[Not Available] / Randnotizen als Lebensspuren?

Are marginal notes marginal? Backed by a book from the private library of Emil von Behring the paper reflects whether annotations are peripheral sources or whether they can give some hints concerning biographical details. Behring's traces of reading are exposed and discussed by using the example of Otto Rot's Arzneimittel der heutigen Medicin (1877). The marginal notes demonstrate Behring's intensive work on hypnotics, sedativs, and analgetics which were possibly used for the therapy of others or himself. The findings will be compared to other sources of Behring's personal papers.

Pain leads the way: the development of evidence-based medicine for pain relief.

This paper describes the development of evidence based methods in pain medicine since the 1980s at the Pain Research Department of the Nuffield Department of Clinical Neurosciences, Oxford University. Pain medicine can be said to have led the way in terms of developing registers of randomized controlled trials (RCTs) and in developing appropriate methodology for assessing clinical trials and developing metanalytical techniques. This paper tells the story of that development which occurred in conjunction with the development of the Cochrane Collaboration. Pain has a larger body of evidence than many medical specialties with more than 30,000 RCTs and over 2,500 published systematic reviews. Our work continues to raise methodological challenges and a number of key ones are described: Size: We have added to the existing literature to show that small studies overestimate treatment effects. We consider studies with less than 50 participants per treatment group to be at high risk of bias. Mean pain scores: We have shown these to be unhelpful and misleading. We illustrate that response to analgesics is a U-shaped curve with a larger proportion of participants having either a poor response or a good response. Imputation: We discuss the problems of current methods. Tiers of evidence: We propose a way to assess evidence for pain studies. Duplicate publication of data can lead to inflated benefits in systematic reviews. In addition we touch on fraud, pharmaceutical company funding. The final sections cover developments in several areas of pain medicine, and suggest some developments going forward.

[Can we speak of the management of pain under the Empire?]. / Peut-on parler d'une prise en charge de la douleur sous l'Empire?

It is essential first to disregard all our knowledge and current certainties to plunge two centuries behind. Pain is recognized: physical, moral, chronic, acute. The story of analgesia finds the use of poppy, but with equal components, in variable quantity, the analgesic potion could be transformed into a poison. In the 17th century Sydenham vulgarizes the use of the laudanum known since the 16th, and the first general anesthesia will take place in 1846, we can say that, under the Empire, we are in the prehistory of the anesthesia. The positioning of the doctors and the surgeons in front of the pain is ambiguous. The pain is lived as inevitable, the first quality of the surgeon is its operating speed which allows to limit the duration of the sufferings. The practitioners in the contact of the suffering are going to try hard to develop clevernesses and subtleties to decrease this daily pain. The physical ways as baths or showers, bloodletting in the inflammatory pains, plants with antispasmodic property (valerian, peony, hemlock) and other more or less trivial pharmacological ways. On the battlefield, the ways are even more rationalized and limited, first the pharmacological ways with the laudanum and the liqueur of Hoffmann, surgery which, by a violent but brief pain, solves the problem of the traumatic pains. Dominique Larrey notices the analgesic effects of the cold, but he does not seem to have voluntarily used it. Acute drunkenness is recognized as dangerous. We are struck by the number of description of violent suicides, in particular at the Hôtel National des Invalides. Just like physical pain, moral suffering is recognized as a disease, described as melancholy but without any practical or therapeutic consequence. Under the Empire, pain is taken care of, according to the criteria of the time, an inescapable fate of which it is necessary to adapt. The field doctors try hard to decrease the pain intensity, but the university medical elites exclude the idea to overcome it totally. Nevertheless, thirty years later, general anesthesia will become possible.

Aspirin: a history, a love story.

Most pharmacists know that aspirin's origins lie with willow bark, but they may be unaware of its role in the development of the pharmaceutical industry. Evolving from salacin (the active ingredient in many plant remedies) to salicylic acid (an analgesic in its own right) to the more effective, less toxic acetylsalicylic acid, this pain reliever cornered the nonsteroidal anti-inflammatory market for more than 70 years. It helped the dye industry branch into pharmaceuticals, and is now used in multiple indications.

The rise and fall of the dolorimeter: pain, analgesics, and the management of subjectivity in mid-twentieth-century United States.

This article describes how two experimental technologies, the Hardy-Wolff-Goodell dolorimeter and the clinical trial, were involved in, and transformed by, American analgesic research. Introduced in 1940, the dolorimeter quickly became popular as an analgesic-testing technology. By the early 1950s, however, the main sources of funding for analgesic evaluation had shifted to Henry K. Beecher's clinical trial methodology. To explain both the initial popularity of the dolorimeter and its displacement by the clinical trial, I examine the demands and resources generated by those who participated-as sponsors, investigators, collaborators, or subjects-in analgesic research and evaluation. These actors linked methodological designs to material resources, social interactions, and epistemological values, changing how pain-relieving efficacy both should and could be evaluated. They also mediated the interaction between specific expectations of, and investments in, analgesic evaluation and broader ideas about the reliability of drug evaluation and the subjectivity of pain. My analysis thus connects the changing social and material configuration of analgesic evaluation to the rise of clinical trials as well as increasingly psychological understandings of pain in order to frame the rise and fall of the dolorimeter.

