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