To the Editor: As one of the first clinicians to use naltrexone implants (in 1997) and author of two references cited by Gibson et al,1 I wish to comment on their article.
In writing that “Treatment with implanted naltrexone has been claimed to prevent . . . fatal opioid overdose”, Gibson et al imply that this claim is untrue, or that anything less than total prevention is not useful. Lowest conventionally effective blood naltrexone levels (1–2 ng/mL) may indeed fail to block opioids, but such instances are extremely uncommon. (In any case, even after 100 mg of supervised oral naltrexone, trough naltrexone levels after 24 hours can be no higher than that.2,3) An article describing three cases of implant breakthrough is in preparation; 4.3 ng/mL was insufficient to prevent obvious opioid effects after one patient smoked about 80 mg of diamorphine equivalent.4 The other cases involve much bigger opioid doses. However, higher naltrexone levels would almost certainly provide adequate blockade. Many patients test out the blockade soon after implantation5 and while “pseudo-breakthrough” is occasionally seen,2 true breakthrough with heroin or methadone is, I must stress, very rare.
Gibson et al cite my report that modest naltrexone levels can block 500 mg of pure diamorphine (an enormous dose).3 They cite no reports of opioid receptor immunity to blockade by naltrexone. Therefore, unlike many drugs, naltrexone probably always does what it says on the packet. Accordingly, it follows that naltrexone implants can indeed prevent opioid overdose deaths, in the same sense that thyroxine prevents hypothyroidism. In all cases, adequate blood levels are important, and some patients, for various reasons, need more than average doses to achieve them. Gibson et al’s article may be an argument for therapeutic drug monitoring or opioid challenge,3,4 but not for therapeutic gloom.
Finally, details of all known coroner-linked “active” implant deaths in Western Australia have already been presented.6 None appeared to be opioid-related; suicide, homicide, medical conditions and non-opioid overdoses caused them. Gibson et al report one apparently certain opioid overdose death despite an unprecedentedly high blood naltrexone level. This is puzzling, but postmortem opiate levels are notoriously misleading,7,8 and the same may be true for naltrexone. Little is known about naltrexone disposition after death, perhaps because, unlike opioids, naltrexone is very rarely found in dead heroin addicts. In contrast, of the small proportion (27%) of patients actually completing a 28-day British inpatient opioid withdrawal program and thus losing their opioid tolerance, 10% died within a few months from resuming heroin.9
- 1. Gibson AE, Degenhardt LJ, Hall WD. Opioid overdose deaths can occur in patients with naltrexone implants. Med J Aust 2007; 186: 152-153. <MJA full text>
- 2. Verebey K, Volavka J, Mule S, Resnick R. Naltrexone: disposition, metabolism and effects after acute and chronic dosing. Clin Pharmacol Ther 1976; 20: 315-328.
- 3. Brewer C. Serum naltrexone and 6-beta-naltrexol levels from naltrexone implants can block very large amounts of heroin: a report of two cases. Addict Biol 2002; 7: 321-323.
- 4. Brewer C, Streel E. Current issues in the use of opioid antagonists. In: Dean RL III, Bilsky EJ, Negus SS III, editors. Opioid receptors and antagonists: from bench to clinic. Totowa, NJ: Humana Press. In press.
- 5. Foster J, Brewer C, Steele T. Naltrexone implants can completely prevent early (1-month) relapse after opiate detoxification: a pilot study of two cohorts totalling 101 patients with a note on naltrexone blood levels. Addict Biol 2003; 8: 211-217.
- 6. O’Neil G, Parsons Z, O’Neil P, et al. A review of mortality of patients entering a naltrexone implant treatment programme over a five year period. 3rd Stapleford-Berlin Conference; 2006 Mar 16–18; Berlin, Germany.
- 7. Levine B, Wu SC, Dixon A, Smialek JE. Site dependence of post-mortem blood methadone concentrations. Amer J Forensic Med Pathol 1995; 16: 97-100.
- 8. Milroy CM, Forrest AR. Methadone deaths: a toxicological analysis. J Clin Pathol 2000; 53: 277-281.
- 9. Strang J, McCambridge J, Best D, et al. Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study. BMJ 2003; 326: 959-960.
Publication of your online response is subject to the Medical Journal of Australia's editorial discretion. You will be notified by email within five working days should your response be accepted.