Volume 173 Issue 5

Research Rates of in-hospital arrests, deaths and intensive care admissions: the effect of a medical emergency team Peter J Bristow, Ken M Hillman, Tien Chey, Kathy Daffurn, Theresa C Jacques, Sandra L Norman, Gillian F Bishop and E Grant Simmons MJA 2000; 173: 236-240 Abstract - Methods - Results - Discussion - Conclusion - Acknowledgements Authors' details - - More articles on Emergency medicine Abstract Objectives: To evaluate the effectiveness of a medical emergency team (MET) in reducing the rates of selected adverse events. Design: Cohort comparison study after casemix adjustment. Patients and setting: All adult (≥ 14 years) patients admitted to three Australian public hospitals from 8 July to 31 December 1996. Intervention studied: At Hospital 1, a medical emergency team (MET) could be called for abnormal physiological parameters or staff concern. Hospitals 2 and 3 had conventional cardiac arrest teams. Main outcome measures: Casemix-adjusted rates of cardiac arrest, unanticipated admission to intensive care unit (ICU), death, and the subgroup of deaths where there was no pre-existing "do not resuscitate" (DNR) order documented. Results: There were 1510 adverse events identified among 50 942 admissions. The rate of unanticipated ICU admissions was less at the intervention hospital in total (casemix-adjusted odds ratios: Hospital 1, 1.00; Hospital 2, 1.59 [95% CI, 1.24-2.04]; Hospital 3, 1.73 [95% CI, 1.37-2.16]). There was no significant difference in the rates of cardiac arrest or total deaths between the three hospitals. However, one of the hospitals with a conventional cardiac arrest team had a higher death rate among patients without a DNR order. Conclusions: The MET hospital had fewer unanticipated ICU/HDU admissions, with no increase in in-hospital arrest rate or total death rate. The non-DNR deaths were lower compared with one of the other hospitals; however, we did not adjust for DNR practices. We suggest that the MET concept is worthy of further study. Certain in-hospital deaths may be preventable.1-3 Nearly 85% of hospital inpatients who suffer a cardiorespiratory arrest have documented observations of deterioration in the eight hours before the arrest.4,5 Recent studies have demonstrated suboptimal care of hospitalised patients before their admission to the intensive care unit (ICU), and that these patients have a higher mortality.6-8 The authors of these studies urge earlier intervention. One approach to providing an early response to at-risk inpatients throughout the hospital is the medical emergency team (MET),9,10 which replaces the conventional cardiac arrest team. The MET responds to specific clinical criteria (such as bradycardia, tachycardia, hypotension and threatened airway) in order to prevent further deterioration. Others have advocated similar approaches to reduce unexpected hospital deaths and morbidity.11,12 In our study, selected outcomes in a hospital with a MET were compared with outcomes in two hospitals with conventional cardiac arrest teams. These outcomes were rates of cardiorespiratory arrest, unanticipated admission to the ICU or high dependency unit (HDU), death, and deaths where there was no prexisting "do not resuscitate" (DNR) order. Methods This study was a prospective cohort comparison of three hospitals, testing whether an early intervention team, the MET, was associated with fewer adverse events among inpatients, after adjusting for casemix differences. The study was approved by the ethics committees of each participating hospital and the University of New South Wales. Setting The hospitals were similarly sized Australian public hospitals, with bed capacities in the range 380-530. At Hospital 1, the cardiac arrest team was replaced by a MET, which any staff member could call for immediate assistance. Staff could summon the MET if concerned about a patient's condition or if the patient's vital signs exceeded certain levels (Box 1).10 An education program explained the MET's role to all new staff. However, calling the MET when criteria were met was not compulsory. The MET consisted of the ICU registrar and senior nurse, and medical registrar. At Hospitals 2 and 3, the arrest team was paged by nursing or medical staff for cardiorespiratory arrest. The arrest team consisted of the ICU registrar, medical registrar, and ICU or coronary care nurse. Data collection We identified all cardiorespiratory arrest calls, deaths, and ICU/HDU admissions at the three hospitals among patients 14 years and over in hospital during the period from 8 July to 31 December 1996. These were designated "events". Soon after an event, the patient's medical record was reviewed for demographic information. In addition, for cardiac arrests and deaths, documentation of a DNR order before arrest or death was recorded. Each ICU/HDU admission was classified as to whether the patient was admitted to ICU/HDU for the same reason he or she was admitted to hospital. If not, the ICU/HDU admission was defined as unanticipated. For example, a patient admitted to ICU with respiratory distress after a cholecystectomy would be unanticipated. Data were collected by three critical care nurses (one at each hospital) trained in the use of a specifically designed form, which was piloted for two weeks before data collection. The nurses were familiar with the medical record at the three hospitals. Where the information contained in the history was unclear, the attending staff were asked for clarification. Data were entered into a database.13 Data cleaning was performed and any anomalies checked by reference to the datasheet or medical record. Data were then exported to SAS14 for analysis. Outcome measures The primary endpoints were the casemix-adjusted rates of ICU/HDU unanticipated admission, cardiac arrest, death, and deaths without a prior DNR order. These were called "total event rates". For any patient, one event could result in additional events (eg, cardiac arrest followed by unanticipated ICU admission and then death). The "index event" was defined as the event the data collectors considered the first in a series of events. The casemix-adjusted rates of index events were compared between the three hospitals as secondary endpoints. To ensure that any decline in the rate of unanticipated admissions was not caused by excess anticipated admissions, the casemix-adjusted rate of all ICU/HDU admissions was calculated as a control measure. Casemix adjustment Demographic and diagnostic data on the patient population (aged ≥ 14 years) admitted to the hospitals for the period were obtained. The study data were merged by medical record number and date of admission with the complete inpatient statistical data to create a dataset with 50 942 records. This enabled us to identify the admissions for which an event occurred and analyse the data at the patient level. Using simple and multiple logistic regression, we modelled the probability of an event occurring during hospitalisation, adjusted for patient demographics and diagnostic characteristics. Models were derived independently for each total event and for each index event. Parameters were added to the model in a stepwise fashion. To prevent overparameterising the models (where minor, non-significant differences cumulatively hide true differences), when C (equivalent to the area under the receiver operator characteristics curve) reached 0.85 no further parameters were added to the model. This always occurred with fewer than six parameters used. Demographic and casemix independent variables that were tested for use in the models are detailed in Box 2. The models developed used groups of diagnostic categories based on ICD-9-CM codes using the principal diagnosis and the stay diagnosis only.15 The ICD-9-CM code groupings used are available from the principal author (PJB). The performance of the models was assessed by Hosmer-Lemeshow goodness-of-fit tests.16 The risk of an event occurring in a hospital compared with the MET hospital was presented as an adjusted odds ratio with 95% confidence intervals. A level of significance of 5% was used in all statistical tests. Results Hospital demographics Characteristics of all patients (aged ≥ 14 years) admitted to the three hospitals during the study period are shown in Box 3. Hospital 2 had fewer admissions than the other hospitals. Hospital 1 had a higher proportion of male patients admitted, and a lower proportion of admissions from the emergency department (ED). This hospital also had a younger patient population, which is reflected in differences in casemix: Hospital 1 had lower proportions of patients with stroke, severe acute heart disease, gastrointestinal disease, and musculoskeletal and connective tissue diseases, but higher proportions with severe trauma and follow-up care without acute diagnosis (eg, dialysis). The rates of DNR orders in dying patients were 77% in Hospital 1, and 64% and 70% in Hospitals 2 and 3, respectively (P = 0.006). Prevalence and characteristics of events A total of 1510 adverse events (unanticipated ICU/HDU admissions, arrest calls, and deaths) were recorded during the study period for the three hospitals. There were 1100 index events. The prevalence and characteristics of events are summarised in Box 4 for total event rates and Box 5 for index