Rebuttal to Dead Men Don't Pull Triggers

Written by Bradley Speers, Note: This is just some comments about the claims written in Dead Men Don't Pull Triggers.. Like all material on the net, you need to scruitinise the information, however you will find that a lot of what I have written is general pharmacological principle. My rebuttal would not disprove claims provided by the essay, and the essay does seem to have interesting points, but you should be weary of a few things.

My addendum (and response to Roger's response) to this critique can be found on those links.

Please note, the calculations in the original rebuttal file are not correct.

Roger's reply to this first rebuttal (consisting of first page, now slightly altered since his reply but not significantly)

Issues in this rebuttal

General Principles behind the issues
Volume of Distribution issue *** Most important
Dose required for overdose issue
Was all the heroin taken in one dose?
My opinion
References

I wish to split this topic into two different perspectives... the first is a misuse of information in the essay, in particular, the calculation of the dose Kurt must have administered is flawed, and hence I shall show that the dose Kurt had taken was significantly lower. The second is related to the first, but focuses more on other factors other than the actual dose which is believed can play a major role in heroin overdose. The second is more hypothetical, and thus may be incorrect, however there is scientific evidence in support of these findings (referenced later).


General Principles behind the issues(1)

Who am I?

I am a 21 year old male who is doing honours in a Bachelor of Science degree at the University of New South Wales.. My honours is in immunology, but one of my majors is Science Pharmacology. Although I may not be the biggest expert in this area, I happen to have a special interest in the opiates (partly due to the hype around certain people in certain bands). I finished the course with a distinction mark. Again, I am not trying to say I am an expert, but I do have a reasonable idea about this topic.

Background Pharmacology information

I shall try to keep this to the point and relevant to opiates.

Tolerance

There are two general mechanisms in which tolerance to drugs can occur. One mechanism involves an increase in the deactivation or the removal of the drug, which is known as Pharmacokinetic tolerance. This is the mechanism by which tolerance to alcohol and barbituates for example is generated. In this tolerance mechanism, there is no change in receptor number and therefore the dose required to cause death is constant, although the clearance (the rate of deactivation of a drug from the blood stream) of the drug increases. The other mechanism is known as pharmacodynamic tolerance, and involves the increase (or decrease) of receptor numbers to regain a drug/receptor ratio which is close to the physiological level. This is the mechanism is which tolerance to opiates and LSD (for example) occurs. As the number of receptors is increased, the dose needed to cause overdose increases, while the clearance remains the same.

The ratio of drug to receptor determines the effects the drugs have. If the drug is an agonist (that is it has positive effects on the receptor), then the number of receptors would increase to decrease the drug/receptor ratio towards physiological levels. If the drug is an antagonist (negative effects or blocks activity of the receptor), then the opposite action occurs in tolerance. It should also be noted that within a certain logarithmic range, the effect of drugs (which have one site of action) is linear with the log of the concentration (hence the ratio between drug and receptor applies). Above and below this range, either near maximum or no effect occurs. (See diagram below for a pictoral explination of this(well maybe later :P)). While most theraputic doses of drugs fall within the linear range, the effect can increase rapidly with a small increase in the log of the concentration of drug (ie the linear coefficient can be very high).

In opiate tolerance, the expression of the mu, kappa and delta receptors is increased. The result is that the amount of drug required for the same effect increases, as does the dose required to cause overdose, and the onset of action is slowed as the drug to receptor ratio increases relatively more slowly. Thus in tolerant people, overdose will tend to slow down, possibly enough for Kurt to take a high dose and still be able to operate a gun (it wouldn't be terribly hard to use), perhaps the drug OD would be a backup to ensure fatality. While all this is relatively straight forward, the real issue is how much tolerance is generated in opiates.

Opiate conversions

While I will accept the numbers given in regards to heroin levels found in Cobain's blood and the like, the first thing I partially question is the conversion values for heroin and morphine. The accepted conversion values for various opiates are listed below..
[From 48th edition Physicians Desk Reference]

Equianalgesic Dose (mg)
Name IM PO
-------------------------------------------------------------------------
morphine 10 60
hydromorphone (Dilaudid) 1.5 7.5
methadone (Dolophine) 10 20
oxycodone (Percocet) 15 30
levorphanol (Dromoran) 2 4
oxymorphone (Numorphan) 1 10 (PR)
heroin 5 60
meperidine (Demerol) 75 --
codeine 130 200
-------------------------------------------------------------------------
Note: All IM and PO doses in this chart are considered equivalent to 10 mg
of IM morphine in analgesic effect. IM denotes intramuscular, PO oral,
and PR rectal.

