Animal & Veterinary
COMPANION ANIMAL ANALGESICS: ASSESSMENT OF PAIN
FDA Veterinarian Newsletter September/October 2000 Volume XV, No. V
Animal pain models are used in laboratory studies in companion animals (dogs, cats and horses) to test the effectiveness of various analgesics used to control acute and chronic pain. Clinical field trials evaluate short-term perioperative pain or long-term osteoarthritic pain in client-owned animals.
Veterinarians and pet owners want to avoid causing pain to animals in their care. One way of reducing pain is to administer safe and effective analgesics. Pain assessment models are used to measure the effectiveness of an analgesic. FDA approval decisions are based on data obtained from some pain assessment models. Many steps are taken to avoid inducing unnecessary pain in the use of these models. Information contained in this article briefly describes some of these models and the criteria used for the assessment of analgesic effectiveness.
1. LABORATORY MODELS FOR ANIMAL PAIN:
Arthroscopic transection of the cranial cruciate ligament induces canine osteoarthritis. This model is probably the best characterized and most commonly used laboratory model for experimental osteoarthritis in dogs. It has been repeatedly used in studies to evaluate analgesia following treatment with NSAIDs, opioids and alpha-2- agonists in the acute perioperative period. Transection of the cranial cruciate ligament results in a mechanically unstable femoropatellar (stifle) joint that reproducibly mimics osteoarthritis. Osteoarthritic changes with osteophyte formation occur in approximately 8 weeks and are progressive. Arthroscopic transection is preferred over the percutaneous stab incision technique because articular surfaces can be carefully examined for any signs of existing osteoarthritis, full ligament transection is assured, and inadvertent iatrogenic damage is minimized. The arthroscopic technique is preferred over arthrotomy because it requires less extensive tissue dissection that results in damage to periarticular soft tissue and articular neurons.
Chronic articular inflammation is commonly modeled using intraarticular Freund’s Complete Adjuvant, carragheenan or sodium urate in dogs and horses. Adjuvant-induced synovitis is characterized by an acute response during the first 24 hours, followed by a subacute response approximately 3 weeks later, that persists for several weeks. However, lameness induced by chemical injection can yield inconsistent results, especially during the acute phase of the inflammatory response. The placebo injected animals may be indistinguishable from the treated animals because rapid self-healing may occur and responses vary among individual lame animals.
Polyvinyl alcohol particles in the equine metacarpophalangeal joint (fetlock) have recently been used in a model of acute synovitis/capsulitis to study the effects of therapeutic analgesics. The inflammatory response is comparable to clinical cases of acute primary synovitis as demonstrated by acute lameness, inflammation of the synovium and joint capsule, increased synovial effusion, and changes in synovial fluid variables. Moderate lameness remains constant for several days after an initial peak. On necropsy, the condition of the articular cartilage was not obviously affected by a single injection of polyvinyl alcohol particles.
Tendinitis (bowed tendon), a common clinical diagnosis in horses, has been modeled by injecting collagenase into the superficial digital flexor tendon of the equine forelimb. The resultant pathophysiology does not closely mimic the clinical condition and the horse’s lameness response is variable.
Visceral analgesia is evaluated in horses when abdominal pain (colic) is induced by inflation of a balloon placed in the lumen of the cecum through a surgically prepared fistula. Rectal balloons have been used similarly in cats.
A lameness model uses force plate data to evaluate the gait of horses after inducing lameness by tightening or loosening screws in modified horseshoes. The resulting pressure pain on the sole enables induction and reversal of three different degrees of lameness and the same horse may be used to generate control data.
2. PAIN MODELS USED IN CLINICAL FIELD TRIALS:
Standardized mechanical and electrical nociceptive stimuli have been adapted from rat and rabbit methodology for the assessment of analgesia in dogs and cats. A mechanical device produces pain without tissue damage and is secured to one hind leg with fiberglass cast material. Using a pneumatic control, a 4 mm pin is gradually extended from within a cuff over the medial, proximal tibia. Stimulation continues to the minimum pressure (mm Hg) that causes an avoidance response (leg movement or vocalization). Similarly, a computer controlled system delivers an electrical stimulus to the tail by an attached electrode for set periods of time. Stimulation increases over time to the minimum intensity (voltage) that produces an avoidance response (tail movement or vocalization).
Analgesics are frequently evaluated in client-owned animals that present for elective surgery. Animal behaviors in response to pain can be difficult to interpret after mildly painful procedures. Therefore, surgeries that are suitable for the evaluation of analgesics have been categorized in dogs and cats:
|MODERATE PAIN||SEVERE PAIN|
|caesarian section||ear canal ablation|
|anal sacculectomy||limb amputation|
|cutaneous mass removal|
EVALUATION OF ANIMAL PAIN:
In general, pain in the laboratory is subjectively scored as a response to the administration of various nociceptive stimuli, such as:
- needle pricks
- toe pinch
- tail clamp
- carragheenan sponge tissue insertion
Pain evaluation in client-owned animals and clinical cases primarily relies on:
- behavioral changes
- withdrawal or avoidance
- decreased appetite
- licking or biting or scratching at the painful area
- abnormal posture or lameness
- increases or decreases in activity
- physiological changes (pulse rate, respiratory rate)
- increases in blood glucose, corticosteroid or catecholamine concentrations
EEG assessments (alpha-2-agonists)
To include analgesia as a part of routine case management, veterinarians need to be able to accurately assess pain status in their patients. Since animals must indirectly communicate that they are in pain, veterinarians rely primarily on behavioral signs, together with blood indicators (increases in blood glucose, corticosteroid, and catecholamine concentrations) and physiological changes (increases in heart rate, respiratory rate, temperature) .
