In recent years, in both medical and veterinary professions, pain relief for has become much more effective and no-one, man or beast, should expect to suffer severe or prolonged pain during the course of their clinical treatment.
Topcat Metrology has played a part in this advance. The company has its roots twenty years ago when Dr Polly Taylor, a veterinary anaesthetist and Michael Dixon, a scientist specialising in measurement techniques, joined forces to develop a method for assessing the analgesic effect of opioids in cats.
The project was successful, contributing to the licensing of buprenorphine as an analgesic for cats in the UK and leading to several other requests for similar equipment. Topcat Metrology Ltd was formed in 2008 and has since developed a wide range of threshold evaluation equipment, allowing researchers to quantify their assessments of analgesia. Most of the systems are now wireless, allowing the animals to be free-ranging and thus behaving naturally.
Thermal
The first modality developed was a thermal system, applying heat to the skin from a miniature probe incorporating both heater and temperature sensor; this is effectively worn by the animal in a band or bracelet and, although the early systems were wired, is now entirely remote controlled.
Mechanical
Mechanical testing was subsequently developed, employing a unique pneumatic actuator driving a blunt ended pin against the skin. This can be used both as a hand held algometer, suitable for use in the clinic, or with the research system, the ProdPro, driving a limb-mounted actuator via simple lightweight tubing. A remote controlled version exists for large animals.
Rodents – MouseMet
Moving on with our experience with larger animals to laboratory rodents, MouseMet was conceived after discussions with researchers who stated that von Frey filaments, while giving a well trusted answer, were time consuming and awkward to use for the measurement of mechanical thresholds. They also commented that the existing electronic von Frey systems, while perhaps acceptable for rats, were insufficiently sensitive or robust for mice. As a result, we spent time watching people testing, participated in a number of studies, and then designed our own system. Then, building on our experience with larger animals, we built a hot probe to be used in the same runs.
Looking behind the measurement
Good measurement is difficult. It is very easy, with technology all around us, to measure something, often with a piece of equipment borrowed from another lab, or another discipline, and to produce numbers that look plausible…even encouraging.
But not necessarily meaningful. Our aim is always to look behind the required measurement, to figure out what is really going on, and then to design equipment that is appropriate. Put another way, we aim to generate data with significant figures that really are significant.
Part of this is education. The physical principles bound up in our measurements are basic, but easily forgotten, or mis-interpreted if you don’t use them regularly. So Topcat provides full training, both on the use of our equipment and on the underlying science.
We have contributed to several conferences and training symposia worldwide. In 2010 we gave a series of lectures across Australia, spanning Sydney, Adelaide and Perth and also hosted a training day at the AVA biennial conference in Santorini. Together with Dr Craig Johnson of Massey University, New Zealand, and Dr Louisa Slingsby of Bristol Veterinary School we presented a program entitled “The Pitfalls of Measurement”. We both formed part of the international panel of invited speakers at the 2013 annual conference of the Australian and New Zealand Laboratory Animal Association in Perth. In 2016 Polly presented “Refinements in mechanical and thermal nociceptive threshold testing in mice” at the Society for Experimental Biology and Laboratory Animal Science Association. In 2022 Polly took part in the first Havemeyer equine pain workshop held in Reykjavik. Since the pandemic most training and conference participation has continued on line.
Nociceptive Threshold Testing
Research in pain – no gain without pain!
In order to study the physiology of pain and to develop analgesic management strategies that work – pain has to be involved.
Nociceptive threshold testing (NTT), under regulated research conditions, is based on causing controlled and damage-limited pain with a measurable stimulus – the magnitude of the stimulus needed to cause pain acts as a surrogate measure of the degree of pain. An increase in the stimulus intensity required to cause pain indicates antinociception, which in the conscious animal corresponds to pain relief. The measured stimulus when pain starts is the nociceptive threshold (NT). Put simply, an increased NT indicates analgesia. Conversely, a decreased NT indicates more pain. NTT is carried out on awake subjects, so can be regarded as indicating not just nociception, but also pain. Nociception still occurs during unconsciousness (eg under anaesthesia), but pain is perceived only when awake.
The most common stimuli are either thermal (usually heat, can be cold) and mechanical
For NTT, the animal’s aversive response is taken as the endpoint at which pain is first perceived – and is called the threshold (NT). Studies in human subjects enable distinction to be made between a whole range of painful and non-painful sensations. In animals, however, the sensation experienced is unknown and we assume that a stimulus that is painful to us and which produces an appropriate response in the animal is the threshold for pain. NTT in animals therefore hinges on interpretation of their behaviour. Reliable results depend on understanding what is normal behaviour for the species concerned – and, as far as possible, that this is not disrupted by the environment and the testers. Any form of restraint will impede such normal behaviour. Here’s a guide to successful NTT.
Topcat has developed a unique system where the stimulating probe is attached to the free ranging animal, allowing as nearly normal behaviour as possible. Application of the stimulus via a light cable or, in particular, remote control revolutionised the thermal stimulation used in NTT ; the same principle has been applied to mechanical stimulation.
Nociceptive threshold testing for research and drug regulation
Nociceptive threshold testing (NTT) is used for both research and the clinical assessment of pain. It is widely used in animal studies to evaluate treatments which either increase the threshold (analgesics) or which decrease it (irritants, trauma, disease). Drug licensing requires laboratory and clinical testing for efficacy and safety; an appropriate dosing protocol is usually also initially determined under laboratory conditions and comparison against a gold standard is generally required prior to drug registration. A similar approach is used in basic research where mechanical and thermal stimuli are used in rodents to determine the presence or absence of pain and its exacerbation or alleviation.