I also will mention that in my pharmacology course, they stated that heroin is 2 to 3 times more potent than morphine. While this table is talking about intramuscular injection opposed to intravenous, this is not relevant to potency, only to onset of action is slower (this is because the essential difference between heroin and morphine is its lipid solubility, and the blood-brain barrier is the barrier while reduces morphine's potentcy (in both IV and IM injections). This means that the amount of heroin required to attain an overdose may be higher than that which is stated in Roger's essay. I like being more conservative about things.

Drug Kinetics and the Volume of Distribution

I really don't want to spend a big deal of time discussion how drug kinetics work... but I wish to critique the calculations used to determine the dose Kurt had taken. There is a formula which is used to describe the association between the dose given to a person and the concentration of a drug in blood (known as the plasma concentration). This is known as V = X / C... where X is the amount of drug, C is the concentration of drug in the plasma and V is known as the volume of distribution. There are two phases during an intravenous drug injection.. known as the distribution phase and the elimination (or log-linear) phase. Initially, when the drug is first injected, it is entirely in the blood.. however, it then begins to distribute around the body and into organs/muscles/fat etc... during this phase, the concentration of the drug in the blood decreases, while the volume of distribution increases. It increases from approximately 5 litres (at time=0, or at injection) to a larger amount, dependant on the type of drug being given. For acidic drugs, the final volume is usually between 8 and 20 L, while basic drugs (such as morphine) the volume can be as high as 500 L. That final volume is known as the volume of distribution, or V in the above formula.

As a final point about the volume of distribution before i discuss it later, the value of V for morphine (as also heroin as it is rapidly converted to morphine) is approximately 150 to 160 litres (2), and the time for peak levels of morphine in the brain from a heroin injection is approximately 10 minutes(3).


Volume of Distribution issue

As seen just above, the volume of distribution determines the final concentration of drug in plasma for any particular dose. However, this whole issue revolves around the idea that Kurt was incapacitated SO quickly that he could not shoot himself. You may have noticed that in my introduction I claimed that the calculations of the dose Kurt took was flawed... and this is correct, because if Kurt DID die straight after he took a dose of heroin, then the volume of distribution is not 160 litres, but rather, is approximately 32 litres (For the calculations, please refer to the addendum). As mentioned above, the peak levels of morphine (from a heroin dose) in the brain is 10 minutes, however it would only take perhaps 30 seconds for Kurt to do what he had to. The end result? The morphine did not completely distribute into his tissues, and thus he did NOT have a high volume of distribution.. which in the end means that the blood concentration of 1.52 mg/L translates into dose much lower than 240mg as claimed by the essay.. there is more information as to why this is so in the second page of this rebuttal.

There is also something else which concerns me. The evidence that Roger uses in regards to immediate incapacitation by heroin is essentially the following: "Additionally, Platt remarks on the amazing rapid action of intravenous heroin by explaining that "...the high uptake of heroin...indicates that an abrupt entrance of heroin into brain tissue probably occurs 10 to 20 seconds after the usual intravenous injection by addicts...15 seconds, 68% uptake into brain with heroin compared to 42% for methadone, 24% for codeine, and morphine too small to measure. "(75)."..

What doesn't make sense to me is.. if 68% of the heroin is in the brain after 15 seconds, how can he justify the fact that plasma heroin has a halflife of 3 minutes? For heroin to be effective, it must be deacetylated into 6-acetylmorphine and morphine. If 68% of the heroin is in the brain at 15 seconds, then are you suggesting that the brain (along with the rest of the body) takes another 2:45 to deacetylate 50% of the heroin in the body? The fact is, it MUST take at least 3 minutes for half of heroin's effects to occur, because heroin itself does not have any activity. To claim that 68% of the heroin is in the brain (and therefore has potential for activity) is unreasonable as heroin is deacetylated rapidly after entering the brain.

Clearly, the 68% of heroin uptake into the brain must be as a proportion of the amount which is being absorbed into tissues... not the total amount of heroin in the body. Otherwise I cannot see how the two facts can stand.

Note: halflife of plamsa heroin was adapted from Foley, K.M. & Inturrisi, C.E., "Analgesic drug therapy in cancer pain: principles and practice," Med Clin North Am, 71:2, 1987, pp. 207-232.

Heroin's halflife of 3 minutes DOES make sense however in the calculations I use in my critique(2.5 minutes is closer to 3 than less than 15 seconds).

In order to explain why the actual levels of morphine in blood don't necessarily have to be high for drug overdose, more pieces of the puzzle is explained in the next section


Other issues relating to the dose required for heroin overdose

The material below ignores the incorrect dose calculation explained above, but rather focuses on other possibilities as to why overdose amounts may be lower than the amount a person is tolerant to (and thus why trying to define a point where tolerance ends is wrong). This is in order to counter the arguement that the fact that levels of heroin can be quite low for overdose means that people can't be tolerant to higher doses (and therefore, how can you prove that Kurt wasn't actually tolerant to the dose he took?).

