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doi:10.1111/jpc.12875
VIEWPOINT
Morphine and children: An Australian perspective Henry A Kilham,1,2 Matthew Grant3,4 and Martha Mherekumombe5 1 General Medicine, 5Pain and Palliative Care, Sydney Children’s Hospitals Network, Children’s Hospital at Westmead, 2Values, Ethics and the Law in Medicine, University of Sydney, Sydney, New South Wales, 3Centre for Palliative Care, St Vincent’s Hospital, and 4Centre for Palliative Care, University of Melbourne, Melbourne, Victoria, Australia
Key words:
ethics; morphine; opiate; opium.
Of all the remedies it has pleased almighty God to give man to relieve his suffering, none is so universal and efficacious as opium. (Thomas Sydenham, 1624–1689)
A Paediatric History of Opioids Opium was used extensively in prehistoric times and in ancient civilisations as an anaesthetic, analgesic, sedative and for ritual purposes. Opium has since had a long and colourful history involving various uses, although not surprisingly use in children goes largely unmentioned.1 Opium is the dried latex obtained from the opium poppy (Papaver somniferum); it contains a variety of alkaloids, including morphine, codeine and thebaine (precursor of oxycodone), as well other non-analgesic alkaloids. Morphine is the major active opioid in opium. It was isolated in 1804 and marketed in 1827, with the advantage of being injectable, in precise dosage. In 1903, Dr Philip Muskett, the Surgeon Superintendent of New South Wales (NSW), wrote in The Illustrated Australian Medical Guide of the great benefits of opioids in treating sick children: ‘A bottle of chlorodyne (a morphine based mixture) is virtually indispensible in every household. There are times when the relief it affords is absolutely beyond question.’2 Prescribing and Treatment in the Diseases of Infants and Children, Muskett’s other text, instructed the use of morphine and opium for a vast range of paediatric maladies from otitis media to intussusception, herpes zoster and night terrors.3 Unfortunately, few effective treatments were available for children at this time and sickness was widespread, with an infant death rate of 125 per 1000 in 1881–1885.4 Infantile diarrhoea was a major culprit, responsible for approximately half of all infant deaths, especially in socially disadvantaged neighbourhoods.5 While public sanitation and nutrition slowly improved with time, doctors and the public
sought an immediate remedy for this problem, which came in the form of opioid medications.6 What may now seem to be a reckless and dangerous therapeutic approach has to be judged according to the times, even if opioid use at times added serious consequences. In part, increasing treatment of children represented a shift towards a greater focus on the health of children.6 In colonial Australia, opioids in various doses and combinations were widely used, sold unregulated by salesmen, chemists and ‘milk bars’.7 They were collectively known as ‘proprietary medications’ or colloquially as ‘soothing syrups’, available in liquid, powder and lozenge forms catering to all ages, even infants under 6 months.7 Initially marketed as anti-diarrhoeal agents, doctors and the public became aware of their utility for a number of paediatric conditions, and they soon developed a reputation as a panacea. Advertising featured widely in newspapers and magazines for many brands of opioid medications, professing remedy for cough, teething, colic and diarrhoea (Fig. 1). In a country where the population was widely spread
Correspondence: Associate Professor Henry A Kilham, Department of General Medicine, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Fax: 02 98453396; email: henry.kilham@ health.nsw.gov.au Conflict of interest: Matthew Grant has previously worked as a pharmacovigilance physician at Merck Sharp and Dohme, but has no ongoing relationship with the company. Martha Mherekumombe received sponsorship from Mundipharma to attend an education course. Henry A Kilham has no conflicts of interests to declare. Accepted for publication 17 February 2015.
482
Fig. 1 Dr Seth Arnold’s Cough Killer, containing morphine. (Reproduced from the Wellcome Images Library.)
