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• 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).

In 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 There are unpublished reports of authorised distribution for peer administration in Jersey (UK) and Berlin (Germany), and underground distribution through needle exchanges in San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.

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.

• 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.

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Reprints: Mr S R Lenton, National Drug Research Institute, GPO Box U1987, Perth, WA 6845.
simonATndri.curtin.edu.au

©MJA 2000
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