Corners Still Unswept
John E. Harkness
Mississippi State University Mississippi State, Miss.
With my rabbit and rodent talk only 2 weeks in the making and with no prior experience among the usual circuit riders of distress and pain, I could think only of introduction after introduction with only modest attempts at discussion and conclusions. So I will give you my four speech introductions and make a stab at the rest.
My Life as a Rat
When I was 7 years old, my intelligent and sensitive linoleum-layer father took me and my brothers for 4th of July fireworks at Edgewater Park on the Rouge River in Detroit. The sun set, slowly, and then the noxious, exploding stimuli began. My nociceptive apparatus activated my physiological and behavioral responses through those rapidly receptive limbic and isocortical parts, especially my amygdala and somatosensory cortex. Then began my perceptions, whose true dimensions were known to me only. The explosions were directly above me. The aerial bombs hurt my ears, so my fingers went into my ear canals. I vocalized, “get me out of here.” I wept. I cringed. I was anxious, fearful, and nauseated. I wanted to escape. I was stressed, in distress, maybe agony. I was suffering and depressed. My well-being, quality of life, welfare, happiness, contentment, life satisfaction, comfort, pleasantness, positive feelings, sense of control, and freedom from frustration, helplessness, and hopelessness were going fast. Even my endogenous opioids failed me. I cannot quantify or define the feelings well, but the sum total was both painful and in retrospect distressing.
There were no child welfare inspectors to be seen, no one around concerned about my experiments in maturation, and no one, including my father, seemed to notice or to care, except my father called me a sissy and told me to stay put and keep quiet. I did. I survived, shaking. But like the residents of Vicksburg, Mississippi, I still have limbic, neuroendocrine, and autonomic reactions on the fourth of July, when we both lost a battle.
Remembering my emotions and pain that night in the late 1940s, I recently asked my neurologist colleague whether the nociceptive anatomy of rodents and rabbits resembled mine. His initial answer was rapid, emphatic, and intuitive: “I believe placental mammals, despite some differences, due to modifiers of the responses, are very similar. ” Period. I learned also from three decades of books and articles that primate nociceptors, A-delta and C sensory fibers, spinal tracts, brain tracts, the limbic system, thalamus, somatosensory cortex, and brain/weight ratio seemed to be very, very similar to those in rats, even more alike than between those beloved cats and us human primates. I was comforted also to learn that most aversive or avoidance behaviors required no isocortex; my prereptilian brain parts could protect or harm me, rodents, and rabbits alike, quite well on its own, without much isocortical or frontal lobe override.
Then, recently, I wanted to know why my father had missed my obvious signs. After all, he had been a kid once. I wanted to know whether proxy assessment by humans of distress and pain in other talking humans, human infants, and in placental mammals was valid, reliable, and sensitive.
Lynne Holton and colleagues (1995, p. 64) of Glasgow and Edinburgh described in JAVMA that “currently, there are no effective objective methods of measuring the intensity of clinical pain.” No mention of distress. Dr. Horton continued to state that one must rely on subjective assessments that must be valid, reliable, and sensitive. She favored having trained teams use a numeric scale for pain evaluation, but that scheme had deficiencies also. Francis J. Keefe and others (1991) at Duke and elsewhere published in ILAR News that well-trained observers using an observation scale with talking children found high correlations between the two groups' interpretations of the test group's behaviors to stressors. I would hope so. Franklin D. McMillan (2000) stated in JAVMA that “Numerous studies provide evidence to suggest that proxy responses by parents correlate poorly with the perceptions of the child they are representing—especially on certain subjective feelings regarding illness and emotional states ” (p. 1908). He believes there is no valid, current instrument for measuring QOL in animals. He advocates assembly of a diverse population of experts to establish measuring instruments and conduct research on their use in animal studies. So do I.
