The Evolution of Opioids in Anesthesia: A Historical Overview with Paul Janssen’s Contribution

The use of opioids in anesthesia has a rich and intricate history that has evolved over the centuries. This article provides a chronological overview of the development of opioids in anesthesia, highlighting key milestones and their impact on medical practice, including the groundbreaking contributions of Dr. Paul Janssen.

Early History

  • Ancient Methods: In ancient times, patients consumed various concoctions of poppy seed pod juice mixed with brandy, wine, or the juices of mandragora, hemlock, hemp, or henbane to alleviate surgical pain, with limited success.
  • Legal Consequences: Some countries, like France, condemned physicians attempting anesthesia with these potions, leading to legal consequences.
  • Sleeping Sponges: “Sleeping sponges” soaked with opium, mandragora, henbane root, and more were used in the Middle Ages, with patients instructed to breathe through them. However, this method had limited effectiveness.

Opioids in Ancient Times

  • Opioids, derived from the poppy plant, Papaver somniferum, have been used for thousands of years to relieve pain and induce sleep. Ancient Egyptians used opium for pain relief, and Avicenna, an 11th-century Persian physician, described opium as a powerful substance for inducing stupor.

Opioids in the Nineteenth and Early Twentieth Centuries

  • 19th Century Advancements: The 19th century saw advancements in the controlled administration of opioids. Serturner isolated morphine from opium in 1803, and other innovations followed.
  • Intravenous Experiments: In 1656, Christopher Wren experimented with intravenous opium solutions, but it did not lead to significant changes in anesthesia practice.
  • Laudanum: In the 18th century, tincture of raw opium, known as laudanum, was used for analgesia.

Table 1: Key Opioids in the Nineteenth and Early Twentieth Centuries

OpioidYear of DiscoveryKey Developments
Morphine1803Isolated from opium in 1803
Codeine1832First isolated in 1832 in France
Heroin1874Synthesized by Bayer in 1874

Balanced Anesthesia and the Introduction of Meperidine

  • Balanced Anesthesia Concept: The concept of “Balanced Anesthesia” emerged in the early 20th century, aiming to balance different components of anesthesia, including analgesia.
  • Meperidine’s Synthesis: Meperidine (pethidine) was synthesized in Germany in 1932 and became available in the U.S. in 1946.
  • Role in Anesthesia: Meperidine played a crucial role in supplying analgesia during anesthesia, particularly with nitrous oxide-oxygen techniques.

Table 2: Introduction of Meperidine

OpioidYear of SynthesisKey Developments
Meperidine1932Synthesized in 1932, introduced in anesthesia in 1946

Germany and World Events Impact Anesthesia

  • World War Influence: World War I and the political events leading to World War II prompted German researchers to synthesize new opioid analogues with strong analgesic activity.
  • Semi-Synthetic Opioids: Several semi-synthetic opioids, such as oxymorphone, oxycodone, hydrocodone, hydromorphone, meperidine, and methadone, were developed between 1914 and 1937.
  • Post-War Confiscation: The Allies confiscated German patents after World War II, delaying the introduction of these opioids in the U.S. and the UK.
  • European Acceptance: In contrast, European countries had early access to these opioids, fostering their acceptance in medical practice.
  • Advancements in Anesthesia: The post-war period saw the development and adoption of intravenous opioids and non-opioid anesthetic compounds, leading to advancements in anesthesia practice.

