Pain experts say greater focus on high-tech non-animal research could help thousands of patients
Science's understanding of human pain remains simplistic, with no safe and effective analgesia for chronic pain despite decades of animal experiments, according to an article published in international peer-reviewed journal Neuroimage1, collaboratively authored by leading pain experts and the Dr Hadwen Trust. Advanced non-animal technologies such as human brain imaging could offer greater hope for a pain-free future for people living with diseases such as osteoarthritis and fibromyalgia.
Thousands of pain experiments on animals are conducted every year across the world, including purposely inflicting pain on conscious animals such as rodents, sheep and primates2. Such experiments are conducted mainly on rodents in Britain by drug companies like AstraZeneca and GlaxoSmithKline as well as universities across the country. As well as being unethical, animal models of pain are simplistic and fail to replicate the multi-dimensional experience of human pain with its complex genetic, biological and psychological aspects.
Recent pain experiments in Britain:
Pharma company AstraZeneca 2007: to study osteoarthritis, they injected the chemical MIA (mono-iodoacetate) into rats? knees, causing ulceration of joint cartilage, deep bone damage and nerve injury close to the spine. Despite pain, the animals were forced to stand. Used 400 animals, some left to suffer symptoms for 35 days with no pain relief3
Pharma company GlaxoSmithKline 2007: to study rheumatoid arthritis, they induced joint inflammation in rodents for up to ten weeks, eventually disabling the animals4
Bristol University 2006: to study arthritis, they injected mice with a chemical to induce painful inflamed joints, causing fluid filled tissue and bone destruction. The animals were poked with a rod and forced to stand on hot plates to test their pain response5
Pain is a major health issue, with back pain affecting 80% of people at some point in their lives and costing the NHS and private health sector a combined ?2.6 billion every year6. With animal models failing to deliver ethical or clinically relevant solutions, some of Britain's most respected and esteemed professors in pain research7 took part in a unique workshop to look at ways to replace animal experiments with cutting-edge technology. The workshop was organised by Focus on Alternatives8, a coalition of not-for-profit organisations funding or promoting alternatives to animal experiments, chaired by the Dr Hadwen Trust.
Reporting our conclusions in Neuroimage, we acknowledge the many limitations of animal research, not least key species differences between rodents and humans in how pain is processed in the body and in the effects of painkilling drugs. Studying basic behavioural responses in animals who cannot verbalise their experiences, is also a very crude approach.
However, the advent of powerful, advanced brain imaging technology in ethical studies of healthy and pain-patient volunteers, could change the outlook for chronic pain patients for whom there are currently no safe and effective painkilling drugs. Replacing failing animal experiments could also provide a more reliable and cost-effective pathway to drug development and better treatment regimes.
Qasim Aziz, Professor of Neurogastroenterology at Barts & the London School of Medicine and Dentistry, has pioneered the use of functional brain imaging to study how the brain interprets pain signals in patients suffering from disorders such as irritable bowel syndrome and unexplained chest pain.
"In my research, animal models don't represent human patients sufficiently well," says Professor Aziz, "and that's a problem that extends across pain research as a whole. New and highly sophisticated brain imaging technology is providing vital insights that animal research has failed to produce. I would like to see far greater uptake of these and other human-relevant approaches to pain research to help us develop the effective treatments that patients so desperately need."
Non-invasive human neuroimaging technologies are relatively new but they are being rapidly developed, and their capabilities are improving with lightning speed. Advanced techniques such as fMRI, PET and MEG are already revolutionising medical research by identifying the brain areas involved in human pain processing, those affected by analgesics, and the duration and nature of these effects.
"It's clear that experimenting on animals isn't an ethical or even relevant route to study the complexity of human pain." says Dr Gill Langley of the Dr Hadwen Trust, "It is critical that these often simplistic experiments are replaced with more advanced techniques that don't involve inflicting animal suffering. Powerful brain imaging machines could help revolutionise pain research globally and speed up the development of pain-killing drugs, providing much needed hope for chronic pain sufferers. But the enormous potential of imaging approaches will only be realised if the government and the research funders make a concerted effort to invest in these human-focused technologies."
