Responses

Questions on Salts, Compression, Chloroquine

We don’t agree with popular press and campaigners all the time. Our material is independently researched and backed by science, not marketing. Yet popular claims can cause unnecessary worry, so here are responses to some of the criticisms. As you can well imagine, ‘criticisms’ often take a few unthinking seconds to write, whereas defending a technical analysis takes much painstaking work. Occasionally our detractors have claimed ‘professional’ authority. Our lengthy answer on chloroquine (below) is a case in point: the group of authors attacking us were either doctors or academics, each competent in their field yet, when confronted, claimed they weren’t sure which of them was “responsible for checking errors in that part”. These notes are purely for rebuttal of criticism of our work. They do not contain specific instructions on euthanasia. For more detailed answers and authoritative information, please see Five Last Acts – The Exit Path.

SALTS

Your books don’t mention salts: does this mean you are not up to date?

Whenever there is a major breakthrough we rush through an update (as we did for instance with nitrogen, and were the first to publish anywhere in the world).

We focus chiefly on methods that are reliable, peaceful and don’t go rapidly out of date. Salts have offered a peaceful death for some people — some of these have been accompanied — but their effects seem unpredictable and may involve worrying periods of confusion or other symptoms. Some right-to-die proponents are against them. The chief proponent in favour of them has altered recommendations on them several times, increasing suggested doses by more than 100% and adding multiple other drugs to be combined. Additionally, authorities are attempting to stop supplies reaching individuals (as opposed to businesses) or making house calls to purchasers. Much as we applaud the pioneering of ‘new’ methods, the data on salts is insufficient we feel to form a fixed opinion on their suitability for self-euthanasia. For these many reasons we suggest extreme caution.

COMPRESSION

I’ve read different figures to the ones you quote for compression of the trachea (windpipe) or the arteries. Does this mean that your figures are wrong?

Standardised figures are listed in physiology textbooks and elsewhere as a benchmark, much like toxicology manuals list a ‘lethal dose’ when, from a protective point of view, they mean “may be lethal”: which is not the same as “will be lethal”!

The truth is that the effect of pressure on the neck varies immensely from one individual to another. A young, healthy person will be able to take far more pressure than an elderly frail person. We noticed this in group role-plays in safe workshops across the country. No painless method of self-euthanasia involves compressing the trachea: that would be very painful. We quote figures in order to show the proportionate pressure between compressing veins, arteries and the windpipe as the difference is considerable, whether with a young or an elderly person. This is to indicate that the necessary pressure is far below that required to cause pain.

Some other objections to the compression method are also answered in Five Last Acts – The Exit Path. While disagreements about Salts are merely a matter of opinion based on the evidence, criticisms of our work on other methods has in all cases so far been due to a failure to understand the evidence itself, or technical oversights leading to wrong conclusions, sometimes even by other researchers.

THE READING LEVEL

Some of the book seems to use complex medical terms…

The Exit Path has a dual audience. Most of the book explains things in down-to-earth, ordinary language. We avoid difficult terms wherever we can. That’s mostly the ideal. A few sections however have been added to provide a necessary technical analysis. When conflicting claims have been made about a method, we believe the reader deserves a proper explanation, not palmed off with bland assurances or the old “trust me, I’m a doctor” attitude. Technical explanations are easy to skip if you just want the basics: all the methods are spelt out simply, and often with diagrams or “dress rehearsal” scenarios. Yet in cases where the techical aspects are controversial you can at least see we have done the research behind the claims, something usually omitted by celebrity ‘recipes’. Part of the response below on chloroquine is one such example – from an appendix to the main volume – but elsewhere in the book you will also find the method described in a non-medicalised way.

CHLOROQUINE

A prestigious study claimed that some of the details in your work on chloroquine were incorrect…

This is a more complex question involving pharmacokinetics and toxicology. It is not a major point, but no, it turns out our details were not incorrect.

Much of the error by the detractors, based in the Netherlands, was based on a book claiming to be a Dutch translation of our earlier work Departing Drugs. That so-called ‘translation’, unknown to us, had altered the drugs specified by ourselves. Unfortunately the researchers based part of their criticism on the Dutch book, wrongly assuming it was our work.

