There is no doubt that the ancient physician Hippocrates
was an advanced thinker in terms of medicine and its conceptualization. He is
widely credited with advancing nosology and diagnostics as well as
professionalism. In the field of medicine, he was studied right up until the
turn of the 19th century by physicians who attended medical schools
in Europe. Like all prominent figures
from the past there is a question of whether invoking Hippocrates these days
represents idealization or rhetoric more than his accurate historical position.
I am referring specifically to a blog by Nassir
Ghaemi, MD entitled Hippocratic Psychopharmacology. After correcting the aphorism “First do no
harm” to “As to diseases, try to help, or at least not harm.” he elaborates on
a few ideas from Hippocrates and the implications for modern medicine. He interprets
the preamble of Hippocrates statement to mean that diseases must be identified
and if you cannot or will not take the disease concept seriously you cannot
help anyone as a doctor. He emphasizes that there should be a focus on not
doing any harm and that overall treatment should be conservative. He
acknowledges a bias that too many medications are being used in modern times.
Hippocrates additional idea is that diseases are a natural
process and they heal naturally and physicians should not get in the way of
that process. He discusses self-limited, treatable, and incurable diseases
suggesting only the treatable illnesses are a focus for physicians.
Hippocrates was apparently not enough so Holmes Rules
and Osler’s rule are added. The explanation of Holmes Rules is inconsistent
because initially it described prescribing based on benefits first and harms
second, but in the elaboration the assumption is supposed to be that the
medication is harmful. If that is your assumption harms would seem to be
prioritized. Here is an excerpt from the
post from 1861:
“……I firmly believe that if the whole materia medica, as
now used, could be sunk to the bottom of the sea, it would be all the better
for mankind, – and all the worse for the fishes.”
In other words, if you wanted to prescribe something – there is nothing useful to prescribe and given the time frame - that is correct. 1861 was before the discovery of germ theory. Of the estimated 750,000 Civil War (1861-1865) deaths at the time about 2/3 died of diseases that are treatable in modern times. The only effective medical treatments at the time were citrus fruits and vegetables to prevent scurvy, smallpox vaccines, and quinine for malaria. Four types of wound infections were described including tetanus, erysipelas, hospital gangrene, and pyemia or sepsis with mortality rates of 46-90%. Since there were no antibiotics infected wounds were treated with repeated debridement or amputation with the hope that remaining healthy tissue would generate an inflammatory and healing response.
In his writings, Hippocrates
describes many forms of orthopedic treatment and general medical treatment for
infections including gangrene and erysipelas. Those afflictions were not likely
to heal without significant medical and surgical interventions. I suppose in
keeping with the stated philosophy they could be reclassified as “untreatable.”
The question might become were untreatable diseases less treatable in
Hippocrates time than during the Civil War? Either way it is likely that
Hippocrates watched at least as many of his patients die as Civil War surgeons
did and those were very high mortality rates.
Ghaemi uses the example of antidepressants in bipolar
disorder as breaking Holmes Rule “egregiously.” Unfortunately, the presentation
of bipolar disorder may not be that clear cut.
As a tertiary care psychiatrist, it was common to see people experience
manic episodes after years of treatment for unipolar depression with
antidepressants or even as an antidepressant is tapered and discontinued. You must
have seen a manic episode along the way in order make the diagnosis and stop
the antidepressant. It also helps if the
patient is under the care of a psychiatrist and it is likely the vast number of
antidepressants in these presentations were prescribed by other specialists or
nonphysicians. I have never heard of a psychiatrist needing more evidence to
stop antidepressants in bipolar disorder.
It was done routinely by my colleagues in acute care.
Osler is quoted in the discussion of Osler’s Rule:
“A man cannot become a competent surgeon without a full
knowledge of human anatomy and physiology, and the physician without physiology
and chemistry flounders along in an aimless fashion, never able to gain any
accurate conception of disease, practicing a sort of popgun pharmacy, hitting
now the malady and again the patient, he himself not knowing which.”
And what exactly was known in Osler’s time about
pathophysiology and pharmacotherapy?
