Non-addictive painkillers: Recent Research and Development

Braden Royer
DuBois Area High School
Honors BioChemistry
Mr. Keith

Abstract

Within modern science and medicine lies some pharmaceutical drugs

with incredible, life-changing effects. Painkillers are no exception, but have
some very controversial side effects and are of the most abused drugs in the
world. Natural painkillers are found within our body, and inhibit the
neurotransmitters that send the signal of pain to our brains. However,
clinically developed and opium-based painkillers have been able to cut off
these pain signals at a rate suitable for severe and intense pain. With this
though, comes a quick and strong developing tolerance - along with a
euphoric feeling hard to mimic naturally. That is why researchers have spent
countless hours and dollars looking for a better way to reproduce the
inhibition of neurotransmitters without the risk of abuse or dependence.
Recent breakthroughs within a primary research technique of many
biomolecules, X-ray crystallography, has led to the ability to deduce
molecule structure and observe function at an incredibly small level, leading
to better understanding of opioid-receptor and peptide interaction. This has
allowed research as recent as January to synthesize alternative ligands
similar to natural endorphins to ultimately relieve pain to a degree of or
beyond morphine, while having little to no adverse effects.

In order to better understand the chemical cycle within painkillers, one

must understand the process of pain. Pain is ultimately an individual
experience, and there are many types of pain. Our body reacts to stimuli and
receptors trigger a series of events. These are initiated with an electric
impulse that travels from the point of stimulus to our spinal cord, which from
there goes to the brain (Stopple, 2014). Inside the brain, most signals end up
at the thalamus and then the cortex, the most sophisticated area of the
brain. It travels through the thalamus because it is the brains storage area so our body is literally saving this impulse for faster future use if it were to
happen again. Upon deeper inspection, pain is a very specific, complex
process that involves complex functions of natural brain and spinal
chemicals. These chemicals come into play when the massive infrastructure
of neurotransmitters produce sensations in the body when activated by
certain chemicals. Our body has a natural way to reduce the pain endorphins (Appendix A), of at least 20 different types found in the pituitary
gland and nervous system (Stopple, 2014). Endorphins react with opiate
receptors in our brain in order to decrease conscious feeling of the pain,
similar to the effects the pharmaceutical industry has mimicked with
painkillers.
There are also many types of pain, to which painkillers treat differently.
To start, there is acute pain - which is brief but can be very intense. The
opposite, chronic pain, can also be intense but is typically milder over a long
period of time. These are classified further, into nociceptive pain and non-

nociceptive pain. Nociceptive pain is when specific pain receptors are

stimulated. These receptors sense heat, movement, and chemical stimuli.
Nociceptive pain is broken down into Somatic and Visceral pain. Somatic pain
is felt on the skin, muscle, joints, bones, and ligaments - or musculo-skeletal
pain. This type of pain has receptors sensitive to inflammation. This kind of
pain is generally sharp and specific. Visceral pain on the other hand, is pain
over a larger area - such as internal organs or main body cavities. The main
body cavities are your thorax, abdomen, and pelvis. These receptors sense
inflammation, oxygen deprivation, and stretch/tears. Often categorized as a
deep ache, visceral pain is hard to pinpoint to a specific location (Nordqvist,
2016). Opioids within analgesics can be used to reduce all types of pains to
some degree.
Opioids are among the oldest known drugs, and have been used long
before written history. They are structurally similar to morphine, and work by
binding to our nervous system through opiate receptors. Opioid receptors are
in a large protein family commonly referred to as G protein-linked receptors
(Harth, 2015). They trigger a chain reaction of cellular responses that alter
our brain (Nordqvist, 2016). When the opioid ligand binds the receptor, the
painful signal given off is greatly reduced and is often accompanied by an
intense euphoric feeling (Appendix B). There are currently three primary
receptors known to bind with our natural opioids within our body. In order to
better understand ways to advance painkillers, we must first research and
develops the specifics of their actions. Although much is known about them,