Journal of Paediatrics and Child Health 51 (2015) 482–485 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
H Kilham et al.
and rapidly growing, often with poor access to medical care, the public embraced Dr Muskett’s advice. Proprietary medications were used widely to treat all manner of illness, with a great deal of anecdotal evidence to suggest some perceived benefit,3,6 often consistent with what is currently accepted on the powerful analgesic, sedative, antitussive and antispasmodic effects of opiates. Regardless of the efficacy of opioids for these conditions, the harms gradually became apparent. In the late 19th century, the Queensland coroner focused on opioid use prior to infant deaths, finding that 15 of the 98 deaths investigated were associated with proprietary medicine use.6 Despite these findings, the widespread use of opioids continued, with Australia having the highest use of these medications per capita worldwide.6 At the turn of the century, medical opinion on the harms of opioids appeared to be turning. Dr William Murrell, a prominent English physician and toxicologist, preached on the evils of proprietary medication as ‘eminently adapted for increasing the infant mortality of the neighbourhood.’7 Coronial inquests into childhood deaths increased, with Murrell estimating that opioid medications were responsible for 15 000 child deaths annually worldwide.6 At the beginning of the 20th century, the Australian legal system had little control over the sale, distribution, quality or constituents of proprietary medications.8 As evidence of harms increased, the law slowly followed, first limiting supply to chemists only (except in small towns) and requiring medical prescription for supply of opioids in 1913.9 The infant death rate continued to fall, to 80 per 1000 live births in 1910–1912, although this was more likely due to improved sanitation and infant feeding practices than better control of opioids.5 Public perception of proprietary medications soon shifted; magazines rejected advertisements for these drugs and doctors refused to write death certificates in cases where opioids might be involved.6 Opioid abuse and non-medical supply were criminalised in NSW in 1927.10
The 20th Century: ‘Morphine Middle Ages’ and a Renaissance of Sorts Legal sanctions against opiate trafficking have spread around the world over the last 100 years. Global illicit drug use now includes many other drug categories and is universally agreed to be an enormous problem, for which current control measures are largely failing. In the context of this paper, there is no doubt that while the non-medical use of opiates has had huge detrimental effects for recreational users who become addicted and for society generally, it has also had serious implications for the medical use of opioids in those whose severe pain cannot be controlled by other means because it has led to withholding or restricting medical opioid use. This appears to result from conflating the risk of addiction, between legitimate and other uses, and using sub-therapeutic doses, to avoid both the risks of addiction and the known serious side effects. At times, opioid abuse control measures have restricted the availability of opioids for medical use, for example, the Harrison Act of 1914 in the US.1 Concern over trafficking and abuse is probably the major factor in the gross current under-use of morphine in less developed countries with the largest populations.
Morphine and children
That the use of opioids for non-therapeutic purposes can co-exist with apparently good health has long been a source of confusion in understanding addiction. Among the Chinese, decades of opium use often coincided with robust good health.1 Even though later studies showed that the use of opiates for acute pain or cancer pain does not predispose to addiction,11,12 this misconception remains widespread. So how was morphine used for severe pain in the second half of the 20th century? In the early 1960s, undergraduate teaching about opioid pharmacology in Australia was thorough and opiates were used commonly in hospitals, often titrated intravenously. Morphine was a superb drug with sometimes troublesome side effects, a drug to be respected and used properly but not feared. In contrast, opioids were used very sparingly in children’s hospitals, usually by intramuscular injection and often in subtherapeutic doses. The 1962 edition of Davidson briefly considers pain in relation to specific diseases, advocating for instance 15–30 mg morphine intravenously with myocardial infarction and the same dose subcutaneously for renal colic.13 Major paediatric textbooks of the 1950s exclude any general mention of pain, and say little about morphine beyond giving a dosage, albeit usually properly expressed in mg/kg.14–16 In contrast, one textbook devotes two full pages to masturbation.16 Overall, good pain management over much of the last century is probably well described as ‘islands of enlightenment, in a sea of misery’.17 A major ‘turn-around’ developed in the 1970s, with increasing attention to the poor management of adult post-operative pain and cancer pain, followed in the 1980s by overdue recognition that newborns and other children could indeed experience severe pain which was often poorly managed. A landmark was the formation in 1973 by Bonica of the International Association for the Study of Pain. In 1983, Mather and Mackie from Adelaide described gross under-use of analgesics post-operatively in children.18 Schechter, in more comprehensive reviews, detailed how children were much less likely to receive opioids than adults for severe pain in many different situations.19,20 Anand and colleagues showed that addition of fentanyl to light anaesthesia in neonates having major cardiac surgery reduced otherwise major changes in metabolic and hormonal parameters and reduced mortality.21,22 Unrelieved, severe pain is not only cruel but also life-threatening. Other childhood studies suggested long-term harmful psychological harm from unrelieved pain in childhood. Pain control was extended to a wide variety of conditions and severities of childhood, including medical procedures such as IV insertion and burns dressings. The 1980s saw a Renaissance of sorts in the recognition and potentially better treatment of childhood pain. Pain and palliative care units were set up in children’s hospitals in some Western countries. Unfortunately, the great majority of the world’s children do not have access to morphine or synthetic opioids when they really need them.1 Opioids provide benefit beyond their use in analgesia. Morphine, methadone and heroin are powerful antitussive drugs, in usual doses. This effect is unreliable with codeine, which is no longer recommended as an antitussive for children.23 It is not seen with synthetic drugs such as meperidine (Pethidine). The sedative and antitussive effects of morphine can be extremely useful as added benefits in cancer pain, including palliative care.