Probably not much more than was known at the time of the Civil War. Paton’s reference (5) contains several
additional quotes to illustrate what he describes as Osler’s nihilism including
that there were no useful treatments for scarlet fever, pneumonia,
and typhoid fever. Diarrhea
and dysentery were common in soldiers leading to both compromised health
status and death. A summary quote from
Osler’s time suggests there were only a few useful treatments including iron
for anemia, quinine for malaria, mercury and potassium iodide for syphilis and
that there were no other drugs supported by experimental evidence. It turns out that that the evidence for potassium
iodide in syphilis was restricted to reducing inflammation in some late-stage
lesions since it was not an anti-spirochetal agent (4).
If Osler was aware of a potentially effective drug – he may
have pushed it beyond what his colleagues were using as evidenced in this quote:
'At times of crisis Sir W. Osler and others have pressed up
the nitrites to huge doses, in persons upon which these drugs had been well
tested. Sir William said he had never seen harm come of large doses if
cautiously approached. I think he used to speak of 20-30 grains of sodium
nitrite per diem. I have administered half as much in a day.' (pp 88-9).” (3)
20-30 grains of sodium nitrite is roughly equivalent to
1,329 to 1,980 mg. In a 70 kg patient
that would be 19-28.3 mg/kg. The
worrisome complication from nitrites is methemoglobinemia. In severe cases it
can result in coma, cardiac arrythmias, and death. PubChem
suggests that intravenous doses of 2.7 – 8 mg/kg can be problematic. A leading
toxicology text suggests that when sodium nitrite is given intravenously to
treat cyanide poisoning the dose is 300 mg given at a rate of 75-150 mg/minute
intravenously with a repeat dose at half the amount if necessary, monitoring
for symptoms of nitrite toxicity. While it is difficult extrapolating oral toxicity
from IV administration there are reports of life threatening and fatal oral
ingestions resulting from taking 12.5-18 g of sodium nitrite. The EPA
recommends limiting exposure to 1.0 mg/kg/day. All of this toxicology
information suggests the the doses that Osler was using were pushing the limit,
but it also points to another deficiency in suggesting that his parsimony (or
nihilism) is a touchstone for modern physicians. That deficiency is that his outcomes were
unknown. The case reports that I have found were generally limited to a case or
two. I could not find any outcomes for high dose versus low dose nitrites for
angina or congestive heart failure. Modern nitrate preparations such as
isosorbide mono and di-nitrates are limited by tolerance to the vasodilating
effect. I may be wrong but I speculate the Osler knew very little about the
pharmacology of nitrites and the mechanisms of tolerance and toxicity.
A common theme for these conservative historical pharmacologists
is that it is easy to be conservative when there are no known effective
treatments. When your category of
treatable diseases is small – it is easy to rationalize watching the
self-limited and untreatable illnesses run their course. There was a very long period of slow progress
in therapeutics between the time of Hippocrates (460-375 BCE) and Osler (1849-1914).
Penicillin was not available to treat syphilis until 1943. Even though there
was some basic science research in pharmacology in the mid 19th
century, Paton’s review shows that potentially effective medications, in pill
form and in significant numbers did not occur until about 1920.
Apart from limited therapeutic options, the doctrine of informed
consent was either nonexistent or much less clear in earlier times. Gutheil and Applebaum (6) trace the early
evolution and consolidation as occurring in the 1950s and 1960s in the US. The earliest clear application was for
surgery and invasive treatments extending to medical treatments. In psychiatry, that also extended to
medication treatment and neuromodulation but at the time of this book whether
it was necessary for psychotherapy or not was not clear. To me one of the clearest reasons for informed
consent is the level of uncertainty in medicine. We know probabilities at the
population level but are rarely able to predict side effects and adverse
reactions at the individual level. I
have written about my approach to this problem on this blog and it is basically
a shared decision-making model where the patient is informed of the uncertainty
of both efficacy and adverse events as clearly as possible. That information
was not available to to earlier physicians. Detailed regulatory information in package
inserts is a relatively recent phenomena starting in 1968 in the US with
several modifications since then.