The second criticism related to the action of a certain benzodiazepine in combination with chloroquine. While this was controversial, they had based their conclusion on outdated studies on animals. If they had read our work more closely they would have seen the error, for we indeed quote the more modern findings based on human studies and which contradict their claims.

Here is the response in full, printed in Five Last Acts – The Exit Path, beginning p.738.

(From the Author:)
I am not aware of any criticisms of Five Last Acts other than some people felt that the suggestion to use a plastic bag in conjunction with compression was not made strongly enough. (Since the first edition, the evidence is that it needs to be made less strongly, if at all, but the criticism is worrying enough to people that it needs to be rebutted.) Additionally, data in Departing Drugs, a booklet I collaborated on in 1993, was criticised, unfairly I believe, by a group of authors working together in 2006. I did not annotate that work as thoroughly as Five Last Acts, but readers have a right to know if what I said then was properly substantiated. It was. Some of the criticism may have been made in good faith, but much seems to have originated with one doctor making assumptions outside of his specialist field of expertise.

On the use of zopiclone with chloroquine:
It was alleged by Wozz that the authors of Departing Drugs had recommended the use of zopiclone as a suitable sleeping drug to be taken for self-deliverance in combination with chloroquine.(1) A case of a person using this combination and experiencing a painful death was quoted.

Response: The quotation was inaccurate and misleading. The authors of Departing Drugs had never made such a recommendation. It transpired that the allegation was based on a version of Departing Drugs which the Dutch society (NVVE – of which one of the Wozz authors is an honorary member), had reissued in their own version and with unauthorised text. NVVE had made the recommendation to use zopiclone with chloroquine, not the authors of Departing Drugs.

On the use of benzodiazepines with chloroquine:
The Wozz authors(2) criticised the Exit/Departing Drugs claim that benzodiazepines are not the best choice of sleeping drug for use with chloroquine.

“Diazepam is indeed used to counteract chloroquine poisoning. But this does not allow us to conclude that diazepam is an antidote to the lethal effect of chloroquine on the heart. Tests on animals have confirmed this. Also on theoretical grounds diazepam would not be expected to prevent cardiac arrest brought on by chloroquine. In our view, diazepam has been used by clinicians in emergency cases against chloroquine poisoning because it suppresses muscular contractions and epileptic seizures. It is also exactly these contractions and seizures that one will want to suppress in the case of a chloroquine overdose for a humane self-chosen death” (3)

The Wozz authors go on to recommend a sleeping tablet combination comprising either a) barbiturate, or b) a combination of short + long-acting benzodiazepine(4), irrespective of the fact that most of these drugs are almost impossible to obtain.

In support of the idea that benzodiazepines do not interfere with the lethal effect of chloroquine – an idea contrary to mainstream clinical practice – the authors curiously quote a retrospective study by Demaziere et al,(5) yet that very study states:

“No statistically significant difference was found between either the control and diazepam groups or between subgroups, concerning the distribution of age, sex, amount of chloroquine supposed to have been ingested, delay in hospital admission and death rate. However, there was a higher death rate in the asymptomatic subgroup not treated with diazepam than in the diazepam group.”

Response:
Wozz quote two other old studies (out of the many, many studies available on chloroquine poisoning), but the findings are inconclusive. One, for instance, speaks of a number of treatments including diazepam and concludes that, “these elements, either singly or in combination, do not appear to have a truly antidotal effect in acute chloroquine poisoning.”(6)

The third is speaking of a trial involving diazepam in the treatment of chloroquine poisoning involving less than 4g of chloroquine, well below the recommended dose for self-deliverance, and makes the conclusion that, “Diazepam, at the dose studied, does not appear to reverse the chloroquine-induced membrane-stabilising effect in acute moderately severe chloroquine intoxication,” an observation which might be of rather limited relevance to the use of chloroquine in large doses.

