What is pain, and how can we eliminate it?
Imagine if I told you that “Over 95% of the world’s population has health problems”, would you be amazed by that? What would happen if I told you that this study was funded by the Bill & Melinda Gates Foundation?
People suffer for multiple reasons, and the more we age, the worse the situation becomes.
Worldwide, the proportion of lost years of healthy life (disability-adjusted life years; DALYs) due to illness rose from around a fifth (21%) in 1990 to almost a third (31%) in 2013.
The disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death.
The disability-adjusted life year is a societal measure of the disease or disability burden in populations. DALYs are calculated by combining life expectancy measures and the adjusted quality of life during a burdensome disease or disability for people. DALYs are related to the quality-adjusted life-year (QALY) measure; however, QALYs only measure the benefit with and without medical intervention and therefore, do not measure the total burden. Also, QALYs tend to be an individual measure and not a societal measure.
Traditionally, health liabilities were expressed using one measure, the years of life lost (YLL) due to dying early. A medical condition that did not result in dying younger than expected was not counted. The burden of living with a disease or disability is measured by the years lost due to disability (YLD) component, sometimes also known as years lost due to disease or years lived with disability.
DALYs are calculated by taking the sum of these two components:
DALY = YLL + YLD
In the US, the most common causes of death are:
- Heart disease (23.1% of the total deaths)
- Cancer (21.7% of the total deaths)
- Accidents (5.9% of the total deaths)
- Chronic lower respiratory diseases (5.6% of the total deaths)
- Stroke (5.18% of the total deaths)
- Alzheimer’s disease (4.23% of the total deaths)
- Diabetes (2.9% of the total deaths)
- Influenza and pneumonia (1.88% of the total deaths)
All these problems involve suffering. But the main question is:
Why do people suffer?
We need to understand that from two points of views:
- an evolutionary point of view
- a biological point of view
Evolutionary perspective
What determines the genetic information of living organisms in the first place?
The simple answer is that the information has been transmitted to them by their ancestors. Different individuals carry certain information in their genes that leads them to be and behave in specific ways. Individuals who exist today had ancestors who managed to reproduce. Indeed, the end of our genes is to procreate.
In case those ancestors would have had a different gene pattern, living organisms would have been different. Generally speaking, there are two kinds of reproduction: asexual and sexual reproduction.
Asexual reproduction is faster and more energy-efficient; sexual reproduction better promotes genetic diversity through new combinations of alleles during meiosis and fertilisation. In other words, if asexual reproduction is faster, sexual reproduction can increase the likelihood of the species' survival. In both cases, the main point here is that only the “optimal” genes (in a precise environment) can survive in the long term.
An animal’s fitness is a measure of its ability, relative to others, to leave viable offspring.
One example is butterflies. During the past centuries, butterflies haven’t always had the same colour. This has been because of the general environment that made them brown or black rather than another colour.
Imagine if two butterflies have different colours but can adapt mimic better the environment, it will be more likely that this butterfly can survive and have more offspring.
Based on that, we say that the second butterfly has a lower level of fitness.
Fitness is a relative thing. A genotype’s fitness depends on the environment in which the organism lives. The fittest genotype during an ice age, for example, is probably not the fittest genotype once the ice age is over. In a certain way, genetics is like business:
What made you successful in the past, will cause you to fail in the future.
But not all genetic information is equally likely to be transmitted. Generally, the more beneficial a gene is to an individual’s inclusive fitness, the more likely it is to be passed on. This is not always the case, since individual circumstances and chance (Gene drift) are involved in whether or not an individual survives to be able to pass on their set of genes.
If a particular genetic information set makes the animals who have it fitter, there will be a higher likelihood of transmitting it. In that case, there will be a greater chance that future animals will have that genetic information.
On the contrary, if genetic information makes the animals unable to transmit that information, no living beings inherit it.
Genetic drift changes the frequency of an existing gene variant in a population due to random sampling of organisms.
The ones that are more common in nature aren’t traits that maximise the animals’ wellbeing; they are traits that maximise the chances that animals who have them will continue to have descendants through time.
Imagine if two people are identical except from one gene.
- The first person, let’s call Suffy, has a gene that makes her feel pain.
- The second person, let’s call her Joy, doesn’t feel the perception of pain.
Even if the life of Joy can be less miserable than Suffy’s life (because you don’t perceive hunger, you don’t feel tired, when you have an accident, nothing happens), in reality, Suffy will be the person that is more likely to survive in the long term.
