Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Sould it be available over the counter? Not without proper evidence!
- Andrew J Ashworth (23 September 2006)
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Naloxone is not the only opioid antagonist that can prevent lethal overdoses and good agonist treatment is also important.
- Colin Brewer (25 September 2006)
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OTC naloxone needs more careful consideration.
- Andrew Byrne (28 September 2006)
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Opiate Antagonist as punishment within drug culture
- Malcolm Bruce (30 September 2006)
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Naloxone as a reagent
- Janusz Knepil (6 October 2006)
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Risk Versus Benefit of Naloxone
- Kate C Tatham, Nick J Bunker (25 October 2006)
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First do no harm
- Alex D Wodak (30 October 2006)
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Andrew J Ashworth, General Practitioner Davidsons Mains Medical Centre, 5 Quality Street, EDINBURGH EH4 5BP
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While Naloxone is a good drug for resuscitation we should beware its other characteristics. Naloxone has a short half life and so may give unskilled users a false sense of security, introducing a “secondary opiate overdose” particularly when used to treat overdose with a long acting opiate such as Methadone. The authors cite 440 “reversals” (an unfortunate misnomer for a competitive antagonist) of 6,000 doses distributed: what happened to the other 5,560 doses? There is a risk that these were used to avoid calling emergency services (Drug users associate emergency ambulance services with police),or that unsuccessful use was unreported and that some patients died despite attempted inhibition: how many died after “reversal” or required further “reversal”?. Furthermore, opiate blocking drugs can provide a useful punishment tool for drug dealers who may use the drug as a method of ensuring compliance with their demands. Elsewhere in this issue Professor Ian Roberts, an epidemiologist, (1) warns that “anecdotal evidence could be highly misleading” citing the use of albumin in resuscitation and steroids in head injury. Richard Lehman (2) opines that “In the current political climate it would take considerable optimism to expect that health policy might be governed by evidence alone. It is the urgent responsibility of our professional leadership to mark out where the evidence lies.” While it may be reasonable to research the wider availability of Naloxone, we need to understand the overall clinical effect, addressing the negative as well as the positive effects of such a change before adding to the illicit drug cocktail available on the street. (1) Dyer O “British Soldiers are guinea pigs for use of new clotting agent" BMJ volume 333 p 616 23 Sep 2006 (2) Lehman R “ Doctors Must debate hospital closures” BMJ volume 333 p 661 23 Sep 2006 Competing interests: None declared |
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Colin Brewer, Research Director The Stapleford Centre. 25a Eccleston St. London SW1W 9NP
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Strang et al correctly state that “Naloxone is an extraordinarily effective drug”[1] presumably meaning that at adequate doses, it always reverses opioid effects. (Incidentally, why does one 400mcg ampoule cost the NHS about £5 when it sells for a small fraction of that in other European countries?) Whether it is true that “Naloxone saves lives”[1] in opioid overdose (OOD) when publicly distributed is, as they recognise, still unproved. Intuitively, it seems worth doing (and monitoring) especially if combined with educating relevant peer-groups about airways and resuscitation.
However, naloxone is not the only extraordinarily effective opioid antagonist. Apart from the possible advantages in acute OOD of nalmefene, with its longer half-life, almost complete prevention of OOD and of relapse to heroin for many months after detoxification are now demonstrably possible with long-acting naltrexone implants.[2] Since the authors note that OOD is particularly dangerous in detoxified, non-tolerant addicts and since naltrexone has negligible organ toxicity, it is equally important (and more evidence-based) to extend studies of these implants. Several NHS GPs have already observed very persuasive outcomes.[3] Distributing naloxone is also no substitute for raising the quality of agonist prescribing programmes. As Strang himself has previously conceded, NHS doses are among the lowest in Europe. Higher doses are associated with better outcome and retention and fewer OOD deaths. If the British addiction establishment had not criticised methadone maintenance treatment (MMT) until the mid-1990s (well after most of Western Europe had accepted the evidence) numerous deaths might have been avoided. When for many years, psychosocial interventions were thus over-valued and MMT discouraged[4] is it surprising that many clinicians still feel very ambivalent about this most evidence-based of all treatments for opiate abuse? REFERENCES. 1. Strang J. et al. Emergency naloxone for heroin overdose BMJ.2006; 333: 614-615 2. Hulse G, Tait R, Comer S. et al. Reducing hospital presentations in opioid overdose in patients treated with sustained release naltrexone implants. Drug Alc Depend. 2005 Sep 1;79(3):351-7. 3. Revill J. An audited 24-month comparison of the O’Neill 3-vial naltrexone implant with supervised methadone in a British general practice population. Paper presented at the 3rd Stapleford Berlin Conference, March 18-20th 2006. Abstract and PowerPoint slides viewable at: www.staplefordcentre.co.uk 4. Caplehorn J. Methadone maintenance treatment: Britain has been over-committed to psychological theories of drug dependence. Brit Med J 1995; 310: 463. Competing interests: None declared |