rates. There was a significantly reduced rate of unanticipated ICU/HDU admissions at the MET intervention hospital after casemix adjustment (for both the total event rate and the index rate). After adjustment, Hospital 2 had 49 (95% CI, 20-87) more unanticipated ICU/HDU admissions over a six-month period, and Hospital 3 had 92 (95% CI, 47-146) more, compared with Hospital 1. The rate of all ICU/HDU admissions was lower at Hospital 1 than at one control hospital, and trended to lower than at the other. There was no statistically significant difference in cardiac arrest rate or death rate after casemix adjustment. The casemix-adjusted death rate in patients where there was no documentation found of a DNR order was significantly higher at Hospital 2, translating to 27 (95% CI, 7-53) extra non-DNR deaths. Model performance Box 6 presents an example of the odds ratios after addition of the most significant variables in the multiple logistic regression models derived from the data for the total arrest data. It shows the C statistic as each variable was added to the cardiac arrest model. In the cardiac arrest models, the variables that were adjusted for were emergency admissions, age over 74, heart disease, lung disease and infectious disease as diagnoses. In the total death models, the terms adjusted for were emergency admissions, age over 74, single day stay emergency admissions, and cancer and infectious disease. The same demographic variables were used in the index death model, although in the total non-DNR death model both age ≥ 75 and age 65-74 were used in the model. In the unanticipated ICU/HDU models, the variables adjusted for were single day admission, emergency admission, and cancer and gastrointestinal disease diagnoses. The total unanticipated ICU/HDU model also included the variables stroke and infectious disease as diagnoses. All models satisfied the Hosmer- Lemeshow test.16 Discussion Rationale for our methods In this study, we attempted to determine if the MET system was associated with a reduced rate of adverse events among inpatients. To do this, we compared the rates of adverse events between three hospitals after casemix adjustment.17-19 This method was chosen as we decided that randomisation at the patient level was impractical. A random pattern of response to calls would probably have dissuaded staff caring for patients from calling the MET. Randomisation by ward would have risked contamination bias and engendered problems of casemix, as wards differ in the nature of their patients. Historical comparison at Hospital 1 between a period before and a period after introduction of the MET team was impractical, as the team had been trialled and evolved for six years before the study. The models we used appear to adequately fit the data, according to the Hosmer-Lemeshow goodness-of-fit tests, and with good model performance measured by C statistics. However, multiple methods of casemix adjustment are possible, and these may give divergent results. This is a limitation of casemix adjustment methodology.20 To avoid concealing real differences by excessive modelling, parameters were added stepwise by multivariate analysis until the models reasonably represented the data. The terms which appeared in the final models were usually those that could be expected to influence the outcomes. Thus, advanced age and emergency admissions were factors in the death and cardiac arrest models. The cardiac arrest models also included the terms for heart disease, lung and infectious disease. Infectious disease was an unexpected variable and was also significant in the total death model. Other differences (such as levels of hospital funding, ICU/HDU capacity, the number and seniority of medical and nursing staff, and the level of out-of-hours cover) may also have contributed to the results. However, to adjust for these would have been more difficult than for the variables studied, which relate directly to the patients at risk and are easily and reliably obtained. Explanation of findings After casemix adjustment, we found reduced rates of both total and index unanticipated ICU/HDU admissions at the MET intervention hospital. There were no differences in the rates of cardiac arrests or deaths. However, at one hospital without the MET, there was a higher rate of non-DNR deaths, the subset of deaths most likely potentially preventable by a MET. The reduction in unanticipated ICU/HDU admissions that was seen in the MET intervention hospital could result from many factors. One possible explanation is that the MET was effective and able to intervene on the wards and prevent further deterioration. Another possible reason may relate to differences in referral practices: perhaps the presence of MET backup engendered a feeling that ICU/HDU referral was not needed. Misclassification of ICU/HDU admissions as anticipated rather than unanticipated was excluded as an explanation of the difference by the finding that the rate of all ICU/HDU admissions was lower at the intervention hospital than one control hospital and trended to lower at the other. The lack of efficacy of the MET to prevent cardiorespiratory arrest and modify death rate may be related to lack of sensitivity of calling criteria, or because pathophysiological processes (eg, shock) become irreversible. Another possible explanation for the lack of effect of the MET on event rates is underutilisation. Based on a previous study,21 up to 706 MET calls could have been expected, and yet only 150 were made. Frequent education is probably also required to ensure the appropriate calling of a MET.22 No special efforts regarding staff education in the study period were made. The clinical staff of the hospital were unaware of the study, to negate any possible Hawthorne effect.23 Finally, organisational changes such as introduction of a MET are difficult to implement in hospitals.24,25 Our results probably reflect the effectiveness of the implementation of the MET system as much as the concept of early intervention. Future directions Our study cannot answer definitively if the MET was the cause of the benefit we observed; it does show that the MET concept is worthy of further study. The study could be likened to a Phase II trial of a drug comparing three hospitals at one point in time. Further studies of the MET system's efficacy are needed, such as a before-after comparison in several hospitals, or a comparison of a larger sample size of intervention and control hospitals. Such studies should be repeated some time after the intervention. Is the benefit observed useful and worth pursuing? If it is possible to reduce unanticipated ICU admissions without increased mortality this may result in cost saving. It has been estimated that the US spends about 1% of its gross national product on intensive care facilities.26 However, any savings in intensive care would be offset by the cost of establishing and maintaining a MET. The MET may also have unexpected costs and benefits on processes such as staff satisfaction with care provided. Again, these need to be quantified. Conclusion In this study, we found that fewer patients were unexpectedly admitted to ICU or HDU at a hospital with the MET system, and this hospital had fewer non-DNR deaths than one of the other hospitals. There was no significant change in the casemix-adjusted rate of arrests or total deaths. This may be an advantage of an early response team, which could have important implications for patient care in hospitals. We believe that the MET concept should be studied further in a larger sample of institutions. Acknowledgements Funding for the study was provided by a Commonwealth Department of Health and Family Services Research and Development Grant (HS338). Associate Professor Robert Gibberd assisted with the statistical analysis. References Brennan TA, Leape LL, Laird N, et al. Incidence of adverse events and negligence in hospitalised patients: results of the Harvard Medical Practice Study I. N Engl J Med 1991; 324: 370-376. Leape LL, Brennan TA, Laird N, et al. Nature of adverse events in hospitalised patients: results of the Harvard Medical Practice Study II. N Engl J Med 1991; 324: 377-384. Wilson R McL, Runciman WB, Gibberd RW, et al. The Quality in Australian Health Care Study. Med J Aust 1995; 163: 458-471. Schein RMH, Hazday N, Pena M, et al. Clinical antecedents to inhospital cardiopulmonary arrest. Chest 1990; 98: 1388-1392. Franklin C, Mathew J. Developing strategies to prevent inhospital cardiac arrest: analyzing responses of physicians and nurses in the hours before the event. Crit Care Med 1994; 22: 246-247. Lundberg JS, Perl TM, Wiblen T, et al. Septic shock: an analysis of outcomes for patients with onset on hospital wards versus intensive care units. Crit Care Med 1998; 26: 1020-1024. Goldhill DR, Sumner A. Outcome of intensive care patients in a group of British intensive care units. Crit Care Med 1998; 26: 1337-1345. McQuillan P, Pilkington S, Allan A, et al. Confidential inquiry into quality of care before admission to intensive care. BMJ 1998; 316: 1853-1858. Lee A, Bishop G, Hillman KM, Daffurn K. The medical emergency team. Anaesth Intensive Care 1995; 23: 183-186. Hourihan F, Bishop G, Hillman KM, et al. The medical emergency team: a new strategy to identify and intervene in