It is mostly due to the gene’s presence that can make Suffy notice some problems that can threaten her survival.
This is also why we focus more on mistakes rather than positive features for survival reasons.
Pain has always been fundamental for our survival.
Now there are two great differences compared to the past.
- The type of diseases
- The way of monitoring your health status
Type of disease
During the past, the majority of the cases of death were due to accidents or infectious diseases.
For example, during the Middle Age, the highest reported cases of deaths were dysentery, malaria, diphtheria, flu, typhoid, smallpox and leprosy.
Some illnesses such as cancer and heart disease were pretty rare even if now they are a daily occurrence.
Now, the majority of people face chronic diseases such as cancer, Arthritis, Diabetes, Parkinson disease, and Alzheimer’s disease. Living those illnesses with the constant presence of pain can just worsen the patient conditions.
The way we monitor our health status
Pain was the only way to see if something of bad was happening in our body.
If there was an injury, people would have noticed it in a super-easy way, and also now it’s in the same way. The main problem with this system is that people can’t understand long term diseases such as cancer but, at that time, it wasn’t a problem considering that the average life span was less than 40 years.
Now, our objective isn’t anymore 40 years, but it’s far beyond.
Jeanne Calment died at the age of 122 years and 164 days in 1997, setting a record as the world’s most long-lived person that is still unsurpassed. There are also some people such as Ray Kurzweil whose mantra is “Live long enough to live forever”. Indeed, we now are a new species that has been empowered by technology.
Thanks to technology, we can understand small changes and significant changes. Some small changes are body pressure, oxygen flow, REM and NREM phases and even how many minutes we are upright. Some examples of significant changes are the long term effects of particular features such as stress (that you can monitor with a Fitbit) to your body.
Having a way not to suffer anymore (or at least to limit it), could be a fantastic opportunity to make people live better and longer.
Biological reasons
Before talking about pain itself, we should clarify that not all tissues give rise to pain.
Indeed, Tissues are sensitive to the kinds of damage likely to occur and not to those that probably will never happen.
Each tissue must be stimulated in an appropriate way to invoke its particular sensation of pain.
Our skin, for example, being the outer covering of the body, easily raises the warning of pain. Still, other tissues that do not directly contact the exterior environment are just the opposite.
Another example comes from our brain. It can be pierced, cut, and burned during neurosurgery while the patient would require only local anaesthesia of the pain-sensitive scalp. The lung, liver, and spleen also do not give rise to pain, no matter how stimulated. Pain arises from hollow viscera when the passage of their contents is obstructed, and the musculature must undergo strong contraction and stretching.
With this perspective, we need to consider why pain is likely to happen and what to do about that.
Acute pain usually comes on suddenly and is caused by something specific. It is sharp in quality. Acute pain usually doesn’t last longer than six months. It goes away when there is no longer an underlying cause for the pain. Causes of acute pain include:
- Surgery
- Broken bones
- Burns or cuts
When Acute pain persists for more than 12 weeks after peripheral trauma has caused the initial inflammation, this pain becomes Chronic.
Usually, it lasts longer than six months. This type of pain can continue even after the injury or illness that caused it has healed or gone away. Pain signals remain active in the nervous system for weeks, months or years. Some people suffer chronic pain even when there is no past injury or apparent body damage. Chronic pain is linked to conditions that include:
- Headache
- Arthritis
- Cancer
- Nerve pain
- Back pain
- Fibromyalgia
If you have chronic pain, the stress affects the body, producing physical conditions like:
- tense muscles
- Limited ability to move around
- A lack of energy
- Changes in appetite
Chronic pain also causes emotional effects, including:
- Depression
- Anger
- Anxiety
- Fear of re-injury
Let’s turn to the first question. How does pain generate?
In our body, particular receptors can perceive pain. They are called Nociceptors. Pain Receptors respond to chemical, mechanical, or other stimuli.
Let’s imagine that a big nail hits our skin. What would happen?
When there is potential or actual tissue damage, some compounds are produced.
One example is prostaglandins that are a group of physiologically active lipid compounds called eicosanoids. They are derived enzymatically from the fatty acid arachidonic acid. The main enzymes that are involved in this process are COX-1 and COX-2.
These inflammatory mediators stimulate the nociceptors (pain receptors in the tissues). Furthermore, when tissue damage occurs, potassium (K+), adenosine triphosphate (ATP), and hydrogen ions from the cells directly stimulate the nociceptors.