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Andrew Byrne, Dependency Physician 75 Redfern St, Redfern, NSW, 2016, Australia
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Dear Editor, Strang and colleagues quote only one unpublished communication (from Mr D. Bigg of Chicago) in support of supplying naloxone to users and associates [ref 1]. Without due consideration of adverse consequences, the authors conclude that since naloxone is “an extraordinarily effective drug” and has been successfully “transferred” to ambulance crews then the “next logical transfer is for take-home naloxone to be given patients at risk, their families, and carers to prevent deaths in the critical minutes before specialist care arrives.” Trials of this theoretically useful intervention should have ethics committee approval, appropriate funding and some meaningful control group in order to assess its usefulness. These authors state that such interventions will save lives, yet they appear not to have considered all of the existing evidence. There is no indication, for example, how adverse events, including deaths, were monitored amongst the street drug users involved in Chicago, nor do they quote the experience from Italy or elsewhere. In their pre-occupation with local UK regulations, these authors omit four essential factors relating to 'over-the-counter' naloxone. A literature search of the adverse effects of injected naloxone reveals many consequences including sudden deaths (refs 5-24). These reports relate only to naloxone used by medically trained people, hence adverse events are more likely where the drug is used by untrained people and especially so if some of those with access to naloxone may be intoxicated themselves. Secondly, unlike delayed ambulance presentations, experience from medically supervised heroin injecting centres would indicate that early overdoses only infrequently require naloxone injection [ref 2]. Breathing assistance and general support is always recommended for cyanosis and hypoventilation, regardless of the cause. The same principles and procedures would apply to cardiac and other emergencies. It may be more “logical” to support better community training in such traditional general resuscitation, especially for those whose friends or relatives use illicit drugs. Thirdly, a complexity these authors fail to address is how such injections should be given and what advice would be given to non-medically trained people who might find themselves at the scene of an overdose. There are disadvantages in using naloxone intramuscularly and yet intravenous use is not always advisable either. Finally, Strang et al seem not to have considered that pre-filled syringes of naloxone could serve as currency, inducements, weapons, punishment, street pay-backs and the like. These matters should all be carefully weighed in deciding on the priority for this novel proposal as against other possible studies to address overdose (such as injecting rooms, better maintenance treatments, etc). And should there be general consensus, a pilot study should go ahead somewhere, using agreed protocols and end points. Sadly, Strang et al are short on details, nor do they lobby on exactly how and where this might be done, except that high risk individuals should be targeted. I presume a regional English city with acute overdose problems might be appropriate, and that widespread distribution should be considered for such a limited area. It is disappointing that such senior authors would write another prominent editorial without considering these major factors. This is especially so knowing the number of British drug users who have died of overdose since Strang first wrote on this subject ten years ago expressing similar sentiments [ref 3]. It is surprising that neither Strang nor senior colleagues have taken the time to write an editorial suggesting a practical strategy to address the abysmal quality of and access to methadone treatment in England as so clearly documented by Strang himself (average dose under 40mg; retention rates so low that one in seven prescriptions was for a new patient). [ref 4] Yours faithfully, Andrew Byrne .. http://www.redfernclinic.com/ REFERENCES: Strang J, Kelleher M, Best D, Mayet S, Manning V. Emergency naloxone for heroin overdose. BMJ 2006 333:614-615 Kimber J, MacDonald M, van Beek I, Kaldor J, Weatherburn D, Lapsley H, Mattick RP. The Sydney Medically Supervised Injecting Centre: Client Characteristics and Predictors of Frequent Attendance During the First 12 Months of Operation. Journal of Drug Issues (2003) 33; 3: Strang J, Darke S, Hall W, et al. Heroin overdose: the case for take- home naloxone. BMJ 1996; 312: 1435. Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Brit J General Practice (2005) 55; 515: 444-451 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. 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. 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. 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. 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. Competing interests: Andrew Byrne charges a fee for dispensing medications for addiction treatments. He is also a member of the Sydney Medically Supervised Injecting Centre Community Liaison Committee. |
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Malcolm Bruce, Consultant Psychiatrist in Addiction Lothian NHS, Scotland EH3 9DU
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A current local drug alert for Naltrexone from the Police confirm that one of two patients in Tayside ended up being hospitalised with severe withdrawals and dehydration. This was following Naltrexone circulating in the guise of MST. Also in Perth prison Naltrexone tablets were used by prisoners (crushed and administered covertly in liquids) as a type of punishment for other prisoners. This inappropriate use needs to come into the balance of any gain made by making opiate antagonist more readily available Competing interests: None declared |