Journal of Paediatrics and Child Health 51 (2015) 482–485 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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Morphine and children
H Kilham et al.
Patent medicines were historically popular for these effects, but opioids are currently considered unjustifiable for cough alone, although no other effective antitussives are available for adults or children.
Current and Future Use of Morphine in Children, in Australia and Elsewhere This section summarises the long-established elements of safe and effective morphine use in children, considers its current status and speculates on how that might change in the future. It is not intended as a practical treatment guideline. Morphine remains the pre-eminent drug for managing moderate-to-severe and severe pain in all age groups. It is also used in specific circumstances for relieving breathlessness and for suppressing cough and is the preferred treatment for neonatal abstinence syndrome.24 Morphine is used both for acute and for chronic pain in a wide variety of both cancer and non-cancer conditions. Comprehensive guidelines for its use in infants and children have long been established25,26 and will not be replicated here.
Current status versus other analgesics In a US study published in 2008, morphine was in the top 10 medications prescribed for hospitalised children.27 Some years before, meperidine (Pethidine) and codeine were often used in preference to morphine for moderate-to-severe pain but both are now usually avoided because of side effects or unreliable effects.25 Occasionally, for long-term use, methadone or morphine analogues are used in place of morphine where the latter has severe continuing side effects or inadequate analgesic effect.25 The synthetic oral opioid oxycodone is increasingly used in place of morphine where oral dosing is possible. Severe pain can sometimes be treated with high-dose paracetamol but this is not first-line therapy and should only be given as single dose therapy.28 Morphine has limited value in neuropathic pain and in some other pain conditions.29,30
Using morphine There are well-described age-related differences in the pharmacokinetic and pharmacodynamic responses during development in children.31 Morphine needs to be given in small dosage increments until good pain control is achieved, while monitoring for side effects. Morphine, like other opioids, has no ‘ceiling’ analgesic effect and the appropriate dose is the dose that achieves pain relief for the individual child.25 In order to achieve this, the child needs frequent pain assessment and adjustment of the analgesic dose. Repeated doses are given as soon as required and not by traditional time intervals. The effective opioid dose varies widely between children and in the same child at different times. Morphine dosage guidelines and other practical implications are available in paediatric and pharmacological textbooks.25,26,31–33 In some advanced medical conditions and in palliative care, opioids can be very valuable in relieving breathlessness.34 Morphine has been used effectively, for this indication, via both oral and parenteral routes.35 Other opioids have been used, although less commonly than morphine, since the late 19th century. While 484
its precise mode of action is unclear, it appears to modulate the perception of dyspnoea directly by affecting inspiratory drive.36,37
Routes of administration Morphine is available for injection and in formulations for oral use. Dosage varies widely between parenteral and oral use. In acute circumstances, injection is required and this should be intravenous, not intramuscular, although the subcutaneous route is sometimes used. For long-term use, oral dosage is preferred when possible. Absorption after rectal administration is unreliable and this should be avoided.25
Side effects and safety Because of the great dosage variations in infants and children, meticulous attention to dosage and observation for side effects is more critical than in other age groups. The greatest concern is respiratory depression which can be fatal, yet can be detected and managed with simple competent observation. Morphine therapy is often accompanied by nausea and vomiting, usually inconsequential, but at times requiring a change to other drugs. Other side effects include sedation, pruritus, urinary retention, constipation, bronchoconstriction, myoclonic movements, and physical and psychological dependence.25 Clinicians experienced in the use of morphine and other opioids become very skilful in their use, to the enormous benefit of sick children.
