SUMMARY

1. Transference of research findings to clinical practice hasbeen a challenge for those managing chronic pain. Generally,pain is not well controlled in hospitals and steps need to be takento make pain control more effective.

2. Clinical trials of opioids have shown that pain can be con-trolled in the great majority of patients. Apart from the use ofthe World Health Organization Analgesic Ladder, a ‘pain diag-nosis’ should be made and a comprehensive view of pain needsto be considered by the clinician. This would include pain andother physical symptoms, psychological issues and social andspiritual stresses.

3. Respiratory depression and tolerance for opioids are oftenseen as negative aspects of opioids and, therefore, may lead toinadequate control of pain. The evidence cited suggests that, inthe long-term treatment of cancer pain, respiratory depressionalmost never occurs. The only situation that warrants cautionis when an anaesthetic block or similar procedure relieves paintreated by opioids, when that patient has been receiving largedoses of opioids. Long-term studies with opioids show thattolerance may occur, but is not a clinical problem and shouldnot impair their use in adequate doses to relieve the patient’spain.

4. The active morphine metabolites, morphine-3-glucuronide(M3G) and morphine-6-glucuronide (M6G) do need to be considered when administering morphine. There seems to be considerable interindividual variation in the production and elimination of metabolites. In cases of renal failure or in the elderly, the ratios of M3G and M6G to morphine accumu-late exponentially, making opioid toxicity more likely. Evendifferent routes of administration seem to be associated with

different ratios of metabolites. A knowledge of these sources ofpharmacokinetic variability may lead to more effective use of the opioids in clinical practice.

Key words: chronic pain, clinical trials, morphine, opioids.

INTRODUCTION

The transference of research findings into clinical practice has beena widely recognized challenge for medical professionals. In spiteof the research on opioids, pain control is still a problem for patientsin our hospitals. In a recent survey that examined pain relief in NHShospitals in Britain, Bruster et al. showed that 33% of patientsreported that pain was present all or most of the time, 87% said thatthe pain was severe or moderate, 42% had to ask for drugs to relievethe pain and 42% of patients felt that the drugs did not arrive in atimely fashion.1

What are some of the factors contributing to this failure to relievepain? The first is the need to train doctors in ‘pain diagnosis’, thefirst step in pain relief. This seeks not only to take all the elementsof the history into account, but also aims to characterize the paininto nociceptive and neuropathic pain at least and then uses theresults of clinical trials in various types of pain to tailor treatmentfor that pain. Pain relief and palliative care programmes that seekto do this still do not have sufficient time in the curricula ofAustralian medical schools, even though there is a publishedcurriculum available.2

VARIATION IN OPIOID EFFECTS

In 1986 the World Health Organization (WHO) Analgesic Ladderwas formulated3 and clinical trials began to assess efficacy of thisrecommendation. By the early 1990s, these clinical trials had shownconsiderable success.4 They had shown that pain could be relievedin 70–90% of patients in different countries. However, in situationslike those at St Christopher’s and St Joseph’s hospices in London,pain relief was reported at rates of 90–99%.5 These rates have beenachieved by the understanding that pain cannot be treated adequatelyunless it is seen in the context of the patient’s life. This means thatother issues, such as physical symptoms, psychological, spiritual andsocial stresses, that impact on the perception of pain should be takeninto account and dealt with as necessary.6

Annual Scientific Meeting of ASCEPT, 1998: Symposium on Opiates and Pain

BEDSIDE PERSPECTIVES ON THE USE OF OPIOIDS:TRANSFERRING RESULTS OF CLINICAL RESEARCH

INTO PRACTICE

Peter Ravenscroft*† and Jennifer Schneider†

*University of Newcastle and †Division of Palliative Care, Newcastle Mater Hospital, Newcastle, New South Wales, Australia

Correspondence: Professor Peter Ravenscroft, Division of Palliative Care,Newcastle Mater Hospital, Locked Bag 7, Hunter Regional Mail Centre,NSW 2310, Australia. Email: mdpr@cc.newcastle.edu.au

Presented at the Annual Scientific Meeting of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Hobart,13–16 December, 1998.

Received 24 February 1999; revision 10 March 2000; accepted 20 March2000.