high risk patients. Clin Intensive Care 1995; 6: 269-272. Frank ED. A shock team in a general hospital. Anesth Analg 1967; 46: 740-745. Goldhill DR. Introducing the postoperative care team [editorial]. BMJ 1997; 314: 389. Microsoft Access [computer program]. Version 2.0. Redmond, Wa: Microsoft, 1994. SAS for Windows [computer program]. Version 6.12. Cary, NC: SAS Institute Inc, 1997. Stremple JF, Bross DS, Davis CL, McDonald GO. Comparison of postoperative mortality and morbidity in VA and nonfederal hospitals. J Surg Res 1994; 56: 405-416. Hosmer DW, Lemeshow S. Applied logistic regression. New York: John Wiley and Sons, 1989. Iezzoni LI. The risks of risk adjustment. JAMA 1997; 278: 1600-1607. Dubois RW, Rogers WH, Moxley JH, et al. Hospital inpatient mortality. Is it a predictor of quality? N Engl J Med 1987; 317: 1674-1680. Green J, Passman LJ, Wintfield N. Analyzing hospital mortality. The consequences of diversity in patient mix. JAMA 1991; 265: 1849-1853. Iezzoni LI, Shwartz M, Ash A, et al. Severity measurement methods and judging hospital death rates for pneumonia. Med Care 1996; 34: 11-28. Hillman KM, Bishop G, Lee A, et al. Identifying the general ward patient at high risk of cardiac arrest. Clin Int Care 1996; 7: 242-243. Daffurn KD, Lee A, Hillman KM, et al. Do nurses know when to summon emergency assistance? Intensive Crit Care Nurs 1994; 10: 115-120. Grufferman S. Complexity and the Hawthorne effect in community trials [editorial]. Epidemiology 1999; 10: 209-210. Garside P. Organisational context for quality: lessons from the fields of organisational development and change management. Qual Health Care 1998; 7 Suppl: S8-15. Koeck C. Time for organisational development in healthcare organisations [editorial]. BMJ 1998; 317: 1267-1268. Cerra FB. Healthcare reform: the role of coordinated critical care. Crit Care Med 1993; 21: 457-464. (Received 15 Feb, accepted 10 Jul, 2000) Authors' details Liverpool Hospital, Sydney, NSW. Peter J Bristow, MB BS, FRACP, Staff Specialist, Department of Intensive Care; Ken M Hillman, MB BS, FFICANZCA, Professor, University of New South Wales Clinical School; Kathy Daffurn, RN, MAppSc, Co-Director, Division of Critical Care; Sandra L Norman, MN, BAppSc, Clinical Nurse Specialist, Department of Intensive Care; Gillian F Bishop, MB ChB, FFICANZCA, Director, Department of Intensive Care; Tien Chey, BSc, MAppStat, Statistician, Epidemiology Unit. Department of Intensive Care, St George Hospital, Sydney, NSW. Theresa C Jacques, MB BS, FFICANZCA, Director. Department of Intensive Care, Illawarra Regional Hospital, Wollongong, NSW. E Grant Simmons, MB BS, FFICANZCA, Director. Reprints will not be available from the authors. Correspondence: Dr P J Bristow, Intensive Care Offices, Alfred Hospital, Commercial Road, Prahran, VIC 3181. p.bristowATalfred.org.au Make a comment 1: Criteria for calling the medical emergency team10 Cardiorespiratory arrest Threatened airway Respiratory rate ≤5 breaths per minute ≥36 breaths per minute Pulse rate ≤40 beats per minute ≥140 beats per minute Systolic blood pressure ≤90mmHg Repeated or prolonged seizures Fall in Glasgow Coma Score >2 points Concern about patient status not detailed above Back to text 2: Variables available for calculation of the various models Sex (binary) Seven age categories (14-24, 25-34, 35-44, 45-54, 55-64, 65-74, ≥75) Same-day admission (binary) (ie, admission and discharge occurred on the same calendar day) Referral from emergency department (binary) Australian born (binary) Casemix categories (16 indicator variables, available from author) Hospital (three indicator variables) Back to text 3: Characteristics of admissions at the three study hospitals from 8 July to 31 December 1996 Hospital* Characteristic 1 2 3 Test of Independence† Number of admissions 18338 13059 19545 Male admissions 44.9% 42.9% 42.8% χ2=21.06‡ (2 df) Same-day admissions 47.7% 47.0% 46.7% χ2=4.35 (2 df) Admission via emergency department 29.6% 36.0% 35.1% χ2=186.53‡ (2 df) Australian born Country of birth not stated 49.3% 6.8% 67.2% 0.5% 50.2% 23.2% Not tested Age distribution 14-24 25-34 35-44 45-54 55-64 65-74 ≥75 9.7% 14.9% 14.3% 12.4% 18.1% 20.5% 10.0% 8.6% 15.2% 9.6% 9.8% 18.5% 22.2% 16.0% 7.8% 13.1% 11.1% 10.4% 14.4% 22.1% 21.1% χ2=1146‡ (12 df) Diagnostic category 1. Cancer 2. Stroke 3. Severe acute heart disease 4. Metabolic and electrolyte disorders 5. Pulmonary disease 6. Ophthalmologic disease 7. Low risk heart disease 8. Gastrointestinal disease 9. Urologic disease 10. Musculoskeletal, connective tissue disease 11. Infectious diseases 12. Symptoms and ill-defined conditions 13. Severe trauma 14. Follow-up care without acute diagnosis 15. Pregnancy, childbirth, puerperium 16. Others 4.4% 1.4% 2.6% 1.3% 3.3% 2.0% 3.5% 6.4% 1.9% 1.8% 1.0% 3.2% 2.9% 34.0% 10.8% 19.5% 4.1% 1.8% 3.0% 1.6% 2.9% 1.2% 2.9% 8.9% 1.7% 3.4% 0.7% 3.0% 2.1% 30.1% 14.1% 18.5% 5.3% 1.6% 3.2% 1.1% 4.2% 0.5% 4.6% 10.2% 1.9% 3.2% 1.0% 6.7% 1.8% 23.4% 11.0% 20.5% χ2=1562‡ (50 df) *Hospital 1 had the medical emergency team. †Test for any difference between the three hospitals. ‡P Back to text 4: Comparisons of total event rates by hospitals Event n Crude rates/10000 Unadjusted ORs Adjusted ORs* Cardiac arrest Hospital 1 Hospital 2 Hospital 3 69 66 99 38 51 51 1.00 1.34 (0.96-1.89) 1.35 (0.99-1.83) 1.00 1.14 (0.81-1.61) 1.00 (0.73-1.37) Death Hospital 1 Hospital 2 Hospital 3 243 240 295 133 184 151 1.00 1.39 (1.16-1.67) 1.14 (0.96-1.35) 1.00 1.08 (0.89-1.30) 0.83 (0.70-1.00) Non-DNR death Hospital 1 Hospital 2 Hospital 3 55 86 88 30 66 45 1.00 2.20 (1.57-3.09) 1.50 (1.07-2.11) 1.00 1.68 (1.19-2.36) 0.94 (0.67-1.33) Unanticipated ICU/HDU admission Hospital 1 Hospital 2 Hospital 3 118 146 234 64 112 120 1.00 1.73 (1.36-2.21) 1.86 (1.49-2.32) 1.00 1.59 (1.24-2.04) 1.73 (1.37-2.16) *Odds ratios (ORs) adjusted for patient characteristics and diagnostic categories. Hospital 1 (which has the medical emergency team) is the reference for the ORs. For shaded ORs, 95% CIs do not cross 1.0. DNR="do not resuscitate" order documented. ICU=intensive care unit. HDU=high dependency unit. Back to text 5: Comparisons of index event rates by hospitals Event n Crude rates/10000 Unadjusted ORs Adjusted ORs* Cardiac arrest Hospital 1 Hospital 2 Hospital 3 60 63 84 33 48 43 1.00 1.48 (1.04-2.10) 1.31 (0.94-1.83) 1.00 1.24 (0.87-1.78) 0.96 (0.69-1.35) Death Hospital 1 Hospital 2 Hospital 3 119 139 191 65 106 98 1.00 1.65 (1.29-2.11) 1.51 (1.20-1.90) 1.00 1.24 (0.97-1.60) 1.05 (0.82-1.33) Unanticipated ICU/HDU admission Hospital 1 Hospital 2 Hospital 3 82 140 222 45 107 114 1.00 2.41 (1.83-3.17) 2.56 (1.98-3.30) 1.00 2.17 (1.65-2.87) 2.35 (1.82-3.04) *Odds ratios (ORs) adjusted for patient characteristics and diagnostic categories. Hospital 1 (which has the medical emergency team) is the reference for the ORs. For shaded ORs, 95% CIs do not cross 1.0. ICU=intensive care unit. HDU=high dependency unit. Back to text 6: An example of how the odds ratios and C statistic changed as variables were added stepwise to the model for total cardiac arrests Odds ratio* (95% CI) Hospital 2 Hospital 3 C statistic Crude odds ratio Admission via emergency department Age ≥75 years Severe acute heart disease Low risk heart disease Infectious disease Pulmonary disease 1.34 (0.96-1.89) 1.16 (0.83-1.63) 1.06 (0.75-1.49) 1.06 (0.75-1.49) 1.07 (0.76-1.50) 1.09 (0.77-1.53) 1.14 (0.81-1.61) 1.35 (0.99-1.83) 1.19 (0.87-1.62) 0.98 (0.72-1.34) 0.99 (0.72-1.35) 0.99 (0.72-1.35) 1.00 (0.73-1.37) 1.00 (0.73-1.37) 0.533 0.755 0.798 0.809 0.826 0.833 0.850 *Hospital 1 is the reference for the odds ratios. Back to text

Peter J Bristow · Ken M Hillman · Tien Chey · Kathy Daffurn · Theresa C Jacques · Sandra L Norman · Gillian F Bishop

For Debate Should we conduct a trial of distributing naloxone to heroin users for peer administration to prevent fatal overdose? Simon R Lenton and Kim M Hargreaves MJA 2000; 173: 260-263 Abstract - Should there be a trial - Suggested trial design - Conclusion - References - Authors' details - - More articles on Drugs and alcohol Abstract Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use). The rate of fatal heroin overdose in Australia has risen from 10.7 per million in 1979 to 67.0 per million in 1995; similar increases have been reported in other developed countries.1 Heroin users have an excess mortality about 13 times that of their age-matched peers,2 with annual mortality rates of between 1% and 3%.3 Although non-fatal overdoses are common among heroin users, overdose remains a major cause of death among this group,4 even in countries with high rates of HIV among injecting drug users.5 The central nervous system (CNS) depressants benzodiazepines and/or alcohol are often also present in the blood of people who died of heroin-related overdose.3,6In many fatal heroin overdoses there is ample opportunity for intervention: approximately 60% of deaths occur in the company of others,3,4,6-8 mostly other users, and sudden death after injecting is rare (about 15% of deaths).6,9 Death occurs more than three hours after injection in 22%-52% of cases.3 Furthermore, most overdoses occur in a home or other dwelling.9 Witnesses to fatal overdoses only call an ambulance in about 10% of cases,6 and there is no intervention before death in 79% of cases.3 Reasons for not calling