Nociceptors are contained in two different places. The first one is A-delta fibres, which are large and myelinated and responsible for acute sharp pain. The second one is C fibres, which are small and unmyelinated and responsible for slow-onset, dull, or achy pain.
Stimulation of the nociceptors’ open voltage-gated ion channels allows calcium and sodium ions to pass into the cytoplasm, raising the resting membrane potential (–70 mV) downstream until the threshold potential (–55 mV) is achieved, leading to action potential formation.
The action potential is an all or nothing phenomenon. It means that to activate the process, the threshold potential must be reached.
There are three main types of Channels:
- Voltage-Gated Channels
They open and close in response to changes in membrane potential.
- Ligand- Gated Channels
They open when a neurotransmitter latches onto its receptors.
- Mechanically-Gated Channel
They open in response to the physical stretching of the membrane.
The signal as an action potential travels up the primary afferent axon, sensory neuron, as the continued reaching of threshold potential propagates it due to the opening of voltage-gated Na+ channels upstream (saltatory conduction). The primary afferent neurons have their cell bodies in the dorsal root ganglion.
The primary afferent neurons link to secondary efferent neurons in the dorsal horn of the spinal cord. The action potential generated in the secondary afferent neuron crosses over to the spinal cord’s other side. The secondary afferent neurons synapse with tertiary afferent neurons in the thalamus (which acts as the relay station between the brain and the rest of the nervous system); and the action potential generated travels to the somatosensory cortex.
Action potential goes to the thalamus thanks to the spinothalamic tract.
Afferent neurons are also crucial for muscle contraction and dilation.
Indeed, primary afferent neurons respond to the rate of change in muscle length and change in velocity, rapidly adapting.
Secondary afferent neurons provide position sense of a still muscle, fire when a muscle is static.
Primary afferents are sensory neurons (axons or nerve fibres) in the peripheral nervous system that transduce information about the body’s mechanical, thermal, and chemical states and transmit it to sites in the central nervous system. Here, it reaches the somatosensory cortex that is the brain’s area associated with sensation (touch, feeling).
There are 4 main ways to stop pain temporally:
- Medicine (NSAIDs)
- Opioid drug (oxycodone and morphine)
- Glucocorticoids
- Local anaesthesia
Nonsteroidal anti-inflammatory drugs NSAIDs
These chemicals block the flood of pain chemicals, but they don’t know exactly how to find the exact site of the pain, so they block all the pain signalling Cox enzymes, preventing them from perceiving pain alarm.
They include
- Aspirin (Acetylsalicylic acid)
It disables the Cox-1 enzyme.
- Ibuprofen, marked as Advil and Motrin, was first derived from Propionic Acid.
It Blocks arachidonic acid from getting into the enzyme sights responsible for pain, but rather than permanently breaking off like aspirin it remains longer your body.
- Naproxen Sodium, including the drug Aleve,
It works by inhibiting Cox enzymes.
Acetaminophen, or paracetamol, isn’t an NSAID. It only takes effect after the chemicals have boned with the enzyme and inhibit some, but not all, the effects caused by compounds they form. That’s why it helps relieve pain and fever, but it doesn’t reduce inflammation. It’s mostly metabolised in the liver. For this reason, talking too much of paracetamol can damage your liver.
Possible side effects of NSAIDs include:
- indigestion — including stomach aches, feeling sick and diarrhoea
- stomach ulcers — these can cause internal bleeding and anaemia
- headaches
- dizziness
- allergic reactions
- problems with your liver, kidneys or heart and circulation, such as heart failure, heart attacks and strokes (it is pretty rare)
Apart from that, other problems can be that some NSAIDs can react unpredictably with other medicines.
This can affect how well either medicine works and increase the risk of side effects.
Opioids
Opioids are different. They don’t kill pain, they make you not recognise it. They relieve suffering by blocking the transmission of pain signals to the brain and altering pain perception.
With the opioids, the intracellular signalling involves potentiating or reducing the production of cyclic adenosine monophosphate (cAMP). At certain sites, it signals the closing of voltage-gated Ca+ channels and the opening of K+ channels, leading to intracellular hyperpolarization of the neuron. For example, at the synapse between the primary and secondary afferent neurons, this leads to a reduction in the release of neurotransmitters presynaptically and a reduction in action potential production postsynaptically.
There are 3 types of opioids:
- Natural Opiates (Morphine and codeine)
- Semi-synthetic (Heroin, Oxycodone, diamorphine)
- Synthetics (Methadone, Demerol, Fentanyl)
Opioids have side effects too.