Ghaemi winds down his critique emphasizing diagnoses over
symptoms. He uses the bipolar disorder
example again and hedges suggesting that is it acceptable to treat symptoms sometimes
but there are no guidelines only the rather extreme criticism that by treating
diseases and developing a Hippocratic psychopharmacology we can avoid the “eclectic
mish-mash which is contemporary psychiatry.”
It is apparent to me that Hippocrates and Osler have very
little to offer present day psychopharmacologists. They both a had very
large body of patients who could not be treated. Both had limited
evidence-based pharmacopeias and both prescribed toxic compounds with no clear
guidelines or suggestion of efficacy. On diseases, syndromes, and
symptoms – the issues are much clearer these days but much is still written
about how these concepts are confusing. That is especially true in psychiatry
where decades of debate has not resulted in any more clarity. It is not as easy to separate out insomnia,
anxiety, and mood disturbance with bipolar disorder as Ghaemi makes it seem,
but treating them all at once in a single point of time is probably not the
best approach. In clinical practice at least some people have insomnia, anxiety
disorders, and depression prior to the onset of any diagnosis of bipolar
disorder. Assuming adequate time to make those historical diagnoses, there are
no clear guidelines about what should be treated first and no clinical
guidelines on when medications should be started and stopped. It all comes down to the judgement and
experience of the physician and patient consent and preference. Evidence based medicine advocates always argue for that approach but it it highly unlikely that there will be clinical trials for every scenario and the trials that do occur are often limited by inclusion and exclusion criteria. Hippocrates and Osler have no better guidance.
As therapeutics has evolved, polypharmacy has become a part
of the clinical environment of all specialists. It is common to see
patients taking multiple medications in order to treat their cumulative
diseases, even before a psychiatric medication is prescribed. Despite all of
the rhetoric – I am convinced that experts can manage polypharmacy environments
if they need to and do it with both therapeutic efficacy and minimal to no side
effects.
For the record, I agree with Ghaemi’s overall message that
you need good indications for medical treatments and that the fewer medications
used the better. Those decisions need to incorporate, current evidence,
informed consent, and frequent detailed follow up visits to reduce the risks of
inadequate treatment and adverse events. That is hard work - not helped by
guidance from the ancients or modern-day philosophers.
George Dawson, MD, DFAPA
References:
1: Ghaemi N. Hippocratic Psychopharmacology. Jun 16, 2023. https://psychiatryletter.com/hippocratic-psychopharmacology/
2: Burns SB. Civil War Disease and Wound Infection https://www.pbslearningmedia.org/resource/ms17.socct.cw.disinf/civil-war-disease-and-wound-infection/ Accessed on 06.20.2023
3: Paton W. The
evolution of therapeutics: Osler's therapeutic nihilism and the changing
pharmacopoeia. The Osler oration, 1978. J R Coll Physicians Lond. 1979
Apr;13(2):74-83. PMID: 374726; PMCID: PMC5373168.
4: Keen P. Potassium
iodide in the treatment of syphilis. Br J Vener Dis. 1953 Sep;29(3):168-74.
doi: 10.1136/sti.29.3.168. PMID: 13094013; PMCID: PMC1053890.
5: Howland MA. Nitrite (amyl and sodium) and sodium
thiosulfate. In:. Nelson LS, Howland M,
Lewin NA, Smith SW, Goldfrank LR Hoffman RS (eds). Goldfrank’s Toxicologic
Emergencies. McGraw-Hill Education; 2019. P. 1698-1701.
6: Gutheil TG,
Appelbaum PS. Clinical Handbook of
Psychiatry and the Law, 3rd ed. Lippincott, Williams and Wilkins;
2000; Philadelphia, PA: 154-157.
7: Writings of
Hippocrates. Translated by Francis Adams. Excercere Cerebrum Publications;
2018.
Graphics Credits:
William Osler aged 32: Notman
photographic archives, Public domain, via Wikimedia Commons. https://upload.wikimedia.org/wikipedia/commons/e/e9/William_Osler_1881.jpg
Hippocrates: ESM, CC BY-SA 4.0
<https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons. https://upload.wikimedia.org/wikipedia/commons/8/82/Facultat_de_Medicina_de_la_Universitat_de_Barcelona_-_Hip%C3%B2crates_de_Kos.jpg
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