Opiate Tolerance and Overdosage

The problem associated with stating the dose required for an opiate overdoses in tolerant people is because this level increases as tolerance increases. This fits in with the pharmacodynamic nature of opiate tolerance. One of the developmental factors of this tolerance is dependent on how fast the dosage increases as time goes on. The development of tolerance occurs rapidly upon regular use of the drug, and adapts quickly (this is read one to two weeks) one way or the other depending on change of the drug level and usage. It should be noted that respiratory depression tolerance is slower than other effects, but still occurs given enough time. There however is no way to definitely define an upper limit for any individual person, it is entirely dependant on the number of receptors present, and thus the dose needed to reach an overdose ratio. All of the doses which are quoted are known as LD50 type doses. This means that if this dose was given to a random group of the population, 50% would die. This also means 50% will not. The LD50 of morphine required to kill a non-tolerant person has been quoted from 80mg to 120mg. For addicts, setting a value is impossible. This is partly due to the fact that opiate tolerance is partially condition based. This is when there are certain cues to the brain which indicate that opiates will be present, and the brain thus "prepares" for the dose(4). A change in the "shooting up" ritual may explain many of the deaths to heroin(4). The fact that tolerance can significantly change due to conditional change (among other factors which I shall mention soon) may account for the fact that the level of heroin actually needed to overdose can be much lower than the level people would be normally tolerant to. While this may suggest more evidence for a drug based death, it also provides reasoning why people may be tolerant to higher doses then what they may overdose on(4). Rather, it is the change in tolerance which causes an overdose, not the actual dose itself.

Another problem in determining overdose levels for tolerant people is due to the fact that many "overdoses" do not involve only the opiate itself, but rather other products in the injection or a combination of drugs, both of which are synonymed as substance X. Substance X is basically any chemical which in combination with heroin can cause rapid overdose and death. It doesn't even have to involve heroin, it may be caused by shock from injecting the combination of various compounds into your body, or from overdose with other impurities in the junk(5). A well known example of cocktail drug mixtures which potentiate respiratory depression is alcohol (and many of the other CNS depressants). In fact, approximately 50% of heroin overdoses are also under the influence of alcohol(6). It may well be possible that many compounds strongly potentiates heroin, explaining why opiate antagonists often stops death from "overdose". Quinine has been accused of causing the rapid version of heroin overdosage, as overdosage on quinine alone also results in a similar death syndrome, hence quinine may well present a false positive heroin overdose(5). There are also other drugs which can augment or reverse morphine tolerance, which is another possible source of why overdose amounts may be lower than what people would normally be tolerant to(7).
These two major factors above partially explain why high doses of "heroin" is not required for overdose in street addicts, as the pro-murder essay emphasised. But this does not mean that tolerance does not develop, nor that it can be great. Only in cases of overdose do these sources of tolerance reversal come into play. It would be pure speculation as to whether Kurt had enough tolerance or not to 50mg of heroin.

Well what about the benzodiazepines in Kurt's blood?

The level of benzodiazepines detected in Kurt's blood was described as "trace amounts". Analytically trace amounts is defined as when there is enough chemical present to detect above noise level (qualitative), but not enough to accurately quantify. The levels of benzodiazepines which can be determined quantitatively is at least 3 days after administration, longer for chronic use(8). Benzodiazepines in trace amounts can detected 30 days after dosage(8). Note: This is for valium, flurazepam, nordiazepam... this is due to the fact that benzodiazepines have long half lives, and thus have a long detection period. The duration of action of valium is approximately 1 hour. This means that the last dose of valium which was taken by Kurt was at least 3 to 7 days before he died (assuming he only took one dose of benzodiazepine.. if it was chronicly used, quantitative detection could be used for up to a four to six weeks), and thus relatively ineffective at death. At these levels, benzodiazepines may not have much (if at all) potentiation effects upon heroin, and thus may not a significant issue in this debate. Depending on the time he last took the drug, it may or may not be a factor, but to conclude that trace levels of benzodiazepines were there to ensure fatality may be a little too optimistic. Obviously this area is speculative.


Did Kurt have to take all this heroin in one dose?

So far everyone has been assuming that the drugs in Kurt's system was all taken at once. However, this is not necessarily the case. It has been demonstrated that tolerance is partially conditioned (as mentioned before), and the tolerance of opiates over a period of time is even larger than for a bolus (or "all at once") dose (such as an addict who tolerated 1800mg of morphine in 2.5 hours without even being sick)(5). It may be possible that there was a resonable level of morphine present in his blood before a final injection, and thus its effects are less pronounced. This is reflected in the fact that many addicts take many hits a day, and although there is morphine there already, they do not exceed a magic level which kills them, rather another factor influences overdose.

