Researchers investigate the ‘pathways of pain’ in NHS Choices, Monday December 7 2015

While rare, there are some people who are unable to feel pain

“Breakthrough could lead to ‘super painkillers’,” the Mail Online reports.

Researchers have investigated a sodium channel that plays a key role in transmitting pain signals to the brain. They wanted to see whether blocking the channel could help relieve chronic pain.

This study builds on the knowledge that animals and humans born with a mutated form of the SCN9A gene are unable to feel pain. The mutation causes them to lack a working form of a particular sodium channel in the sensory nerves that transmit pain signals to the brain.

This research in mice and humans further explored the reasons why this causes them to be unable to feel pain. It seems that lack of this sodium channel leads to increased production of the body’s naturally occurring opioid painkillers.

The idea is that if drugs that could block these sodium channels were developed, they could replicate some of the painkilling attributes seen in the people who carry the SCN9A mutation. The researchers suggest that such a drug could be used in the treatment of a variety of chronic pain conditions. It would be likely that the effects of such a drug would need to be boosted with other opioid drugs.

This research is at an early stage, so it could be some time, if ever, before a “next generation” combination painkiller comes on the market.

The purpose of pain
At first glance, it might seem like a bonus to be born without the ability to feel pain – known as congenital insensitivity to pain. However, pain plays a vital role in “warning” the brain that something in the body is – or is being – damaged.

For example, people with congenital insensitivity could burn themselves or seriously cut a part of their body, but be unaware that anything is wrong.
A toothache is never pleasant, but it does alert you to a problem in your tooth, which you can then do something about.

Where did the story come from?

The study was carried out by researchers from University College London and received funding from several sources, including the Medical Research Council and the Wellcome Trust.
The study was published in the peer-reviewed scientific journal Nature Communications on an open-access basis, so it is free to read online.
The Mail Online’s headlines are premature in suggesting that the answer to combating all pain has been found. In particular, its reference to migraines is inaccurate.

The sodium channels under investigation were in the sensory nerves transmitting pain signals from the body’s peripheral tissues – such as the arms and legs – to the spinal cord and brain. We don’t yet know what pain conditions sodium channels could be effective for.
However, at this stage, it is thought more likely to be effective for chronic (long-term) pain conditions involving the peripheral sensory nerves, rather than conditions such as migraine, where people have acute episodes of pain.

What kind of research was this?

This was a predominantly animal study that built on the knowledge that both mice and people lacking a particular gene are born with insensitivity to pain.

The researchers report that about 7% of the population suffer debilitating chronic pain and the search to try and develop new and effective painkilling treatments is ongoing. Working out a way to block the sensory nerve cell pathways that transmit pain signals from the tissues to the brain was the focus of research.

A gene called SCN9A codes for a sodium channel (a protein which allows sodium to cross the membrane of the cell) called Nav1.7 in these sensory nerve cells.
Mice and humans who are born with a non-functioning version of Nav1.7 cannot make a working form of this sodium channel and do not feel pain. This suggests the channel could be a possible target for pain relief. However, previous studies of chemicals that target this channel have not found any of them to have notable painkilling effects.

This research describes experiments that explore the reason for pain insensitivity in humans and mice lacking a working Nav1.7 sodium channel. The researchers hoped that if they understood this better, they would be able to design drugs that could reduce pain by reproducing this effect.

What did the research involve?

The study involved normal mice and those genetically engineered to lack the Nav1.7 channel in their sensory nerve cells. They also compared them with mice genetically engineered to lack other sodium channels in their sensory nerve cells: Nav1.8 and Nav1.9.
Under anaesthetic, the researchers examined the nerve cells in the spinal cord of these mice. They looked at gene activity and examined the effect different drugs had on the transmission of pain signals.

The researchers also conducted behavioural experiments in the mice when they were awake, looking at their response to heat and mechanical pain, and how this was affected by giving them the drug naloxone. Naloxone is a medical treatment that reverses the action of a strong group of painkilling drugs called opioids.

A human component to the study involved a 39-year-old woman born with insensitivity to pain, who was compared with three healthy controls. The researchers similarly examined these people’s responses to heat pain and how this was affected by giving them naloxone.

What were the basic results?

The researchers found that the different sodium channels have slightly different functions – for example, Nav1.8 seems to play a role in transmitting low levels of heat pain. Nav1.7 seemed to play the most essential role in the release of chemical transmitters that transmit pain signals through the sensory nerve cells.

Absence of Nav1.7 channels had a greater effect on gene activity in the nerve cells compared with lack of other sodium channels. Lack of the Nav1.7 channel altered the activity of 194 other genes. In particular, they found that sensory nerves lacking Nav1.7 channels were producing increased levels of small protein molecules called enkephalins.
Enkephalins are, in effect, the body’s naturally occurring opioid painkillers. When the researchers used the opioid blocker naloxone on mice lacking the Nav1.7 channel, they found that the mice were now able to feel both heat and mechanical pain (e.g. applying pressure to the tail).

The human study gave similar results: naloxone reversed pain relief in the woman born with insensitivity to pain due to a SCN9A mutation. This meant that when given naloxone, the woman could now feel pain from heat when she could not before. She also reported feeling pain in a leg which she had previously fractured several times.

However, other tests in the mice suggested that enkephalins alone may not provide the whole answer to insensitivity to pain.

How did the researchers interpret the results?

The researchers conclude that increased activity of the body’s naturally occurring opioids is responsible for a significant portion of the pain-free state in people and mice lacking Nav1.7 channels.

They suggest that while Nav1.7 channel-blockers alone may not replicate the complete pain-free state in people with SCN9A mutations, they may be effective when given in combination with painkilling opioid drugs.

Conclusion

This study builds on the knowledge that people born with particular mutations in the SCN9A gene do not have functioning Nav1.7 sodium channels in their sensory nerve cells and do not feel pain. The researchers have further explored the possible reasons behind this. They found that it seems to be – at least for the most part – because absence of this channel leads to increased activity of the body’s naturally occurring opioid painkillers.

The theory is that if drugs were developed to block these sodium channels, they could replicate some of the painkilling attributes seen in people with the SCN9A mutation. The researchers suggest these could be used in the treatment of a variety of chronic pain conditions – although will probably need to be boosted with other opioid drugs.

However, we have some way to go; the researchers believe Nav1.7 channel blockers would have few side effects, but would need to be developed in the laboratory and undergo various levels of testing in animals and then humans to see whether they were safe and effective, and for what conditions.

A possible risk that would need to be assessed is whether such a treatment plan would leave patients vulnerable to the complications experienced by people with congenital insensitivity to pain, due to not having the warning signal of pain.

These are valuable findings that open another avenue in investigating potential future treatments of pain conditions. However, it is too early to say what the long-term implications might be.

Analysis by Bazian. Edited by NHS Choices.

Links to the headlines:

No more bad backs or migraines! Scientists crack the secret of why some people can’t feel pain – and the breakthrough could lead to ‘super painkillers’. Mail Online, December 4 2015
Woman feels pain for the first time aged 39 after being born with rare condition. The Independent, December 6 2015

Link to the science:

Minett MS, Pereira V, Sikandar S, et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nature Communication. Published online December 4 2015

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