Yet, despite these questions of variability among individuals and groups in linking overt behaviors with degrees of distress and pain, several excellent sources, including those published by J. Wallace Fiat (Convenor and others) in 1990 in Laboratory Animals; in Recognition and Alleviation of Pain and Distress in Laboratory Animals (NRC 1992); and in Carstens and Moberg's (2000)
“Recognizing Pain and Distress in Laboratory Animals” in ILAR Journal. These publications listed acceptable, realistic, believable signs of pain and even distress in rodents and rabbits. Those lists are of critical importance and should be assembled, reviewed, and known much more widely by those who use rabbits and rodents in teaching and research. The challenge is to inculcate into our institutions those signs and their significance. Some investigators do not always listen or read their mail. My experiences in 1947 in Edgewater Park continue in our animal facilities.
My Ignorant Colleagues
I alone at this session, with the possible exception of Dr. Karas from Tufts, am involved full time working as a Johnny-on-the-spot, university-wide laboratory animal veterinarian with mostly veterinarians as investigators. Despite how you react to Trent Lott, the movies about Mississippi, or the many Connie Chung-Dan Rather magazine shows about Mississippi, our college of veterinary medicine has a fine facility, faculty, and staff. We are fully accredited by everybody interested, including AAALAC. The research investigators and active coinvestigators often have veterinary and PhD degrees, private and institutional practice experience, and speciality boards. They do not see distress and pain as I do, however, and both in 1994 and in 1997 our surgeons and anesthesiologists argued vigorously with the AAALAC visitors over valid signs of pain (no one mentioned distress) and what to do, if anything, with analgesics. Non-pain induced distress was never mentioned. Their position was to use “when needed” or “professional judgment, ” popular catch words in our domain, to determine when pain relief was appropriate and when it was not. The revised USDA Policy 3, especially the section on records, which I have placed under their noses at least three times, does not impress them; only intensive IACUC oversight of protocols and procedures, very time consuming, gets their attention. Now the HSUS draft proposal comes along and tells me that even our IACUC's and my rather strict placement of procedures into the usual pain categories nowhere meets the level of recognition of emotional distress and perceived pain that is standard in Europe. I wonder how we would rank with the norms in the advanced cultures of Asia, Africa, Southern Europe, and Latin America.
One of our best clinical researchers, with a PhD in pharmacology from the University of Illinois, e-mailed me last week saying, “ John, enough is enough” when I told him to refine and describe his potentially painful surgical procedures on dogs that would not recover from anesthesia. He told me to do it; he apologized later. He remains a believer in the outdated concept of a vertical phylogenetic scale. Even our experienced 15-person IACUC is refractory to expanded legal promulgations, and instead the committee champions professional judgment because they have been given that encouragement on many occasions. I myself can still manage to influence the committee and meet the mark, almost, because I
experienced similar resistance in the 1970s and 1980s and became accustomed to the recalcitrant. But I am getting tired and hard to replace. My newly hired, very competent, young clinical laboratory animal veterinarian places compliance assessment low on her list of concerns and future rolls. I will continue to handle that aspect until some compliance officer with an MBA can take over when I retire in 5 years.
My colleagues do believe, however, what I read often: There are many tried and true methods for the reduction of distress and pain in animals if drugs and nondrug procedures used properly are study compatible and if considerable effort is made to define in clear, legal language the terms distress, pain, and perhaps some other, related terms.
Rats and Your Cousins, I Love You
In my 17 years, 8 on the AAALAC Council, as a site visitor and also as a part-time consultant to small Mississippi colleges with domestic rat and mice colonies only, I have seen hundreds to thousands of rodents and rabbits in their barren, sanitized twice a week plastic or metal or wire cages, on treadmills, abdomens open on surgery tables, burned by infrared light, injected with turpentine, living but with skin burned in a −17° F freezer, operated on without shaving, having their skulls drilled and spinning on rotating bits, carrying ulcerated tumors, all with no USDA oversight, little if any IACUC concern, scant environmental enrichment, and no perioperative distress and pain relief, drugs or otherwise. I just reviewed two “big journal ” manuscripts for studies involving surgery in rodents in which there was no description for relieving distress and pain, not even “as needed” in someone's eyes. Presumably their IACUCs approved of this. I did not. There are certainly many more studies I could describe, but with my memory more limbic than cerebral, I remember no more. I only wish I had time to tell you how complex is the behavior of rabbits and rodents; their brains are marvelous organs, and they must perceive more than we really want to know. For example, each mouse whisker has a special sensory section processing in the somatosensory cortex, which gives consensual barbering among cagemates a new dimension.
