlawful. This can present clinicians with difficult decisions, and is the subject of intense debate on assisted dying. This issue is often referred to as the principle of double effect.
Older people are particularly susceptible to the adverse effects of drugs in general and opioids in particular. As long ago as 1981, Ramsay and Tucker, a consultant physician and clinical pharmacologist respectively, were among the first health professionals to point this out.7 They wrote:
“The risk of adverse reactions overshadows all other considerations when prescribing for the elderly, although there is some suggestion that general practitioners, who are responsible for the bulk of prescribing, may not be fully aware of this. Elderly patients are more likely than the young to react adversely to drugs prescribed in hospital and they are also more likely to be admitted to hospital or to die because of adverse reactions.”
They noted that increased sensitivity to opioids was a “common or serious cause of adverse reactions in the elderly” and that doses should therefore be reduced.
The principle that older people need special care and consideration – especially if they are very old – from prescribers soon became well established. There are two main reasons for this. First, the nervous system of older people is inherently more sensitive to the effects of opioids and also other sedative drugs such as midazolam and hyoscine. Second, the elimination of these drugs by the body – mainly through the kidneys and liver – is often impaired. These factors combine to alter the balance of benefit and harm and can put older people at considerable risk from adverse effects on the nervous system such as confusion, drowsiness and slurred speech, with the serious possibility of respiratory arrest. A degree of renal (kidney) impairment is common in older people and is known to increase and prolong the effects of opioids. In 1984, Regnard and Twycross were the first to report this. They found that, of their palliative care patients receiving morphine, those with renal impairment needed less than half of the average dose given to all their patients when titrating upwards until pain was controlled.8
By 1987, the BNF was therefore cautioning that opioids should be avoided in older people, or used with caution and reduced doses:9
“In general, narcotic analgesics should be used with caution, if at all, in patients with hepatic and renal impairment … dosage should be reduced in elderly and debilitated patients.”
Successive editions of the BNF have continued to carry warnings about the hazards of opioids and other drugs acting on the nervous system in elderly people or those with renal impairment.
HM Government, 2013. Consultation on prescription drug tramadol.
HM Government, 2014. Home Office Circular 008/2014.
National Patient Safety Agency, 2006. Safer practice notice 12: Ensuring safer practice with high dose ampoules of diamorphine and morphine.
Care Quality Commission, 2010. Investigation into the out-of-hours services provided by Take Care Now. Part 1: The death of Mr David Gray and previous incidents involving overdoses of diamorphine.
HM Government, 2002. The Shipman Inquiry. First report, Volume 1: Death disguised.
http://webarchive.nationalarchives.gov.uk/20090808163951/http://www.the-shipman-inquiry.org.uk/images/firstreport/narrative/pdf/vol1.pdf (accessed 27 November 2017). pp160–1.
National Institute for Health and Care Excellence, 2017. Morphine: indications and dose.
https://bnf.nice.org.uk/drug/morphine.html (accessed 27 November 2017).
Ramsay RE and Tucker GT, 1981. Today’s treatment: Drugs and the elderly. British Medical Journal, 282, pp125–7.
Regnard FB and Twycross RG, 1984. Metabolism of narcotics. British Medical Journal, 288, p860.
British Medical Association and Royal Pharmaceutical Society of Great Britain, 1987. Narcotic analgesics. British National Formulary, 13, p168.