an ambulance include fear of police involvement,8,10 ambulance costs,7 and previous negative experiences with hospital staff.10 Since the early 1990s, experts have suggested that naloxone hydrochloride, an opioid antagonist (Box), which has long been used to treat opioid overdose, should be provided to heroin users for administration by their peers in an overdose situation.8,24,38-40 This is one of a range of interventions aimed at reducing the incidence of fatal overdose, including: overdose prevention (eg, educating heroin users about risk factors for overdose and ways of reducing the risks, and increasing numbers in methadone maintenance treatment); and overdose management (eg, providing basic first aid training to heroin users, with emphasis on the need to call an ambulance).41 Naloxone has been available over-the-counter from pharmacies in Italy since 1995 and therefore available for peer administration. There are unpublished reports of authorised distribution for peer administration in Jersey (UK) and Berlin (Germany), and underground distribution through needle exchanges in San Francisco and Chicago, USA. However, to our knowledge, its use by heroin users and their peers has not yet been evaluated. In July 1998, the Health Department of Western Australia (HDWA) commissioned the National Drug Research Institute to explore the feasibility of conducting a trial of naloxone provision for peer administration. We discuss the issues to be considered in deciding whether or not a trial should proceed. The views expressed here are ours and not necessarily those of the HDWA. Should there be a trial of naloxone for peer administration? Distribution of naloxone for peer administration is clearly an intervention with potential to reduce the number of fatal heroin overdoses. However, from a public health perspective, questions remain regarding the impact of naloxone on the uptake and effectiveness of other overdose prevention strategies. Additionally, there is a risk of subsequent morbidity or mortality if no medical follow-up occurs after naloxone administration. These concerns can best be addressed by a multisite longitudinal study of naloxone provision within a carefully monitored group. Below, we summarise the issues to be considered in recommending such a trial. Method of administration The preferred route for peer administration would be intramuscular (see Box). Shelf life and stability Naloxone has a shelf life of 18 months to 2 years, depending on the product form and preparation. Because of this short shelf life, a trial would attempt to determine whether drug users replace expired stock. Furthermore, there are concerns about naloxone's stability and susceptibility to environmental factors. If it is made available for peer administration, it is likely to be left in the glove box of cars or carried in pockets or bags for extended periods of time. Although it is preferable that naloxone be stored in accordance with the manufacturers' recommendations, one manufacturer reports it has been stored at 40ºC for six months, and frozen for up to a month, without compromising its chemical stability (Brenda Fox, Medical Affairs Pharmacist, Fauldings Ltd, 1998, personal communication). Half-life and recurrent overdose Another major concern about the wider availability of naloxone relates to its short duration of effect: its elimination half-life is estimated to be 30-90 minutes, with individual differences due to variations in metabolism.12 Although evidence to date suggests that recurrent overdose is rare,18,23,42 there is the potential for resedation to occur, particularly when longer-acting opioids such as methadone have been used, or additional drugs have been consumed after naloxone administration. Thus, it will often be necessary to administer subsequent doses of naloxone. Research in Victoria suggests that, when ambulance staff administer an intramuscular dose of up to 1.6 mg total dose, few, if any, problems arise, with 90% of patients regaining consciousness (Dr Paul Dietze, Senior Research Fellow, Turning Point Drug and Alcohol Centre Inc, 1999, personal communication). As part of a trial, it may be appropriate to supply two 0.8 mg/2 mL prefilled syringes of naloxone for intramuscular administration (to allow a subsequent dose if necessary), accompanied by appropriate instructions on administration, polydrug intoxication, and the need for medical review. Airway management and first aid In many overdose situations all that is necessary to improve an individual's condition is to provide ventilatory support.27 Even after naloxone is administered, ventilatory support is required until it takes effect. The ability to administer first aid, in particular expired air resuscitation, should therefore be viewed as an integral part of any education provided for peer-administered naloxone. Information about possible complications and how to identify them should also be included. Polydrug use The use of other CNS depressants, particularly alcohol and benzodiazepines, is common in overdoses involving heroin,3,6,8,43,44 but should not preclude a trial of naloxone. Removal of the opioid effect with naloxone could prevent a fatality,40 minimise associated morbidity, and provide time in which to use other interventions. If CNS stimulants are used in conjunction with opioids, naloxone has the potential to unmask their associated toxicity and produce aggression, hypertension, acute pulmonary oedema, cardiac arrhythmia, or seizures.45,46 This may be more of a concern where cocaine use, particularly "speedballs" (heroin mixed with cocaine), is increasingly common among heroin users.47 Overdose prevention strategies should continue to warn users about polydrug use. Solitary heroin users Using heroin alone is a significant risk factor for overdose, as is using heroin in the company of others and then being left to "sleep it off". One of the arguments against the distribution of naloxone for peer administration is that it will have no impact on the death rate among solitary injecting drug users. The dangers of using drugs alone or failing to monitor sleeping drug users should be emphasised in a trial of naloxone. Naloxone administration by intoxicated peers Concern has been expressed that peers available to administer naloxone may be intoxicated, but this is also likely with other overdose management strategies. Some current strategies are quite complex and require vigilance, such as expired air resuscitation, monitoring, checking the pulse, and so on. Naloxone administration, particularly with a prefilled syringe, seems no more complicated, and its use should not be precluded because the person administering it may be affected by drugs. Undermining other overdose strategies Availability of naloxone for peer administration may undermine existing overdose prevention and management strategies, notably calling an ambulance. Research supports this, with many heroin users believing that peer administration of naloxone would negate the need to call an ambulance.8,40,48 Thus, some non-fatal overdose victims may not be transported to hospital.48 This is similar to what occurs in many Australian States after naloxone administration -- overdose patients refuse to be transported to hospital or, alternatively, leave hospital against medical advice. In these situations, wherever possible, the individual is placed in the care of a "responsible person", and in several States ambulance staff provide a pamphlet which outlines potential risks and gives basic first aid information. A similar intervention should be included in any trial of naloxone provision, with users encouraged to seek medical review after peer-administration of naloxone. Impact on heroin use among current users It has been suggested that some heroin users, if they believe that their peers can revive them with naloxone, might take more risks with their use of heroin.38 It is unlikely that this behaviour would become widespread, not least because of the unpleasant effect of naloxone in precipitating withdrawal in opioid-dependent people.8,24,39 According to heroin users, factors other than the likelihood of overdose or strategies available to prevent it influence drug use.48 Removing barriers to first use Naloxone provision could make heroin use appear safer and therefore encourage its uptake by novices. However, similar concerns were raised about the wider availability of needles and syringes, and there is no evidence that these measures have encouraged injecting among those previously not using needles.49 Rapid detoxification There is anecdotal evidence to suggest that some people take opioid antagonists to lower their tolerance and reduce the amount of heroin needed to achieve their desired level of intoxication. This has the potential to increase the individual's risk of overdose. Naltrexone, an oral opioid antagonist, is now more readily available for the treatment of opioid dependence and therefore people are more likely to use this treatment to lower their opioid tolerance than naloxone. However, the extent to which naloxone is used to reduce dependence should be assessed as part of a trial. Suggested trial design As peer administration of naloxone would take place within drug-using networks, a network sampling strategy is appropriate. This would