Chapter 2: Prescribing and administration of drugs and the deaths that resulted

A range of opioids was used at the hospital, including morphine in various dosage forms – two oral solutions, one weaker and one more concentrated (oral morphine), and slow-release tablets (modified release morphine) of various strengths. Diamorphine was used both as single injections and, more commonly, by continuous subcutaneous infusion using a syringe driver. Fentanyl was used in the form of skin (transdermal) patches, which were first introduced in the UK in 1994.

Fentanyl can be very useful in patients who cannot take oral medicines and whose veins or skin are too fragile for intravenous or subcutaneous administration. The drug is absorbed by the skin, is a very effective analgesic, and invasive procedures are avoided. However, use of fentanyl can be problematic.

Fentanyl is much more potent than morphine or diamorphine: a patch delivering 25 micrograms of fentanyl per hour (600 micrograms per 24 hours) is approximately equivalent to 90 mg of oral morphine over 24 hours, or 30 mg of diamorphine given by syringe driver. It is therefore some 150 times more potent than oral morphine or 50 times more potent than infused diamorphine. The risks of miscalculation or dosing error are obvious. But the huge difference in potency is not a problem provided dosing is accurate and changes to and from fentanyl patches are managed properly.

Fentanyl patches should therefore be used with great care, particularly in patients who are not known to have previously tolerated strong opioids; that is, people who are opioid naïve. The BNF has warned that it could take 24 hours for the full effects of fentanyl to become evident, and that replacement of fentanyl with other opioids should be initiated at a low dose and increased gradually.¹⁰ A starting dose of 25 micrograms per hour was initially recommended for opioid-naïve patients, but this was recognised to be excessive. In 2008, responding to reports of serious and fatal overdoses of fentanyl patches, the Medicines and Healthcare products Regulatory Agency issued a warning that they should only be used in patients who have previously tolerated opioids.¹¹ This advice was incorporated in all subsequent editions of the BNF. Because fentanyl is very long acting when given by the transdermal route, the drug can take up to five days to be completely eliminated from the body after a patch is removed. Any replacement opioid must be introduced cautiously at a low dose and increased gradually, with careful monitoring for any adverse effects. In the absence of these precautions, concurrent use of fentanyl patches with other opioids can be fatal.

The very wide range of opioid dosage forms and strengths can be confusing for professionals, especially those not expert in palliative care. The calculation of equivalent doses and dose intervals when changing patients from one opioid to another or from one dosage form to another needs great care. Both accidental overprescribing and accidental over-administration – which can be lethal – have been the subject of NHS patient safety alerts. In 2008, reviewing 4,223 patient safety incidents involving opioids, the National Patient Safety Agency stated:¹²

Despite the emergence of many newer drugs, morphine remains the drug of choice for many indications, including palliative and post-operative care. The UK is unique in that diamorphine has also been widely used in healthcare. In most other countries, its use is discouraged or unlawful because of its reputation as the street drug heroin. Diamorphine was formerly believed to be particularly effective in relieving severe pain. It is more potent than morphine (about three times stronger) and some forms are more water-soluble and can be formulated into injections with very small volumes, which is useful for subcutaneous infusion. It was for many years therefore the opioid of choice for severe pain, particularly in palliative care.

The failure in 2004 of the only diamorphine production line in the UK led to the urgent transfer of large numbers of patients to equivalent doses of morphine. This was found to be just as effective and diamorphine never regained its former therapeutic niche. Morphine is now invariably recommended as the opioid of choice in analgesic and palliative care guidelines.

The main use of opioids is for the relief of severe and intractable pain; they are also used in anaesthetics and post-operative care. Potent opioids such as morphine, diamorphine and fentanyl can eliminate pain or at least render it tolerable and they also have sedative effects. They induce a state of relaxation, tranquillity, detachment and well-being (euphoria) that can be a valuable adjunct to pain control. Occasionally, they can cause an unpleasant reaction (dysphoria) and they frequently cause nausea and vomiting.

Opioids are not normally used for agitation or confusion in the absence of pain. They are generally unsuitable for terminal agitation, anguish or distress and, if used inappropriately, may cause or exacerbate these problems. In the absence of pain or in excessive doses, they can cause sleep disturbances, hallucinations, sweating and confusion. If a patient needs sedation the BNF recommends haloperidol or other tranquillisers.

The risk of misuse and dependency means that opioids are tightly regulated in most jurisdictions. In the UK, the Misuse of Drugs Act 1971 and its regulations govern all aspects of their use. Internationally, they are governed by the UN Single Convention on Narcotic Drugs 1961 and its protocols, to which the UK and virtually all UN member states are signatories.

Strong opioids such as morphine, diamorphine and fentanyl are known as ‘class A controlled drugs’ under UK legislation. Penalties for their unlawful use or supply can be severe. However, the culture in the British and most western healthcare systems is that, providing legal and professional frameworks are respected, the great therapeutic value of these drugs is recognised and they may be prescribed without undue restriction when they are clinically needed.

The legal and NHS management frameworks for controlled drugs were tightened significantly following Dame Janet Smith’s reports into the crimes of Harold Shipman.¹³ Custody, prescribing and record-keeping requirements for controlled drugs in hospitals are discussed below. Most prescribers adopted a more cautious approach to the use of opioids following the trial of Shipman, the Inquiry reports and the changed legal and professional environment. Nevertheless, the UK legal and professional frameworks for clinical use of opioids remain relatively liberal in contrast to some jurisdictions – for example, eastern Europe, where very stringent controls mean that many patients cannot access opioids and are denied essential relief for severe pain which would be routine in this country. In the UK, although theft and diversion of therapeutic opioids does occur, it is generally not a major cause of drug dependency and crime – the murders committed by Shipman being of course a striking exception.