Side effects of pain and analgesia in animal experimentation

Focus on Reproducibility Review Side effects of pain and analgesia in animal experimentation © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Paulin Jirkof This review highlights selected effects of untreated pain and of widely used analgesics such as  opioids, non-steroid anti-inflammatory drugs and antipyretics, to illustrate the relevance of carefully planned, appropriate and controlled analgesia for greater reproducibility in animal experiments  involving laboratory rodents. A potential cause of suffering in experimental animals is pain induced by procedures, diseases and injuries. Pain is a complex state arising from many sources, involving several systems in the body. Pain is more than nociception and has been defined as a ‘‘subjective, sensory and emotional experience’’1 in man. It can be assumed that pain, as an affective experience, also exists in other mammals. In light of these considerations, pain treatment becomes an ethical, and in most countries legal, obligation in any animal experiment that induces more than mild pain of short duration. Nevertheless, pain management is more than an animal welfare concern, as it has important scientific and methodological implications for the design of experiments and the quality of the resulting data. A recent review on reporting practices for anesthesia and analgesia protocols after invasive animal procedures revealed that many published studies do not include pain relief and do not report, or do not completely report, the anesthetic and analgesic measures involved2. The pain management protocol chosen, as well as any untreated pain, has the potential to affect scientific results and increase the variability of data, thereby hampering the reproducibility of experiments substantially. Pain management includes the choice of anesthesia and analgesia agents, their dose, administration method, duration and frequency of treatment, and a painmonitoring scheme for each individual animal. It is therefore an important part of experimental design, and determining the appropriate protocol is mandatory when planning animal experiments. As a complement to such important preparatory work, this review aims to highlight some effects of untreated pain, as well as side effects of widely used analgesics, to illustrate the relevance of appropriate and controlled analgesia, as well as the proper reporting of all analgesic measures2 for greater reproducibility in animal experiments. As mice and rats are the most abundant laboratory species, this article focuses on these rodent species. Effects of untreated pain The sensory component of pain is nociception, which depends on specifically dedicated receptors, nociceptors, and associated pathways. Different brain structures and a network of neurons with a complex pattern of connections are then involved in the processing of pain and the resulting responses. Although some components of the system mediate sensory discriminant aspects, others convey information about affective-motivational aspects such as the unpleasantness that accompanies painful stimuli3. When tissue is traumatized, the release of local chemical agents such as inflammatory mediators may also cause excitation of nerve endings. This can lead to hyperalgesia, a state in which stimuli that are normally perceived as slightly painful are perceived as substantially more painful. A consequence of nerve damage can be allodynia, an increase in the excitability of neurons, which results in pain following a stimulus that is not normally perceived to be painful3. Untreated pain may hamper the healing of tissues. Bone healing, for example, is promoted by mechanical stimulation. Thus, as has been shown in rats, effective pain relief and the consequent increased use of the affected body part are important for healing4. Besides local mechanisms, ascending painful impulses lead to hypothalamic activation and increased sympathetic-adrenergic system activity. This activation results in substantial cardiovascular effects, such as changes in heart rate and heart rate variability, as has been shown in mice5. Pain, similar to distress, affects the secretion of many hormones, neurotransmitters and enzymes. For example, untreated pain increases the secretion of catecholamines such as noradrenalin, corticoids, glucagon, adrenocorticotrophic hormone (ACTH) and antidiuretic hormone (ADH), and decreases the secretion of insulin and testosterone in many species6,7. In addition, untreated pain can affect the immune system detrimentally by leading to a reduction of natural killer cells and mixed lymphocyte reactivity8. In humans, unrelieved pain may contribute to psychological distress, sleeplessness and impaired rehabilitation. Changes in behavior that might be indicative of negative affective states are also observed in animals. Typical changes in rodent behavior include reduced food and water intake, changes in activity, reduced sleep, a flattened circadian rhythm, loss of behavioral diversity, and changes in social grooming, nest building or burrowing behavior7,9–11. Division of Surgical Research, University Hospital Zürich, University of Zürich, Zürich, Switzerland. Correspondence should be addressed to P.J. (). LabAnimal Volume 46, No. 4 | APRIL 2017    123 Review © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. This exemplary list illustrates how pain affects a multitude of body systems via several pathways. Pain states following surgical trauma and painful diseases are complex in nature and cannot be easily predicted or controlled. Omitting pain relief to reduce side effects of analgesic drugs might be a double-edged sword, and is justifiable only in a few well-founded cases. Effect of analgesia protocols The choice of analgesia protocol for a specific research question is challenging and might best be solved with the help of an expert in veterinary analgesia. The optimal analgesia protocol should relieve pain reliably and lack side effects that might hamper animal welfare. In addition, it should have a controllable effect on the specific system targeted by the experiment or on experimental procedures. In light of the many aspects that have to be considered—species, type of pain, research question—there is no one-size-fits-all analgesia. Pain is, in many cases, never relieved completely, but should be minimized and controlled. To choose a potent analgesia protocol, one must identify the type of pain (nociceptive, neuropathic, idiopathic or mixed), as well as its intensity and duration. There are distinct differences in the features of acute and chronic pain, and acute pain, if not well managed, can lead to chronic pain that persists even if the underlying cause has been treated. Although the course of pain in spontaneously developing diseases such as cancer may differ substantially in the individual, in most rodent surgeries pain peaks around the first 4–6 h post operation. Although t (...truncated)