I do not know how many domestic rats and mice are used in research, teaching, or testing each year, few people seem to know exactly, nor do I know into which pain categories they fit or should fit; all I hear is that mouse use is “exploding.” But the common mouse-rat usage is usually stated to be between 18 to 22 million with each animal with nociceptive structures and responses to distress and pain very much like ours. All this possible distress; and so little known outside of locked IACUC file drawers. For regulated rodent relatives and for rabbits used in 1998, some numbers are known: 160,000 guinea pigs; 200,000 hamsters; and 285,000 rabbits. Of those, 100,000 guinea pigs, 100,000 hamsters, and 135,000 rabbits were reported in pain categories D or E: 335,000 of 745,000
total—45% in categories D or E. In my opinion, more should have been placed in Category E. But 45% compares well with reports in the Netherlands. But these animals' populations in research are declining rapidly, unlike those of mice.
When Ralph Dell asked me 3 weeks ago to talk, I asked our librarians to do a 1995-2000 Medline and Agricola literature search on key words: rats-pain, mice-pain, and rabbits-pain. In a few hours, Mrs. Grimes called to say that Medline had 3000 rat-pain articles and 2000 mouse pain articles, and Agricola had many also. So much information, so little coordination, so few journal reviews.
Someone out there must think, are thinking, about distress and pain in rodents and rabbits and preaching convincingly. Yet, the open positions and salaries for persons willing to do what I do seem to be expanding while the number of available, qualified applicants with clinical training is declining. Even NIH does not train John Harkness types any more.
Establish definitions of distress and pain, using the ones we have as a basis. In all the papers and books I have read, I have seen many very understandable, useful definitions. How much more time needs to be spent? But if you flood us with other subjective, unmeasurable terms and flow charts, we will laugh and lose interest. Speak to us as does the New York Times, as busy 12 year olds, not as desk-bound philosophers.
Promulgate again and again in palatable form with one voice the signs of pain and non-pain induced distress. We accept those oft published lists for rabbits and rodents. We know the signs. Now we need on that subject more communicators and fewer committees.
Develop valid, reliable, sensitive and model scales for groups to evaluate and rank our perceptions of an animal's perceptions. Publish the research results and keep the language simple.
After doing the above, or after promising to revise whatever you do prematurely, give us more detailed ways to categorize distress and pain, even if the purpose is to inform the IACUCs of the nature of distress and pain of the study under review. You will find me and our IACUC very receptive.
In addition, I think in this country only the Guide and the USDA regulations, but regulations above all, can accomplish these goals, if the authors are sufficiently research wise and are willing to compromise on details, reduce debate, and promulgate practical and reasoned doctrines.
Carstens E., and G.P. Moberg. 2000. Recognizing pain and distress in laboratory animals. ILAR J 41: 62-71.
Fiat J.W., J. Sanford, and M.W. Smith. 1990. The assessment and control of the severity of scientific procedures on laboratory animals. Lab Anim 24: 97-130.
Holton L., E.M. Scott, A.M. Nolan, J. Reid, E. Welsh, and D. Flaherty. 1995. Comparison of three methods used for assessment of pain in dogs. JAVMA 212: 61-66.
Keefe F.J., R.B. Fillingim, and D.A. Williams. 1991. Non-verbal measures in animals and humans. ILAR News 33: 3-12.
McMillan F.D. 2000. Quality of life in animals. JAVMA 216: 1904-1910.
NRC [National Research Council]. 1992. Recognition and Alleviation of Pain and Distress in Laboratory Animals . Washington, D.C.: National Academy Press.