The future Other promising uses of morphine include topical use for malignant and non-malignant ulcers and oropharyngeal mucositis, although further research is needed before use for these indications could be recommended.38 Other emerging uses lacking strong evidence of safety and efficacy include sublingual, intranasal and nebulised morphine.25,39–43 As in adults, medium and longer-term use of morphine and other opiates now occurs in non-cancer, non-terminal situations in children, although to a far lesser extent, probably reflecting the lower incidence of severe chronic pain in children. Although legitimate, such use demands a high level of skill, experience and patient supervision. In conclusion, except in the unlikely event of discovery of a new, superior, powerful analgesic, morphine will continue as the drug of choice for severe pain in many situations affecting children. Overall, the major problems with the medical use of morphine in children across the world are lack of knowledge and lack of availability, when really needed.
References 1 Grant M, Philip J, Ugalde A. A functional dependence? A social history of the medical use of morphine in Australia. Med. J. Aust. 2014; 200: 231–2. 2 Muskett PE. The Illustrated Australian Medical Guide. Sydney: William Brooks, 1903. 3 Muskett PE. Prescribing and Treatment in the Diseases of Infants and Children. Edinburgh: Pentland, 1891. 4 Warsh CK, Strong-Boag V. Children’s Health Issues in Historical Perspective. Waterloo, ON: Wilfrid Laurier University Press, 2006. 5 Lewis MJ. The People’s Health: Public Health in Australia, 1788–1950. Westport, CT: Praeger, 2003.
Journal of Paediatrics and Child Health 51 (2015) 482–485 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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6 Finch L. Soothing syrups and teething powders: regulating proprietary drugs in Australia, 1860–1910. Med. Hist. 1999; 43: 74–94. 7 Manderson DRA. The first loss of freedom: early opium laws in Australia. Aust. Drug Alcohol Rev. 1988; 7: 439–53. 8 Truth NZ. Slaughter of the Innocents. Issue 123, 26 October 1907. Available from: http://paperspast.natlib.govt.nz/cgi-bin/paperspast?a =d&d=NZTR19071026.2.49 [accessed 14 August 2014]. 9 Marks R. A freer market for heroin in Australia: alternatives to subsidising organised crime. J. Drug Issues 1990; 20: 131–76. 10 McCoy AW. Drug Traffic Narcotics and Organised Crime in Australia. Sydney: Harper and Row, 1980. 11 Porter J, Jick H. Addiction rare in patients treated with narcotics. N. Engl. J. Med. 1980; 302: 123. 12 Twycross RC. Pain and analgesics. Curr. Med. Res. Opin. 1978; 5: 497–505. 13 Davidson S. The Principles and Practice of Medicine. A Textbook for Students and Doctors, 6th edn. Baltimore: Williams & Wilkins, 1962. 14 Cannon Eely R. The Child in Health and Disease. Baltimore: Williams & Wilkins, 1948. 15 Gainsford W, Lightwood R. Paediatrics for the Practitioner. London: Butterworth, 1953. 16 Nelson WE. Textbook of Pediatrics. Philadelphia: Saunders, 1954. 17 National Health and Medical Research Council. Management of Severe Pain. Canberra: NHMRC, 1988. 18 Mather L, Mackie J. The incidence of post-operative pain in children. Pain 1983; 15: 271–82. 19 Schechter NL. Pain and pain control in children. Curr. Probl. Pediatr. 1985; 5: 1–67. 20 Schechter NL, Allen DA, Hanson K. Status of pediatric pain control: a comparison of hospital analgesic usage in children and adults. Pediatrics 1986; 77: 11–15. 21 Anand KJS, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and post-operative analgesia in neonatal cardiac surgery. N. Engl. J. Med. 1992; 326: 1–9. 22 Rogers MC. Do the right thing: pain relief in infants and children. N. Engl. J. Med. 1992; 326: 55–6. 23 Isbister GK, Prior F, Kilham HA. Restricting cough and cold medicines in children. J. Paediatr. Child Health 2012; 48: 91–8. 24 Grim K, Harrison TE, Wilder RT. Management of neonatal abstinence syndrome from opioids. Clin. Perinatol. 2013; 40: 509–24. 25 WHO. WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses. Geneva, WHO, 2012. Available from: http://whqlibdoc.who.int/publications/2012/ 9789241548120_Guidelines.pdf [accessed 16 August 2014]. 26 Analgesic Expert Group. Therapeutic Guidelines: Analgesic, Version 6. Melbourne: Therapeutic Guidelines Limited, 2012. 27 Lasky T, Greenspan J, Ernst FR, Gonzalez L. Morphine use in hospitalized children in the United States: a descriptive analysis of data from pediatric hospitalizations in 2008. Clin. Ther. 2012; 34: 720–7.