Clinical and Experimental Pharmacology and Physiology (2000) 27, 529–532

530 P Ravenscroft and J Schneider

In spite of evidence such as this, a major issue is the doctor’s andpatient’s perception of the risks of opioid therapy. Two major factorshave had an impact on these attitudes. They are respiratorydepression and tolerance. Much of what is known of opioid-inducedrespiratory depression and tolerance has been gained by animalexperiments or observations of acute administration of opioids, such as in intermittent use of opioids for recreational purposes and the use of opioids in acute pain situations. The transference ofthese data to the management of long-term cancer patients hasdifficulties.

RESPIRATORY DEPRESSION

Goodman and Gilman’s textbook The Pharmacological Basis ofTherapeutics contains this statement:

Morphine-like opioids depress respiration … The respiratory depressionis discernible even with doses too small to disturb consciousness andincreases progressively as the dose is increased.7

This statement would seem to apply to all uses of opioids. In contrast,if we read palliative care texts, we find statements such as:

Clinically significant respiratory depression is rarely seen in patientswith severe pain due to malignant disease even when receiving largedoses of morphine.8

The cause of this apparent paradox seems to be that data collectedfrom the acute use of the drug in naïve patients have been trans-ferred to the long-term experience with the drug.

In long-term clinical use, where the dose of opioid is matched tothe intensity of the pain, respiratory depression seldom, if ever,occurs. The first reason is that the respiratory centre becomesrelatively resistant to the depressant effects of the opiates over time.This explains why we do not see unexpected deaths in palliative carepatients on large doses of morphine. Doses of morphine of the orderof grams may not cause adverse effects in patients with pain. It isalso the reason that euthanasia is not performed using opioids. Thesedrugs simply do not work for this purpose when patients have beenon them for some time!

The second reason is that pain and emotional distress are power-ful counteracting factors to the effect of opioids. When a patient hassevere pain, opioids in large doses may be given to suppress the pain,often without major side effects. However, if the pain is relieved,for example, by an anaesthetic block or similar intervention, thepatient is likely to experience exaggerated opioid effects, such assedation and some respiratory depression, from the morphine andthe dose should be reduced.9

One of the questions that is often raised is what is the relativeadvantage of the use of heroin for chronic pain? In the studypublished by Twycross,10 a prospective trial has been performed inover 700 subjects. The patients, who received either heroin or mor-phine orally, did not perceive any differences in pain relief or sideeffects, nor did the clinicians caring for them. Therefore, we do notthink it would be an advantage to have an oral formulation of heroinin this country for use in palliative care patients.

TOLERANCE

The second factor is tolerance. The definition of tolerance is ‘… areduction in response to the drug after repeated administrations’.7

The axiom of this is that if you are trying for a successful effect ofa drug, in our case pain relief, then the effect of tolerance will bethat you will have to progressively increase the dose of the drug toget the same effective pain relief. This is generally true for the inter-mittent use of opioids for recreational use or in the treatment of otherconditions.

Two studies address this issue as it applies to the use of opioidsin patients with cancer. The first is a study of 418 consecutive patientsadmitted with advanced cancer.11 The group median daily dose ofdiamorphine was plotted against the median duration of treatment.Overall, the median dose rose from approximately 50 mg/day at 1.5 weeks to approximately 145 mg/day at 24 weeks. Approximately12% of this rise occurred between 1.5 and 3 weeks; 31% occurredbetween 3 and 6 weeks; 31% between 6 and 12 weeks and 26%between 12 and 24 weeks. This study suggests that tolerance, if it

Fig. 1 The graph shows the relationship of the area under the curve (AUC) for morphine (r) and its metabolites morphine-6-glucuronide (m) and morphine-3-glucuronide (j), which is a measure of the patients’ exposure to the drug, and metabolites versus the oral dose of morphine. These patients with normalrenal function were given oral morphine for 3 days and their steady state concentrations were measured by high-performance liquid chromatography.19

These graphs indicate that there may be substantial differences in exposure to the drug and metabolites due to pharmacokinetic variability.

Bedside perspectives on the use of opioids 531

is a factor in cancer patients, is not the problem that it seems to bein drug-dependent patients.

