Pain at Christmas

While we may not think so, pain can be positive. Acute pain is the body’s alarm system; it drives action and teaches us what situations or stimuli to avoid in the future. So said Professor Irene Tracey (University of Oxford), Head of the Nuffield Department of Clinical Neuroscience and Nuffield Chair of Anaesthetic Science, giving a fascinating introduction to the complex world of pain.

Chronic pain is the dark side. One in five people in the adult population suffer from pain which lasts for more than three months. This can be broken down into three categories – nociceptive or inflammatory pain, neuropathic pain (from nerve injury, as seen in multiple sclerosis and phantom limb pain), and pain without a known origin (idiopathic pain, seen in irritable bowel syndrome and fibromyalgia). 

Chronic pain is estimated to cost between $560 billion and $635 billion in the USA each year and €200 billion in Europe. Medications have not been forthcoming for the various conditions for chronic pain; Tracey explained some medications used in conditions such as epilepsy have been prescribed for some chronic pain conditions but the efficacy of these is mixed. They don’t work for many and may merely take the edge off some people’s pain. 

In assessing pain we rely on subjective self-report or look at behaviour and indirect physiology – all coarse and limited methods. Tracey said our personal, individual experience in life shapes how we view our own pain and the pain of others – from tropes about pain in childbirth being a good and noble thing, to men being expected not to show pain. All these things bias our attitudes about the experience of pain. 

There are many risk factors for experiencing chronic pain, including being older, female and having experienced adverse life events. Tracey asked how these factors might be shaping the brain to lead to a higher likelihood of someone experiencing chronic pain, and said the field has a desperate need for objective pain biomarkers. 

If you’ve ever watched House you may have seen Hugh Laurie’s character kidnap an amputee and force him into mirror-box treatment to alleviate his phantom limb pain. This trick of the mind allows amputees to ‘see’ their amputated limb using a mirror to help relieve this pain. The maladaptive plasticity theory suggests that amputation leads to sensory deprivation in the brain, which in turn leads to cortical reorganisation and phantom pain. Mirror box treatment works on the basis that reinstating the brain’s representation of an amputated limb can help in treating pain. However, Professor of Cognitive Neuroscience Tamar Makin (UCL) and leader of the plasticity lab asked how we have reached 2019 with a neurological trick as the mainstream treatment for phantom limb pain. She said the treatment had been meeting with increasing objection due to its efficacy and concerns over the quality of evidence. 

Makin has asked, through her research, whether the brain truly maladaptively reorganises itself post-amputation. When people who have had hand amputations are asked to ‘move’ their amputated hand, the activity in the brain area which represents the hand and its five fingers shows a level of activity similar in scale and amplitude to the representation of their intact hand. In fact, Sanne Kikkert, who has been trying to identify detailed hand maps and finger representations in the brain, found that some regions still respond to the movement of phantom digit 30 years post-amputation. 

Makin’s colleague Hunter Schone has worked with people scheduled for hand amputation due to cancer, looking at their brains’ representation of their hands pre- and post-amputation. He has found that these patients’ finger maps in their brain are consistent after amputation. 

Makin asked how these findings fit with the maladaptive plasticity theory; that sensory deprivation leads to reorganisation of the missing limb cortex that in turn leads to phantom limb pain. A further study found that those with chronic phantom pain had higher levels of activity in the part of the cortex which represented the missing hand. Kikkert, Makin and colleagues wanted to test whether modulating phantom pain impacts on brain representations. They used electrical stimulation on patients with phantom limb pain and found that patients experienced a relief in their pain which persisted until a week after the stimulation. This relief in phantom pain was associated with reduced activity in patients’ missing hand cortex, and Makin found that areas in the insula and somatosensory cortex, parts of the brain’s pain network, had a role in modulating phantom limb pain. While the textbooks suggest that phantom pain is caused by maladaptive reorganisation, Makin said her and colleagues’ evidence shows that representations of missing hands remain intact, and this could inspire new methods for treating phantom limb pain. 

Professor of Psychopharmacology Val Curran (University College London), founding member of the charity Drug Science, asked a rather coy audience about their experience with cannabis. For the apparently uninitiated she shared a quote from Alfred Gingold: ‘A small amount… induces laughter, hunger, random silliness and great interest in boring items. Highly recommended for long camping trips, family reunions, first dates and gloomy Sundays.’   