It is clear that there is room for debate on the issue of diazepam’s interaction with acute chloroquine overdose. Even the Wozz authors’ claim that the theory is backed up by experiments with animals is strongly contested, especially if we examine more up-to-date material than that quoted by the Wozz authors. For instance, we find, “Studies in animals and humans suggest that early aggressive management of severe chloroquine intoxication has a cardioprotective effect and reduces the fatality rate.”(7)

And in enumerating the specific types of aggressive management, the author is quite clear:

“Diazepam (0.1–0.3mg/kg) given by slow intravenous injection, repeated as necessary, is effective at controlling convulsions. In addition, diazepam at approximately 10 times higher doses has been reported to have a specific cardio-protective action in severe chloroquine poisoning.”(8)

Brent (above) goes into considerable detail and with considerable supporting evidence over the cardioprotective effect of diazepam and writing some fifteen years later than the journal studies quoted by Wozz. This suggests that Wozz’s claim that, “Diazepam and the other benzodiazepines . . . are not an antidote to the lethal effect of chloroquine on the heart,”(9) must be viewed with considerable scepticism.

These studies querying the effect of diazepam on chloroquine toxicity have been well-known for many years, but the majority of modern authorities, like Brent, while admitting that the action is not completely understood, come down clearly on the side of the mainstream that concludes the opposite of the Wozz authors. As Olson states:

“. . . diazepam has been reported to antagonise the cardiotoxic effect of chloroquine (the mechanism is unknown, but diazepam may compete with chloroquine for fixation sites on cardiac cells).”(10)

Similarly a paper from Hammersmith Hospital and published in the British Medical Journal(11) had cited studies that diazepam increases the urinary excretion of chloroquine and went on to explain the effect as far as it is understood:

“The action of diazepam at central nervous system receptors may contribute to its beneficial effects in chloroquine poisoning, but there is increasing evidence that a specific action of diazepam at binding sites on heart muscle is important. These putative receptors on cardiac myocytes are quite distinct from diazepam receptors in the central nervous system, being y-aminobutyric acid independent, and until recently had no known function. Benzodiazepine analogues at these receptors have been shown to shorten the duration of intracellular action potential in animal myocardium and may have anti-arrhythmic properties. Moreover, diazepam has been reported to reduce the concentration of chloroquine in rat cardiac muscle despite increasing blood concentrations.”

The use of diazepam in treating chloroquine toxicity originates from a fortuitous observation in Africa in the 1970s. Several large series of cases of chloroquine intoxication found that patients seemed more likely to survive if they had also taken large amounts of diazepam. The protective effect was backed up backed up by subsequent animal experiments and a later prospective trial.(12) Although often discussed, the accumulated wisdom has been reinforced many times in subsequent years.

On the basis of leading theoretical analysis, practical results, current clinical practice, and combined weight of opinion, it would seem likely that the Wozz authors simply failed properly to understand the action of diazepam in chloroquine overdose.

Some practical advantages of zolpidem include: the small size of the tablets compared to other sleeping drugs; that zolpidem interferes with sleep architecture and periods of deep sleep noticeably less than sleeping drugs such as temazepam; and that zolpidem is absorbed more readily from the gastrointestinal tract.

For instance, in comparing zolpidem and temazepam, a multi-centre study using double-blinded protocol, with data collected in 13 sleep laboratories, found that,

“For two sleep maintenance variables, wake time during sleep and number of awakenings, zolpidem produced significantly better results than placebo while temazepam did not. With regard to sleep architecture, zolpidem and placebo groups spent a similar percentage of time in the various sleep stages, while the temazepam group had significantly less Stage 3/4 sleep than the zolpidem group and significantly more Stage 2 sleep than the zolpidem or placebo groups. Zolpidem significantly improved sleep compared to temazepam for many subjective measures (total sleep time, number of awakenings, ease of falling asleep, wake time after sleep onset, and sleep quality).”(13)

These findings are supported by a number of other reputable studies.(14) It is difficult to find ideal sleeping drugs for the various methods of self-deliverance, but the evidence for zolpidem as an adjunct to other drugs or physical methods is not without foundation.

