From Addiction to Wonder Drug, Will Opioids Win this Battle?

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Pain treatment is a subject that has garnered ample attention from the medical fraternity since the days of recorded medical history. From the times of Sushruta till the era of IoT, treating pain in its various formats has kept researchers’ interest alive. Opium in its natural and synthetic forms has been used in the past to… (Featured image source: http://maxpixel.freegreatpicture.com/Garden-Poppy-Raw-Pods-Papaver-Capsules-Opium-87112)

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Pain treatment is a subject that has garnered ample attention from the medical fraternity since the days of recorded medical history. From the times of Sushruta till the era of IoT, treating pain in its various formats has kept researchers’ interest alive.

Opium in its natural and synthetic forms has been used in the past to treat pain. Opiate, an alkaloid derived from the opium poppy, was once a popular ingredient in making painkillers. However, with regulations coming in the way, scientists have opened up the world of molecules and chemicals to replicate opiate and create its laboratory twin called opioid.

Structure of heroin. Image source: https://en.wikipedia.org/wiki/Morphine

Structure of heroin.
Image source: https://en.wikipedia.org/wiki/Morphine

Opioids (sometimes called opiates as it replicates its natural counterpart) are powerful pain-reducing forms of medicine that include prescription oxycodone, hydrocodone and morphine. Similar to their naturally existing cousins, opioids offer benefits and also package along potentially serious risks when consumed in wrong dosages.

How do opioids work?

When administered, opioids bind themselves to opioid receptors in the body’s central nervous system, the gut and certain other parts of the body, thus increasing tolerance for pain. Prolonged use of opioids leads one towards tolerance for and dependence on the drug. In worse case scenarios, the user may get addicted, but it isn’t a common occurrence.

The first opiate drug to be isolated was morphine sometime between 1803 and 1805 by a German pharmacist Friendrich Sertürner. This is generally believed to be the first isolation of an active ingredient from a plant. Subsequently, Merck marketed it commercially in 1827. Morphine was more widely used after the invention of the hypodermic syringe in the 1850s. More than 200 years later, morphine is still among the most powerful painkillers we know, and it remains an essential tool in medicine for controlling severe pain – despite its side-effects.

text1Soon after Sertürner’s death in 1841, chemists started looking for opioid compounds that could retain morphine’s painkilling properties but removed the harmful side-effects. These included tolerance or reduction of the drug’s effect after repeat doses, addiction, constipation and respiratory depression that can kill victims of overdose.

In 1873, diacetylmorphine became the first derivative of morphine to be ever synthesized into its acetylated form. It was independently re-synthesized by chemists at Bayer Pharmaceutical Company in 1896, which soon started to sell it under the brand name ‘heroin’ for the supposedly heroic impact it had on users. However, it continued to carry morphine’s addiction issue.

Faced with lack of effective drugs to help patients in pain, doctors in the mid-1980s prescribed powerful opioids such as oxycodone – a close structural relative to morphine – for chronic pain. The powerful painkilling effect of these compounds makes them exceptional drugs for short-term control of acute pain, but their side-effects make them a high-risk option for chronic conditions.

FDA approved an oxycodone drug, Xtampza ER, which was an extended-release opioid analgesic that was used to treat severe pain which required round the clock, long-term opioid treatment. The drug was prescribed to patients for whom alternative pain treatments proved inadequate. In fact, Massachusetts-based Collegium Pharmaceutical has been engaged in developing abuse-deterrent opioids and owns a diverse portfolio with 18 granted patents in this space.

Structure of Pethidine Image source: https://en.wikipedia.org/wiki/Pethidine

Structure of Pethidine
Image source: https://en.wikipedia.org/wiki/Pethidine

In 1996, Purdue Pharma introduced a new drug — a time-released formulation of oxycodone, an opioid painkiller. OyxContin, as it was called, was touted as having a low risk of addiction, while the results seemed otherwise as the drug seemed to produce a heroin-like high and some patients showed signs of addiction. By 2004, the controversy over OxyContin blew into a crisis where doctors found it increasingly difficult to treat patients in pain – one for fear of its side effects, and second due to their inability to quell patients’ fears about ingesting opioids. In a contrary situation, OxyContin had entered into the black market and was said to be misused. The Los Angeles Times carried an investigative story on this in its article titled – ‘You Want A Description Of Hell?’ Oxycontin’s 12-Hour Problem – on May 5th, 2016.

Chemists revisited opium poppy to test the effects of thebaine. In a series of oxidation and reduction steps, chemists at the University of Frankfurt Martin Freund and Edmund Speyer synthesized oxycodone from thebaine in 1916. But the tolerance, addiction and abuse liabilities typical of the opioids remained. The properties stayed on in various synthetic opioids such as meperidine (pethidine) discovered in 1939, and fentanyl which was discovered in 1960. Scientists stripped the morphine molecule back to its nitrogen-containing six-membered ‘piperidine’ ring before adding various structural embellishments.

Activating the body’s painkillers

text2Parallely, scientists were also exploring the biology of body–opioid interaction. In the 1970s, they seem to have discovered a way to crack the side-effect problem. In 1977, Hans Kosterlitz and his team from the University of Aberdeen proved that the body produced its own pain-killing ‘endogenous opioids’, which activated not one, but a series of opioid receptor subtypes. This discovery raised the tantalizing possibility that if scientists could come up with drugs that could selectively target one of the four opioid receptor subtypes – perhaps by using or adapting one of the endogenous opioids, they could separate the painkilling effect from side-effects.

But it didn’t turn out that way. Morphine itself, as well as fentanyl, turned out to be very selective for one of the subtypes, the μ-opioid receptor. Hitting only that subtype seemed to trigger both the good and the bad effects. Hope evaporated. The two sides of opioid behavior seemed inseparable.

FDA approved Arymo ER (morphine sulfate extended-release tablets), an extended-release opioid analgesic to treat pain severe enough to require daily, round-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Arymo ER is the eighth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties and is manufactured by Egalet Ltd. It has been patented against US9044402 and US9549899.

List of important FDA-approved opioid drugs between 2014 and 2016. Source: Electronic Orange Book of FDA (http://www.accessdata.fda.gov/scripts/cder/ob/)

List of important FDA-approved opioid drugs between 2014 and 2016.
Source: Electronic Orange Book of FDA (http://www.accessdata.fda.gov/scripts/cder/ob/)

Searching for a safe opioid

text3Whether or not opioids are found to be effective for long-term treatment of chronic pain, their issues related to addiction and overdose, and various adverse effects will continue to make these highly beneficial products less than ideal treatment agents. Innovation of similarly effective, but safer, drugs is also a key part of solving the main opioid addiction problem.

The need of the day is to create a non-addictive opioid drug that is abuse-deterrent or abuse-resistant and should provide safe and effective pain relief. The drugs that are needed should not only be targeting opioid receptors but should also block addictive effect induced by normal opioids. The new opioid drugs should also have opioid receptors selectivity and substantial signaling bias. They also should not cause respiratory depression which is mainly associated with deaths.

In the second part of this series on Opioids, our blogger will analyze popular medication to treat withdrawal symptoms from opiates, and associated patented medication.

Disclaimer: Biological targets for the development of new abuse-deterrent opioids are beyond the scope of this blog but remain an important goal for future research.

Dr. Nalini Mohan Koutha
Dr. Nalini Mohan Koutha

Dr. Nalini is a Pharmaceutical patent expert and has extensive experience as a technical and Intellectual Property Specialist in Generic Pharmaceutical manufacturing. His quest for analytical thinking extends to his deep interest in philately.


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