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In late 2004, a shortage of diamorphine injections forced prescribers to find alternatives. Now that supplies have been restored, it is time to reappraise the role of diamorphine
Christine Clark
Contributing Editor
HPE
Diamorphine has been extensively used in British medicine, and a wealth of experience has been accumulated. The sudden, unexpected shortage of supply in the UK in recent years caused difficulties for practitioners and patients and resulted in calls for better systems to anticipate and cover such events. In many ways the outcry itself was testimony to the value of diamorphine in clinical practice. In this article I explore the reasons for the supply problems and present a brief overview of the properties of diamorphine and its clinical applications.
The shortage of supply
In December 2004, Chiron, one of two UK manufacturers of diamorphine, discontinued production. At that time the chief medical, nursing and pharmaceutical officers of the Department of Health[1] and the corresponding authorities for Northern Ireland and Scotland published guidance on conservation of existing stocks and the alternatives available.
Chiron had been responsible for approximately two-thirds of all the diamorphine supplied in the UK, so there was a significant shortfall. The other manufacturer, Wockhardt, stepped in to make up the shortfall. However, the issue was not straightforward diamorphine injection is a freeze-dried preparation, and there was no alternative licensed preparation available in Europe in the strengths required. The freeze-drying capacity at Wockhardt was not sufficient immediately to make up the shortfall, but measures were put in place to increase capacity over the next few months.
The chief medical officer’s guidance indicated that the supply situation was likely to remain uncertain for some time. Many practitioners expected the shortage to last for no more than two or three months. In the event the shortage persisted for much longer. The guidance also made recommendations for alternative injectable analgesics for most common situations in
which diamorphine is used. Therapeutic switches to morphine and oxycodone appear to have worked satisfactorily, but many patients in drug treatment programmes experienced difficulties when they were switched to oral methadone.
The problems became so severe that even representatives of the BMA suggested that Afghan opium should be purchased to correct the deficiency.[2] However, the problem was not shortage of the raw material, but shortage of the processing (freeze-drying) capacity.
Prescribing patterns showed that there was a marked fall in the use of injectable controlled drugs during the third and fourth quarters of 2004-5, coinciding with the announcement of supply problems. The level of use increased and returned to the previous level by the end of 2006.[3] It is not known what proportion of this is accounted for by diamorphine, but it seems reasonable to suppose that the improved supply position
allowed prescribing of diamorphine to increase.
Since late 2007, Wockhardt has had the production capacity and sufficient stock to meet 100% of UK diamorphine needs.
The need for diamorphine
Some commentators have pointed out that is not available for therapeutic use in many other countries and therefore, they argue, we could also manage without it in the UK. For example, in Switzerland it is used only in the treatment of opioid addiction.
Diamorphine is not used in countries outside Europe for historical rather than clinical reasons. The USA banned Heroin (Bayer’s trade name for diamorphine) in 1924 due to concerns over its misuse and exerted vigorous pressure to have it banned universally. Britain resisted the pressure, unlike most other countries. However, diamorphine has some properties that make it particularly useful and, in addition, there is a wealth of
experience with the therapeutic use of this drug, and many texts and clinical guidelines refer to it specifically.
Diamorphine (diacetyl morphine) is a prodrug with no intrinsic activity. In the body it is rapidly de-acetylated in two steps to form morphine. Intramuscular diamorphine has a faster onset of action than intramuscular morphine. This is thought be due to the higher lipid solubility of diamorphine. The situation is reversed for intravenous administration, which is presumed to
be because diamorphine has first to be metabolised to active compounds and it is also protein-bound to a greater extent than is morphine.
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One great advantage of diamorphine is that it is more soluble than either morphine or oxycodone (see Table 1). This makes it particularly suitable for administration in small volumes, such as subcutaneous infusions, epidural infusions or administration to small or emaciated patients who may be unable to tolerate large volumes of fluid. Diamorphine is described as the strong opioid of choice in the UK because large amounts can be given in very small volumes in the Palliative Care Formulary.[4]
Diamorphine, unlike morphine, is suitable for intranasal administration because of its higher lipid solubility. It also may cause less nausea and hypotension than morphine.[5]
Another advantage is that diamorphine is better tolerated than methadone by many intravenous drug addicts.
Uses of diamorphine
It should be noted that a number of the clinical applications
of diamorphine that have slipped into common use are still unlicensed indications for this drug. At present, diamorphine is licensed for the treatment of:
- Severe pain associated with surgical procedures.
- Myocardial infarction.
- Pain in the terminally ill.
- The relief of dyspnoea in acute pulmonary oedema.
- The intramuscular, intravenous and subcutaneous routes of administration are licensed for diamorphine, but the intranasal, epidural and intrathecal routes are not.
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Acute trauma pain
Parenteral opioids are often used to treat pain induced by trauma or injury, and diamorphine has a place here. The provision of pain relief for children can be challenging because young children are often distressed by the use of needles. One study compared the use of intranasal diamorphine with intramuscular morphine in 404 children and teenagers with clinical fractures.[6] Because of its high solubility, the diamorphine dose can be presented in a small volume as a spray in this study the dose (0.1 mg/kg) was delivered in a 0.1 ml volume. This minimises the chance of swallowing a portion of the dose and thereby ensures that first-pass metabolism
is avoided as far as possible. The relatively high lipidsolubility
of the drug means that it is well absorbed through the nasal mucosa. The results showed that intranasal diamorphine spray (0.1 mg/kg) gave the same degree of pain relief as intramuscular morphine (0.2 mg/kg) but had a faster onset of action and was more acceptable to patients, parents and staff.