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28 Shann F. Paracetamol: use in children. Aust. Prescr. 1995; 18: 33–5. 29 NICE. The Pharmacological Management of Neuropathic Pain in Adults in Non-Specialist Settings. 2013. Available from: http://www.nice.org.uk/guidance/CG173/chapter/Introduction [accessed 16 August 2014]. 30 McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database Syst. Rev. 2013; (8): CD006146. doi: 10.1002/14651858.CD006146.pub2. 31 Chau K, Koren G. Principles of pain pharmacology in paediatrics. In: McGrath PJ, Stevens BJ, Walker SM, Zempsky WT, eds. Oxford Textbook of Paediatric Pain. Oxford: OUP, 2013; 429–35. 32 RCH Melbourne. Royal Children’s Hospital Paediatric Pharmacopoeia. 13th Edition. Melbourne, RCH, 2012. Available from: http://www.rch.org.au/pharmacy/business_development/Paediatric _Pharmacopoeia/ [accessed 16 August 2014]. 33 Pain management. In: Kilham H, Alexander S, Wood N, Isaacs D, eds. Paediatrics Manual: The Children’s Hospital at Westmead Handbook, 2nd edn. Sydney: McGraw-Hill, 2009; 57–66. 34 Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnea. BMJ 2003; 327: 523–8. 35 Jennings AL, Davies AN, Higgins JPT, Anzures-Cabrera J, Broadley KE. Opioids for the palliation of breathlessness in advanced disease and terminal illness. Cochrane Database Syst. Rev. 2001; (3): CD002066. doi: 10.1002/14651858.CD002066. 36 Oertel BG, Preibisch C, Wallenhorst T et al. Differential opioid action on sensory and affective cerebral pain processing. Clin. Pharmacol. Ther. 2008; 83: 577–88. 37 Hallenbeck J. Pathophysiologies of dyspnea explained: why might opioids relieve dyspnea and not hasten death? J. Palliat. Med. 2012; 15: 848–53. 38 LeBon B, Zeppetella G, Higginson IJ. Effectiveness of topical administration of opioids in palliative care: a systematic review. J. Pain Symptom Manage. 2009; 37: 913–17. 39 Coluzzi PH. Sublingual morphine: efficacy reviewed. J. Pain Symptom Manage. 1998; 16: 184–92. 40 Reisfield GM, Wilson GR. Rational use of sublingual opioids in palliative medicine. J. Palliat. Med. 2007; 10: 465–75. 41 Zernikow B, Michel E, Craig F, Anderson BJ. Pediatric palliative care: use of opioids for the management of pain. Paediatr. Drugs 2009; 11: 129–51. 42 Cohen SP, Dawson TC. Nebulized morphine as a treatment for dyspnea in a child with cystic fibrosis. Pediatrics 2002; 110: e38. 43 Brown SJ, Eichner SF, Jones JR. Nebulized morphine for relief of dyspnea due to chronic lung disease. Ann. Pharmacother. 2005; 39: 1088–92.
Journal of Paediatrics and Child Health 51 (2015) 482–485 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
485
doi:10.1111/jpc.12875
VIEWPOINT
Morphine and children: An Australian perspective Henry A Kilham,1,2 Matthew Grant3,4 and Martha Mherekumombe5 1 General Medicine, 5Pain and Palliative Care, Sydney Children’s Hospitals Network, Children’s Hospital at Westmead, 2Values, Ethics and the Law in Medicine, University of Sydney, Sydney, New South Wales, 3Centre for Palliative Care, St Vincent’s Hospital, and 4Centre for Palliative Care, University of Melbourne, Melbourne, Victoria, Australia
Key words:
ethics; morphine; opiate; opium.