recruit heroin users (and their peers) who have experienced and/or witnessed multiple overdose events. The trial could compare "first aid plus naloxone access and training" with "first aid only" across three Australian States over a 12-month period. An initial intake of 450 heroin users should produce a final sample of 250 individuals at 12 months, and about 180 overdose events for investigation.48 Power calculations for logistic regression analyses on a final sample of 250 would produce a power of 97% for events with a probability of 0.2, and 88% for events with a probability of 0.1, with an odds ratio of 2.0 with variables correlated at 0.4. Contamination between the intervention and control groups is a potential problem. In States with large populations of users in regional centres, geographical distance could be used to counteract this. It may also be possible to have a larger control group and place control respondents who gain access to naloxone into a third group. This would maintain the integrity of the control group, while allowing some analysis of the diffusion of the "naloxone training and access" intervention into other groups. Economic cost We estimate the cost of running a trial at three sites to be about $300 000, of which the cost of naloxone would be about $25 000 (1250 doses) at full retail price. Trial results could contribute to an economic modelling of the potential cost effectiveness of naloxone distribution. Dietze et al50 have estimated the cost of ambulance attendance for heroin overdoses in Victoria at over $1 million per annum, which they regard as cost effective in terms of preventing serious injury and death. If naloxone is recommended for more widespread distribution in the future, research suggests that many heroin users (75%) would be willing to pay for their own naloxone,51 which would further reduce the cost of the intervention. Legal issues A number of legal issues are raised by the possibility of conducting a trial of peer-administered naloxone. Central to this is the mechanism of providing naloxone to trial participants. If provided on prescription under Schedule 4, both the patient and the prescriber would be legally compromised when, as is likely, a third person administers the drug. Trial participants could be issued with a permit to access the drug, but this would compromise confidentiality. The drug could be rescheduled from Schedule 4 to Schedule 3 (dispensed by pharmacists only and stored out of public access) for the purposes of the trial, although the requirement for supervised dispensing could not be guaranteed given that the drug is likely to be passed to a third person. The drug could be removed from scheduling for persons involved in a possible future trial under an agreement between the research consortium and the relevant statutory body. While, to our knowledge, this has not been done before, it would enable the identity of trial participants to remain confidential. This would simplify the issue of naloxone provision and/or administration by a third person, and may also limit the exposure of participating agencies to civil action. Conclusion Faced with increasing heroin overdose deaths, the provision of naloxone to heroin users for peer administration is one of a range of interventions worth trialling. However, questions remain as to whether it can appropriately be used by peers as part of a comprehensive first aid intervention, and whether it improves outcomes, or results in net increases in harm. Net harm could increase as a result of undermining existing strategies, naloxone-related complications, or riskier heroin use. Many of these questions could be answered by a multisite longitudinal study of naloxone provision within a carefully monitored group. References Darke S, Ross J. Fatal heroin overdoses resulting from non-injecting routes of administration, NSW, Australia, 1992-1996. Addiction 2000; 95: 569-573. English DR, Holman CDJ, Milne E, et al. The quantification of drug caused morbidity and mortality in Australia. 1995 edition. Canberra: Commonwealth Department of Human Services and Health, 1995. Darke S, Zador D. Fatal heroin "overdose": a review. Addiction 1996; 91: 1765-1772. Darke S, Ross J, Hall W. Overdose among heroin users in Sydney Australia. 1. Prevalence and correlates of non-fatal overdose. Addiction 1996; 91: 405-411. Davoli M, Perucci CA, Rapiti E, et al. A persistent rise in mortality among injection drug users in Rome, 1980 through 1992. Am J Public Health 1997; 87: 851-853. Zador D, Sunjic S, Darke S. Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances. Med J Aust 1996; 164: 204-207. Loxley W, Davidson P. Forgetting to breathe: opioid overdose and young injecting drug users in Perth. Perth: Curtin University of Technology, National Centre for Research into the Prevention of Drug Abuse, 1998. McGregor C, Darke S, Ali R, Christie P. Experience of non-fatal overdose among heroin users in Adelaide, Australia: circumstances and risk perceptions. Addiction 1998; 93: 701-711. Darke S, Ross J. Heroin-related deaths in South Western Sydney: 1992-1996. Sydney: The University of New South Wales, National Drug and Alcohol Research Centre; 1998. Gore C. Report of the Pilot Heroin Overdose Peer Education project -- March 1997. NSW: Centre for Education and Information on Drugs and Alcohol, 1997. MIMS (Australia). 1998 MIMS Annual. Sydney, NSW: Intercontinental Medical Statistics (Australasia), 1998: 1176-1177. Chamberlain JM, Klein BL. A comprehensive review of naloxone for the emergency physician. Am J Emerg Med 1994; 12: 650-660. David Bull Laboratories (Australia). Naloxone hydrochloride injection. USP product information. Melbourne Vic: David Bull Laboratories; 1992. Boots Pharmaceuticals (Australia). Narcan injection and Narcan Neonatal injection. Product information. Sydney, NSW: The Boots Company (Australia) Pty Ltd, 1993. Moore RA, Rumack BH, Conner CS, Peterson RG. Naloxone: underdosage after narcotic poisoning. Am J Dis Child 1980; 134: 156-158. Jasinski DR, Martin WR, Haertzen CA. The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone). J Pharmacol Exp Ther 1967; 157: 420-426. Barsan WG, Olinger CP, Adams HP, et al. Use of high dose naloxone in acute stroke: Possible side-effects. Crit Care Med 1989; 17: 762-767. Jacobs I, Oxer H. The use of naloxone in the pre-hospital management of narcotic overdose. Perth: Western Australian Pre-Hospital Care Research Unit; 1998. Bernard S, Barger W. An audit of two different doses of intramuscular naloxone in prehospital narcotic overdose. Melbourne: Melbourne Ambulance Service, 1995. Sporer KA, Firestone J, Isaacs SM. Out-of-hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med 1996; 3: 660-667. Schwartz JA, Koenigsberg MD. Naloxone-induced pulmonary edema. Ann Emerg Med 1987; 16: 1294-1296. Osterwalder JJ. Naloxone -- for intoxications with intravenous heroin and heroin mixtures: harmless or hazardous? A prospective clinical study. Clin Toxicol 1996; 34: 409-416. Seidler D, Sthülinger GH, Fischer G, et al. After antagonization of acute opiate overdose: a survey at hospitals in Vienna. Addiction 1996; 91: 1479-1487. Strang J, Darke S, Hall W, et al. Heroin overdose: the case for take-home naloxone. BMJ 1996; 312: 1435. Kanof PD, Handelsman L, Aronson MJ, et al. Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. J Pharmacol Exp Ther 1992; 260: 355-363. Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th edition. New York: McGraw Hill, 1996: 549-551. Moss J. Ambulances say "no" to Narcan. Connexions 1997; 17: 29. Gaddis GM, Watson WA. Naloxone-associated patient violence: an overlooked toxicity? Ann Pharmacother 1992; 26: 196-198. Judson BA, Himmelberger DU, Goldstein A. The naloxone test for opiate dependence. Clin Pharmacol Ther 1980; 27: 492-501. Neal JM. Complications of naloxone. Ann Emerg Med 1988; 17: 765-766. Ward S, Corall IM. Hypertension after naloxone. Anaesthesia 1983; 38: 1000-1001. Andree RA. Sudden death following naloxone administration. Anesth Analg 1980; 59: 782-784. Azar I, Turndorf H. Severe hypertension and multiple atrial premature contractions following naloxone administration. Anesth Analg 1979; 58: 524-525. Flacke JW, Flacke WE, Williams GD. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977; 47: 376-378. Brimacombe J, Archdeacon J, Newell S, Martin J. Two cases of naloxone-induced pulmonary oedema -- the possible use of phentolamine in management. Anaesth Intensive Care 1991; 19: 578-580. Harrington LW. Acute pulmonary edema following use of naloxone: a case study. Crit Care Nurse 1988; 8: 69-73. Yealy DM, Paris PM, Kaplan RM, et al. The safety of prehospital naloxone administration by paramedics. Ann Emerg Med 1990; 19: 902-905. Darke S, Hall W. The distribution of naloxone to heroin users. Addiction 1997; 92: 1195-1199. Strang J, Farrell M. Harm minimisation for drug misusers: when second best may be best first. BMJ 1992; 304: 1127-1128. Strang J, Powis B, Best D, et al. Preventing opiate overdose fatalities with take-home naloxone: pre-launch study of possible impact and acceptability. Addiction 1999; 94: 199-204. Hall W. Reducing the toll of opioid overdose deaths in Australia. Drug Alcohol Rev 1999; 18: 213-220. Vilke GM, Buchanan J, Dunford JV, Chan TC. Are heroin overdose deaths related to patient release after prehospital treatment with naloxone? Prehosp Emerg Care 1999; 3: 183-186. Bammer G, Sengoz A. Non-fatal heroin overdoses. Med J Aust 1994; 161: 572-573. Coleridge J, Cameron PA, Drummer OH, McNeil JJ. Survey of drug-related deaths in Victoria. Med J Aust 1992; 157: 459-462. Hsu W, Rao RB, Nelson LS. Naloxone hazards overstated. Clin Toxicol 1997; 35: 215-217. Buchwald A. Naloxone use: side effects may occur. Ann Emerg Med 1988; 17: 765. Hando J, Darke S. NSW Drug Trends 1997. Findings from the Illicit Drug Reporting System (IDRS). Sydney: The University of New South Wales, National Drug and Alcohol Research Centre, 1998. Hargreaves K, Lenton S. The Naloxone Feasibility Study. Perth, Western Australia: National Drug Research Institute, Curtin University of Technology, 2000. In press. Des Jarlais DC, Friedman SR. AIDS and the use of injected drugs. Sci Am 1994; February: 56-62. Dietze PM, Cvetkovksi S, Rumbold G, Miller P. Ambulance attendance at heroin overdose in Melbourne: the establishment of a database of Ambulance Service records. Drug Alcohol Rev 2000; 19: 27-33. Darke S, Ross J, Cohen J, Hall W. Context and correlates of non-fatal overdose among heroin users in Sydney. Sydney: The University of New South Wales, National Drug and Alcohol Research Centre, 1994. Authors' details National Drug Research Institute, Curtin University, Perth, WA. Simon R Lenton, MPsych(Clin), Research Fellow. Kim M Hargreaves, BA, Research Associate. Reprints: Mr S R Lenton, National Drug Research Institute, GPO Box U1987, Perth, WA 6845. simonATndri.curtin.edu.au Make a comment Naloxone hydrochloride NALOXONE HYDROCHLORIDE is an opioid antagonist that competitively binds to µ-opiate receptors to reverse the respiratory depression, sedation and hypotension associated with opioids. It does not reduce the respiratory depression caused by non-opioid central nervous system (CNS) depressants, such as alcohol and benzodiazepines, and lacks pharmacological activity in the absence of opioids.11 Naloxone is classified under Schedule 4 of the Poisons Schedule (prescription only) and is available either as ampoules or prefilled syringes (Min-I-Jet [CSL Ltd]). It is effective when given by intravenous, intramuscular or subcutaneous injection,12 being rapidly distributed to the brain and other body tissues. Effects are observed within 1-2 minutes of intravenous administration and 2-5 minutes of intramuscular or subcutaneous administration.13,14 Naloxone has been administered millions of times in emergency departments for opioid overdose;12 in very large doses (eg, 20 times the recommended dose in a 30-month-old15 and up to 24mg/70kg in adults16); and over a number of weeks to evaluate efficacy and toxicity in patients with acute stroke,17 without major complications. Naloxone in the prehospital setting When used to treat opioid overdose, naloxone has been reported to improve consciousness and alertness in 64%-80% of patients within 10 minutes of administration,18,19 and in other patients it improved respiration. As long as blood pressure can still be recorded, its administration can be beneficial.20 Naloxone-related complications have been reported after treatment of opioid overdose.20-22 However, many of the apparent drug reactions observed could also have resulted from the overdose itself.22,23 Treatment of heroin overdose in the United Kingdom and Australia suggests that such reactions are rare, with no significant problems reported after hundreds of administrations.24 Naloxone does have the potential to precipitate opioid withdrawal symptoms when administered to opioid-dependent people,25,26 and may result in generalised convulsions.11,22 Those in acute withdrawal can become aggressive and endanger themselves and others.27,28 Withdrawal symptoms are typically less severe after intramuscular than intravenous administration.29 With the correct equipment (eg, prefilled syringes), intramuscular administration is also easier to perform and has a longer duration of action. The disadvantage of intramuscular administration is the delayed onset of action. Naloxone in the postoperative setting Naloxone is used after surgery to reverse the CNS depression caused by opioids administered during the procedure. Naloxone complications have been documented in this setting,30 with an increased risk when pre-existing hypertension and cardiovascular disease are present.31 Many of the complications reported - hypertension, atrial and ventricular tachycardia, fibrillation, left ventricular failure, pulmonary oedema, and sudden death12,32-34 - occurred in patients with underlying cardiac or pulmonary disease. Pulmonary oedema attributed to naloxone administration has also been reported among individuals with no underlying medical conditions.21,34-36 Many patients who experience adverse effects do so after an operation when multiple medications have been administered, so the causal role of naloxone is uncertain.12,37 Back to text

Simon R Lenton · Kim M Hargreaves

Personal Perspective The New South Wales Drug Summit: a view from a local foreign observer Jeffrey H Samet MJA 2000; 173: 264-265 1. "The Drug Summit was just a political exhibition" - 2. "All agree on one thing" - 3. "I hope that this forum does not end up as some sort of factionalised debate" - Acknowledgements - References - Authors' details - - More articles on Drugs and alcohol In December 1998, on sabbatical leave from Boston University School of Medicine, I spent time at the University of Sydney's Faculty of Medicine, because I thought that the Australian experience had something special to teach those of us in the United States working on the "drug problem". The timing was remarkable -- illicit drug policy became a captivating major news topic, culminating in the Drug Summit in Sydney in May 1999.1 Drug abuse, despite its importance from personal, public health, public safety and economic perspectives, has not received comparable concerted public attention within the United States in a generation or more. The dynamics of the Australian discussion were fascinating, but certain opinions expressed seemed in need of reconsideration. 1. "The Drug Summit was just a political exhibition -- nothing useful will come of it." This point of view, prevalent before and during much of the Drug Summit, was extremely cynical and not constructive. Not acknowledging the existence of a problem is a very well known practice in the world of drugs and alcohol. In fact, the first goal in the treatment of patients who misuse drugs is getting them to acknowledge that a problem exists.2No one expects to fix the problem the first few times it is addressed. The same perspective should frame the discussion about activities that recently took place in the New South Wales Parliament. Firstly, it was significant that the drug issue was widely acknowledged as a major societal problem. Secondly, it was remarkable that politicians joined together with the most experienced professionals and affected individuals to search for understanding and common ground on how to address the issue. This phenomenon should be recognised for what it was: major progress. The summit enabled politicians to gain, at minimum, a basic understanding of the issues of addiction and substance misuse. Politicians will in future be better able to assess drug policy proposals. The extensive media coverage educated Australia's citizens, both adults and young people, about the realities of falling victim to mind-altering substances. It reminded members of society that drug abuse is a scourge and the reality of drug addiction is painful and sad. History teaches us that this lesson is all too quickly forgotten, and such refresher lessons play a valuable role.3 The Drug Summit's very existence was a very important and useful event. Cynicism was inappropriate. 2. "All agree on one thing, nothing in the past has been successful." One early conclusion, announced after the first day of the Summit, was a condemnation of past efforts. Australian newspaper headlines echoed the theme of past failures. This summary critique was not an appropriate keynote to an Australian drug summit. Absence of either a cure or a recipe for prevention does not equate with a past record of failure. Clearly, the drug problem is huge and ever in need of innovative approaches to combat it; nonetheless, Australia has much about which to be proud in its approach to illicit drug use. One in four injecting drug users in the United States are infected with HIV.4 As a consequence, the individual suffering, high costs of medical care, and transmission to non-injecting partners and newborns are immense burdens on society. This scenario has been largely avoided in Australia, where fewer than 3 in 100 injecting drug users are infected with HIV.5,6 This is success, incredible success, and hopefully not ephemeral success. The existence of a treatment system in which thousands of individuals each year in Australia get help in their struggle to deal with their addiction is progress. Of course, striving to expand and improve the quality of those services and the institution of trials to find innovative new approaches are required, but there has been unequivocal progress in this field. Research successes are also notable. The best data in the world on heroin overdose have been collected and analysed by the Australian National Drug and Alcohol Research Centre.7,8 As a result, approaches to intervention have been developed and this "silent epidemic" is no longer silent in Australia. HIV prevention, extensive treatment (even if insufficient), and innovative practical research are recognised Australian successes in this field. 