Breathlessness and opioids

We’ve recently published a paper on how opioids can modulate breathlessness. (The whole manuscript is open access here). Low-dose opioids can be used for treating chronic breathlessness, but we don’t know exactly how they work.

Opioid receptors exist across the brain. These are part of the internal opioid system (endogenous opioid system) for natural pain relief. When opioids are used in the clinical setting to treat negative stimuli, such as pain, they influence the unpleasantness and the intensity of the stimulus in different ways(1). In terms of breathing, opioids lower breathing by influencing brainstem respiratory centres(2), causing breathing to stop completely in high doses, and they can also affect higher brain centres(3).

Opioids also have behavioural effects, and may, amongst other things, influence associative learning. Associative learning is when an association between two stimuli is learnt by pairing these together. For example, in chronic breathlessness this could be previously neutral stimuli (e.g. a flight of stairs) and breathlessness. This could create an anticipatory threat response, which means that simply seeing a flight of stairs is enough to bring about breathlessness or the fear associated with breathlessness. This can worsen the breathlessness for the patient in the long run.

In this study, we hypothesized that opioids improve breathlessness in part through changing the anticipatory response to breathlessness. We focused on two brain regions in particular: the amygdala and hippocampus. Both are strongly involved in associative learning(4) and are rich in opioid receptors(5,6).

What did we do? First, we asked healthy volunteers to do a breathing test where we paired three different degrees of breathlessness and three symbols. The symbols were presented immediately before the volunteer was made breathless and were matched to the level of breathlessness that they signified. We invited those volunteers who learnt to associate each different symbol and its corresponding breathlessness to undertake two MRI scans in random order. Before one scan they received a low-level opioid (remifentanil) infusion, and before the other they received a control (saline) infusion. During the scans, the volunteers repeated the breathlessness/symbol task. Below is a schematic of the breathing circuit used for the study, showing how different levels of breathlessness was induced.

breathingsystemFigure 1. Breathing circuit for inducing breathlessness

What did we find? We were able to show that breathlessness anticipation in the control condition was processed in the right anterior insula and operculum, and that the breathlessness itself was processed in the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex, primary sensory cortices and motor cortices. These regions have been identified in other studies on breathlessness (as discussed in a previous blogpost).

However, in the opioid condition, we saw the following:
1. Opioids reduced breathlessness unpleasantness (Figure 2)
2. This reduction correlated with reduced activity in the amygdala and hippocampus during anticipation of breathlessness (Figure 3)
3. This reduction also correlated with increased activity in the anterior cingulate cortex and nucleus accumbens during the actual breathlessness (Figure 3)
4. During the actual breathlessness, the opioid infusion directly reduced activity in the anterior insula, anterior cingulate cortex and sensory motor cortices (Figure 4).

opioid_res1Figure 2. Ratings of breathlessness and intensity. Abbreviation: Remi=remifentanil

Reduction in unpleasantness. The reduction in unpleasantness with opioids was expected – the different effect of opioids on intensity and unpleasantness has been shown in many other negative conditions, including pain(1). Interestingly, we could confirm that this lowered unpleasantness correlated with reduced activity in brain regions linked with associative learning and memory (amygdala and hippocampus) before the breathlessness began (Figure 3, bottom). This reduced activation in the amygdala and hippocampus, regions that are needed for formation of unpleasant memories, may explain how low-dose opioids gradually become more efficient as a therapy over the first week of administration. The reduction in amygdala/hippocampus activation may mean that fewer new negative memories and reaction patterns are formed.

opioid_res2.jpgFigure 3. Brain activity linked to lowered unpleasantness, relating to breathlessness (top) and anticipation of breathlessness (bottom). NA=nucleus accumbens, paraCC=paracingulate cortex, ACC=anterior cingulate cortex, PC=precuneus, ant hipp=anterior hippocampus, amyg=amygdala. 

We also see that the reduced unpleasantness correlates with activation during the actual breathlessness in the anterior cingulate cortex and nucleus accumbens (Figure 3, top). These are parts of the endogenous opioid system which reduces the perception of negative stimuli. This means that the reduced unpleasantness our volunteers felt is linked with these regions being more active. In other words, they may act to further dampen the negative sensation. Less unpleasantness during the breathlessness means that even less negative memories are likely to be formed.

Reduction in breathlessness activation. Finally, opioids directly reduced activity in the anterior insula, anterior cingulate cortex, sensory motor cortices and brainstem (Figure 4). The activation during control (saline) in the figure below is typical of breathlessness, and has been found in several other studies using breathing challenges.

opioid_res3.jpg

Figure 4. Brain activity during breathlessness in the control (saline) condition (top) and where it is reduced by the opioid (remifentanil, bottom). Increased activation is shown in red-yellow, and decreased in blue. M1/S1=primary motor & sensory cortices, OP=operculum, dlPFC=dorsolateral prefrontal cortex, Thal=thalamus, ACC=anterior cingulate cortex, vmPFC=ventromedial prefrontal cortex, PAG=periaqueductal grey, SMG=supramarginal gyrus.

The areas that are reduced in activation with opioids are commonly activated in breathlessness and central to respiratory sensation. For example, the anterior insula, the most commonly activated brain region during breathlessness, is believed to assess the quality of the stimulus and help control interpretation. The anterior cingulate cortex, which is also commonly activated in breathlessness, is similarly involved in control of negative emotions. These regions may be part of an interpretation process that is shaped by expectation and learning(7) similar to other control systems in the body (e.g.(8)).