The second study12 examined the dose changes in 115 cancerpatients treated with opioids who survived longer than 3 months.Patients’ dosage of opioid was assessed according to survival at12–17 weeks, 18–25, 26–41 and greater than 42 weeks. The averagechange in dosage was 11.0, 11.0, 10.3 and 0.02 mg/day, respec-tively, for those periods. Further analysis showed that in the 12–17thweeks, 80% had their dose increased, 13.3% had their dosedecreased and 6.7% had no change in their dose. By the 42nd weekplus group, 57.9% had their dose increased, 36.8% had their dose

decreased and 5.3% had no change made to their dose. These find-ings suggest that the longer the patient survived, the smaller werethe changes in the dose of opioids. In quite a number of patients,the dose was able to be decreased. These results confirm the findingsof the first study and indicate that unmanageable tolerance is not aclinical problem in patients with pain from cancer.

The conclusions from these studies should lead us to use opioidsin sufficient doses to relieve the pain of terminal disease withoutthe concern for respiratory depression and tolerance that have beenproblems for recreational drug use. There is a need for pharmacolo-gists to teach this information about long-term opioids and to assistto eliminate the opiophobia that seems to prevent the adequate useof opioids for pain relief.

VARIATION IN OPIOID PHARMACOKINETICS

Following the development of high-performance liquid chroma-tography (HPLC) methods for morphine approximately two decadesago, it became apparent that morphine had a number of metabolites,of which morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were of most interest. Morphine-6-glucuronideis approximately four- to 20-fold more potent than morphine13,14 andM3G seems to be an antagonist of M6G and morphine, althoughthe latter effect is still controversial.15,16

A good deal of the individual variation in the response to theopioids seems to be related to individual differences in metaboliteturnover. Figure 1 gives an example of the relationships of morphine,M3G, M6G and morphine concentrations in two patients who havebeen studied in our department. They had normal renal function andwere studied at steady state as they took increasing doses ofmorphine ordered by their physician. The differences in the areasunder the curves (AUC) at steady state concentrations of themetabolites, which represent the exposure of the patient to the drugor metabolite and the different rates of accumulation of the drugs,suggest a pharmacokinetic basis for the individual differences in theresponses to the drug in different individuals.

Whereas morphine is metabolized by the liver, M3G and M6G are excreted by the kidneys. In the presence of renal failure

Fig. 2 This graph shows the results of monitoring 18 patients for chronic cancer pain whose doses of morphine were determined by their physicians. Theplasma ratios were measured at steady state and the ratio of (a) morphine-3-glucuronide (M3G) and (b) morphine-6-glucuronide (M6G) to morphine (M)was plotted against estimated creatinine clearance.17 The graph indicates that, as the estimated renal function deteriorates, there is an exponential rise in theratios of M3G:M and M6G:M. This at least partly explains why toxicity may occur if excessive doses of morphine are given to patients with impaired renalfunction.

Fig. 3 The mean plasma ratios of morphine-3-glucuronide (M3G) andmorphine-6-glucuronide (M6G) to morphine (M) were measured19 at steadystate during different routes of administration of morphine. (h), subcu-taneous morphine (n 5 16); ( ), oral morphine mixture (n 5 8); (j),sustained-release morphine (MST Continus; Douglas Pharmaceuticals Ltd,Auckland, New Zealand) given rectally (n 5 10); ( ), sustained-releasemorphine (MS Contin; Mundipharma Pty Ltd, Sydney, NSW, Australia)given orally (n 5 6). Different doses of morphine and different routes wereused; therefore, the mean metabolite concentrations are divided by the mor-phine concentrations occurring at the same time. This graph indicates thevariability of metabolite ratios with route of administration.

532 P Ravenscroft and J Schneider

particularly, or if the dose exceeds the ability of the kidney to excretethe metabolites, such as may occur in the elderly, toxicity may occur.Allodynia and myoclonic jerks seem to be hallmarks of metabolitetoxicity in these situations. Figure 2 shows the relationship of steadystate M3G:morphine and M6G:morphine ratios to creatinine clear-ance estimated from the serum creatinine by the Cockcroft–Gaultmethod17 in 18 patients studied over 4–26 weeks. As the estimatedcreatinine clearance decreases, the ratios of the metabolites rise exponentially. This explains the extreme sensitivity of patients withreduced renal function to dosing with morphine and indicates whycaution needs to be exercised by clinicians in giving opioids topatients with renal failure or the elderly, who may have reduced renal function.