Acute cardiac pain and left ventricular failure
The British National Formulary recommends the use of slow (1 mg/min) intravenous diamorphine in the initial management of suspected acute myocardial infarction. A dose of 5 mg should be given followed by a further 2.5-5 mg if necessary; in elderly or frail patients the dose should be reduced by half.[5] Many local guidelines have also included diamorphine. The diamorphine not only relieves pain and anxiety but also acts as a venodilator and reduces cardiac preload. This, in turn, reduces acute pulmonary oedema.
Cancer-related pain
Diamorphine has an established place in the management of cancer pain in patients who are unable to take opioids orally, as it can be used in subcutaneous infusions.
Labour pain
Epidural infusion of local anaesthetics is an established technique for the provision of pain relief during labour. It has been suggested that diamorphine is particularly suitable for this purpose as it is readily available to the opioid receptors in the spinal cord and can be delivered in a small volume. A recent study confirmed previous findings that epidural diamorphine alone can provide good pain relief during labour.[7] The combined spinal epidural (CSE) technique for initiation of mobile analgesia for labour is now commonly used. The main reason for this is that it is believed to offer the advantage of rapid onset of analgesia via the spinal route with the flexibility of later topups via the epidural route. A study that used intrathecal diamorphine instead of the usual fentanyl (in combination with bupivacaine) found no increase in side-effects but a faster onset of action.[8]
Postoperative pain
There is an extensive literature on the use of diamorphine for postoperative pain relief. In addition to intramuscular injection, the high solubility of diamorphine means that it can be prepared in small volumes for delivery by subcutaneous, epidural, spinal (intrathecal) and nasal routes. Patient-controlled epidural and
intranasal and subcutaneous administration is also reported.
Sedation for ventilation
In preterm babies with respiratory failure who require mechanical ventilation, sedation with opiates or opioids is believed to be preferable to paralysis with neuromuscular blockers. A study that compared diamorphine with morphine for this indication found that the two drugs were equally efficacious, but that diamorphine had a more rapid onset of action and, unlike morphine, was not associated with an initial hypotensive effect.[9]
Sickle-cell anaemia
The acute pain of sickle-cell disease can be sudden, unpredictable in onset and intense. Severe acute pain can be treated with subcutaneous doses of 2.5-5 mg diamorphine in opioid-naive patients, but opioidtolerant individuals could need doses of 5-10 mg.[10]
Opioid dependency
Some opioid-dependent individuals tolerate diamorphine better than methadone, and during the shortage many of these were severely disadvantaged.[11] Current guidelines recommend that injectable diamorphine should be available for this small number of individuals. [12] Only doctors who hold a special licence from the Home Office can prescribe intravenous diamorphine for opioid dependency.
Conclusions
The physicochemical properties of diamorphine, along with its pharmacodynamic profile, make it particularly suitable in a number of situations and comfortably justify its place in present-day formularies. Moreover, modern methods of administration are enabling more effective use of this tried-and-tested product. Now that the supply problems of the past few years have been resolved, it is time to take a fresh look at the situations where diamorphine can make a positive impact
on patient care.
References
1. Department of Health. Guidance on use and supply of diamorphine injections. London: DH; 2004 Dec. CEM/CMO/2004/14.
2. Brimelow A. Afghan poppies ‘could help NHS’. BBC News. 2007 Jan 23 [cited 2008 Oct 3]. Available from: http://news.bbc.co.uk/1/hi/health/6287975.stm
3. Healthcare Commission. The safer management of controlled drugs — annual report 2007. London: Healthcare Commission; 2008 Jul.
4. Twycross RG, Wilcock A, Charlesworth S, Dickman A. Palliative care formulary. 2nd ed. Oxford: Radcliffe Publishing; 2002.
5. British national formulary. 56th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2008 Sep.
6. Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ 2001;322;261-5.
7. McLeod GA, Munishankar B, Columb MO. Is the clinical efficacy of epidural diamorphine concentrationdependent when used as analgesia for labour? Br J Anaesth 2005;94:229-33.
8. Vaughan DJA, Ahmad N, Lillywhite NK, Lewis N, Thomas D, Robinson PN. Choice of opioid for initiation of combined spinal epidural analgesia in labour — fentanyl or diamorphine? Br J Anaesth 2001;86:567-9.
9. Wood CM, Rushforth JA, Hartley R, Dean H, Wild J, Levene MI. Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates. Arch Dis Child Fetal Neonatal Ed 1998;79:F34-9.
10. Okpala JR, Tawil A. Management of pain in sickle-cell disease. J R Soc Med 2002;95:456-8.
11. White R, Cox D, Charnaud B. Lessons from the UK diamorphine shortage. Psychiatr Bull 2005;29:316.
12. National Treatment Agency for Substance Misuse (NTA). Drug misuse and dependence — UK guidelines on clinical management. London: NTA; 2007 Sep.