Summary: Opioids manipulate brain regions associated with learning, negative memory formation and negative stimulus control. We have shown that the opioid remifentanil may alter breathlessness perception and the brain regions associated both with anticipation of and actual breathlessness. This suggests that opioids work to reduce breathlessness in part through direct effects on respiratory control mechanisms in the brainstem, insula and anterior cingulate cortex, and in part through changes in how breathlessness is anticipated, by changing associative learning processes in the amygdala/hippocampus.

References:
1. Pain, 22 (1985), pp. 261–269
2. Br J Anaesth, 100 (2008), pp. 747–758
3. J Neurosci, 29 (2009), pp. 8177–8186
4. Curr Opin Neurobiol, 14 (2004), pp. 198–202
5. Life Sci, 83 (2008), pp. 644–650
6. Pain, 96 (2002), pp. 153–162
7. Nat Rev Neurosci, 16 (2015), pp. 419-429
8. Exp Physiol, 92 (2007), pp. 695-704

DOI: http://dx.doi.org/10.1016/j.neuroimage.2017.01.005
Link: https://www.ncbi.nlm.nih.gov/pubmed?term=10.1016%2Fj.neuroimage.2017.01.005
All images presented with permission, creative commons licence.

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Predicting trouble: EEG, NO and stroke

We’ve recently published a paper titled “Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage” on how electroencephalography (EEG for short) can be used to figure out which patients with a certain type of stroke (subarachnoid hemorrhage) will develop a complication after the initial brain bleed and which will not.

Subarachnoid hemorrhage is a type of stroke that can happen at any age. It is a bleed on the surface of the brain, in a space between the arachnoid membrane and the pia mater surrounding the brain (see figure below).

Meninges-en

The bleed is usually caused by an aneurysm (a bulging, weak section of a blood vessel) bursting, causing blood to escape into the subarachnoid space. Here, it puts pressure on the brain tissue (causing tissue damage) which can also reduce blood flow to other parts of the brain (causing lack of oxygen and cell death). The released blood may be toxic to the brain tissue and could cause inflammation. At worst, a subarachnoid hemorrhage results in death or severe brain damage.

Some of the damage is caused directly by the bleed (e.g. the pressure on the brain), and some is caused by how the bleed disrupts the normal control of blood flow in the brain. In particular, it is bad when the nitric oxide pathway stops functioning properly. Nitric oxide helps preserve the circulation in small blood vessels in the brain, partly through enlarging the blood vessels (vasodilation) and lowering the gathering of blood-clot forming platelets. After a bleed, nitric oxide levels in the brain are often reduced. This could be because hemoglobin in the blood stops enzymes responsible for producing nitric oxide from working properly. Another contributing factor is that the nitric oxide that is already present in the brain reacts with superoxide (part of the immune response) which leads to the levels of nitric oxide being even further lowered.

Nitric oxide disruption appears to be involved in delayed cerebral ischemia, which is the most common complication after a subarachnoid hemorrhage. For example, people with genetically lower activity in an enzyme that produces nitric oxide have a higher risk of this complication. Delayed cerebral ischemia is the unpredictable lack of oxygen to the brain leading to severe, even fatal, brain damage. This typically happens 3-14 days after the initial subarachnoid hemorrhage.

Which brings us to our question:

Patients who have the same clinical severity, no measurable genetic differences in nitric oxide production, and who seem exactly the same can go on to show very different outcomes. One can develop ischemia and suffer devastating new brain injuries, and the other return to normal without complications. How can we tell who will get it and who will not?

EEG measures neuronal (electrical) activity using electrodes placed on your scalp. It picks up fluctuations in voltage from the electric currents in the neurons, and in the clinical setting it is used to measure the spontaneous electrical activity in a brain over time. Different parts of the brain generate different signals. Some parts show signal with low frequencies (long waves, delta and theta frequencies) and some with short frequencies (rapid waves, alpha frequencies). The signal is linked to blood flow. In subarachnoid hemorrhage, it can be used to see cerebral ischemia develop naturally at an early stage, because as the blood flow is reduced, short frequencies begin to fade and long frequencies steadily increase. In short, the ratio of alpha to delta (for example), will be reduced in the ischemic patients. However, it can take several days of recording to get a result with this method. It is possible, but not practical.

However, we know that nitric oxide disruption seems to be critically involved in delayed cerebral ischemia. This means that we can give patients a nitric oxide donor (sodium nitrite) to stimulate the nitric oxide pathway, and use EEG to measure how well they respond. By doing this, we can speed the process up. We can see if the patient responds well to the sodium nitrite, or not. This means, in short, that we can see which patients show nitric oxide pathway disruption.

Using this method, we showed in our paper that patients who later went on to develop delayed cerebral ischemia showed no change (or a decrease) in the EEG signal whilst infused with sodium nitrite. Those that did not develop delayed cerebral ischemia did the exact opposite, and showed a strong increase in EEG signal.

temp3EEG spectrograms from a patient that did not develop delayed cerebral ischemia, and one who did, plus a scatter plot with the group differences in spectrogram ratio (alpha delta ratio (ADR))

So we have not only shown how the nitric oxide pathway is important in the development of delayed cerebral ischemia, but this also means we now quite possibly may be able to relatively quickly determine who is at risk for this life-threatening complication, and who is not.

Reference: Garry, P.S., Rowland, M.J., Ezra, M., Herigstad, M., Hayen, A., Sleigh, J.W., Westbrook. J., Warnaby, C.E. and Pattinson, K.T.S. (2016) Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage. doi: 10.1097/CCM.0000000000001950