PAIN is an ancient sensory system, embedded into our bodies and brain, that serves as a crucial warning system of actual or impending damage. But, when the pain becomes persistent, its biological value is lost and people’s quality of life is disrupted.
Pain is signalled by many neural pathways that run from peripheral nerves to spinal cord and then up into the brain. The experience of pain is both a sensory event (where the pain is, and how much it hurts) and an emotional response (fear, anxiety, depression, sleep issues, etc). As the pain-signals arrive in the brain, a unique personal experience is generated. Events in the brain, such as aversion and fear, but also coping and distraction, can trigger descending controls that run back to the spinal cord.
Thus, vast networks of neurones are interacting to increase or decrease the pain-signals. This interplay between sensory and psychological events in pain-processing is the rationale for using behavioural therapies for chronic pain.
Another complication is that change is inherent in the sensory pathways: the peripheral and central neuronal systems alter in different pain-states, as the pain moves from acute to chronic.
THERE are two main types of pain: neuropathic (damage to nerves), and inflammatory (damage to tissue). Low-back pain and certain cancer pains can be one or the other — or a combination.
The peripheral mechanisms of these types of pain are very different; yet within the central nervous system, the signalling systems appear to overlap. The nervous system at rest is at a balance between excitatory and inhibitory systems, but pain signals from the body, whether from damaged tissue or nerves, shift the balance to excitation.
Therapies may decrease excitations or increase inhibitions by acting on the function of the neurotransmitter systems which are signalling painful messages.
Much is now known about pain sensors in the periphery. Many receptors on pain-nerves in the body show that pain can be caused by a myriad of stimuli: heat, cold, pressure, chemicals, etc.
Scientists have isolated particular sodium channels that lead to the electrical events in nerves that send the pain messages onwards to the nervous system — some are unique to pain-signalling. They have discovered human mutations that alter pain perception. These have the potential to provide new selective local-anaesthetic-like drugs.
Of the existing drugs available, aspirin and Ibuprofen work to block the production of a certain pain-producing chemical at the site of damaged tissue, such as that produced by a trauma, surgery, or a disease such as osteoarthritis. But they are unable to control severe levels of pains.
New therapies acting on other pain chemicals are being developed for these types of pain, and also migraines.
If nerves are damaged, such as in diabetic neuropathy, then different drugs are needed — those that normalise the abnormal electrical activity of the damaged sensory nerves.
THE next step in the way that the peripheral nerves talk to brain neurones is the release of a transmitter into the spinal cord. Gabapentin and pregabalin act to alter this transmission process in neuropathic pains; but they cause side-effects, because their targets play different parts in many brain processes.
If pain-messages are not stopped where they start in the body, pain-signals arrive in the spinal cord and head to the sensory and emotional areas of the brain. In this way, they can interfere with how we look at the world within and the world around us. Tellingly, if the incoming pain-signals continue to bombard the spinal cord, then a state of “wind-up”, or spinal hypersensitivity, arises. The neurones shift their responsivity, and there is now more pain, there are greater areas of pain. Even touch and cold can become painful.
The brain receives enhanced pain-messages. In this way, a peripheral problem that appears minor to a doctor on a scan, or during an examination, none the less generates high levels of pain for the patient.
This process is a key target for drug therapies. Ketamine can block wind-up; but again, it has side-effects.
BLOCKING the generation of excitability is one approach; but increasing inhibitions may also offer effective analgesia. The opioid system, the target for drugs such as morphine, is a major inhibitory system, and acts to control painful messages at the spinal cord and also the brain.
These drugs, too, are not without problems. For many, the right dose for the right type of pain does not cause any issue. In the developing world, the lack of access to morphine leads many people to live in needless agony. But use of high doses with no clear pain problem leads to abuse, addiction, overdose, and diversion. These problems are particularly prevalent in the United States, and are increasingly recognised in the UK.
Another transmitter, noradrenaline, plays a related inhibitory function in some of the descending pathways from the brain to the spinal cord, whereas serotonin can enhance pain. The balance is lost when pains become persistent and inhibitory controls are lost.
These bidirectional pathways are embedded in the emotional areas of the brain, which explains how depression, fear, anxiety, sleep, coping, distraction, etc., can alter pain. The descending controls are hijacked by placebo and nocebo (the patient’s positive and negative expectations), and can be manipulated by anti-depressant drugs that act on these two main transmitters.
Their efficacy in neuropathic pains has no effect on mood, but this is not always explained to patients, who may be surprised to be offered a prescription for anti-depressants.
The connection of the limbic brain to the spinal cord through diffuse pathways may be an explanation for widespread pains such as fibromyalgia and irritable bowel syndrome, where peripheral processing may remain normal, yet central modulation goes awry, and leads to several symptoms, including differing degrees of pain.
Where will we be in the future? There has been an identification of several novel targets for pain control; so better drugs should emerge. The importance of combined pharmacological and social and psychological approaches is recognised.
The most useful development could be better ways of predicting which pain in a particular patient will respond to a particular drug. Using pain profiles from individual patients, it may become possible to use existing and new drugs in a far better way.
Professor Tony Dickenson is Professor of Neuropharmacology at University College, London.