[A short history of anti-rheumatic therapy--V. analgesics]. / Piccola storia della terapia antireumatica--V. Gli analgesici.

The pharmacological treatment of pain has very ancient origins, when plant-derived products were used, including mandrake extracts and opium, a dried latex obtained from Papaver somniferum. In the XVI and XVII centuries opium came into the preparation of two compounds widely used for pain relief: laudanum and Dover's powder. The analgesic properties of extracts of willow bark were then recognized and later, in the second half of the XIX century, experimental studies on chemically synthesized analgesics were planned, thus promoting the marketing of some derivatives of para-amino-phenol and pyrazole, the predecessors of paracetamol and metamizol. In the XX century, nonsteroidal anti-inflammatory drugs were synthesized, such as phenylbutazone, which was initially considered primarily a pain medication. The introduction on the market of centrally acting analgesics, such as tramadol, sometimes used in the treatment of rheumatic pain, is quite recent.

Taming the ketamine tiger. 1965.

Pharmacologic actions of CI-581, a chemical derivative of phencyclidine, were determined in 20 volunteers from a prison population. The results indicate that this drug is an effective analgesic and anesthetic agent in doses of 1.0 to 2.0 mg per kilogram. With intravenous administration the onset of action is within 1 min and the effects last for about 5 to 10 min, depending on dosage level and individual variation. No tachyphylaxis was evident on repeat doses. Respiratory depression was slight and transient. Hypertension, tachycardia, and psychic changes are undesirable characteristics of the drug. Whether these can be modified by preanesthetic medication was not determined in this study. Recovery from analgesia and coma usually took place within 10 min, although from electroencephalographic evidence it may be assumed that subjects were not completely normal until after 1 to 2 h. No evidence of liver or kidney toxicity was obtained. CI-581 produces pharmacologic effects similar to those reported for phencyclidine, but of shorter duration. The drug deserves further pharmacologic and clinical trials. It is proposed that the words "dissociative anesthetic" be used to describe the mental state produced by this drug.

The development of new analgesics over the past 50 years: a lack of real breakthrough drugs.

Fifty-nine drugs identified as analgesics were introduced from 1960 to 2009 and remain in use. Seven can be regarded as having novel molecular targets; however, only one, sumatriptan, was sufficiently effective to motivate the introduction of many similar drugs acting at the same target (triptans). Publication productivity in the area of pain grew exponentially during this period. Pain-related publications on morphine were dominant among other analgesics. Very intensive research efforts directed at diverse molecular targets related to pain mechanisms produced thousands of publications, but those efforts have not yet yielded new analgesics with sufficient effectiveness to change the share of publications on opioids or nonsteroidal antiinflammatory drugs. Morphine and aspirin, introduced for the treatment of pain more than a century ago, continue to dominate biomedical publications despite their limited effectiveness in many areas (e.g., neuropathic pain) and multiple serious adverse effects. The present assessment reveals the lack of real breakthroughs in analgesic drug development despite intense research efforts. Possible factors contributing to the apparent drought of novel analgesics are discussed.

Transient receptor potential channels in pain and inflammation: therapeutic opportunities.

In ancient times, physicians had a limited number of therapies to provide pain relief. Not surprisingly, plant extracts applied topically often served as the primary analgesic plan. With the discovery of the capsaicin receptor (transient receptor potential cation channel, subfamily V, member 1 [TRPV1]), the search for "new" analgesics has returned to compounds used by physicians thousands of years ago. One such compound, capsaicin, couples the paradoxical action of nociceptor activation (burning pain) with subsequent analgesia following repeat or high-dose application. Investigating this "paradoxical" action of capsaicin has revealed several overlapping and complementary mechanisms to achieve analgesia including receptor desensitization, nociceptor dysfunction, neuropeptide depletion, and nerve terminal destruction. Moreover, the realization that TRPV1 is both sensitized and activated by endogenous products of inflammation, including bradykinin, H+, adenosine triphosphate, fatty acid derivatives, nerve growth factor, and trypsins, has renewed interest in TRPV1 as an important site of analgesia. Building on this foundation, a new series of preclinical and clinical studies targeting TRPV1 has been reported. These include trials using brief exposure to high-dose topical capsaicin in conjunction with prior application of a local anesthetic. Clinical use of resiniferatoxin, another ancient but potent TRPV1 agonist, is also being explored as a therapy for refractory pain. The development of orally administered high-affinity TRPV1 antagonists holds promise for pioneering a new generation of analgesics capable of blocking painful sensations at the site of inflammation and tissue injury. With the isolation of other members of the TRP channel family such as TRP cation channel, subfamily A, member 1, additional opportunities are emerging in the development of safe and effective analgesics.

