Showing posts with label Hippocrates. Show all posts
Showing posts with label Hippocrates. Show all posts

Tuesday, June 27, 2023

Hippocrates the Projective Test

 



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