Who's to say that he even injected heroin anyway? If the autopsy report only measured morphine levels (and not 6-AM), there is no proof to differentiate between heroin and morphine. I haven't seen the report, but if this is the case then injecting morphine (of the same dose) would again reduce the risk of overdose. The purity of heroin on the street is highly variable, as well as adjuvants which may effect overdose (see all the substance X stuff above)(2,5).

I may seem to be semi-supporting the essay I'm attacking, but my point is that putting overdose values for tolerant subjects is futile.


My Opinion

I personally do not think that Kurt overdosed on heroin, perhaps he took a large dose, perhaps it may have killed him, but I think he probably had the time to end things the way he did... His friends had tried to send him to a detox farm in California from which he escaped back to Seattle, so he obviously had a habit and probably the tolerance with it. The fact is, for the essay "Dead Men Don't Pull Triggers" to hold water, it requires Kurt to be immediately incapacitated. For this to happen however, it means that the actual distribution of drug in his body was still primarily in the blood, and as the volume of blood in humans is approximately 5 litres (average man, Kurt would have even less), the dose of heroin taken was lower than proposed in the essay. The fact he also had tolerance means that it would take longer for him to reach the drug/receptor ratio to cause overdose, and the fact that you cannot reasonably determine a limit of tolerance means that you can't really be sure that a dose will kill any particular individual (unless it is blatantly obvious). If Roger was to redo the calculation at say 50 mg of heroin (ie a volume of distribution of approx 30L which would be reasonable after 30 seconds) instead of 240 mg, I would be positive Kurt's "dose" is not extreme. He still could be right, Kurt may have lost his tolerance and overdose may have occured... but given the proviso he had significant tolerance, 50mg of heroin certainly isn't always lethal.

If you're asking why Kurt had such a higher level of morphine in his blood at death than most people who overdose on heroin, it's because he shot himself at a earlier time than what would have killed most people... the blood concentration drops as the drug enters the brain and other tissues.. where the maximum effect occurs (and where the volume of distribution is greatest). It all makes sense, Kurt may well have still been on the way out, but he would have had enough time to do the deed.


References

These references do not completely have all of the information in this critique.. some of the information came from lecture material/conversations with academic staff. Most of the pharmacological theory will be found in any good pharmacological textbook, such as Goodman and Gilman's The pharmacological basis of theraputics, or Rang, Dale and Ritter's Pharmacology at a glance.

Specific references include:
(1) Goodman, L.S. and Gilman, A., The pharmacological basis of therapeutics, (9th ed.), New York: Pergamon Press, 1990.

(2) Lewis, R.,Dead Men Don't Pull Triggers: Observations on the Death of Kurt Cobain, Jan 1998.

(3)Kotob, HI. et al., Intrathecal morphine and heroin in humans: six-hour drug levels in spinal fluid and plasma. Anesth Analg;65(7):718-722

(4)Siegel, S.; Drug dissociation in the nineteenth century. In F. C. Colpart & J. L. Slangen (Eds.), _Drug discrimination: Applications in CNS pharmacology pp. 257-262. Amsterdam: Elsevier Biomedical Press.

(5)Chapter 12 of the Consumers Union Report on Licit and Illicit Drugs

(6)Personal Communication, Courtesy of Professor Gary Graham, School of Physiology and Pharmacology, University of New South Wales (Retired).

(7) Tiseo, PJ and Inturrisi, CE; Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614. J. Pharmacol. Exp. Ther. 264:1090-1096

(8)Detection of various drugs (conservative conversion for blood in the case of benzodiazepines)

Note: You may notice that a few of these references are to web pages or personal communications... admittedly, I really couldn't be bothered finding every reference in the library.. but I am confident that the information above is not misleading. If everyone honestly has a problem with this, perhaps this critique will be reviewed with additional references as required. Be cautious with the information, but realise the most important points (relating to the volume and dose calculations) is standard pharmacological theory, in which you will find the relevant information (relating to drug kinetics) in any good pharmacological textbook.

Below are a couple of extra references which I did not use but may be interesting to read.. Again these are internet references so handle with care.

Chapter 12 of the Consumers Union Report on Licit and Illicit Drugs - This provides an interesting aspect about heroin overdose, but it is on the web thus it may be different to what was printed (however this is unlikely), but it could possibily be found in a suitable library.

Various newsgroup postings about opiates (including possible tolerance mechanisms and opiate conversions) - This is generally all opinion, however they are written by those who probably know the most.. the users themselves.

Comments, Questions: bspeers@fl.net.au