The rise and demise of pain exterminator Thomas S. McNeil: Every rose has its thorns.

United Brethren minister Thomas S. McNeil formulated an analgesic nostrum in 1848, most likely from opium, alcohol, ether, and other proprietary ingredients. Massaged on externally as a pain liniment, his so-called pain exterminator could also be mixed in sweetened water and imbibed as an analgesic, antitussive, and antidiarrheal. A familiar antebellum remedy for both Union and Confederate forces in the Civil War, McNeil's Pain Exterminator would be manufactured by McNeil's pastor and then successors, for more than a half-century after McNeil's accidental drowning in 1874.

The Anesthesiologist's Armamentarium: From Recreation to Medication and Back.

For millennia, mankind has sought a means of altering consciousness, often aided by naturally occurring elements. Psychotropic substances have been an integral part of spiritual, medicinal, and recreational aspects of life. The origin of anesthesiology stems directly from the use of recreational drugs; early inhaled anesthetics were first used as a means of entertainment. Hence, it is no surprise that many medications in the anesthesiologist's armamentarium are diverted for recreational use. In the 172 years following the first successful public demonstration of ether anesthesia, many drugs with abuse potential have been introduced to the practice of anesthesia. Although anesthesiologists are aware of the abuse potential of these drugs, how these drugs are obtained and used for recreational purposes is worthy of discussion. There are articles describing the historical and recreational use of specific drug classes. However, to the best of our knowledge, this is the first comprehensive review focusing on the breadth of drugs used by anesthesiologists.

The Reincarnation of Methoxyflurane.

Methoxyflurane was an inhaled agent commonly used for general anesthesia in the 1960s, but its clinical role gradually decreased in the 1970s because of reports of dose-dependent nephrotoxicity. In 1999 its manufacturer, Abbott Laboratories, discontinued distribution of methoxyflurane in the United States and Canada. Outside of North America, however, methoxyflurane has been reborn as an inhaled analgesic used for pain relief in the prehospital setting and for minor surgical procedures. First used in Australia and New Zealand, and subsequently in over thirty-seven other countries, low concentrations of methoxyflurane are administered with a hand-held inhaler which provides conscious sedation, so that patients can self-assess their level of pain and control the amount of inhaled agent. The Penthrox inhaler, originally developed in Australia after several other hand-held vaporizers were tried, is currently being used worldwide as a portable and disposable self-administered agent delivery system. Methoxyflurane-induced nephrotoxicity continues to be a major concern, but with cautious administration of recommended doses methoxyflurane has been established as a remarkably safe analgesic agent with minimal side effects for patients in need of rapid and potent pain relief.

Problems with Developments of Breakthrough Analgesics: Recent History via Scientometric Analysis.

This study evaluated 13 specific topics representing molecular targets for pain during the period 1982-2016. The evaluation was performed by measuring research efforts via a scientometric approach on one hand and by assessing successful outcomes of these efforts, as indicated by the development of FDA-approved analgesics, on the other. A number of new analgesics were developed during this period, some of them with a completely novel mechanism of action. However, the main problems with approved drugs, as well as drug candidates, are relatively low levels of clinical superiority in effectiveness and narrow spectrum of action in different types of pain, compared to opioids or NSAIDs. The most interesting feature of the scientometric analysis of the 13 analgesic discovery topics is the long-lasting growth in the number of articles. The total number of all PubMed articles persistently increased over each of many 5-year periods in every topic even without any success in the development of new analgesics. Scientometric indices of NIH-supported studies are not better at predicting successes in the discovery of new analgesics than indices applied to all publications without regard to the category of support. Thus, even the highly valued NIH-based funding system did not demonstrate a clear advantage for discovery efforts centered on pain-related molecular targets. The evaluated research efforts did not result in breakthrough analgesics that could demonstrably affect the current use of opioids or NSAIDs. Orthodox thinking-both in research and research funding-might be the main reason for the absence of breakthrough analgesics.

Caelius Aurelianus' textbook on medicine of the fifth century: rhythm in asthma, pain, and drug effects.

Caelius Aurelianus was a Greek-Roman physician in the fifth century. He translated the work of Soranus from Ephesus into Latin and extended the medical knowledge of his time in several textbooks. His book "De Morbis acutis et chronicis" was reprinted many times up to the 19th century and served as the handbook for physicians. Aurelianus aready described in detail the rhythmic pattern - daily and seasonally - of asthma. Tooth pain was also first described by Caelius Aurelianus to peak at night and that drugs were not able to fully suppress the pain, a first indication of chronopharmacology.

Perry Davis' Pain Killer: America's First Nationally Advertised Drug for Analgesia?

Perry Davis' Pain Killer, a combination of opium, alcohol, and other substances, was formulated in 1839 and marketed successfully worldwide within 4 decades as both an internal and external pain remedy.