Of all the remedies it has pleased almighty God to give man to relieve his suffering, none is so universal and efficacious as opium. (Thomas Sydenham, 1624–1689)
A Paediatric History of Opioids Opium was used extensively in prehistoric times and in ancient civilisations as an anaesthetic, analgesic, sedative and for ritual purposes. Opium has since had a long and colourful history involving various uses, although not surprisingly use in children goes largely unmentioned.1 Opium is the dried latex obtained from the opium poppy (Papaver somniferum); it contains a variety of alkaloids, including morphine, codeine and thebaine (precursor of oxycodone), as well other non-analgesic alkaloids. Morphine is the major active opioid in opium. It was isolated in 1804 and marketed in 1827, with the advantage of being injectable, in precise dosage. In 1903, Dr Philip Muskett, the Surgeon Superintendent of New South Wales (NSW), wrote in The Illustrated Australian Medical Guide of the great benefits of opioids in treating sick children: ‘A bottle of chlorodyne (a morphine based mixture) is virtually indispensible in every household. There are times when the relief it affords is absolutely beyond question.’2 Prescribing and Treatment in the Diseases of Infants and Children, Muskett’s other text, instructed the use of morphine and opium for a vast range of paediatric maladies from otitis media to intussusception, herpes zoster and night terrors.3 Unfortunately, few effective treatments were available for children at this time and sickness was widespread, with an infant death rate of 125 per 1000 in 1881–1885.4 Infantile diarrhoea was a major culprit, responsible for approximately half of all infant deaths, especially in socially disadvantaged neighbourhoods.5 While public sanitation and nutrition slowly improved with time, doctors and the public
sought an immediate remedy for this problem, which came in the form of opioid medications.6 What may now seem to be a reckless and dangerous therapeutic approach has to be judged according to the times, even if opioid use at times added serious consequences. In part, increasing treatment of children represented a shift towards a greater focus on the health of children.6 In colonial Australia, opioids in various doses and combinations were widely used, sold unregulated by salesmen, chemists and ‘milk bars’.7 They were collectively known as ‘proprietary medications’ or colloquially as ‘soothing syrups’, available in liquid, powder and lozenge forms catering to all ages, even infants under 6 months.7 Initially marketed as anti-diarrhoeal agents, doctors and the public became aware of their utility for a number of paediatric conditions, and they soon developed a reputation as a panacea. Advertising featured widely in newspapers and magazines for many brands of opioid medications, professing remedy for cough, teething, colic and diarrhoea (Fig. 1). In a country where the population was widely spread
Correspondence: Associate Professor Henry A Kilham, Department of General Medicine, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Fax: 02 98453396; email: henry.kilham@ health.nsw.gov.au Conflict of interest: Matthew Grant has previously worked as a pharmacovigilance physician at Merck Sharp and Dohme, but has no ongoing relationship with the company. Martha Mherekumombe received sponsorship from Mundipharma to attend an education course. Henry A Kilham has no conflicts of interests to declare. Accepted for publication 17 February 2015.
482
Fig. 1 Dr Seth Arnold’s Cough Killer, containing morphine. (Reproduced from the Wellcome Images Library.)
Journal of Paediatrics and Child Health 51 (2015) 482–485 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
H Kilham et al.