3. "I hope that this forum does not end up as some sort of factionalised debate ... -- a war on drugs versus legalisation; zero tolerance versus harm reduction." The discourse at the Drug Summit covered important issues, but the terms used in the illicit drug policy discussion often got confused. Consequently, some messages were at risk of misinterpretation. "Harm reduction" is not synonymous with "legalisation". The goals are different. The message is different. Equating these terms does injustice to both issues. There are data to support the effectiveness of some harm reduction efforts and there is a desire to collect data for other proposed harm reduction efforts.9,10 This situation is quite different from a theoretical discussion of the harms and benefits of legalisation of certain aspects of illicit drug use. The latter is a public policy question with enormous potential consequences unlikely to be subjected to the rigours of scientific testing to assess efficacy. On the other hand, it is very useful to subject novel approaches to harm reduction to the careful scrutiny of clinical trials before broader dissemination. The inappropriate equating of these terms is detrimental and should be strongly resisted. It is important to realise that drug problems are an area where agreement on desirable outcomes is possible. The path to those outcomes has been hampered by a disturbing and remarkable amount of factional debate. In this most useful public health discussion, absence of cynicism, recognition of past success, and clarity of terms will serve to remove impediments from a struggle that will continue long after the wonderfully focused efforts of the NSW Drug Summit have become a fading memory. We in the United States can learn from Australia's willingness to publicly confront these issues. Acknowledgements I am indebted to Drs James Rankin, Paul Haber, Alex Wodak and Wayne Hall, who were so kind to me during my sabbatical term in Australia and who provided feedback about this manuscript. Without their openness and generosity of spirit I would not have had the opportunity to see what I saw or write what I wrote. References Swan N. Drug doings down under. JAMA 1999; 281: 1782-1783. Samet JH, Rollnick S, Barnes H. Beyond CAGE: a brief clinical approach after detection of substance abuse. Arch Intern Med 1996; 156: 2287-2293. Musto D. The American disease: origins of narcotic control. New York: Oxford University Press, 1987. Centers for Disease Control and Prevention. HIV/AIDS surveillance report. 1997; 9(2): 1-44. Kaldor JM, Elford J, Wodak AD, et al. HIV prevalence among IDUs in Australia: a methodological review. Drug Alcohol Rev 1993; 12: 175-184. MacDonald M, Wodak AD, Ali R, et al. HIV prevalence and risk behaviour in needle exchange attenders: a national study. Med J Aust 1997; 166: 237-240. Darke S, Ross J, Hall W. Overdose among heroin users in Sydney, Australia I. Prevalence and correlates of non-fatal overdose. Addiction 1996; 91: 405-411. Darke S, Ross J, Hall W. Overdose among heroin users in Sydney, Australia I. Responses to overdose. Addiction 1996; 91: 413-417. Hurley SF, Jolley DJ, Kaldor JM. Effectiveness of needle-exchange programmes for prevention of HIV infection. Lancet 1997; 349: 1797-1800. Drucker E, Lurie P, Wodak A, Alcabes P. Measuring harm reduction: the effects of needle and syringe exchange programs and methadone maintenance on the ecology of HIV. AIDS 1998; 12(Suppl A): S217-S230. Authors' details Section of General Internal Medicine and the Clinical Addiction Research and Education (CARE) Unit, Departments of Medicine and Social and Behavioral Sciences, Boston University Schools of Medicine and Public Health, Boston, MA. Jeffrey H Samet, MD, MPH, Associate Professor of Medicine and Public Health. Reprints: Associate Professor J H Samet, Section of General Internal Medicine, Research Unit, 91 East Concord Street, Suite 200, Boston Medical Center, Boston, Massachusetts, 02118 USA. jsametATbu.edu Make a comment

Jeffrey H Samet

Viewpoint An analgesic role for cannabinoids Christopher W Vaughan and Macdonald J Christie Cannabinoids have significant analgesic properties in animal models, particularly for chronic pain states, but there are few human studies. An endogenous cannabinoid system, with specific receptors and transmitters, has recently been discovered. This discovery has led pharmacologists to explore the potential of synthetic cannabinoids to selectively target chronic pain disorders without producing the side effects associated with cannabis. Well-controlled clinical trials on cannabinoids, and cannabinoid delivery systems, are now required. MJA 2000; 173: 270-272 The endogenous cannabinoid system and pain - Evidence for analgesic efficacy - Adverse effects - The place for analgesia - Conclusion - References - Authors' details - - More articles on Drugs and alcohol Natural and synthetic cannabinoids produce a range of pharmacological effects with a number of potential therapeutic applications, including the treatment of pain.1-3 However, the political climate prevailing for much of the latter half of the 20th century has censored investigation of its potential therapeutic properties. Recently, expert groups convened by the British Medical Association, the House of Lords, and the United States National Institutes of Health have concluded that cannabinoids may have therapeutic efficacy under some conditions.1,4,5 These groups have recommended further study into the therapeutic benefits of cannabis and cannabinoids, particularly in relation to the relief of chronic pain. Several developments provide compelling arguments to re-examine the medical use of cannabis and cannabinoids. Recent studies on the molecular nature of cannabinoid receptors and their endogenous ligands have provided a rational basis to understand and extend empirical observations of therapeutic efficacy. The development of synthetic cannabinoids, some of which are currently the subject of controlled human trials, has raised hopes of enhanced benefits and reduced side effects. Widespread illicit use, partial relaxation of legal sanctions, and dispassionate assessments of the severity of adverse effects have eased some of the public concern over the dangers of cannabis. The endogenous cannabinoid system and pain The actions of Δ-9-tetrahydrocannabinol (THC), the principal active component in cannabis, can be understood in terms of the natural functions of the endogenous cannabinoid system, which has only recently been identified. Functional, cellular and molecular studies suggest that cannabinoids might have important applications in specific pain conditions (more detailed reviews are available elsewhere2,3). There are at least two distinct human cannabinoid receptors: CB1 and CB2 receptors (more types may yet be found).6 CB1 receptors are located in brain regions involved in mood, motor control, memory formation, regulation of food intake, autonomic control and processing of noxious or painful information, and in peripheral autonomic and reproductive systems. CB2 receptors are found within immune and reproductive tissues. The distinct localisation of CB1 and CB2 receptors is consistent with many of the therapeutic and adverse effects of cannabinoids, and raises the possibility that synthetic agents (unlike THC, which acts on both CB1 and CB2 receptors) can be developed to selectively target different physiological systems. THC mimics a group of natural substances produced within the body, including anandamide.7 These endogenous cannabinoids are partly similar to other neuromodulators in that they are synthesised within the brain, are released from neurones after stimulation, activate specific receptors, and undergo rapid uptake and degradation. However, there is still a great deal to be learned about this novel class of neuromodulators. There is now an intensive research effort to design drugs that will modify the metabolism of endogenous cannabinoids to influence these physiological functions in novel ways.8 Animal studies have clearly demonstrated that THC, synthetic cannabinoids, and endogenous cannabinoids produce analgesia and potentiate opioid analgesia.2,3 In many respects, the analgesic actions of cannabinoids and opioids are similar, although the two classes of drugs act on different receptors and act via partially distinct cellular mechanisms in pain control systems.2 Recent studies predict that cannabinoids might be effective in specific chronic pain states. The efficacy of cannabinoids is increased in nociceptive and inflammatory pain.9 In addition, cannabinoids (unlike opioids) maintain their analgesic activity in neuropathic or nerve injury induced pain and reduce the associated allodynia and hyperalgesia.10,11 Evidence for the analgesic efficacy of cannabinoids in humans Although opioids are the most important drugs used to treat moderate to severe pain, some clinically important pain states, particularly neuropathic