Further on the use of benzodiazepines . . .
Benzodiazepines are categorized as either short-, intermediate- or long-acting. The WOZZ authors, in their criticism of Departing Drugs, also make much of these differences in suggesting a combination of short and long acting benzodiazepines to ensure both a quick and long-lasting sleep when used in conjunction with chloroquine.(15)

The ‘half-life’ of a drug is the time required for half the quantity of the drug to be metabolized or eliminated by normal biological processes. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety. This style of classification can be mis- leading to right-to-die researchers as it is based on the drug’s ‘half-life’ – the time it takes to be eliminated from the body. Although this is an important indicator, there are many factors that influence whether a particular sedative will put you to sleep soundly enough for self-deliverance (used in combination with the plastic bag or other drugs). Benzodiazepine hypnotics/tranquillizers have been classified by the Committee on the Review of Medicines as short or long-acting according to whether their elimination half-lives are less than or greater than 10 hours(16). Whilst seemingly attractive for its simplicity, such a classification incorporates certain anomalies because the elimination half-life is not necessarily the major determinant of the rate at which benzodiazepine hypnotic action is terminated.(17) Pierce and Franklin, in stating such a conclusion, expanded on the process in considerable detail, suggesting the classification should be abandoned. It wasn’t, but a simplified explanation that arrives at the same conclusion is presented by Dundar and Boland et al, “Although pharmacokinetic parameters are important, as we shall see, the elimination half-life is a poor guide to duration of action, particularly as some of these drugs have active metabolites.”(18) Half life calculations appear to be most useful for doctors when calculating when there is a possibility of side-effects such as next-day drowsiness. This is not directly related to its specific hypnotic properties as used in self-deliverance.

Neither is the classification a reliable guide to the speed of action of these drugs. As the comprehensive volume on sleep medicine by Lee-Chiong Jr points out, agents that are rapidly absorbed from the gastrointestinal tract have a quick onset of action.(19) This includes diazepam and flurazepam, normally classified as long-acting.

The WOZZ authors make some interesting speculative points about the use of sedatives with chloroquine, particularly the idea of combining different sedatives. What could have been outstanding work would appear to be deeply flawed by misquotation, simplistic acceptance of drug classifications, and the stating of generalisations as fact. The key data is not a drug’s half-life, but its effectiveness in initiating and maintaining daytime sleep.

If we look at data rather than classifications, there are some crossovers. Two studies found flunitrazepam(20) and flurazepam(21) seem to be more effective than other benzodiazepines for daytime sleep. But, as the Wozz authors admit, these are exceedingly difficult to obtain. Which leaves us with diazepam as a benzodiazepine known to be useful for daytime sleep.(22)

Theoretically, diazepam is attractive as it possesses anti-convulsant properties – which zolpidem does not. But the primary aims of a self-deliverance are sure death and freedom from discomfort. If the person is properly sedated, restlessness or convulsions are not an issue; diazepam appears a potential option in sedating and limiting convulsions – but also in neutralising the effect of chloroquine. More research is needed on this issue. Sadly, even the usefulness of any benzodiazepine for a lengthy sleep of many hours is not readily proven in studies. In a meta-analysis of 45 valid studies, benzodiazepines increased total sleep duration (compared to a placebo) by only 61.8 minutes.(23)

On the amount of barbiturate needed for self-deliverance
The WOZZ authors say that “Departing Drugs suggests 3.5 grams as the lethal dose for secobarbital.”(24) They go on to say, “This may be true in some cases but we think that a dose of 30 tablets of Vesparax (which contains 6 grams of barbiturates totally) is more reliably effective in all cases.”

Response:
Vesparax was an interesting combination drug,(25) but apart from the fact that it has been virtually unavailable worldwide for many years, the implication that Departing Drugs recommended 3.5 grams of secobarbital for self-deliverance is entirely incorrect and based on a quotation taken completely out-of- context. In the Glossary to Departing Drugs, it is stated that 3500mg of secobarbitone is commonly lethal. This is entirely correct – many people have died from such a dose; but nowhere does Departing Drugs recommend it as a reliably effective dosage for self-deliverance. The Departing Drugs authors’ recommendation at their time of writing (1993) was 10000mg,(26) based on the oral dosage of barbiturates used in the Netherlands. A smaller amount is probably sufficient. (ed.: This drug has been withdrawn from the market in most countries.)

