1. OVERVIEW: STANDARD OF CARE IN ANIMAL PAIN MANAGEMENT
Animal anesthesia, analgesia and pain management are crucial components of research involving animal subjects. The standard of care at Boston University is to prevent animal pain as far as possible and to treat animal pain whenever diagnosed. Exceptions to these principals are permitted only in the minority of protocols approved by the Institutional Animal Care and Use Committee as USDA Category E with adequate scientific justification.
Multi-modal anesthetic and analgesic regimens combine drugs from a variety of classes. They are designed to maximize the desired effects while minimizing those undesirable side effects that occur with over-reliance on a single agent.
Animals must be acclimated to their surroundings for several days prior to major procedures. In all instances, animals must have been released from quarantine, or the acclimatization period as established by BU LASC or LACF must be completed.
1.1 The ideal anesthetic/analgesic regimen
The ideal anesthetic/analgesic regimen must balance several goals. It will:
- Provide pre-emptive analgesia so that animal pain is already being treated as the general anesthetic is wearing off, to prevent sensitization (“ramp-up”) of pain sensory mechanisms, and to lower the overall amount of general anesthetic required for the procedure.
- Provide a pre-procedural tranquilizer as appropriate for the species.
- Include the administration of an anticholinergic to protect cardiovascular function during anesthesia.
- Be precisely titratable to assure that animals receive adequate anesthesia to block pain sensation, to produce unconsciousness, and to produce immobility without experiencing hemodynamic instability or life-threatening anesthetic overdoses.
- Not interfere with the study that the animals are on.
- Not result in excessive undesirable post-operative side-effects.
- Not cause pain or distress on induction or recovery.
- Be compatible with available equipment and available medications.
To meet the first goal, LASC, LACF and IACUC advocate pre-emptive analgesia, using one or more of three drug classes 30 minutes prior to the start of surgery, or, if that is not practical, as soon as possible after the animal has been induced. The three classes of injectable drugs are:
- opioid analgesics (such as buprenorphine or morphine);
- non-steroidal anti-inflammatory drugs (such as carprofen, meloxicam, ibuprofen);
- local/regional anesthetics (lidocaine, bupivacaine, proparacaine).
Pre-emptive use enhances pain management during the immediate post-surgical period. The disadvantages of this approach are that they add a pre-anesthetic injection that may be distressful to the animals. To avoid this issue, it is acceptable to administer the pre-emptive analgesia as soon as the animal has been induced. By the time the animal is aseptically prepared and moved to the operating table or area (in the case of rodents) and the surgeon makes the first incision, the pre-emptive analgesic, if administered intravenously (IV) or intraperitoneally (IP), will have had time to take effect. Other possible drawbacks with the administration of pre-emptive analgesia is that anesthesia will be deepened and anesthetic doses may need to be reduced, anesthesia recovery may be delayed, and that some are Controlled Substances requiring special storage and records keeping.
Administration of a tranquilizer prior to induction
This may be considered when working with anxious or fractious animals, notably cats. The administration of acepromazine together with an anticholinergic 30 minutes before induction may significantly reduce stress to both the the animal and the handler. The animal should be kept in a quiet room while the medication takes effect.
Administration of an anticholinergic prior to or at the same time as induction of anesthesia
Atropine or glycopyrrolate is routinely administered to large animals undergoing general anesthesia. Atropine is acceptable but glycopyrrolate is recommended due to the fact that it has a longer half life and fewer side effects than atropine. The anticholinergic may be administered before induction to anesthesia but it is commonly administered at the same time as the animal is induced. Atropine or glycopyrrolate prevent bradycardia and cardiac arrhythmias which are especially prone to occur if xylazine is part of the general anesthetic regimen; however, an anticholinergic is strongly recommended to be administered when isoflurane anesthesia is used as well. While anticholinergics are not required or usually used in rodents, if there are any problems with the general anesthesia of using ketamine and an α2 agonist such as xylazine or medetomidine, it is strongly recommended, especially for longer procedures.
Be precisely titratable
Volatile anesthetics (isoflurane, sevoflurane) delivered via a precision vaporizer best meet this goal. Adjusting the inhaled percentage of anesthetic gas to deepen anesthesia is far safer than repeated redosing of injected drugs. Volatile anesthetics are easier to decrease as well, even compared to drugs for which there is an injectable antagonist or reversal agent. A major shortcoming of the inhalant anesthetic agents is the lack of residual analgesia once the vaporizer has been turned off.
The investigator should determine the best option for a particular study and include it in their proposal to the IACUC. Veterinary consultation is required when planning any potentially painful study.
1.2 Ophthalmic Ointment
Sterile ophthalmic ointment must be used anytime animals are anesthetized, to prevent corneal trauma. If ketamine alone is used, as is common practice for chemical restraint of nonhuman primates, and the procedure is short, less than 30 minutes, then ophthalmic ointment may be omitted. In all other cases it must be used.
1.3. Preanesthesia fasting
Most animal species are routinely fasted overnight prior to undergoing anesthesia and surgery. Food deprivation is done to prevent the vomiting and aspiration of gastric contents when anesthesia is induced. In a laboratory animal setting, where staff may leave at 5 pm and the surgery may be scheduled for 9 am the next day, overnight fasting may be equivalent to 16 hours or longer. The recommended time interval is at least 12 hours. Feed deprivation is not recommended in rats and mice for two reasons: First, because of their gastric anatomy, mice and rats are not able to vomit, thus making it unnecessary to withhold food. Secondly, since mice and rats are nocturnal eaters, removing food overnight means that in effect the animal may not have eaten anything during the previous 24 hours. Rabbits also do not vomit and are usually fed overnight prior to anesthesia and surgery; however, in some studies it may be advisable to fast them overnight.
IT IS NOT NECESSARY OR ADVISABLE TO WITHHOLD WATER BEFORE ANESTHESIA AND SURGERY IN ANY SPECIES. IF WATER IS WITHHELD, IT SHOULD BE LIMITED TO ONE (1) HOUR.
Any deviations from these procedures must be stated in the protocol and approved by the IACUC.
1.4 Drug dosages and frequencies of administration
Drugs must be listed in the protocol with approximate dose ranges (e.g. 2.0-3.5 mg/kg) and routes of administration. These are starting points which must be titrated up or down for the individual animal, or for the particular application (procedures conducted, animal age, health status and strain differences). When laboratory experience finds that recommended dose ranges are consistently too high or too low for the particular application, the veterinarian should be informed, and a protocol modification submitted to the Institutional Animal Care and Use Committee.
Anesthetics are always titrated to effect. It is not acceptable to conduct surgical procedures unless the animal is fully anesthetized.
Analgesic doses and frequencies are more difficult to gauge. Caution is required for overnight pain management. Most analgesics administered at 5 pm will not still be effective at 8 am the next morning. Newer, longer-lasting non-steroidal anti-inflammatory analgesics may have longer durations of action than available opioids; they are frequently co-administered with an opioid to combine potency of effect with duration of action. Another option for management of postoperative pain after major surgical procedures is the use of fentanyl patches. These are applied to a shaved area of the skin usually on the back of the animal under where a bandage will be placed. Morphine is administered pre-emptively and 4 hours and 8 hours later. The fentanyl patch is fully active after 12 hours and lasts for approximately 72 hours, providing 3 days of post-operative pain relief.
1.5 Safe and effective animal anesthesia
Plans for intra- and post-operative monitoring must be included in the IACUC protocol application, and then practiced as written and according to IACUC guidelines.
Supplemental administration of warmed fluids (lactated ringers solution or isotonic saline) and maintenance of body temperature will improve anesthetic safety for the animals.