Understanding Opioid Actions, Pain and Analgesia: A Tribute to Dr. Gavril Pasternak.

This special issue is a tribute to our mentor, colleague and friend, Gavril W. Pasternak, MD, PhD. Homage to the breadth and depth of his work (~ 450 publications) over a 40 career in pharmacology and medicine cannot be captured fully in one special issue, but the 22 papers collected herein represent seven of the topics near and dear to Gav's heart, and the colleagues, friends and mentees who held him near to theirs. The seven themes include: (1) sites and mechanisms of opioid actions in vivo; (2) development of novel analgesic agents; (3) opioid tolerance, withdrawal and addiction: mechanisms and treatment; (4) opioid receptor splice variants; (5) novel research tools and approaches; (6) receptor signaling and crosstalk in vitro; and (7) mentorship. This introduction to the issue summarizes contributions and includes formal and personal remembrances of Gav that illustrate his personality, warmth, and dedication to making a difference in patient care and people's lives.

Why Would the Pope Have A Private Audience with Anesthesiologists? The Origin of the "Doctrine of Double Effect" and Its Application to Pain Control.

Sunday February 24, 1957 was a pivotal day in the history of anesthesiology and pain medicine. The leader of the Roman Catholic Church, Pope Pius XII met with anesthesiologists attending an international symposium sponsored by the Italian Society of Anesthesiologists entitled, "Anesthesia and the Human Personality". The purpose of this audience was to seek clarification about the use of opioids at the end of life to reduce suffering. Three questions had been formulated from the previous year's Italian Congress of Anesthesiologists and sent to the Holy See on this specific issue. The Pope responded during this audience remarking that there was no moral obligation to withhold pain medication that could elevate suffering. He further remarked that the suppression of consciousness that can occur with opioids was consistent with the spirit of the Christian gospels. Finally, he also stated that it was not morally objectionable to administer opioids even if it might shorten life. The moral philosophy behind these answers is the doctrine of double effect. In essence, administering medications to relieve pain, the primary effect, may also hasten death, the unintended secondary effect. In seeking answers to these questions, the Italian anesthesiologists were at the forefront of a larger and ongoing debate. As new therapies are developed that may have unintended consequences, when it is morally permissible to use them?

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.

Peggy's Pain and the Creation of Gone With the Wind.

Margaret Mitchell (1900-1949), author of the best-selling novel Gone With the Wind had chronic, widespread pain for most of her adult life. She was accident prone and sustained injuries leading to unexpectedly prolonged periods of recovery and had unusual illnesses that puzzled her physicians. Starting at an early age, Mitchell, or "Peggy" as she was called by family and friends, had a burning ambition to be a writer, and her painful, chronic illness created conditions that allowed her to achieve this goal. In this report, the details of her health problems are reviewed. During her life, her diagnoses were problematic and remain so now, but would most likely include fibromyalgia and irritable bowel syndrome.

[Medicine and pain: history of a relationship]. / Médecine et douleur: histoire d'une relation.

The vagueness surrounding the terms "suffering" and "pain" invites us to reflect upon the relationships between a physiological fact and a constitutive dimension of the human experience. History shows a constant medical preoccupation facing pain as a clinical symptom, endowed with a rich terminology, many ways of relieving pain and speculations on its diagnostic value. In the contemporary era, pain is revealed as a proper scientific object. This development accompanies an evolution of medical practices on pain that, far from representing continuous progress, adopts rather uneven and sometimes surprising outlines. As a whole, medicine is characterised by an important ambivalence when confronting pain, valuating it as an useful auxiliary or on the contrary denying the painful experience.

[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.

Some (mostly Scottish) local anaesthetic heroes.

In 1884 a young Viennese doctor, Carl Koller, was the first to recognise the significance of the topical effects of the alkaloid cocaine and thus introduced drug-induced local anaesthesia to clinical practice. Most subsequent development took place in Europe and the United States, with British interest not becoming apparent for over twenty years. This is surprising because a number of doctors working in Scotland, or with Scottish connections, had made important contributions to the earlier evolution of local anaesthetic techniques. This paper reviews the relevant work of James Young Simpson, Alexander Wood, James Arnott, Benjamin Ward Richardson and Alexander Hughes Bennett and the role of John William Struthers in the later promotion of the techniques.

A history of intraspinal analgesia, a small and personal journey.

INTRODUCTION: There is a large and robust literature on the spinal use of opioids and non-opioids alike, but unless one is my age and older, very few persons know how we got here. This small history offering tells us how we got to where we are today regarding the science, clinical uses, and management of intraspinal analgesia. METHODS: I have reviewed the literature bases of Google Scholar and the National Library of Medicine using the key words: history, opium, spinal analgesia, spinal morphine, intrathecal (IT), opioid receptors, endogenous opioids, IT delivery of opioids, and IT side-effects/complications. RESULTS: In this personal review of the history of intraspinal analgesia, I relate my own early and later experiences of the science and clinical uses of intraspinal morphine, other opioids, and non-opioids alike to a historical context. This review outlines a rather small history of opium, the historical use of opium and its various compounds, and the search for and answer to the question, "why was the poppy created for wondrous medicinal uses for mankind?" This search led to the discovery of endogenous opioid like chemicals, the discovery of opiate receptors for these endogenous opioids, the first uses of intraspinal opioids in animal models and man, and, finally, our understanding of the appropriate and inappropriate clinical uses of intraspinal analgesia. Within this paper, I acknowledge the works of my colleagues and the "heroes" who have laid the foundation for our understanding of intraspinal analgesia. CONCLUSIONS: The history of the use of intraspinal analgesia is rich and guides us to advance the science and clinical use of intraspinal analgesia without reinventing the wheel.

The business of pain medicine: the present mirrors antiquity.

The practice of pain medicine is often considered a fledgling field, as are the economic, business, and related ethical issues associated with providing these services. This article first traces the history of pain care and its relationships to industry and business, as well as the impact of government regulations over the ages. The authors challenge the view that the commonly discussed health care issues facing pain medicine are new by tracing the business and regulatory-related antecedents of pain care practice from the first through 21st century. The controversies associated with the practice of delivering pain-related health care services in an ethical manner are discussed with specific reference to the early work of clinicians, health care activists, and policy makers. The early activities of noteworthy individuals such as Pliny the Great, Hua T'o, John Locke, Benjamin Franklin, Oliver Wendell Holmes Sr., William Morton, Henry and William James, Heinrick Dresser, and other recent health care activists are reviewed. Issues of practitioner liability and regulatory restrictions on practice are also discussed in a historical context. The authors conclude that familiar ethical dilemmas commonly arose in past centuries, and history may be repeating itself with respect to the concerns now being discussed within our field. These arguments are reflected against the pain medicine Ethics Charters of the American Academy of Pain Medicine throughout the document. Finally, we outline the challenges for the present and future. With an understanding of these eight historical events as a backdrop, we may be at an opportune time to better address these issues in a manner that could provide the most effective pain care in our society.

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.