Evolution of the Spinal Delivery of Opiate Analgesics

Delivery System

The notion of delivering agents into the body led to the development of hollow needles and plunger/barrel systems. Several individuals are credited in the 19th century with contributing to various degrees to the final product, which appeared around 1870: a calibrated glass barrel with a removable needle attached to the barrel and a tapered nose, introduced by Hermann Woolf Leur (i.e., a Leur fitting) and permitting sterilization and minimizing leakage ( ).

Drugs

It was appreciated that chewing of coca leaves by Peruvian Indians led to oral numbness ( ). Niemann in , using differential solubility, produced pure white crystals which numbed the tongue. He named the product cocaine. Halsted and Hall in the United States demonstrated its clinically efficacious regional or local anesthesia by perineural delivery to most of the somatic nerves, and its MOA was considered to be “conduction anesthesia” ( ).

Opium or “poppy tears” is harvested from the dried latex of the opium poppy. The word itself is derived from the Greek “opus,” which means vegetable juice. An alternative name for opiates (narcotics) is derived from the Greek word “narco,” which means to numb or deaden. Opium was most likely used farther back than can be dated, at least as far back as 4200 BC, and appears to have been cultivated for ritualistic functions, at least as far back as the Neolithic Age ( ). Opium was enjoyed by the Sumerians, who called it Hul Gil, the joy plant. ¹

1 http://www.poppies.ws/poppies/opium-effects.html

The Sumerians passed it on to the Assyrians, who shared it with the Babylonians, who then gave it to the Egyptians. ²

2 http://opioids.com/timeline/

It was used in various ways, including eating it, drinking it in teas, and smoking it; moreover, it was used for many differing purposes, including insomnia, headache, and, of course, pain and anesthesia. Serturner in 1803 isolated an alkaloid product in alcoholic extracts of the poppy and, by differential solubility, identified pure crystals that led to sedation in animals and humans. He christened this fraction morphine, from Morpheus, the Greek god of sleep and dreams ( ). Though opiate concoctions such as laudanum were typically given orally, the development of purified, water-soluble morphine ( ) and the introduction of hypodermic-needle technology permitted delivery of opiates at specific sites for pain alleviation.

Spinal Anesthesia

In the late 19th century the dangers of general anesthesia (ether, chloroform) were widely appreciated. The utility of cocaine for regional procedures (perineural block and infiltration) was well known ( ). As August Bier noted, “ General anesthesia is dangerous, and its scope has fortunately and none too soon been greatly reduced by the advent of Schleich’s infiltration anesthesia and Oberst’s regional method of cocainization. However, for truly major operations, those two approaches have only limited application. I have therefore sought to render large areas of the body insensitive to pain by cocainizing the spinal cord ” ( ).

This therapeutic use of intrathecal (IT) delivery was enabled by water-soluble purified cocaine; the syringe and needle; and the extensive work performed by Heinrich Quincke characterizing the lumbar IT tap ( ). In his well-known work, Bier and his assistant Hildebrand demonstrated the robust, reversible anesthesia resulting from the spinal delivery ( ). It was reported in the Lancet ( ) that “by January 1901 there has been very nearly 1000 publications on the use of medullary narcosis…” This was proof of the rapid spread of this therapeutic procedure around the world. by January 1901 there has been very nearly 1000 publications on the use of medullary narcosis… This was proof of the rapid spread of this therapeutic procedure around the world

Neuraxial Morphine

While the primary agents employed for neuraxial delivery were molecules that produced conduction block (e.g., local anesthetics), it was not lost on early clinicians that other agents might prove useful. Alexander Wood, considered by many to be among the first to use hypodermic drug delivery, published early descriptions of delivering drugs (water-soluble muriatic morphine, e.g., morphine HCl) for pain relief through the skin using a hollow needle ( ). Following the Civil War, wounded soldiers were discharged and issued syringes with morphine tablets to manage pain that was secondary to nerve injury and amputation ( ). Accordingly, it is not unexpected that morphine, compatible with delivery by a syringe and needle, would be considered for use by the IT route.

Shortly after the initial report by Bier showing the clinical utility of IT cocaine, the Romanian surgeon Racoviceanu-Pitesti first reported the use of morphine for IT analgesia ( ). In 1901 Rudolph Matas, a vascular surgeon in New Orleans, supplemented his spinal anesthetics of synthetic local anesthetics for surgical anesthesia with morphine. In 1901 a Japanese physician, Otojiro Katagawa, reported the first use of IT morphine solely for uncontrolled back pain ( ). He injected 10 mg of morphine and local anesthetic into two patients, and both achieved superb pain relief. Given the quantity, likely his patients survived without respiratory depression because most of this solution leaked out into the epidural space. But after these early reports the neuraxial delivery of drugs, other than local anesthetics, largely disappeared from clinical therapy.

Preclinical Studies on the Analgesic Actions of Neuraxial Opiates

During the latter half of the 20th century an increasing interest in the MOA of opiate analgesia developed. At this time, three important observations were made.

• 1.

  By the late 1960s the specific and precise pharmacology of the biological effects of opiates in in vitro and in vivo assays led to the conclusion that the opiate agents were acting though specific site(s) (receptors) ( ). This data laid the groundwork for subsequent studies describing the presence of specific high-affinity binding sites in brain tissues for opiates, using stereospecific displacement of a radioligand ( ).

• 2.

  Early work on the clinical actions of opiates emphasized their effects on the emotive components of pain behavior, with their actions described as the pharmacological equivalent of a prefrontal lobotomy, in that the pain sensation remained but the affective component was missing ( ). Consistent with the presumed actions on affect, opiates were found to have a potent analgesic effect that was mediated through an action at specific brain sites, notably the periaqueductal gray, and most importantly when delivered by local microinjection of morphine through stereotactically implanted microinjection cannulae. These effects were dose dependent, site specific, and naloxone reversible in species from the mouse through primates ( ).

• 3.

  While opiates indeed had a potent effect in the brain, early work showed that morphine could also block spinal reflexes ( ) and reduce the firing of spinal neurons ( ) in a spinally transected animal. The question of whether or not these local actions of opiates on spinal function had any direct bearing on the organized response of the intact and behaving animal to strong and otherwise aversive stimuli was absent at this point. The subsequent preclinical demonstration that IT opiates specifically blocked nociceptive responses led to the conclusion that opiates with an action limited to the spinal cord would have behaviorally relevant effects in animals ranging from mice through primates ( ). In these studies, opioids, bolused into the IT space demonstrated inhibition of spinal nociceptive reflexes such as tail flick ( ) and skin twitch ( ), as well as more organized responses to nociception, as in responses to hot plate, pinch, or shock titration, in multiple species ( ). Studies also confirmed that nonnociceptive reflexes were not diminished with the spinal delivery of opiates; autonomic reflexes and light touch were unaffected ( ), and parturition was not altered in rats and rabbits, which opened the way for the use of spinal opiates for labor and delivery ( ).