The route of administration appears to be another source of vari-ation in morphine metabolite concentrations. Figure 3 shows the datafrom our studies. Patients were given morphine by different routesand concentrations of morphine and metabolites were measured atsteady state.18 The first study was with morphine given subcu-taneously. In the second, oral morphine mixture was given. The thirdincluded sustained-release tablets given rectally19 and the fourth wassustained-release morphine given orally. The graph shows that themean ratios of metabolite to morphine change with different methodsof administering the drug. The implications of these observationsare that if a patient was to get adverse reactions on one preparationof morphine, for example, oral sustained-release morphine, it maybe reasonable to try the mixture or the subcutaneous route beforechanging to another opioid.

ACKNOWLEDGEMENTS

We acknowledge the assistance of Dr J Cavenagh (Division ofPalliative Care, Newcastle Mater Hospital) for assisting withrecruiting patients and Mrs AM Brown (Princess AlexandraHospital, Brisbane, Qld, Australia) for assisting with the studies. Partof the studies were supported by a Grant from the QueenslandCancer Fund.

REFERENCES

1. Bruster S, Jarman B, Bosanquet N et al. A national survey of hospitalpatients. BMJ 1994; 309: 1546–9.

2. Australian and New Zealand Society of Palliative Medicine.

Australasian Undergraduate Medical Palliative Care Curriculum.Australian and New Zealand Society of Palliative Medicine, Melbourne.1996.

3. World Health Organization. Cancer Pain Relief, 2nd edn. WHO,Geneva. 1996.

4. Stjernsward J. WHO pain relief programme and future challenges. In:Takeda F (ed.). Cancer Relief and Quality of Life. WHO CollaboratingCenter for Cancer Pain Relief and Quality of Life, Saitama, Japan. 1991;40–2.

5. Twycross R. Pain Relief in Advanced Cancer. Churchill Livingstone,Edinburgh, 1994.

6. Woodruff R. Palliative Medicine, 2nd edn. Asperula Pty Ltd, Melbourne.1996.

7. Hardman JG, Limbird LE, Gilman AG (eds). Goodman and Gilman’sthe Pharmacological Basis of Therapeutics, 9th edn. McGraw-Hill, NewYork. 1996.

8. Twycross RG, Lack SA. Symptom Control in Far Advanced Cancer:Pain Relief. Pitman, London. 1983.

9. Hanks GW, Twycross RG, Lloyd JW. Unexpected complication ofsuccessful nerve block. Morphine induced respiration precipitated byremoval of severe pain. Anaesthesia 1981; 36: 37–9.

10. Twycross RG. Choice of strong analgesic in terminal cancer:Diamorphine or morphine? Pain 1977; 3: 93–104.

11. Twycross RG. Clinical Experience with diamorphine in advanced malig-nant disease. Int. J. Clin. Pharmacol. Ther. Toxicol. 1974; 9: 184–98.

12. Twycross RG, Wald SJ. The long-term use of diamorphine in advancedcancer. In: Bonica JJ, Albe-Fessard D (eds). Advances in Pain Researchand Therapy. Raven Press, New York. 1976; 653–61.

13. Osborne R, Joel S, Trew D, Sleven M. Analgesic activity of morphine-6-glucuronide. Lancet 1988; i: 828.

14. Osborne R, Thompson P, Joel S, Trew D, Patel N, Slevin M. Theanalgesic activity of morphine-6-glucuronide. Br. J. Clin. Pharmacol.1992; 34: 130–8.

15. Smith MT, Watt JA, Crammond T. Morphine-3-glucuronide: A potentantagonist of morphine analgesia. Life Sci. 1990; 47: 579–85.

16. Gong Q, Hedner J, Bjorkman R, Hedner T. Morphine-3-glucuronideinduced antinociception and ventilatory depression in the rat. Pain 1992;48: 249–5.

17. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serumcreatinine. Nephron 1976; 16: 31–41.

18. Joel SP, Osbourne RJ, Slevin ML. An improved method for the simul-taneous determination of morphine and its principal glucuronidemetabolites. J. Chromatogr. 1988; 430: 394–9.

19. Wilkinson TJ, Robinson BA, Begg EJ, Duffull SB, Ravenscroft PJ,Schneider JJ. Pharmacokinetics and efficacy of rectal versus oral sus-tained-release morphine in cancer patients. Cancer Chemother.Pharmacol. 1992; 31: 251–4.