pain, are relatively insensitive to opioid treatment.12 Anecdotal evidence suggests that cannabinoids produce relief from pain in humans, but there are few well controlled clinical trials.1,4,5,13 Some studies have reported that THC and related analogues have acute analgesic activity, and relieve postoperative pain and chronic pain associated with cancer, multiple sclerosis and familial Mediterranean fever;14-17 others have reported that these compounds have no analgesic effect, or even produce hyperalgesia.18,19 It is difficult to reconcile the results of these studies given the different doses or purity of cannabinoid extracts, routes of administration (smoked, oral, intramuscular, intravenous), subject numbers and selection (naive or habitual users, patients with chronic pain), and the methods of analgesia testing.5 Adverse effects of cannabinoids There is a risk of serious adverse effects of cannabis, but these have often been overstated.20 The adverse effects, although sufficiently serious to restrict legitimate medical use, should be considered in the context of potential benefits and the severity of disorders for which its use is contemplated. Many drugs (including opioids) currently used for similar indications, particularly intractable pain, are associated with much more serious risks, such as respiratory depression. More extensive comparisons of the therapeutic benefits and adverse effects of cannabinoids are available elsewhere.1,2,5,13,21-23Cannabis is sufficiently intoxicating to impair ability to carry out critical tasks safely for several hours after consumption.23 Although intoxication is sought by recreational users, it is often cited as a reason to discontinue therapeutic use. Cannabis can produce temporary distress and panic, transient psychosis, exacerbation of pre-existing mental illness, particularly schizophrenia,23 and has been linked to an increased risk of suicide.24 Medical use of cannabis would be contraindicated in individuals with a history of these responses or predispositions. Regular recreational use of cannabis can lead to dependence, as defined by standard criteria for substance-misuse disorders.23 While the incidence of serious cannabis dependence is difficult to estimate, regular heavy use, producing a state of near-continuous intoxication, occurs in 5%-10% of regular recreational users. The potential for dependency disorders among medical cannabis users is uncertain, but, by analogy with other addictive drugs such as opioids, prevalence of addiction would be expected to be relatively low with appropriate therapeutic use. In this regard, the US Drug Enforcement Administration has recently transferred oral THC (dronabinol) from a Schedule II to a Schedule III non-narcotic drug.25 Cannabis produces acute tachycardia, and long term exposure produces postural hypotension and bradycardia.2,5,13,23 The severity of this risk has not been established, but is of sufficient concern to exclude individuals with a history of cardiovascular disorders from clinical trials. Smoked cannabis carries similar risks of respiratory disorders as smoked tobacco, which restricts the circumstances for which this route of administration can be considered. The place of smoked cannabis for analgesia Some disorders seem to respond better to smoked cannabis, whereas others are relieved just as well by oral THC, which is legally available for clinical use (as dronabinol) in many parts of the world.5,13 The reasons for these differences are still unknown. Subjective reports indicate that smoked cannabis produces a more rapid and reliable effect than oral THC, permitting the patient to titrate desired actions while minimising side effects.2,22 Cannabis smoke contains carcinogens and airway irritants which increase the risk of cancers of the mouth, throat and lung, but the severity of this risk has not been established. However, smoked cannabis might prove more beneficial to some patients if the risks of smoking are outweighed by benefits such as relief from intractable pain. Limited availability of smoked marijuana was recommended by both the House of Lords committee4 and the Institute of Medicine21 as an interim solution. In the long term, delivery systems such as inhalation devices are needed to provide patients with non-smoked, rapid-onset cannabinoid delivery systems for rapid, precise control over both beneficial and adverse effects.5,13,21 Such developments and licensing are expected to take at least five years. Conclusion There is some experimental evidence to suggest that cannabinoids may have therapeutic efficacy in various pain states, but there is an urgent need for well controlled clinical trials to establish the utility of both natural and synthetic cannabinoids, and cannabinoid delivery systems. Pharmacologists have only just begun to explore the therapeutic potential of synthetic cannabinoids that might avoid the undesirable side-effects of psychomotor impairment, cognitive disruption and intoxication. Smoked cannabis does not have long term prospects as a therapeutic agent, but there is some evidence and sufficient pharmacokinetic grounds to expect this mode of administration to have benefits in terms of patient control over desired and adverse effects. Major international expert groups have therefore recommended on compassionate grounds that smoked cannabis be made available to patients with severe debilitating diseases while superior cannabis delivery systems are being developed. References British Medical Association. Therapeutic uses of cannabis. Amsterdam: Harwood Academic Publishers, 1997. Grotenhermen F, Russo E. Cannabis and cannabinoids -- pharmacology, toxicology and therapeutic potential. New York: Haworth Press. In press. Howlett AC. Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol 1995; 35: 607-634. House of Lords Select Committee on Science and Technology. Cannabis: the scientific and medical evidence. HL Paper 151. London: The Stationery Office, 1998. Available at <http://www.parliament.the-stationery-office.co.uk/pa/ ld199798/ldselect/ldsctech/151/15101.htm>. National Institutes of Health. Report on the medical uses of marijuana. 1997. <www.nih.gov/news/medmarijuana/MedicalMarijuana.htm>. Accessed 24 July 2000. Devane WA, Dysarz FA 3d, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605-613. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946-1949. Beltramo M, Stella N, Calignano A, et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 1997; 277: 1094-1097. Jaggar SI, Hasnie FS, Sellaturay S, et al. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain 1998; 76: 189-199. Bian D, Nichols ML, Ossipov MH, et al. Characterization of the antiallodynic efficacy of morphine in a model of neuropathic pain in rats. Neuroreport 1995; 6: 1981-1984. Mao J, Price DD, Lu J, et al. Two distinctive antinociceptive systems in rats with pathological pain. Neurosci Lett 2000; 280: 13-16. National Health and Medical Research Council. Acute pain management scientific evidence. Canberra: NHMRC, 1999. Ashton CH. Biomedical benefits of cannabinoids? Addiction Biol 1999; 4: 111-126. Noyes R Jr, Brunk SF, Avery DAH, et al. The analgesic properties of delta- 9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975; 18: 84-89. Staquet M, Gantt C, Machin D. Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther 1978; 23: 397-401. Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 1981; 21: 320S-326S. Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997; 52: 483-486. Hill SY, Schwin R, Goodwin DW, Powell BJ. Marihuana and pain. J Pharmacol Exp Ther 1974; 188: 415-418. Raft D, Gregg J, Ghia J, et al. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlates of the analgesic response. Clin Pharmacol Ther 1977; 21: 26-33. Chesher GB, Christie MJ, Morgan JP. Science signals a new understanding of marihuana. Drug Alcohol Rev 1994; 13: 307-317. Joy JE, Watson SJ, Benson JA, editors. Marijuana and medicine: assessing the science base. Washington, DC: National Academy Press, 1999. Gowing LR, Ali RL, Christie P, et al. Therapeutic use of cannabis: clarifying the debate. Drug Alcohol Rev 1998; 17: 445-452. Hall W, Solowij N, Lemon J. The health and psychological consequences of cannabis use. National Drug Strategy Monograph Series No. 25. Canberra: AGPS, 1994. Beautrais AL, Joyce PR, Mulder RT. Cannabis abuse and serious suicide attempts. Addiction 1999; 94: 1155-1164. Department of Justice, Drug Enforcement Administration. Schedules of Controlled Substances: rescheduling of the Food and Drug Administration approved product containing synthetic dronabinol [(-) Δ9-(trans)-tetrahydrocannabinol] in sesame oil and encapsulated in soft gelatin capsules from Schedule II to Schedule III. (Doc. 99-16833) Federal Register 1999; 64(127): 35928-35930. Available at <http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=1999_ register&docid=99-16833-filed>. Authors' details Department of Pharmacology, University of Sydney, Sydney, NSW. Christopher W Vaughan, PhD, MBiomedE, R D Wright Research Fellow; Macdonald J Christie, PhD, BSc(Hons), Head of Department and Medical Foundation Fellow. Reprints: Dr C W Vaughan, Department of Pharmacology, The University of Sydney, Sydney, NSW 2006. chrisvATpharmacol.usyd.edu.au Make a comment

Christopher W Vaughan · Macdonald J Christie