One of the major advantages of these advanced techniques is that the species of relevance (humans) is studied and that volunteers are able to verbally communicate their experience of pain and pain relief in a way that is impossible with animals. Patients can also be stratified into sub-groups, to help develop more specific treatment strategies. For example, human studies are revealing gender differences in pain processing, and showing that painkillers appear to work differently in men and women.
We recommend replacing animal experiments wherever possible with an expanded programme of human-based pain research. We would like to see: the establishment of co-ordinated regional human tissue banks to make human tissues and cells more available for research, as well as a UK Human Pain Research Network to encourage collaborative research, greater dialogue and a strategy for multi-disciplinary human volunteer studies9.
1 Langley CK, Aziz Q, Bountra C, Gordon N, Hawkins P, Jones A, Langley G,
Nurmikko T, Tracey I (2008) Volunteer studies in pain research -- Opportunities and challenges to replace animal experiments. The Report and recommendations of a Focus on Alternatives Workshop. NeuroImage 42:467?473.
2 To induce pain, animals can have chemicals injected into their joints, have capsaicin (from chilli peppers) applied to the skin or have a paw crushed by applying pressure. In analgesia trials some groups of animals are used to test new painkillers but control groups receive no painkillers at all and are forced to endure unabated pain, often until they die.
3 In an experiment from 2007, researchers at AstraZeneca studying osteoarthritis, injected the chemical MIA (mono-iodoacetate) into rats' knees, causing ulceration of joint cartilage, deep bone damage and injury to nerves close to the spine. These experiments used 400 animals, some of whom were left to suffer these painful symptoms for 35 days with no pain relief. Despite their symptoms, the rats were forced to stand so that limping and pain reflexes could be observed. Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: Increased expression of ATF-3 and pharmacological characterisation. Pain, 2007, 128(3): 272-282.
4 In a rheumatoid arthritis experiment at GlaxoSmithKline in 2007, rodents were subjected to substantial suffering for up to ten weeks when joint inflammation was induced, eventually disabling the animals who became unable to walk.
Methionine aminopeptidase-2 blockade reduces chronic collagen-induced arthritis: potential role for angiogenesis inhibition Arthritis Res. Ther. 2007; 9(6): R127.
5 In a 2006 arthritis experiment at Bristol University, mice were injected with a chemical giving them painful inflamed joints, and causing fluid filled tissue and bone destruction. In this painful state, the animals were then poked and forced to stand on hot plates to test their reactions. Sex differences in inflammation and inflammatory pain in cyclooxygenase-deficient mice Am. J. Physiol. Regul. Integr. Comp. Physiol. 291: R327-R334.
6 Maniadakis A, Gray A. The economic burden of back pain in the UK. Pain 2000; 84:95-103
7 Authors are: Dr Chris Langley, ScienceSources Consultancy, Hitchin, Hertfordshire; Professor Qasim Aziz, Centre for Gastroenterology, Wingate Institute of Neurogastroenterology, London; Dr Chas Bountra, GlaxoSmithKline, Harlow, Essex; Nicky Gordon, Dr Hadwen Trust, Hitchin; Dr Penny Hawkins, Research Animals Department, RSPCA, Southwater; Professor Anthony Jones, Rheumatic Diseases Centre, University of Manchester; Dr Gill Langley, Dr Hadwen Trust, Hitchin; Professor Turo Nurmikko, Pain Research Institute, Clinical Sciences Centre, University of Liverpool, Liverpool; Professor Irene Tracey, University Department of Clinical Neurology and Nuffield Department of Anaesthetics, University of Oxford.
8 Members: Dr Hadwen Trust (Chair), FRAME (Fund for the Replacement of Animals in Medical Experiments), Humane Research Trust, UK Human Tissue Bank (UKHTB), St Andrew Animal Fund (part of Advocates for Animals), RSPCA and Lord Dowding Fund. For info see www.focusonalternatives.org.uk
9 Data from neuroimaging research could be further enhanced by other human-based approaches such as microdialysis, human genetic studies, epidemiology (population studies) and in vitro (test-tube) research using human cells and tissues, in a multi-disciplinary effort to replace animals.