Cannabis is the most widely used drug in the world – despite its association with harms including addiction, an increased risk of psychosis in vulnerable young people, and relapses in people with schizophrenia who have been stabilised with other medication. Curran said that while we see cannabis psychosis reported in the media a great deal, this is often without context. Around 9 per cent of cannabis users become dependent and experience withdrawal, while with legal drugs such as alcohol and tobacco the rate of addiction and dependency is much greater. However, the numbers of people seeking treatment for cannabis addiction is on the increase.

Curran asked why this 9 per cent of users may become dependent on the drug. The younger someone starts using cannabis, along with frequency and amount of use, are risk factors alongside genetic influences. When a teenager’s brain is developing, adding cannabis to the mix can alter white matter development. Adolescents respond completely differently to a dose of cannabis than adults and experience more cognitive harm, impulsivity and less satiety after one dose. 

Around 12 years ago Curran began to question whether the type of cannabis matters in terms of addiction. Cannabis contains 144 cannabinoids and of these two have been extensively studied – THC and CBD. THC gives users a feeling of being stoned, can cause psychotic-like effects, and impairs memory and learning. CBD has an almost opposite effect; it is non-intoxicating, decreases anxiety and psychosis-type effects, and can increase memory and learning. In recent years the potency of cannabis has increased… when Curran was at university, levels of THC averaged around 5 per cent, while now most types of cannabis have at least 15 per cent THC. 

Analyses of cannabis sold in coffee shops in the Netherlands have been analysed over the years and show a similar increase in levels of THC. There appears to be parallels, Curran said, between this average increase in THC levels and people seeking addiction treatment for cannabis. 

Users of skunk, a type of cannabis which tends to be higher in THC than cannabis resin, report a higher level of dependence and craving and use more cannabis in less time. Curran has also looked into cannabis users’ attentional bias for drug-related photographs. Those who use higher-CBD products did not show this attentional bias. 

Interestingly, CBD could be useful in treating those who are addicted to higher-THC cannabis. Curran compared a placebo with 400mg or 800mg of oral CBD over four weeks, and through urinary tests confirmed both doses helped users lower their exposure to THC. In the 400mg condition, users were 2.2 times more likely than the placebo condition to abstain from cannabis for a day.

Hair contains a good deal of information about a person’s exposure to cannabis and helpfully grows at 1cm per month, allowing researchers to look at the time-course of cannabis exposure. Curran found that people whose hair contained only THC had a greater rate of psychotic-like symptoms than those who had CBD, or CBD and THC. 

Cannabis has been a medicine for thousands of years, even in the UK until the 1960s. Curran said that given the addiction issues associated with opiates, many people with chronic pain were crying out for it. In the USA attitudes are shifting in favour of cannabis: the National Academies of Sciences, Engineering and Medicine released a positive statement that cannabis products could be useful in chronic pain condition. Many in the USA receive a cannabis prescription for chronic pain, and New York and Illinois have added opioid replacement therapy as a qualifying condition for cannabis to be prescribed.

The picture in the UK is very different. In an evaluation of the evidence NICE concluded cannabis medicine did not reduce chronic pain, and the British Pain Society concluded there was no positive evidence for cannabis to be used in pain management. UK doctors can now prescribe cannabis medications in certain circumstances, but Curran said only a handful of prescriptions had been given out, driving some pain patients to buy the drug illegally or visit private healthcare practices. 

Some people have also taken to buying products containing CBD from various health food shops. But Curran said this was the biggest placebo effect she had ever seen, as these products contain miniscule amounts of CBD. Given this messy picture, Curran suggested two ways forward. First, prevention – state regulation of the cannabis market to allow people to buy cannabis with balanced levels of CBD and THC along with harm reduction advice. Second, the evidence base needs vast improvement. While a randomised control trial would be hugely expensive, at Drug Science Curran is hoping to recruit 20,000 patients with various conditions and monitor their progress while taking medicinal cannabis. 

The BNA also handed out its awards at the symposium. Pia Siegele (University of Edinburgh) won the undergraduate award, and James Phillips (University of Cambridge) received the postgraduate award. Dr Dean Burnett – neuroscientist, lecturer, author, blogger and podcaster – won the public engagement of neuroscience award. Professor Steve McMahon (Kings College London) won the outstanding contribution to neuroscience award for his work in the pain field.