it has yet been determined their specific mechanism. Researchers are now
creating synthetic opiate ligands, and testing ways to retain their main
properties while limiting side effects (Harth, 2015).
Recently, X-ray crystallography has been able to show detailed
structure of the opioid receptors used in pain relief, and synthetic drugs can
be further developed. These developments can lead to new analgesics which
are able to function just as well but do not lead to an addictive dependency.
The first research conducted was from Peta Fromme of Arizona State
University along with an international team. They published their research in
the current issue of the journal Nature Structural and Molecular Biology.
Fromme, who is the director of ASUs Biodesign Institute Center for Applied
Structural Discovery, claims the new crystallography advancements, using
very high-speed lasers, has permitted a detailed examination of the vital
binding of peptide to the human opioid receptor - a phenomenon that has
widely escaped possibility of being researched (Harth, 2015). It is the
cutting-edge research needed to unleash a generation of medical painkiller
advances.
X-ray crystallography has been a core component of biochemical
research for deducing the structure and function of a wide variety of
molecules. It is still the primary method of characterizing and classifying new
materials, along with their properties. However, traditional X-ray
crystallography has the possibility of destroying the fragile structure of
compounds under investigation. In order to avoid this factor, the research

conducted used a newly developed, advanced method known as serial

femtosecond crystallography with a device known as an X-ray Free Electron
Laser (XFEL). The devices uses much smaller crystals to defract instead of Xrays, hence smaller structure can be deduced without risk of harming the
target molecule. This technology led to the research publishing some
unprecedented structural details of new molecular determinants of the
peptide interaction with the receptor, as well as identifying a new key
structure contributing to ligand activity and specificity (Harth, 2015).
Therefore, ligand analysis now presents the pharmaceutical research
industry with a new challenge - synthesizing new ligands for better
management of pain without the side effects commonly abused painkillers
have.
This research has already been used in pharmaceutical research. Just
this year researchers at Tulane University, along with Southeast Louisiana
Veterans Healthcare System have tested multiple synthetically engineered
variants of the neurochemical endomorphin (Appendix C) - a naturally
occurring peptide opioid. It was compared to morphine, and the results were
rather shocking. Not only did the tested rats show reduced or no side effects,
the drug produced longer pain relief than morphine. A similarly potent dose
of morphine cause significant respiratory depression and led to a
dependence, where the research drug had far less of a tolerance build up. In
the research, only rats treated with morphine showed increased efforts to

obtain their dose of treatment. The drug is to reach clinical trials within the
next 2 years (Brannon, 2016).
As many may already know, opium-based painkillers are a massive
medical staple, but very dangerous. Patients often build a tolerance and are
required to take harmful doses of painkillers to get the same effect - leading
to physical problems, or an addiction (Brannon, 2016). Countless hours and
money has been spent relentlessly researching the mechanism of opioid pain
receptors, and it is still unknown (Harth, 2015). However, recent research has
deduced a more detailed analysis of the peptide ligands involved, as well as
their interaction with the opioid receptor - allowing for new synthetic variants
similar to morphine to be created, while lacking major side effects. This
research is still in early development, and only time will tell how well it goes.
One thing is certain, the pharmaceutical research industry is going nowhere
but forward, and it is only a matter of time until we uncover the next wave of
groundbreaking research to improve our common medicine.

Appendix A
Endorphin

Appendix B
G Proteins role with Neurotransmitters

Shows G-Proteins (opioid receptors) action in the cells to inhibit the

reaction releasing neurotransmitters - therefore reducing our brains
perception of the pain.

Appendix C
Endomorphin

Works Cited
Brannon, K. (2016, January 28). Study: New drug could be safer, nonaddictive alternative
to morphine. Retrieved March 20, 2016, from

http://tulane.edu/news/releases/new-drug-could-be-safer-non-addictivealternative-t
o-morphine.cfm

Harth, R. (2015, March 2). New study brings medicine closer to non-addictive
painkillers.
Retrieved March 19, 2016, from
http://phys.org/news/2015-03-medicine-closer-non-addictivepainkillers.html

Nordqvist, C. (2016, March). What is pain? What causes pain? Retrieved

March 19, 2016,
from http://www.medicalnewstoday.com/articles/145750.php

Stopple, M. (2014, December). Endorphins: Natural Pain and Stress Fighters.

Retrieved
March 17, 2016, from http://www.medicinenet.com/script/main/art.asp?
articlekey=55001