Does anaesthesia make pain worse?

Scientists have discovered that “Drugs which ensure that patients are unconscious during surgery can make them more sensitive to pain when they wake up”, The Daily Telegraph reported. The newspaper said that a study has found that general anaesthetics, which work by suppressing the central nervous system, can cause inflammation in other parts of the body, causing pain for the patient when they wake up.

The study on mice identified certain nerve cells that became sensitive when the animals were exposed to a type of general anaesthetic. The newspapers said the scientists believe “that it is these cells which can cause some patients to feel high levels of pain after their surgery”.

This laboratory study, carried out in cells and in mice, identified a protein (not specific cells) involved in the activation of pain-sensing neurons by some general anaesthetics. Although some general anaesthetics are known to cause a burning sensation when they are injected in some patients, it is less clear whether any have actually increased post-operative pain in humans. Although the study did not address this question, it may help researchers to develop better general anaesthetics in the long term. In the meantime, the benefits of general anaesthesia definitely outweigh this potential harm.

Where did the story come from?

Dr José A Matta and colleagues from Georgetown University in the US carried out the research. The study was funded by the National Multiple Sclerosis Society and the National Institutes of Health. Georgetown University has filed a provisional patent related to this work. The study was published in the peer-reviewed medical journal Proceedings of the National Academy of Sciences of the USA (PNAS ).

What kind of scientific study was this?

This experimental laboratory study looked at the effects of general anaesthetics in cells grown in the laboratory and in mice. Although general anaesthetics suppress the central nervous system and make people unaware of painful surgical procedures, some general anaesthetics can actually activate pain-sensing nerves around the body. One group of proteins that are potentially involved in this process are the TRP family, and this study investigated how these proteins responded to general anaesthetics. TRP proteins are known to be involved in sensing irritant substances such as capsaicin, wasabi, and irritant gases (such as those found in tear gas), and in sending pain messages to the brain. These proteins form channels which, when active, open up to allow passage of electrically charged atoms (called ions) through the membranes of pain-sensing nerve cells. These flows of ions allow nerve cells to send and receive messages.

The researchers grew human embryonic kidney cells in the laboratory, which contained different members of the TRP protein family: TRPA1, TRPM8, or TRPV1. They exposed these cells to a pungent, volatile (i.e. that can be inhaled and have a strong smell which may cause irritation to the airways) general anaesthetic called isoflurane, and looked at whether this activated these channels (that is, whether they caused the channels to open). This experiment was then repeated with different volatile general anaesthetics (pungent and non-pungent), and with intravenous general anaesthetics that were known to cause pain on injection.

The researchers then obtained nerve cells from normal mice and mice which had been genetically engineered to lack the TRPA1 channel. These cells were then exposed to two different general anaesthetics, and the effects on the cells were observed.

In the next set of experiments, the researchers applied a general anaesthetic known to cause a burning sensation (propofol) into the noses of either normal mice or mice lacking the TRPA1 protein. These experiments were repeated using a simple mineral oil as a control.

In their final set of experiments, the researchers anaesthetised mice with either isoflurane (a pungent anaesthetic shown to activate TRPA1 in earlier experiments) or sevoflurane (an anaesthetic that had no effect on TRPA1. The ears of one set of mice were exposed to an irritant chemical, while another set were not exposed. The researchers compared the level of swelling of the exposed and unexposed ears in the different groups of mice.

What were the results of the study?

The researchers found that exposing human embryonic kidney cells in the laboratory to intravenous or pungent inhaled general anaesthetics (including isoflurane) activated the TRPA1 channel, but not the TRPM8, or TRPV1 channels. Non-pungent volatile general anaesthetics, such as sevoflurane, did not activate the TRPA1 channel.

When nerve cells from normal mice were exposed to general anaesthetics, there was an inflow of calcium ions into the cells, but this was not seen in nerve cells from mice genetically engineered to lack the TRPA1 channel. This suggested that TRPA1 played a major role in the response of sensory nerve cells to general anaesthetic.

Normal mice exposed to the general anaesthetic propofol showed signs of pain, but no such response was seen in mice lacking the TRPA1 channel, or in either set of mice exposed to the non-irritant control. Mice anaesthetised with isoflurane showed greater swelling in ears exposed to an irritant chemical than mice exposed to sevoflurane. When given alone, neither anaesthetic caused ear swelling, suggesting that it is the joint effect of the irritant chemical and isoflurane that leads to increased swelling.

What interpretations did the researchers draw from these results?

The researchers concluded that the TRPA1 channel is “essential for sensing noxious [general anaesthetics. This means that the TRPA1 channel needs to be present for general anaesthetics to produce irritation of the airways when inhaled or burning sensations on injection.

They also say that the combination of surgical trauma and activation of pain-sensing nerves by general anaesthetics could lead to increased post-surgical pain and inflammation.

What does the NHS Knowledge Service make of this study?

This study has identified one protein that plays a role in the activation of pain pathways by some general anaesthetics. This knowledge may help researchers to develop better general anaesthetics in the long term.

Although some general anaesthetics are known to cause a burning sensation in some patients on injection, it is less clear whether they cause increased post-surgical pain or inflammation in humans.

Sir Muir Gray adds...

There is much more research now on how an operation, although successful in the theatre can slow recovery. ‘Fast track surgery' is surgery in which every aspect of the operation, including the anaesthetic, is chosen for its post-op effects.