Table 3: Key Opioids and Their Year of Synthesis

OpioidYear SynthesizedChemist and/or Company
Oxycodone1916Freud and Speyer, Frankfurt
Hydrocodone1920Mannich and Lowenheim
Hydromorphone1924Launched by Knoll, 1926+
Meperidine1932Eisleb, launched by IG Farber 1938–1939+
Methadone1937Launched by IG Farber, 1939

Paul Janssen’s Revolutionary Contribution

  • Dr. Paul Janssen: Dr. Paul Janssen, a Belgian pharmacologist and entrepreneur, made an indelible mark on the field of anesthesia and analgesia.
  • Fentanyl’s Synthesis: In the 1950s, Janssen’s team synthesized fentanyl, an extraordinarily potent opioid, which quickly gained recognition for its remarkable analgesic properties.
  • Fentanyl’s Impact: Fentanyl’s potency revolutionized anesthesia by enabling lower dosages and reducing side effects, making it especially valuable in cardiac surgery and other procedures.
  • Janssen’s Company: Janssen’s pharmaceutical company, Janssen Pharmaceutica, played a pivotal role in the distribution and popularization of fentanyl worldwide.

Table 4: Fentanyl – A Game Changer

1959Paul Janssen and his team at Janssen Pharmaceutica synthesize fentanyl.
1960sFentanyl’s potent analgesic properties revolutionize anesthesia.
1968Janssen Pharmaceutica introduces fentanyl as Sublimaze.

Re-introduction of High-Dose Opioid Anesthesia

  • Revival of High-Dose Anesthesia: The practice of high-dose opioid anesthesia saw a revival in the 1960s, notably with morphine and fentanyl.
  • Cardiac Anesthesia Changes: Patients with severe cardiac valvular disease were observed to require large doses of morphine for tracheal tube tolerance, significantly changing the practice of anesthesia for severe cardiac disease.
  • Fentanyl’s Popularity: Fentanyl gained popularity in Europe and the United States for its potency, ease of administration, and faster postoperative recovery.

Table 5: Re-introduction of High-Dose Opioid Anesthesia

ApproachKey ElementsImpact
High-Dose Morphine AnesthesiaLarge doses of morphine for tracheal tube toleranceSignificantly changed cardiac anesthesia practice
High-Dose F

entanyl Anesthesia | Use of high-dose fentanyl with improved potency and safety | Replaced high-dose morphine in cardiac and non-cardiac surgery |
| Development of Sufentanil, Alfentanil, and Remifentanil | More potent opioid compounds | Expanded options for opioid anesthesia |

The Birth of Remifentanil and Target-Controlled Infusion (TCI)

  • Ultra-Short-Acting Opioids: In the late 1980s, ultra-short-acting opioids like remifentanil were introduced.
  • TCI Development: The development of computerized pharmacokinetic-driven infusion devices and better drugs renewed interest in Total Intravenous Anesthesia (TIVA).
  • Remifentanil’s Approval: Remifentanil, approved in 1996, represented a significant leap forward in opioid anesthesia, providing unparalleled control and predictability during surgery.
  • Precision with TCI: Target-Controlled Infusion (TCI) systems, including TCI of opioids, enhanced the precision of anesthesia administration.

Table 6: Remifentanil and TCI

1980sIntroduction of ultra-short-acting opioids like remifentanil.
1996Remifentanil approved, offering precise control in anesthesia.
Late 1990sTarget-Controlled Infusion (TCI) systems for opioid delivery gain popularity.

Impact on Anesthesia Practice

  • Regional Differences: In the United States, there was initial resistance to these innovations due to established practices, while Europe saw more rapid adoption, especially in Total Intravenous Anesthesia (TIVA) for cardiac and non-cardiac surgeries.
  • Pain Management Shift: Opioid innovations influenced perioperative pain management, shifting from intramuscular opioids to more precise intravenous administration.
  • Patient-Controlled Analgesia: Patient-controlled analgesia (PCA) became a common method for self-administered pain relief.

The evolution of opioids in anesthesia has been marked by a series of innovations, from early, rudimentary methods to the development of balanced anesthesia and the introduction of specific opioids like meperidine. However, it was the pioneering work of Dr. Paul Janssen, particularly the synthesis of fentanyl, that stands out as a revolutionary contribution that transformed anesthesia practice. The historical journey of opioids has greatly shaped modern anesthesia practices, leading to enhanced patient care and safety.


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