1. Admiraal P, Chabot B, Ogden R, Rietveld A, Glerum J, Guide to Humane Self-Chosen Death, WOZZ Foundation, Macdonald 2006. pp. 57-58.
2. Wozz, Ibid. p.56
3. Wozz, Ibid. pp.56-57.
4. Wozz, Ibid. p.59
5. Demaziere J, Saissy JM, Vitris M, Seck M, Ndiaye M, Gaye M, Marcoux L. Effects of diazepam on mortality from acute chloroquine poisoning, Ann Fr Anesth Reanim. 1992;11(2):164-7.
6. Clemessy L, Taboulet P, Hoffman R, Hantson P, Barriot P, Bismuth C, Baud F, Treatment of acute chloroquine poisoning: a 5-year experience, Crit Care Med. 1996 Jul;24(7):1189-95.
7. Brent J, Critical care toxicology, Mosby 2005, p.675.
8. Brent, Ibid.
9. Wozz, p.57.
10. Olson K (ed), Poisoning & Drug Overdose, McGraw Hill 2007, pp.419-421.
11. Meeran K, Jacobs M, Scott J; Mcneil N, Lynn W, Cohen J, Pusey C, Phillips J, et al., Grand Rounds – Hammersmith-Hospital – Chloroquine Poisoning. BMJ 1993, 307:49- 50.
12. This short history can be found in Chloroquine poisoning, BMJ 1993;307:49.
13. Erman M, Erwin C, Gengo F et al, Comparative efficacy of zolpidem and temazepam in transient insomnia, Human Psychopharmacology Clinical Experience 2001:16:169-176, pp.175-176.
14. See also, for instance, Dundar Y, Boland A, Strobl J, et al, Newer hypnotic drugs for the short term management of insomnia: a rapid and systematic review, Health Technology Assessment 2003 (Produced by: Liverpool Reviews and Implementation Group on behalf of The National Institute for Clinical Excellence): “Zolpidem with temazepam – One study reports significantly favourable results for sleep latency and sleep quality in the zolpidem group.” And (p.28) “Kerkhof 1996 reported significant improvements with regard to subjective estimates of sleep quality for the zolpidem group compared to the temazepam group.” The way benzodiazepines adversely affect the deep sleep phases of sleeping – shortening the period when a person is immobilised – is well- established. See for instance, “Benzodiazepines . . . increase NREM stage 2 sleep (more sleep spindles), decrease NREM stages 3 and 4 sleep, and decrease REM sleep,” whereas with, “NBBRAs (eg zolpidem, zaleplon, zopiclone, and eszopi- clone) . . . There is no reduction in NREM stages 3 and 4 sleep or REM sleep.” (ibidem). Similarly, “Unlike the benzodiazepines at usual hypnotic doses, the nonbenzodiazepines drugs, zolpidem, zaleplon, and eszopiclone, do not significantly alter the various sleep stages and, hence, are often preferred hypnotics” (Champe P, Finkel R, Clark M, Cubeddu L, Pharmacology (4th ed.) Lippincott Williams and Wilkins 2008 p.108.)
15. e.g. pp.25-27, 31.
16. Systematic review of the benzodiazepines BMJ 1980;280:910-912
17. Pierce D, Franklin R, The classification of benzodiazepine hypnotics, British Journal of Clinical Pharmacology 1983(16): 345-347.
18. Dundar Y, Boland A, Strobl J et al, Newer hypnotic drugs for the short term management of insomnia: a rapid and systematic review, Health Technology Assessment 2003, Liverpool Reviews and Implementation Group on behalf of The National Institute for Clinical Excellence: Health Technology Assessment 2004: 8(24).
19. Lee-Chiong Jr T, Sleep Medicine – Essentials and Review, OUP 2008:119.
20. Nicholson N, Stone B, Pascoe P, Efficacy of some benzodiazepines for day-time sleep, Br J Clin Pharmacol. 1980 November; 10(5): 459–463.
21. Kales A, Kales J, Sleep laboratory studies of hypnotic drugs: efficacy and withdrawal effects, J Clin Psychopharmacol 1983;3(2):140-150.
22. Nicholson, supra.
23. Holbrook A, Crowther R, Lotter A et al, Meta-analysis of benzodiazepine use in the treatment of insomnia, CMAJ 2000;162(2):225-233.
24. Ibid. p.42.
25. Contained 50 mg brallobarbital, 150 mg secobarbital and 50 mg hydroxyzine.
26. Departing Drugs, p.39.