In the short term, opioids can relieve pain and make people feel relaxed and happy. However, opioids can also have harmful effects, including:
- drowsiness
- confusion
- nausea
- constipation
- euphoria
- slowed breathing
Opioid misuse can cause slowed breathing, which can cause hypoxia, a condition that results when too little oxygen reaches the brain. Hypoxia can have short- and long-term psychological and neurological effects, including coma, permanent brain damage, or death. Researchers are also investigating the long-term effects of opioid addiction on the brain, including whether the damage can be reversed.
Glucocorticoids
The glucocorticoids, such as hydrocortisone and dexamethasone, are a class of steroid hormones.
They can reduce inflammatory pain by blocking the intracellular conversion of phospholipids to arachidonic acid, thereby inhibiting prostaglandins’ production, as already present with NSAIDs, and leukotrienes, a family of eicosanoid inflammatory mediators.
They decrease the transcription of proinflammatory genes and increase the transcription of anti-inflammatory genes.
Glucocorticoids have also been shown to reduce spontaneous action potential firing in injured nerves.
Also, in this case, there are different potential side effects:
- Increase in blood pressure, triglycerides, cholesterol, or glucose level
- Water retention, including swelling in the feet, ankles, lower legs, or hands
- Increased appetite and weight gain
- Unwanted hair growth
- Headache, dizziness, and vertigo
- Mood swings
- Osteoporosis, broken bones
- Thrush in mouth
- Cataracts
- Glaucoma
- Getting sick more easily, or wounds that heal more slowly than normal (with long-term use of the drug)
Local anaesthesia
Action potentials are propagated by the opening of sodium (Na+) channels within the axons reaching threshold potentials downstream by saltatory conduction. Na+ channels exist in 3 phases: closed, open, and inactive. The inactive state is when the axon segment is still depolarised, but sodium cannot pass through, and its structure is distinctly different from the closed state.
Local anaesthetics can only block the channels when they are in the open or inactive states, and they block the receptors from within the cytoplasm, meaning the drug must pass into the cell to be effective. Only the un-ionized form can pass through the cell membrane; therefore, as a weak base, there is less available drug within the cytoplasm in an acidic environment. This is why local anaesthetics are less effective in inflamed or infected tissues.
Some sides effects are.
- dizziness
- headaches
- blurred vision
- twitching muscles
- continuing numbness, weakness or pins and needles
In general, anaesthesia doesn’t have many side-effects, but the main problem here is that it can’t last more than about 2 hours. For this reason, it is generally used during surgery but not during treatments.
Synthetic biology
What is Synthetic biology?
We can define synthetic biology as a new interdisciplinary area that involves applying engineering principles to biology. It aims to (re-)design and manufactures biological components and systems that do not exist in the natural world.
There is a difference between synthetic biology and gene editing.
Synthetic biology studies complex natural biological systems as complete systems using modelling and simulation tools, focusing on taking parts of natural biological systems, characterising and simplifying them, and using them as components of an engineered biological system. Instead, genetic engineering is based on transferring individual genes from one microbe or cell to another. From another perspective, we can define synthetic biology as gene engineering with more functions and more variables, considering the whole cell rather than just the DNA.
Synthetic biology is based on four main fields:
- Genomics
- Transcriptomics
- Proteomics
- Metabolomics
If you want to know more, you can read this article, too.
Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. This feature can be caused by 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel.
People with CIP condition have an intact axon reflex arc and no discernable autonomic disturbances.
Nav1.7 represents a target that might be inhibited by small molecules in a subtype-specific or state-dependent manner during ectopic discharge, producing pain relief while sparing other neuronal functions. The development of subtype selectivity of potentially therapeutically useful molecules has proven to be a challenge
Thanks to synbio we may genetically engineer SCN9A to limit the function of Nav1.7 channels during some treatments.
Some examples are during cancer treatments.
In most cases, chemotherapy drugs can cause painful side effects, such as aching in the muscles and joints, headaches and stomach pains. Pain may be felt as burning, numbness, tingling or shooting pains in the hands and feet.
KEY TAKEAWAYS
- There are biological and natural reasons why pain exists.
- Pain is a fundamental feature for our survival, even if in chronic diseases, it damages our wellbeing.
- There are different drugs to cure of pain even if they all have some side effects.
- Synthetic biology may be able to eliminate pain sensation for a period of time to improve people wellbeing during treatments