and rapidly growing, often with poor access to medical care, the public embraced Dr Muskett’s advice. Proprietary medications were used widely to treat all manner of illness, with a great deal of anecdotal evidence to suggest some perceived benefit,3,6 often consistent with what is currently accepted on the powerful analgesic, sedative, antitussive and antispasmodic effects of opiates. Regardless of the efficacy of opioids for these conditions, the harms gradually became apparent. In the late 19th century, the Queensland coroner focused on opioid use prior to infant deaths, finding that 15 of the 98 deaths investigated were associated with proprietary medicine use.6 Despite these findings, the widespread use of opioids continued, with Australia having the highest use of these medications per capita worldwide.6 At the turn of the century, medical opinion on the harms of opioids appeared to be turning. Dr William Murrell, a prominent English physician and toxicologist, preached on the evils of proprietary medication as ‘eminently adapted for increasing the infant mortality of the neighbourhood.’7 Coronial inquests into childhood deaths increased, with Murrell estimating that opioid medications were responsible for 15 000 child deaths annually worldwide.6 At the beginning of the 20th century, the Australian legal system had little control over the sale, distribution, quality or constituents of proprietary medications.8 As evidence of harms increased, the law slowly followed, first limiting supply to chemists only (except in small towns) and requiring medical prescription for supply of opioids in 1913.9 The infant death rate continued to fall, to 80 per 1000 live births in 1910–1912, although this was more likely due to improved sanitation and infant feeding practices than better control of opioids.5 Public perception of proprietary medications soon shifted; magazines rejected advertisements for these drugs and doctors refused to write death certificates in cases where opioids might be involved.6 Opioid abuse and non-medical supply were criminalised in NSW in 1927.10
The 20th Century: ‘Morphine Middle Ages’ and a Renaissance of Sorts Legal sanctions against opiate trafficking have spread around the world over the last 100 years. Global illicit drug use now includes many other drug categories and is universally agreed to be an enormous problem, for which current control measures are largely failing. In the context of this paper, there is no doubt that while the non-medical use of opiates has had huge detrimental effects for recreational users who become addicted and for society generally, it has also had serious implications for the medical use of opioids in those whose severe pain cannot be controlled by other means because it has led to withholding or restricting medical opioid use. This appears to result from conflating the risk of addiction, between legitimate and other uses, and using sub-therapeutic doses, to avoid both the risks of addiction and the known serious side effects. At times, opioid abuse control measures have restricted the availability of opioids for medical use, for example, the Harrison Act of 1914 in the US.1 Concern over trafficking and abuse is probably the major factor in the gross current under-use of morphine in less developed countries with the largest populations.
Morphine and children
That the use of opioids for non-therapeutic purposes can co-exist with apparently good health has long been a source of confusion in understanding addiction. Among the Chinese, decades of opium use often coincided with robust good health.1 Even though later studies showed that the use of opiates for acute pain or cancer pain does not predispose to addiction,11,12 this misconception remains widespread. So how was morphine used for severe pain in the second half of the 20th century? In the early 1960s, undergraduate teaching about opioid pharmacology in Australia was thorough and opiates were used commonly in hospitals, often titrated intravenously. Morphine was a superb drug with sometimes troublesome side effects, a drug to be respected and used properly but not feared. In contrast, opioids were used very sparingly in children’s hospitals, usually by intramuscular injection and often in subtherapeutic doses. The 1962 edition of Davidson briefly considers pain in relation to specific diseases, advocating for instance 15–30 mg morphine intravenously with myocardial infarction and the same dose subcutaneously for renal colic.13 Major paediatric textbooks of the 1950s exclude any general mention of pain, and say little about morphine beyond giving a dosage, albeit usually properly expressed in mg/kg.14–16 In contrast, one textbook devotes two full pages to masturbation.16 Overall, good pain management over much of the last century is probably well described as ‘islands of enlightenment, in a sea of misery’.17 A major ‘turn-around’ developed in the 1970s, with increasing attention to the poor management of adult post-operative pain and cancer pain, followed in the 1980s by overdue recognition that newborns and other children could indeed experience severe pain which was often poorly managed. A landmark was the formation in 1973 by Bonica of the International Association for the Study of Pain. In 1983, Mather and Mackie from Adelaide described gross under-use of analgesics post-operatively in children.18 Schechter, in more comprehensive reviews, detailed how children were much less likely to receive opioids than adults for severe pain in many different situations.19,20 Anand and colleagues showed that addition of fentanyl to light anaesthesia in neonates having major cardiac surgery reduced otherwise major changes in metabolic and hormonal parameters and reduced mortality.21,22 Unrelieved, severe pain is not only cruel but also life-threatening. Other childhood studies suggested long-term harmful psychological harm from unrelieved pain in childhood. Pain control was extended to a wide variety of conditions and severities of childhood, including medical procedures such as IV insertion and burns dressings. The 1980s saw a Renaissance of sorts in the recognition and potentially better treatment of childhood pain. Pain and palliative care units were set up in children’s hospitals in some Western countries. Unfortunately, the great majority of the world’s children do not have access to morphine or synthetic opioids when they really need them.1 Opioids provide benefit beyond their use in analgesia. Morphine, methadone and heroin are powerful antitussive drugs, in usual doses. This effect is unreliable with codeine, which is no longer recommended as an antitussive for children.23 It is not seen with synthetic drugs such as meperidine (Pethidine). The sedative and antitussive effects of morphine can be extremely useful as added benefits in cancer pain, including palliative care.