Behavioral Signs Of Pain By Species:
|SPECIES||SIGNS OF PAIN AND/OR STRESS|
|dogs||increased or decreased activity; stiff movements; unwillingness to move; abnormal posture to minimize discomfort; loss of appetite; anxious expression; shivering; panting; whimpering; howling; aggression|
|cats||quiet; creased forehead; hiding; crouched or hunched; stiff movement; incessant licking; ungroomed appearance; loss of appetite; hissing; growling; yowling|
|horses||restless; reluctance to be handled; food held in mouth without eating; flared nostrils; profuse sweating; rigid stance; lowered head; dilated pupils; abdominal pain: looking, kicking, biting at abdomen, lying down repeatedly, rolling, pawing, tucked-up abdomen|
Lameness examinations are most commonly employed for the evaluation of chronic pain. Subjective lameness examinations use graded scoring systems, are very standardized and can yield meaningful results if the lameness is consistent prior to treatment with analgesics. Traditional lameness evaluations may make use of measurements of stride length using ink and paper (dogs) or hoofprints on sand (horses).
Clinical Scoring Of Lameness:
|1||slightly lame at trot|
|2||slightly lame at walk, moderately at trot|
|3||moderately lame at walk, severely at trot|
|4||severely lame at walk, trot not possible|
FORCE PLATE TECHNOLOGY:
Technologically complex measurements of force plate analysis have become sufficiently repeatable, reproducible and appropriate for the quantitative evaluation of lameness in dogs and horses. Vertical and craniocaudal force measurements are used for the evaluation of gait. Vertical force measurements are described as vertical peak force and vertical impulse. Craniocaudal force is divided into braking (peak force and impulse) and propulsion (peak force and impulse). Adjunctive use of computer analyzed kinematics measures joint range of motion and compares pre-treatment and post-treatment parameters. Training of both animals and investigators is required. The practical use of this complex technology may depend on the expertise of the operator. Force plate results should always be accompanied by simultaneously recorded subjective lameness scores.
Recent years have demonstrated an increased awareness within the veterinary profession of the necessity to provide effective pain relief for their patients. Clients now expect veterinarians to recognize and control pet both acute and chronic pain and suffering. The need to provide adequate analgesia has increased since anesthetic drugs (for example, propofol and sevoflurane) provide rapid post-operative recovery times. Rapid recovery can result in intense immediate post-operative pain. Also, the use of balanced anesthetic regimens allows, more lengthy and invasive procedures, potentially causing greater tissue damage and longer post-operative pain.
Studies that evaluate companion animal drug pain frequently take place within the university setting. Study design must comply with the Institutional Animal Care and Use Committee (IACUC). The Institutional Animal Care and Use Committee is composed of at least five members, including a veterinarian, an experienced investigator and an individual not affiliated with the institution. The committee determines that research projects are conducted in accordance with the Animal Welfare Act. The Act is administered by the United States Department of Agriculture. Some pain models may not be acceptable to these committees.
Minimizing pain and distress in well-controlled laboratory studies using research animals can enhance scientific results. Animals that experience unnecessary pain may introduce confounding variables into study design. The fewest numbers of animals that are exposed to the least noxious stimuli for the shortest period of time can still provide the clearest results in a well-controlled study.
- Marshall, K.W., and Chan, A.D.M. "Arthroscopic Anterior Cruciate Ligament Transection Induces Canine Osteoarthritis." The Journal of Rheumatology; 23:2 (1996)
- Cornelisson, B.P.M., et.al. "Experimental model of synovitis/capsulitis in the equine metacarpophalangeal joint." AJVR, 59:8 (1998)
- Boatwright, C.E., et.al. "A comparison of N-butylscopolammonium bromide and butorphanol tartrate for analgesia using a balloon model of abdominal pain in ponies." Can J Vet Res, (60) 1 (1996)
- Merkens, H.W., and Schamhardt, H.C. "Evaluation of equine locomotion during different degrees of experimentally induced lameness." Equine Vet J Suppl, 6 (1988)
- Personal communication: William Muir, DVM, PhD, Ohio State University, College of Veterinary Medicine, 610 Tharp Street, Columbus, Ohio, USA (1999)
- Tranquilli, W., et.al. "Factors to Consider in Selecting an Anesthetic and Pain Management Protocol in Stable Patients", Veterinary Proceedings, The North American Veterinary Conference, Orlando, Florida (1998)
- Waterman, A.E. and Kalthum, W. in Animal Pain, ed. Short, C.E. and Van Poznak, A. (1992)
- National Research Council, "Recognition and Alleviation of Pain and Distress in Laboratory Animals", Washington, DC, National Academy Press (1992)
- Waterman-Pearson, A.E. "Peri-operative analgesia", Proceedings, 6th International Congress of Veterinary Anaesthesia, Thessaloniki, Greece (1997)
- Committee for Research and Ethical Issues of the International Association for the Study of Pain: "Ethical guidelines for investigations of experimental pain in conscious animals.", Pain 16 (1983)
Dr. Germaine Connolly is the Anesthetics Reviewer in CVM’s Division of Therapeutic Drugs for Non-Food Animals.