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Janusz Knepil, Principal Biochemist (Toxicology) Biochemistry Deoartment, Gartnavel General Hospital, Glasgow. G12 0YN
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Naloxone and/or nalorphine are in common use in toxicology laboratlories as internal standards for chromatographic identification and quantitation of opiates and other basic drugs. Therapeutic (whether administered by professional or lay persons) use of naloxone (if known) should be notified to an investigating laboratory to allow approporiate changes to be made to analytical methods. Such notification is particularly important when a rapid analytical response is required (e.g. in the identification of substances that may obfuscate clinical examination to determine brain death). Failure to notify will lead to failure of the analysis through failure of quality assurance checking procedures thus delaying analysis for entirely avoidable reasons. Competing interests: None declared |
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Kate C Tatham, SHO Anaesthetics & ITU Ealing Hospital, UB1 3HW, Nick J Bunker
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Sir, We have concerns regarding the potential side-effects resulting from widespread use of naloxone in the drug-using community, as reported by Strang et al.(1) Naloxone is a potent opiate antagonist with a relatively short half-life compared to street heroin, as has already been highlighted in earlier correspondance.(2) Previous case reports (3-5) have reported severe pulmonary oedema, hypertensive crises and arrhythmias, all related in time to naloxone use. Good evidence is lacking as not only can heroin, (and its cutting agents), cause similar presentations, but furthermore the patients involved are a difficult group to study. Before we make naloxone freely available to the drug-using community, it is imperative we are confident that the risks of widespread use, by this particular patient group, do not outweigh the benefits. Furthermore, we would suggest that, prior to introduction of this scheme, there is clear evidence supporting over-the-counter naloxone compared to paramedic use alone. Dr Kate Tatham, SHO
1. Strang J, Kelleher M, Best D, Mayet S, Manning V. Emergency naloxone for heroin overdose. BMJ 2006;333: 614-5. (23 September.) 2. A. J Ashworth. Emergency naloxone for heroin overdose: Beware of naloxone's other characteristics. BMJ, October 7, 2006; 333(7571): 754 - 754. 3. Flacke JW, Flacke WE, Williams GD. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977;47:376–8. 4. Lawrence JR, Lee FR. Ventricular fibrillation after narcotic withdrawal (letter). Lancet 1975;2:717 5. Levin ER, Sharp B, Drayer JIM, et al. Case report: severe hypertension induced by naloxone. Am J Med Sci 1985;290:70–2. Competing interests: None declared |
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Alex D Wodak, Director, Alcohol and Drug Service St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia
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Dear Sir, re: Emergency naloxone for heroin overdose Strang et al 1 provide a measured endorsement for distributing naloxone to injecting drug users to prevent heroin overdose deaths. For some years, these deaths have remained at unacceptably high levels in many counties. They have been increasing in recent years in a few countries. This makes naloxone distribution seem very attractive, especially as the theoretical rationale for this intervention appears to be quite plausible. However, in these days of evidence based medicine, it has to be acknowledged that the evidence for the efficacy, safety and cost effectiveness of naloxone distribution is weak. In addition, the efficacy and safety (and cost effectiveness) of other measures to reduce heroin overdose deaths, such as methadone and buprenorphine maintenance treatment, is supported by compelling evidence. But demand for methadone and buprenorphine treatment still far outstrips supply in almost all countries reporting large numbers of heroin users. The lack of strong evidence for naloxone distribution is for good reason. Randomised control trials and other rigorous study designs seem incapable of execution. Therefore, policy makers (and researchers, treatment providers and drug users) are faced with a real dilemma. Should naloxone be distributed to injecting drug users because of the importance of reducing the large number of heroin overdose deaths in young people and the strong theoretical arguments, even though the empirical evidence for efficacy and safety is weak? Or should policy makers try harder to overcome the barriers to providing sufficient methadone and buprenorphine treatment? Or should they do both? These are difficult questions to answer. But the case for an informed debate, with injecting drug users also involved, seems overwhelming. A number of interventions for illicit drugs have been implemented over the years because of high plausibility, despite the lack of supporting evidence. Many of these interventions, such as oral naltrexone to treat heroin dependence, turned out to be both ineffective and unsafe. The history of these many false dawns suggests the need for caution. The starting point in a debate about naloxone distribution has to be an acknowledgement that evidence for efficacy and safety of this intervention is unavailable at present. Yours sincerely, Dr A Wodak, Director, Alcohol and Drug Service St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia References: 1 John Strang, Michael Kelleher, David Best, Soraya Mayet, and Victoria Manning. BMJ 2006 333: 614-615. Competing interests: None declared |
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