Journal of Paediatrics and Child Health 51 (2015) 482–485 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
483
Morphine and children
H Kilham et al.
Patent medicines were historically popular for these effects, but opioids are currently considered unjustifiable for cough alone, although no other effective antitussives are available for adults or children.
Current and Future Use of Morphine in Children, in Australia and Elsewhere This section summarises the long-established elements of safe and effective morphine use in children, considers its current status and speculates on how that might change in the future. It is not intended as a practical treatment guideline. Morphine remains the pre-eminent drug for managing moderate-to-severe and severe pain in all age groups. It is also used in specific circumstances for relieving breathlessness and for suppressing cough and is the preferred treatment for neonatal abstinence syndrome.24 Morphine is used both for acute and for chronic pain in a wide variety of both cancer and non-cancer conditions. Comprehensive guidelines for its use in infants and children have long been established25,26 and will not be replicated here.
Current status versus other analgesics In a US study published in 2008, morphine was in the top 10 medications prescribed for hospitalised children.27 Some years before, meperidine (Pethidine) and codeine were often used in preference to morphine for moderate-to-severe pain but both are now usually avoided because of side effects or unreliable effects.25 Occasionally, for long-term use, methadone or morphine analogues are used in place of morphine where the latter has severe continuing side effects or inadequate analgesic effect.25 The synthetic oral opioid oxycodone is increasingly used in place of morphine where oral dosing is possible. Severe pain can sometimes be treated with high-dose paracetamol but this is not first-line therapy and should only be given as single dose therapy.28 Morphine has limited value in neuropathic pain and in some other pain conditions.29,30
Using morphine There are well-described age-related differences in the pharmacokinetic and pharmacodynamic responses during development in children.31 Morphine needs to be given in small dosage increments until good pain control is achieved, while monitoring for side effects. Morphine, like other opioids, has no ‘ceiling’ analgesic effect and the appropriate dose is the dose that achieves pain relief for the individual child.25 In order to achieve this, the child needs frequent pain assessment and adjustment of the analgesic dose. Repeated doses are given as soon as required and not by traditional time intervals. The effective opioid dose varies widely between children and in the same child at different times. Morphine dosage guidelines and other practical implications are available in paediatric and pharmacological textbooks.25,26,31–33 In some advanced medical conditions and in palliative care, opioids can be very valuable in relieving breathlessness.34 Morphine has been used effectively, for this indication, via both oral and parenteral routes.35 Other opioids have been used, although less commonly than morphine, since the late 19th century. While 484
its precise mode of action is unclear, it appears to modulate the perception of dyspnoea directly by affecting inspiratory drive.36,37
Routes of administration Morphine is available for injection and in formulations for oral use. Dosage varies widely between parenteral and oral use. In acute circumstances, injection is required and this should be intravenous, not intramuscular, although the subcutaneous route is sometimes used. For long-term use, oral dosage is preferred when possible. Absorption after rectal administration is unreliable and this should be avoided.25
Side effects and safety Because of the great dosage variations in infants and children, meticulous attention to dosage and observation for side effects is more critical than in other age groups. The greatest concern is respiratory depression which can be fatal, yet can be detected and managed with simple competent observation. Morphine therapy is often accompanied by nausea and vomiting, usually inconsequential, but at times requiring a change to other drugs. Other side effects include sedation, pruritus, urinary retention, constipation, bronchoconstriction, myoclonic movements, and physical and psychological dependence.25 Clinicians experienced in the use of morphine and other opioids become very skilful in their use, to the enormous benefit of sick children.
The future Other promising uses of morphine include topical use for malignant and non-malignant ulcers and oropharyngeal mucositis, although further research is needed before use for these indications could be recommended.38 Other emerging uses lacking strong evidence of safety and efficacy include sublingual, intranasal and nebulised morphine.25,39–43 As in adults, medium and longer-term use of morphine and other opiates now occurs in non-cancer, non-terminal situations in children, although to a far lesser extent, probably reflecting the lower incidence of severe chronic pain in children. Although legitimate, such use demands a high level of skill, experience and patient supervision. In conclusion, except in the unlikely event of discovery of a new, superior, powerful analgesic, morphine will continue as the drug of choice for severe pain in many situations affecting children. Overall, the major problems with the medical use of morphine in children across the world are lack of knowledge and lack of availability, when really needed.
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